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ABSTRACT Objective: To study associations between polymorphisms in the angiotensin converting enzyme (ACE I/D), actinin 3 (ACTN3 R577X) and paraoxonase 1 (PON1 T(-107)C) genes and chronic diseases (diabetes and hypertension) in women. Materials and methods: Genomic DNA was extracted from saliva samples of 78 women between 18 and 59 years old used for genetic polymorphism screening. Biochemical data were collected from the medical records in Basic Health Units from Southern Brazil. Questionnaires about food consumption, physical activity level and socioeconomic status were applied. Results: The XX genotype of ACTN3 was associated with low HDL levels and high triglycerides, total cholesterol and glucose levels. Additionally, high triglycerides and LDL levels were observed in carriers of the TT genotype of PON1, and lower total cholesterol levels were associated to the CC genotype. As expected, women with diabetes/hypertense had increased body weight, BMI (p = 0.02), waist circumference (p = 0.01), body fat percentage, blood pressure (p = 0.02), cholesterol, triglycerides (p = 0.02), and blood glucose (p = 0.01), when compared to the control group. Conclusion: Both ACTN3 R577X and PON1 T(-107)C polymorphisms are associated with nutritional status and blood glucose and lipid levels in women with diabetes/hypertense. These results contribute to genetic knowledge about predisposition to obesity-related diseases.

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ABSTRACT Objective: To investigate nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatic fibrosis in biopsies of people with obesity who underwent bariatric surgery and examine the possible association of different variables with a diagnosis of NAFLD and NASH. Materials and methods: Epidemiological, clinical and laboratory data from 574 individuals with obesity of both genders seen by the same physician between 2003 and 2009 who had a liver biopsy during bariatric surgery were examined. Results: Of the 437 patients included, 39.8% had some degree of liver fibrosis, 95% had a histologic diagnosis of NAFLD, and the risk factors were age ≥ 28 years and Homeostatic Model Assessment (HOMA) ≥ 2.5 (p = 0.001 and p = 0.016, respectively). In the NAFLD group, NASH was present in 26% of patients and the associated factors were aspartate aminotransferase and alanine aminotransferase index (AST/ALT) > 1, high-density lipoprotein cholesterol (HDL-c) < 40 mg/dL, total cholesterol (TC) ≥ 200 mg/dL, gamma-glutamyl transferase (GGT) > 38 U/L and triglycerides (TG) levels > 150 mg/dL. The independent risk factors were low HDL-c, elevated AST/ALT and high TG. Conclusion: The variables associated with a diagnosis of NAFLD were HOMA ≥ 2.5 and age ≥ 28 years. NASH was associated with low HDL-c, high TG and AST/ALT ≤ 1.

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ABSTRACT Objective: COVID-19 is a multisystem immunoinflammatory disorder, and the hypothalamo–pituitary-adrenal (HPA) axis may be affected by SARS-CoV-2 as well as by steroid treatment during the illness. Information on the HPA axis after recovering from COVID-19, especially in those treated with steroids, is sparse. Hence, this study was performed to evaluate the hypothalamo-pituitary-adrenal axis during the post-COVID-19 period in patients treated with steroids during the illness. Subject and methods: This prospective study involved 60 patients aged 18-60 years who had recovered from moderate or severe COVID-19 and had received steroid treatment during the illness. The HPA axis was assessed with a low-dose (1 mcg) adrenocorticotropic hormone stimulation test at 3, 6 and 9 months in the post-COVID period. Results: The HPA axis was suppressed in 31.66% of the patients at 3 months and 5% at 6 months; however, all patients recovered at 9 months. Cumulative steroid use during the illness was inversely correlated with stimulated cortisol at 3 months in the post-COVID period. Fatigue was present in 58.33% of the patients at 3 months and was more prevalent in those with HPA axis suppression. Conclusion: Nearly one-third of the patients with moderate to severe COVID-19 who were treated with steroids had suppressed HPA axis at 3 months, with gradual recovery over a period of 9 months. Cumulative steroid equivalent dose, but not disease severity, was predictive of HPA axis suppression at 3 months.

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ABSTRACT Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

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ABSTRACT Objective: To explore the diagnostic value of the TUIAS (SW_TH01/II) computer-aided diagnosis (CAD) software system for the ultrasound Thyroid Imaging Reporting and Data System (TI-RADS) features in thyroid nodules. Materials and methods: This retrospective study enrolled patients with thyroid nodules in Shanghai East Hospital between January 2017 and October 2021. The novel CAD software (SW_TH01/II) and three sonographers performed a qualitative analysis of the ultrasound TI-RADS features in aspect ratio, margin irregularity, margin smoothness, calcification, and echogenicity of the thyroid nodules. Results: A total of 225 patients were enrolled. The accuracy, sensitivity, and specificity of the CAD software in “aspect ratio” were 95.6%, 96.2%, and 95.4%, in “margin irregularity” were 90.7%, 90.5%, and 90.9%, in “margin smoothness” were 85.8%, 88.5%, and 83.0%, in “calcification” were 83.6%, 81.7%, and 82.0%, in “homogeneity” were 88.9%, 90.6%, and 82.2%, in “major echo” were 85.3%, 88.0%, and 85.4%, and in “contains very hypoechoic echo” were 92.0%, 90.0%, and 92.4%. The analysis time of the CAD software was significantly shorter than for the sonographers (2.7 ± 1.6 vs. 29.7 ± 12.7 s, P < 0.001). Conclusion: The CAD system achieved high accuracy in describing thyroid nodule features. It might assist in clinical thyroid nodule analysis.

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ABSTRACT Objective: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and a growing global epidemic. In NAFLD, liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Given the link between NAFLD and insulin resistance, the possible association between the rs2854744 (−202 G>T) promoter polymorphism of insulin-like growth factor binding protein 3 (IGFBP3) gene and NAFLD was investigated in this study. Materials and methods: In this genetic case-control association study, the IGFBP3 rs2854744 genotypes of 315 unrelated individuals, including 156 patients with biopsy-proven NAFLD and 159 controls, were determined using polymerase chain reaction/restriction fragment length polymorphism analyses. Results: The “GT+TT” genotype of the IGFBP3 rs2854744 polymorphism, compared with the “GG” genotype, was associated with a 2.7-fold increased risk of NAFLD after adjustment for confounding factors (P = 0.009; odds ratio [OR] = 2.71; 95% confidence interval [CI] = 1.19-3.18). Additionally, the IGFBP3 rs2854744 “T” allele, in comparison with the “G” allele, was significantly overrepresented in NAFLD patients than the controls (P = 0.008; OR = 1.85; 95%CI = 1.23-2.94). Conclusion: Our findings first indicated that the IGFBP3 rs2854744 “GT+TT” genotype is a marker of increased NAFLD susceptibility; however, it needs to be supported by further investigations in other populations.

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ABSTRACT Objective: We aimed to analyze the association of diabetes and subclinical hypothyroidism with subclinical atherosclerosis measured by coronary artery calcium (CAC) in the baseline of the ELSA-Brasil study. Materials and methods: CAC was measured using a 64-detector computed tomographic scanner. The association of CAC > 0 was presented as an odds ratio (OR) and 95% confidence intervals (95%CI) in logistic models and as β (95%CI) in linear models after multivariable adjustment for confounders. Results: We analyzed 3,809 participants (mean-age (SD) 50.5 (8.8); 51.7% women). In the main analysis, we did not find an association of diabetes and subclinical hypothyroidism with CAC. However, in stratified analysis according to age strata, we found no significative interaction terms, an important heterogeneity between the groups, with the younger age strata showing an association of the group with both diseases and CAC > 0 (OR 7.16; 95%CI, 1.14; 44.89) with a wide but significative 95%CI, suggesting that the smaller number of participants in the younger group may influence the results. Our findings also showed an association of CAC > 0 and log (CAC+1) with diabetes in logistic (OR, 1.31; 95%CI, 1.05-1.63) and linear models (β, 0.24, 0.16, 0.40), respectively. Diabetes was independently associated with CAC > 0 in linear models. Discussion: In conclusion, our results showed a great heterogeneity in stratified analysis based on age in the younger age strata. Although we found no significant interaction factors, the smaller sample size for the analysis may influence the negative findings.

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ABSTRACT Objective: The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel based on next generation sequencing analysis and to establish the relationship between genotype and phenotype. Subjects and methods: Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSightTM Exome panel. Results: Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In 2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Conclusion: Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

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ABSTRACT Objective: This research aimed to evaluate retrospectively the effect of anastrozole on height gain and sex hormone levels in pubertal boys receiving growth hormone (GH). Materials and methods: Pubertal boys who received both GH and anastrozole (GH+A) were one-to-one matched with boys who received only GH (GH-Only) for chronological and bone age, pubertal stage and height before the GH initiation, treatment duration and midparental height. Anthropometric measurements throughout treatment and adult heights were compared between the groups. Sex hormone levels were evaluated longitudinally in the GH+A group. Results: Forty-eight cases (24 in each group) were included. There was no statistical difference in adult height between the GH+A and GH-Only (p = 0.071). However, when the analysis was limited to those receiving anastrozole for at least 2 years, mean adult height was higher in the GH+A than in the GH-Only group (173.1 ± 6.2/169.8 ± 5.6 cm, p = 0.044). Despite similar growth rates between the two groups, bone age advancement was slower in the GH+A than in the GH-Only in a mean anastrozole treatment period of 1.59 years (1.37 ± 0.80/1.81 ± 0.98 years, p = 0.001). The greatest increase for FSH, LH, total and free testosterone and decrease for estradiol levels were observed in the third month after anastrozole was started, albeit remaining within the normal ranges according to the actual pubertal stages. Conclusions: Using anastrozole with GH for at least 2 years decelerates the bone age advancement resulting in adult height gain with no abnormality in sex hormone levels. These results suggest anastrozole can be used as an additional treatment to GH for further height gain in pubertal boys.

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ABSTRACT Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population ( p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = −13.869, p = 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients’ QoL and it might serve as a marker for early identification of patients at risk of depression.

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ABSTRACT Objective: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India. Materials and methods: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical (inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas. Results: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, median largest dimension 40 mm, range 33–60 mm) and six TSHomas (median age 34.5 years, four women, two TSHomas cosecreting GH, median largest dimension 42.5 mm, range 13–60 mm). Symptoms of sellar mass effects led to pituitary imaging in most patients with FGA. Patients with TSHomas had symptoms of excess hormone secretion (GH/TSH) or sellar mass effects. The TSHomas that cosecreted GH/FSH were larger than those secreting only TSH. Transsphenoidal resection was the most common first-line therapy but significant residual disease was frequent (3 out of 6 FGAs and 4 out of 5 TSHomas). Conclusion: This is the first and second case series of FGAs and TSHomas, respectively, from India. In this study, TSHomas presented at younger age, were larger and had low surgical cure rates.

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ABSTRACT Objective: Recent studies have shown a relationship between adipose tissue and coronary artery disease (CAD). The ABCA1 transporter regulates cellular cholesterol content and reverses cholesterol transport. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) R230C, C-17G, and C-69T and their expression in epicardial and mediastinal adipose tissue in Mexican patients with CAD. Subjects and methods: The study included 71 patients with CAD and a control group consisting of 64 patients who underwent heart valve replacement. SNPs were determined using TaqMan probes. mRNA was extracted using TriPure Isolation from epicardial and mediastinal adipose tissue. Quantification and expression analyses were done using RT-qPCR. Results: R230C showed a higher frequency of the GG genotype in the CAD group (70.4%) than the control group (57.8%) [OR 0.34, 95% CI (0.14-0.82) p = 0.014]. Similarly, C-17G (rs2740483) showed a statistically significant difference in the CC genotype in the CAD group (63.3%) in comparison to the controls (28.1%) [OR 4.42, 95% CI (2.13-9.16), p = 0.001]. mRNA expression in SNP R230C showed statistically significant overexpression in the AA genotype compared to the GG genotype in CAD patients [11.01 (4.31-15.24) vs. 3.86 (2.47-12.50), p = 0.015]. Conclusion: The results suggest that the GG genotype of R230C and CC genotype of C-17G are strongly associated with the development of CAD in Mexican patients. In addition, under-expression of mRNA in the GG genotype in R230C is associated with patients undergoing revascularization.

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ABSTRACT Objective: To assess the association between leptin/adiponectin ratio (LAR) and insulin resistance surrogates in prepubertal children. Subjects and methods: Study based on data from the Growth and Obesity Chilean Cohort Study (GOCS) involving 968 Chilean prepubertal children. Plasma insulin, leptin, and adiponectin were determined by immunoassays. Several common insulin resistance surrogates were calculated, including the homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride/HDL cholesterol index, triglyceride-glucose (TyG) index, and the TyG index corrected for body mass index (BMI; TyG-BMI) and waist circumference (WC; TyG-WC). Associations among variables were assessed using multiple linear and logistic regression analysis. Results: There was a significant direct association between plasma leptin and LAR with BMI z-score but no association between plasma adiponectin and adiposity. After adjustments for sex and age, LAR was significantly associated with all insulin resistance surrogates (which were categorized using the 75th percentile as the cutoff point), with the TyG-WC index emerging as the surrogate with the highest magnitude of association (odds ratio [OR] 2.44, 95% confidence interval [CI] 2.05-2.9). After additional adjustment for BMI z-score, only the association between LAR and TyG-WC remained significant (OR 1.64, 95% CI 1.27-2.12). Conclusion: Plasma leptin and LAR were strongly associated with several common insulin resistance surrogates in prepubertal children, most notably with the TyG-WC index. Associations between LAR and insulin resistance indexes were mainly driven by the effect of plasma leptin, which is also directly associated with increased adiposity.

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ABSTRACT Objective: Mutations in DICER1 are found in differentiated thyroid carcinoma (DTC) and in multinodular goiter (MNG) at a younger age with other tumors, which characterizes DICER1 syndrome. DICER1 is one driver to DTC; however, it is also found in benign nodules. We speculated that patients with mutations in DICER1 may present long-lasting MNG. Our aim was to investigate the frequency of DICER1 variants in patients with MNG. Subjects and methods: Patients who submitted to total thyroidectomy due to large MNG with symptoms were evaluated. DICER1 hotspots were sequenced from thyroid nodule samples. To confirm somatic mutation, DNA from peripheral blood was also analyzed. Results: Among 715 patients, 154 were evaluated with 56.2 ± 12.3 years old (28-79) and the thyroid volume was 115.7 ± 108 mL (16.2-730). We found 11% with six DICER1 variations in a homo or heterozygous state. Only rs12018992 was a somatic DICER1 variant. All remaining variants were synonymous and likely benign, according to the ClinVar database. The rs12018992 was previously described in an adolescent with DTC, measuring 13 mm. There were no significant differences according to gender, familial history of goiter, age, thyroid volume, TSH and TI-RADS classification between DICER1 carriers. Free T4 were lower in patients with DICER1 polymorphisms (13.77 ± 1.8 vs. 15.44 ± 2.4 pmol/L, p = 0.008), regardless of TSH levels. Conclusions: We conclude that germline DICER1 variants can be found in 11% of large goiters but no second-hit somatic mutation was found. DICER1 is one driver to thyroid lesion and a second-hit event seems unnecessary in the MNG development.

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ABSTRACT Objective: To evaluate the effects of medical education on hospital hyperglycemia on physician's technical knowledge and the quality of medical prescriptions, patient care, and clinical outcomes. Subjects and methods: The intervention included online classes and practical consultations provided by an endocrinologist to medical preceptors and residents of the Department of Internal Medicine. A pretest and a post-test (0 to 10 points) were applied before and after the intervention and patients medical records were reviewed before and after the intervention. The outcomes were improvement in medical knowledge, in the quality of prescriptions for patients in the clinical area, and clinical outcomes. Results: The global mean of correct answers improved with the intervention [before: 6.9 points (±1.7) versus after the intervention: 8.8 points (±1.5) (p < 0.001)]. The number of patients who did not have at least one blood glucose assessment during the entire hospitalization for acute illness decreased from 12.6% before to 2.6% (p < 0.001) after the intervention. There was also a significant reduction in hospital hypoglycemia rates (p < 0.026). The use of sliding-scale insulin as the main treatment was quite low before and after the intervention (2.2% and 0%). After 6 months, medical knowledge did not show significant reduction. Conclusion: Medical education on hospital hyperglycemia can improve medical knowledge and clinical outcomes for patients. The improvement in medical knowledge was maintained after 6 months.

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ABSTRACT Objective: As the most prevalent type of thyroid malignancy, papillary thyroid carcinoma (PTC) accounts for over 80% of all thyroid cancers. Circular RNAs (circRNAs) have been found to regulate multiple cancers, including PTC. Materials and methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to analyse RNA and protein levels. Fluorescence in situ hybridization (FISH) was used to detect the distribution of the target genes. Functional experiments and animal experiments were implemented to analyse the biological functions of target genes in vitro and in vivo. Luciferase reporter, RNA pulldown, RNA binding protein immunoprecipitation (RIP) and mRNA stability assays were used to probe the underlying mechanisms. Results: CircSEMA6Awas found to be upregulated in PTC tissues and cells, and its circular structure was verified. CircSEMA6A promotes PTC cell migration and invasion. Moreover, circSEMA6A functions as a competing endogenous RNA (ceRNA) to upregulate proline rich and Gla domain 4 (PRRG4) expression by sponging microRNA-520h (miR-520h). CircSEMA6A recruits ELAV1 to stabilize PRRG4 mRNA and drives PTC progression via PRRG4. Conclusion: CircSEMA6A upregulates PRRG4 by targeting miR-520h and recruiting ELAVL1 to affect the invasion and migration of PTC cells, offering insight into the molecular mechanisms of PTC.

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ABSTRACT Objective: To evaluate glycemic control according to the number of daily basal rates (BRs) in type 1 diabetes patients using continuous subcutaneous insulin infusion (CSII). Subjects and methods: Cross-sectional study of patients treated with an open-loop CSII for at least 6 months and using a flash glucose monitoring system. Patients were divided into 2 groups: group 1 (G1) and group 2 (G2), with ≤4 and >4 BRs/24h, respectively. The groups were compared regarding HbA1c, time in range (TIR), time above range (TAR), time below range (TBR), glucose management indicator (GMI), glucose variability and data related to hypoglycemia. Regression models were performed. Results: The study included 99 patients (n = 55 in G1; n = 44 in G2). Median (Interquartile range) overall age was 30 (17) years, with 19.5 (48) and 51 (77) months of CSII use, respectively. The median number of different BRs was 3 (2) for G1 and 6 (2) for G2. There were no differences concerning age, sex, educational stage, weight, and insulin analog used. G2 had longer disease duration, longer CSII use, and higher total basal daily dose/kg. No significant differences regarding HbA1c, median glucose, GMI, TIR, TAR, and CV were found. G2 patients had more hypoglycemia, more asymptomatic hypoglycemia, and higher TBR. After adjusting for potential confounders, G1 maintained a lower risk of asymptomatic hypoglycemia. Conclusion: Programming open-loop CSII devices with more than 4 BRs does not improve metabolic control. Additionally, it seems to be a risk factor for hypoglycemia and was an independent predictor for asymptomatic hypoglycemia.

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ABSTRACT Objective: Enlargement of the adrenal glands and variable adrenocortical function have been reported in patients with pulmonary tuberculosis and, in a few studies, in patients with extrapulmonary tuberculosis (EPTB). However, none of the studies have evaluated the course of the adrenal morphology in these patients. Subjects and methods: Prospective study including 37 patients with EPTB and 37 healthy age- and sex-matched controls. The adrenal function was evaluated by measurement of cortisol levels at baseline and after stimulation with ACTH (Acton Prolongatum) before and 6 months after antituberculosis treatment. The size of both adrenal glands was evaluated using 64-slice computed tomography (CT) scanning before and 6 months after treatment. The findings were compared with those in a group of healthy matched controls. Results: Clinical and biochemical parameters were comparable between groups. The mean baseline serum cortisol level was significantly lower in the EPTB group (397.1 ± 184.9 nmol/L) compared with the control group (696.3 ± 101.8 nmol/L). Compared with controls, patients with EPTB had significantly lower mean cortisol levels at baseline and 1 hour after ACTH, both before (397 ± 184.9 nmol/L and 750.7 ± 176.8 nmol/L, respectively) and after (529.7 ± 100.4 nmol/L and 1017.2 ± 119.7 nmol/L, respectively) antituberculosis treatment. Both the length and thickness of the right and left adrenal glands were greater in patients with EPTB than in controls but became comparable to those in controls after treatment completion. Conclusions: Patients with EPTB have an enlarged adrenal size and low baseline and stimulated serum cortisol levels. After treatment completion, cortisol levels increased significantly, and the adrenal size normalized in these patients.

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ABSTRACT Objective: To investigate the relationship between fasting blood glucose (FBG) and carotid intima-media thickness (IMT) in premenopausal and postmenopausal women. Subjects and methods: The study enrolled 2,959 women seen at the Maanshan People's Hospital of Anhui Province from December 2013 to December 2018. Carotid IMT was measured using Doppler ultrasound. Linear regression and R smoothing curves were used to analyze the relationship between blood glucose level and carotid IMT in the premenopausal and postmenopausal groups. Results: Postmenopausal compared with premenopausal women had higher mean IMT (mIMT; 0.81 ± 0.23 mm versus 0.70 ± 0.14 mm, respectively, p < 0.001) and maximum IMT (maxIMT; 0.86 ± 0.35 mm versus 0.74 ± 0.16 mm, respectively, p < 0.001) values. On linear regression analysis, mIMT values increased with increasing FBG values when FBG level was ≤ 7 mmol/L, but no significance was found between FBG and maxIMT. After stratification by menopausal status, mIMT and maxIMT increased with increasing FBG when FBG was ≤ 7 mmol/L in the premenopausal group. In the postmenopausal group, mIMT and maxIMT increased with increasing FBG. After adjustment for covariate factors, the relationship between FBG and mIMT remained the same as before the adjustment, but when FBG was ≤ 11 mmol/L, the maxIMT increased with increasing FBG. In the stratification analysis, maxIMT increased with increasing FBG when FBG was ≤ 7 mmol/L in the premenopausal group, while both mIMT and maxIMT increased with increasing FBG when FBG was > 10 mmol/L in the postmenopausal group. Conclusion: Levels of FBG contributed more to increased IMT in postmenopausal than premenopausal women. The influence of FBG was greater on maxIMT than mIMT. Additionally, FBG was helpful in assessing focal thickening of the carotid intima.

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ABSTRACT Objective: Despite its recognized importance, primary hyperaldosteronism (PHA) remains an underdiagnosed condition in clinical practice. The objective of the present study was to evaluate PHA screening practices by general practitioners and specialists in endocrinology and cardiology. Subjects and methods: This cross-sectional, observational study invited physicians to respond voluntarily to an online survey. The survey collected the respondents’ sociodemographic data and answers to five hypothetical clinical cases meeting Endocrine Society criteria for PHA screening. Results: In all, 126 physicians responded to the online survey. Endocrinologists were the specialists who most often chose PHA screening, although the screening rates were overall low, ranging from 36.5% to 92.9%, depending on the case and the respondents’ specialty. The survey also assessed the reasons for not choosing PHA screening, which included limited availability of tests within the public health services, interference of antihypertensive medications on hormone levels, and failure to identify the screening indication. Being an endocrinologist was an independent predictor for choosing PHA screening for the patients in Cases #1 and #5 (p = 0.001 and p = 0.002, respectively). Conclusion: Endocrinologists were the specialists who most often chose PHA screening, although the screening rates were overall low among all specialists. These findings highlight a need for continuing medical education programs addressing PHA screening and making the diagnosis of PHA more present in the daily clinical practice of physicians treating patients with hypertension.

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ABSTRACT Objective: To evaluate the cumulative incidence, risk factors, and outcomes of COVID-19 in patients with Cushing's disease (CD). Subjects and methods: In all, 60 patients with CD following up in our outpatient clinic answered via phone interview a questionnaire about the occurrence of COVID-19 infection documented by RT-PCR (including the diagnosis date and clinical outcome) and vaccination status. Clinical and biochemical data on disease activity (hypercortisolism) and comorbidities (obesity, diabetes mellitus, and hypertension) were obtained from the patients' electronic medical records. Risk ratios (RRs) of risk factors were obtained using univariate and multivariate analyses. Results: The cumulative incidence of COVID-19 in patients with CD during the observation period was 31.7%, which was higher than that in the general reference population (9.5%). The cumulative incidence of COVID-19 was significantly higher in patients with hypercortisolism (57% versus 17% in those without hypercortisolism, p = 0.012) and obesity (54% versus 9% in those without obesity, p < 0.001) but not in patients with hypertension or diabetes mellitus. On multivariate analysis, hypercortisolism and obesity were each independent risk factors for COVID-19 (RR 2.18, 95% CI 1.06-4.46, p = 0.033 and RR 5.19, 95% CI 1.61-16.74, p = 0.006, respectively). Conclusion: The incidence of COVID-19 in patients with CD was associated with hypercortisolism, as expected, and obesity, a novel and unexpected finding. Thus, correction of hypercortisolism and obesity should be implemented in patients with CD during the current and future COVID-19 outbreaks.

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ABSTRACT Objective: Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification). Subjects and methods: We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy. Results: After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-risk to high-risk patients with postoperative s-Tg ≥ 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification. Conclusions: The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based on dynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.

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ABSTRACT Objective: This study aimed to evaluate the cardiovascular risk of patients with post-surgical hypoparathyroidism through coronary calcium score (CACS) evaluation and cardiovascular risk calculators. Subjects and methods: Patients with post-surgical hypoparathyroidism (HG = 29) were compared to a control group (CG = 29), matched by sex and age. Demographic and clinical data were captured by a questionnaire or patient files. Both groups performed a thoracic-computed tomography to evaluate the CACS and the cardiovascular risk was calculated by two risk calculators. Results: In the HG, the supplementation of calcium varied between 500 to 2,000 mg/day and the mean calcitriol was 0.5 ± 0.29 mcg/day. The mean serum calcium and phosphorus were 8.32 ± 0.68 and 4.92 ± 0.87 mg/dL, respectively, and in the range recommended for hypoparathyroidism. The Brazilian Society of Cardiology's risk calculator showed a difference among groups, with no patient in the HG with low risk, but the CACS was similar. A positive CACS in the HG was associated with obesity and high BMI but not with calcium and/or vitamin D supplementation. Conclusion: In conclusion, patients with hypoparathyroidism did not show increased CACS, and it was not related to supplementation.

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ABSTRACT Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, it can also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT) and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastases of MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

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ABSTRACT Objective: Thyroid nodules are very common in clinical practice, and ultrasound has long been used as a screening tool for their evaluation. Several risk assessment systems based on ultrasonography have been developed to stratify the risk of malignancy and determine the need for fine-needle aspiration in thyroid nodules, including the American Thyroid Association (ATA) system and the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS). The aim of this study was to compare the performance of the ATA and ACR TI-RADS systems in predicting malignancy in thyroid nodules based on the nodules' final histopathology reports. Materials and methods: We performed a retrospective review of medical records to identify patients who underwent thyroid surgery at King Abdulaziz University from 2017 to 2022. The ultrasound features of the nodules with confirmed histopathology (benign versus malignant) were evaluated. Both ATA and ACR TI-RADS scores were documented. Results: The analysis included 191 patients who underwent thyroid surgery and fulfilled the inclusion criteria. Hemithyroidectomy was performed in 22.5% of the patients, and total thyroidectomy was performed in 77.0% of them. In all, 91 patients (47.6%) were found to have malignant nodules on histopathology. We then compared the histopathology reports with the preoperative ultrasonographic risk scores. The estimated sensitivity and specificity in identifying malignant nodules were, respectively, 52% and 80% with the ATA system and 51.6% and 90% with the ACR TI-RADS system. Conclusion: Both ATA and ACR TI-RADS risk stratification systems are valuable tools for assessing the malignancy risk in thyroid nodules. In our study, the ACR TI-RADS system had superior specificity compared with the ATA system in predicting malignancy among high-risk lesions.

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ABSTRACT Objective: The aim of this study was to evaluate the glycated hemoglobin (HbA1c) levels before and after sustained virologic response (SVR) and investigate the baseline characteristics associated with improved glycemic control in patients with chronic hepatitis C (CHC) achieving SVR after direct-acting antivirals (DAA) therapy. Materials and methods: Consecutive adult patients with CHC who achieved SVR after DAA treatment between January 2016 and December 2017 at Hospital de Clínicas de Porto Alegre (RS, Brazil) were prospectively included. Levels of HbA1c were measured up to 24 weeks before DAA therapy and 12 weeks after SVR. Exclusion criteria were decompensated cirrhosis, HIV and/or hepatitis B virus, liver disease of other etiologies, and/or modification of prediabetes/type 2 diabetes mellitus (PDM/T2DM) management. The primary outcome was a comparison of HbA1c levels before and after SVR. Secondary outcomes were the baseline variables associated with improved glycemic control. Results: The study included 207 patients with a mean age of 60.6±10.7 years, of whom 51.7% were women, 56% had cirrhosis, 37.7% had HCV genotype 3, and 54.5% had baseline T2DM or PDM. The median HbA1c level reduced significantly after SVR (5.5%, interquartile range [IQR] 4.9%-6.3%) compared with baseline (5.7%, IQR 5.3­%-6.7%; p = 0.01). The baseline characteristics associated with improved HbA1c after SVR were cirrhosis, genotype 3, and age ≤ 60 years. Conclusion: Among patients with CHC, SVR after DAA was associated with HbA1c reduction, particularly in those with cirrhosis, genotype 3, and age ≤ 60 years.

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ABSTRACT Objective: Neuroendocrine tumors (NETs) are a set of diseases that originate from neuroendocrine cells, which comprises a diffuse endocrine system present in various organs of the body. These tumors are more frequent in the gastrointestinal tract (70%) and the bronchopulmonary system (20%-30%). A NET incidence rate of 1-5 per 100,000 inhabitants has been estimated for several European countries and the USA employing 20 years of data. However, no comprehensive studies on this rare neoplasm are available in Brazil. In this context, the aim of this study was to characterize the epidemiological NET profile in the country. Material and methods: This is a retrospective descriptive observational study based on data from Hospital Cancer Records available at the Brazilian National Cancer Institute and the São Paulo Oncocentro Foundation. Demographic, clinical and treatment-related variables were analyzed from selected cases employing descriptive statistics. Results and Conclusion: A total of 15,859 cases were identified, most occurring in males (53.4%) and in individuals under 65 years old (63.3%). Small cell carcinoma was the most frequent histological type (46.7%). Bronchopulmonary tumors were the most frequent NETs, followed by pancreatic tumors, with cases mostly concentrated in high complexity centers in the Brazilian Southeast and treated mainly with surgery and chemotherapy, with over half of the patients diagnosed in advanced stages of the disease.

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ABSTRACT Objective: After initial treatment, up to 30% of patients with papillary thyroid cancer (PTC) have incomplete response, mainly cervical lymph node (LN) disease. Previous studies have suggested that active surveillance (AS) is a possible option for these patients. Our aim was to report the results of AS in patients with PTC and cervical LN disease. Materials and methods: In this retrospective observational study, we included adult patients treated and followed for PTC, who presented with cervical LN disease and were managed with AS. Growth was defined as an increase ≥ 3mm in either diameter. Results: We included 32 patients: 27 (84.4%) women, age of 39 ± 14 years, all initially treated with total thyroidectomy, and 22 (69%) with therapeutic neck dissection. Cervical LN disease was diagnosed 1 year (0.3-12.6) after initial management, with a diameter of 9.0 mm (6.0-19.0). After a median AS of 4.3 years (0.6-14.1), 4 (12.5%) patients had LN growth: 2 (50%) of whom were surgically removed, 1 (25%) was effectively treated with radiotherapy, and 1 (25%) had a scheduled surgery. Tg increase was the only predictive factor of LN growth evaluated as both the delta Tg (p < 0.0366) and percentage of Tg change (p < 0.0140). None of the included patients died, had local complications due to LN growth or salvage therapy, or developed distant metastases during follow-up. Conclusions: In selected patients with PTC and suspicious cervical LNs diagnosed after initial treatment, AS is a feasible and safe strategy as it allows effective identification and treatment of the minority of patients who progress.

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ABSTRACT Objective: This study sought to investigate the regulation of long noncoding RNA (lncRNA) XIST on the microRNA (miR)-101-3p/vascular endothelial growth factor A (VEGFA) axis in neovascularization in diabetic retinopathy (DR). Materials and methods: Serum of patients with DR was extracted for the analysis of XIST, miR-101-3p, and VEGFA expression levels. High glucose (HG)-insulted HRMECs and DR model rats were treated with lentiviral vectors. MTT, transwell, and tube formation assays were performed to evaluate cell viability, migration, and angiogenesis, and ELISA was conducted to detect the levels of inflammatory cytokines. Dual-luciferase reporter, RIP, and RNA pull-down experiments were used to validate the relationships among XIST, miR-101-3p, and VEGFA. Results: XIST and VEGFA were upregulated and miR-101-3p was downregulated in serum from patients with DR. XIST knockdown inhibited proliferation, migration, vessel tube formation, and inflammatory response in HG-treated HRMECs, whereas the above effects were nullified by miR-101-3p inhibition or VEGFA overexpression. miR-101-3p could bind to XIST and VEGFA. XIST promoted DR development in rats by regulating the miR-101-3p/VEGFA axis. Conclusions: LncRNA XIST promotes VEGFA expression by downregulating miR-101-3p, thereby stimulating angiogenesis and inflammatory response in DR.

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ABSTRACT Objective: Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy. Materials and methods: Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis. Results: A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/HMG therapy (P < 0.05). Conclusion: For CHH patients with prior poor response to one year of HCG/HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

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ABSTRACT Objective: To evaluate the association of TSH, free T3 (FT3), free T4 (FT4), and conversion (FT3:FT4) ratio values with incident hypertension. Materials and methods: The study included data from participants of the ELSA-Brasil study without baseline hypertension. Serum TSH, FT4 and FT3 levels, and FT3:FT4 ratio values were assessed at baseline, and incident hypertension (defined by blood pressure levels ≥ 140/90 mmHg) was estimated over a median of 8.2 years of follow-up. The risk of incident hypertension was evaluated considering a 1-unit increase in TSH, FT4, FT3, and conversion ratio values and after dividing these variables into quintiles for further analysis using Poisson regression with robust variance. The results are presented as relative risks (RR) and 95% confidence intervals (CIs) before and after adjustment for multiple variables. Results: The primary analysis incorporated data from 5,915 euthyroid individuals, and the secondary analysis combined data from all euthyroid individuals, 587 individuals with subclinical hypothyroidism, and 31 individuals with subclinical hyperthyroidism. The rate of incident hypertension was 28% (95% CI: 27%-29.3%). The FT4 levels in the first quintile (0.18-1.06 ng/dL) were significantly associated with incident hypertension (RR: 1.03, 95% CI: 1.01-1.06) at follow-up. The association between FT4 levels in the first quintile and incident hypertension was also observed in the analysis of combined data from euthyroid individuals and participants with subclinical thyroid dysfunction (RR: 1.04, 95% CI: 1.01-1.07). The associations were predominantly observed with systolic blood pressure levels in euthyroid individuals. However, in the combined analysis incorporating euthyroid participants and individuals with subclinical thyroid dysfunction, the associations were more pronounced with diastolic blood pressure levels. Conclusion: Low FT4 levels may be a mild risk factor for incident hypertension in euthyroid individuals and persons with subclinical thyroid dysfunction.

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ABSTRACT Objective: To evaluate the association between neck circumference (NC) measured during pregnancy and markers of glucose metabolism measured 2-6 months postpartum in women with overweight/obesity with and without gestational diabetes (GDM). Subjects and methods: This prospective study enrolled 100 pregnant women (including 50 with GDM) with pregestational body mass index (BMI) ≥ 25 kg and < 40 kg/m². The cohort was stratified according to NC tertiles during pregnancy. Glucose metabolism was assessed in the postpartum period. The association between NC during pregnancy and markers of glucose metabolism postpartum was tested using linear regression analysis. Results: Participants with NC in the third tertile, compared with those with NC in the second and first tertiles, had higher levels of glycated hemoglobin (HbA1c; 5.6 ± 0.4% versus 5.4 ± 0.3% versus 5.3 ± 0.2%, respectively, p = 0.006), fasting insulin (13.2 ± 6.6 µIU/mL versus 11.1 ± 5.8 µIU/mL versus 9.5 ± 4.9 µIU/mL, respectively, p = 0.035), homeostasis model for insulin resistance (HOMA-IR; 3.1 ± 1.7 versus 2.5 ± 1.3 versus 2.1 ± 1.2, respectively, p = 0.035) and triglyceride-glucose index (TyG; 4.6 ± 0.2 versus 4.5 ± 0.2 versus 4.5 ± 0.3, respectively, p = 0.010). In crude linear regression analysis, NC measured during pregnancy was significantly associated with levels of fasting plasma glucose, 2-hour glucose, HbA1c, log HOMA-IR, and TyG index. The association remained after adjustment for age, family history of diabetes, and number of pregnancies. When adjusted for pregestational BMI and gestational weight gain, NC remained independently associated with fasting plasma glucose and HbA1c levels. Conclusion: The NC measured during pregnancy was positively associated with worse glucose metabolic profile in the postpartum among women with obesity/overweight with and without GDM. The NC measurement may be a feasible tool for early identification of women at a higher risk of developing type 2 diabetes mellitus.

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ABSTRACT Objective Subacute thyroiditis is also known as subacute granulomatous thyroiditis, giant cell thyroiditis, painful thyroiditis, and De Quervain’s thyroiditis. Immature granulocytes (IG) and neutrophil-to-lymphocyte ratio (NLR) are new inflammatory markers that are easily detected in routine complete blood count (CBC) tests. The aim of this study was to investigate the role of IG and NLR as markers of treatment response in patients with subacute thyroiditis. Subjects and methods The study included 41 patients with subacute thyroiditis treated and monitored in our outpatient clinic between April 2020 and April 2022. From a retrospective review of medical records, we recorded results of IG, NLR, thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) from blood tests obtained routinely before and after treatment. Results Overall, 31 (75.6%) patients were women and 10 (21.4%) were men. The median age was 41 years (range 22-68 years). The laboratory tests showed the following median (range) results: IG, 0.03 (0.01-0.08); NLR, 3.6 (1.2-5.2); TSH, 0.02 mIU/L (0.01-3.35 mIU/L); fT4, 2.3 ng/dL (1.0-7.0 ng/dL); fT3, 5.6 pmol/L (2.6-15.2 pmol/L); ESR, 49 mm/h (17.0-87 mm/h); and CRP, 73 mg/dL (3.0-188 mg/dL). Conclusion Early diagnosis and treatment of subacute thyroiditis is fundamental. In the present study, the new inflammatory markers IG and NLR, measured routinely on CBC tests, decreased significantly after subacute thyroiditis treatment relative to pretreatment values. After treatment, the NLR change correlated with ESR and CRP changes, while the IG change correlated only with CRP change. These findings suggest that the markers IG and NLR may be used to evaluate treatment response in patients with subacute thyroiditis.

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ABSTRACT Objective The aim of this observational, cross-sectional study was to investigate physicians’ preferences for radioiodine (RAI) treatment in patients with differentiated thyroid cancer (DTC) in Brazil and the factors influencing RAI indications. Materials and methods A survey was distributed to physicians potentially involved in DTC care in Brazil to understand the factors influencing RAI indications. The survey collected information on the profiles of the physicians, along with the characteristics of their workplaces and their preferences regarding RAI indications in three hypothetical clinical cases. Cases 1, 2, and 3 described the cases of patients with DTC and variations to the case that included different scenarios to assess how the respondents would change their RAI recommendations. The analysis included the RAI indications across different medical specialties. Results A total of 175 physicians answered the survey. There was considerable variability in RAI recommendations in all three cases. The training background influenced the respondents' preferences for RAI indications and their approaches to preparing patients for RAI treatment. Conclusion The findings of this study reaffirm the need for a Brazilian consensus among physicians across multiple specialties to help guide health care professionals treating patients with DTC in Brazil.

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ABSTRACT Objective The aim of this study was to evaluate the efficacy of a self-assessment questionnaire for hirsutism using the latest cutoff values recommended by the Endocrine Society (ES) for Latin-American women and by the European Society for Human Reproduction and Embryology (ESHRE). Subject and methods Female premenopausal outpatients (n = 188) completed a self-assessment questionnaire, scoring hair presence across the nine areas evaluated by the modified Ferriman-Gallwey (mFG) scale. The results were compared with clinician-assessed scores rated independently by two trained physicians. Scores in the Hirsuta questionnaire, derived from self-assessment of five areas of the mFG scale, were also evaluated. Results The ethnic composition of the sample was as follows: 23.1% white, 25.8% black, 48.9% mixed, and 2.1% other backgrounds (Indigenous, Asian). The participants had age and BMI of (mean ± standard deviation) 33.7 ± 9.9 years and 29.8 ± 7.21 kg/m2, respectively. The most common areas of excessive hair growth were the chin, upper and lower abdomen, and thighs. Relative to clinician-assessed mFG scores, self-assessed mFG scores had an accuracy of 80% using ES criteria for hirsutism diagnosis, with a sensitivity of 95.45%, specificity of 56.25%, positive predictive value of 30.10%, and negative predictive value of 98.40%. Self-assessed mFG had lower accuracy (71%) for diagnosing hirsutism when the ESHRE criteria were applied. Conclusions Self-assessed mFG had low specificity, limiting its application. The results of this study do not support the use of the self-assessed mFG or Hirsuta scores for diagnosing hirsutism in a clinical setting, although both scoring systems may be useful for screening hirsutism in epidemiological studies.

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ABSTRACT Objective To evaluate, characterize and search for trends in the underreporting of diabetes mellitus (DM) as the cause of death in Bauru, São Paulo, Brazil, over 40 years. Subjects and methods This was a documental study. Clinical and mortality data were collected from individuals known to have type 1 (DM1) and type 2 diabetes mellitus (DM2), residing in Bauru, State of São Paulo, followed at a local endocrinology clinic from 1982 to 2021, who deceased during this period. Results A significant underreporting of DM as the cause of death (64.41%) was found, mostly associated with male gender (OR = 1.59 [95% CI: 1.18; 2.15]; p < 0.01), DM2 (OR = 2.64 [95% CI: 1.32; 5.26]; p < 0.01), dying in the first decade of the study (OR = 4.07 [95% CI: 1.54; 10.71]; p < 0.001) and shorter DM duration (OR = 1.02 [95% CI: 1.01; 1.04]; p < 0.01). Age, type of treatment, body mass index, marital status and ethnicity, did not show a significant association with DM underreporting. There was a decreasing trend in DM1 underreporting (Decade Percentual Change = -7.10 [95% CI: -11.35; -3.40]), but a stationary trend for DM and DM2. The main primary cause of death was cardiovascular-related complications. Conclusion The underreporting of DM as the cause of death was very frequently found, and was associated with male gender, decade of death, shorter DM duration and DM2. If our data could be applied to the whole country, DM would possibly emerge as a more prominent cause of death in Brazil. Future studies in other cities and geographic regions are warranted to confirm our findings.

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ABSTRACT Objective Thyroid diseases pose a substantial socioeconomic burden globally. The aim of this study was to evaluate the correlation between estradiol-to-testosterone (E2/T) ratio and thyroid peroxidase antibody (TPOAb) positivity in male patients with hypothyroidism or euthyroidism. Subjects and methods Cross-sectional observational study including 115 male patients with hypothyroidism or euthyroidism. The patients were divided into two groups based on positive or negative TPOAb results, with TPOAb positivity defined by a serum TPOAb value ≥ 35 IU/mL. Results Patients with positive TPOAbs, compared with those with negative TPOAbs, had a higher prevalence of goiter and obesity and higher levels of total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol. The median estradiol level was higher, and the median total testosterone and sex-hormone binding globulin (SHBG) levels were lower in the TPOAb-positive versus the TPOAb-negative group (p < 0.001). In subgroup analysis including only patients with hypothyroidism (n = 80), the median E2/T ratio was higher in the TPOAb-positive group (p = 0.016). The prevalence of TPOAb positivity increased with the increase in E2/T ratio quartiles, from 37.9% in the lowest quartile to 96.2% in the highest quartile (p value for trend across all quartiles < 0.001). On adjusted multivariate analysis, the E2/T ratio emerged as an independent predictor of TPOAb positivity. An E2/T ratio cutoff value of 6.565 x10-3 demonstrated the best diagnostic accuracy, with a sensitivity of 78.2% and specificity of 67.6%. Conclusion The present study provides insights into the role of the E2/T ratio as a predictor of thyroid disorders.

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ABSTRACT Objective To evaluate the profile of patients with diabetic kidney disease (DKD) with and without concomitant diabetic retinopathy (DR) to identify clinical predictors of the development of both complications together. Subjects and methods Cross-sectional study including patients with type 1 and type 2 diabetes and DKD followed at the endocrinology division of a public hospital in Southern Brazil and referred for retinography assessment. The definition of DR was the occurrence of any diabetes-related damage identified in color fundus photographs under mydriasis. Urinary albumin excretion ≥ 14 mg/L and/or glomerular filtration rate < 60 mL/min/1.73 m2 (CKD-EPI equation) were used to define DKD. Factors evaluated included the clinical differences of the participants according to the presence or absence of DR. Multiple regression models were used to identify predictors of DR presence according to the clinical characteristics evaluated. Results The study included 517 patients with DKD, 433 (83.7%) of whom had type 2 diabetes (median age 64.7 years [interquartile range 59-73 years] years, 59.8% women, 83.4% white) and 84 (16.3%) had type 1 diabetes (median age 46.6 years [interquartile range 33.5-54.2 years], 46.4% women, 91.7% white). Patients with type 2 diabetes and DR (versus those without DR) were more often on insulin (odds ratio [OR] 3.63, 95% confidence interval [CI] 1.89-7.00), had diabetes for longer (OR 1.04, 95% CI 1.02-1.07), and had higher systolic blood pressure (OR 1.01, 95% CI 1.00-1.02). No predictors of DR presence were identified in participants with type 1 diabetes. Conclusion Among patients with DKD and type 2 diabetes, insulin use, longer diabetes duration, and higher systolic blood pressure level were associated with the presence of DR.

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ABSTRACT Objective Weight regain is a common outcome of weight loss interventions. Mental health-related comorbidities, among other factors, can mediate weight regain regardless of the implemented treatment modality. This study explores whether postoperative psychopathological comorbidities are associated with weight regain after bariatric surgery. Subjects and methods This cross-sectional study recruited 90 outpatients who underwent Roux-en-Y gastric bypass surgery. Anthropometric measurements were collected retrospectively from medical charts. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) Axis I Disorders (SCID-I) was applied to evaluate psychiatry diagnoses. Validated self-report instruments were used to assess depression, anxiety, alcohol use, impulsivity, binge eating, and body image dissatisfaction. Weight regain was defined as a ≥20% increase from the maximum weight lost. Level of evidence: Level III, cross-sectional study based on a well-designed study. Results Overall, 55.6% of participants experienced weight regain. Notably, mental disorders such as current binge-eating disorder and lifetime diagnoses including bulimia nervosa, alcohol abuse/dependence, and obsessive-compulsive disorder were significantly associated with weight regain. However, controlled analysis found that, for mental disorders, only current binge-eating disorder (odds ratio [OR] 6.3, 95% confidence interval [CI] 1.26-31.06, p = 0.024) remained associated with weight regain. Eating-related psychopathologies also associated with weight regain included binge eating (d = 0.55; p = 0.013), eating disinhibition (d = 0.76; p = 0.001), higher hunger levels (d = 0.39; p = 0.004), and non-planning trait impulsivity (d = 0.69; p = 0.0001). Conclusion Postoperative presence of psychopathological comorbidities, such as eating psychopathology and trait impulsivity, were associated with weight regain after bariatric surgery. These findings highlight the importance of addressing mental health in individuals experiencing postsurgical weight regain.

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ABSTRACT Objective To compare the long-term medical costs of active surveillance (AS), partial thyroidectomy (PT), and total thyroidectomy (TT) in patients with low-risk papillary thyroid microcarcinoma (PTMC) receiving care covered by the Brazilian Public Health System. Materials and methods After reviewing AS cohorts and our own data, we created a model of AS, PT, and TT flow care for low-risk PTMC over 10, 20, and 30 years. The medical costs included those associated with diagnosis, surgery, and follow-up. We considered that 13.3% of the patients on AS would require surgery after a mean of 21.3 months, 4% undergoing TT would develop permanent hypoparathyroidism, and 43% undergoing PT would develop hypothyroidism. Results The most economical alternative was AS. The costs of TT per patient were higher than those of AS by 182.8% over 10 years (866.89 versus 306.49 US dollars [USD], respectively), by 152.9% over 20 years (1,023.66 versus 404.73 USD, respectively), and by 134.7% over 30 years (1,180.42 versus 502.96 USD, respectively). The costs of PT per patient were higher than those of AS by 16.0% over 10 years (355.66 versus 306.49 USD, respectively), by 16.9% over 20 years (473.41 versus 404.73 USD, respectively), and by 17.5% over 30 years (591.17 versus 502.96 USD, respectively). Conclusion The AS approach was less costly than immediate surgery throughout 30 years of follow-up. Hence, the implementation of AS in Brazil should not be hindered by cost considerations.

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ABSTRACT Objective Leukocytosis is often observed among children presenting with diabetic ketoacidosis (DKA). This study compares detailed parameters of leukocytosis in children presenting with DKA versus infection. Subjects and methods In this comparative cohort study, we collected data from two groups of children, one hospitalized with DKA and another with community-acquired pneumonia (CAP). The primary objective was to compare the neutrophil-to-lymphocyte ratio (NLR) between the groups. Total leukocyte count (TLC), absolute neutrophil count (ANC), platelet-to-lymphocyte ratio (PLR), and platelet-to-monocyte ratio (PMR) were also compared. The correlation of these hematological parameters with the clinical outcomes in the DKA group was also explored. Results Data from 35 children with DKA (mean age 7.4 years, 12 boys) and 40 children with CAP (mean age 7.9 years, 15 boys) were available for comparison. No significant NLR difference was observed between the DKA and CAP groups. Similarly, no significant difference was observed in TLC and ANC between the groups. However, significant differences between the DKA and CAP groups were observed regarding mean (standard deviation) PLR (108.26 [67.51] versus 166.60 [163.83], respectively, p = 0.01) and mean PMR (1,795.40 [4,307.00] versus 886.33 [1,726.41], p = 0.01). Among children with DKA, ANC and PMR correlated positively and hemoglobin level correlated negatively with unfavorable outcomes. Conclusions Specific parameters of leukocytosis (PLR and PMR) differed significantly in children with DKA versus CAP. Some widely available and inexpensive hematological parameters of inflammation (hemoglobin, ANC, and PMR) may predict outcomes in patients with DKA.

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ABSTRACT Objective The aim of this study was to estimate the budget impact of adding cabergoline to the Brazilian Unified Health System (SUS) formulary for the treatment of patients with Cushing’s disease (CD) who do not achieve disease control after transsphenoidal surgery. Materials and methods We conducted a budget impact analysis (BIA) from the perspective of the Brazilian SUS over a 5-year time horizon. We compared two scenarios: ketoconazole (Scenario 1) versus including cabergoline as a treatment option (Scenario 2). All analyses were conducted using Microsoft Excel. Uncertainty was explored in univariate sensitivity analyses. Results The total costs were BRL $25,596,729 for Scenario 1 and BRL $32,469,169 for Scenario 2. The budget impact of adding cabergoline to the formulary for CD treatment within the SUS would be BRL $6,091,036 over 5 years. On univariate analyses, variations in the rates of surgical failure and CD recurrence had the greatest potential to affect the final costs associated with cabergoline. Conclusions The estimated budget impact of adding cabergoline to the formulary for CD treatment within the Brazilian SUS would be about BRL $6 million. While cost savings cannot be expected, the budget impact of adding cabergoline would be lower than that of adding other treatment options for CD.

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ABSTRACT Objectives To evaluate the accuracy of routinely available parameters in screening for GCK maturity-onset diabetes of the young (MODY), leveraging data from two large cohorts – one of patients with GCK-MODY and the other of patients with type 1 diabetes (T1D). Materials and methods The study included 2,687 patients with T1D, 202 patients with clinical features of MODY but without associated genetic variants (NoVar), and 100 patients with GCK-MODY (GCK). Area under the receiver-operating characteristic curve (ROC-AUC) analyses were used to assess the performance of each parameter – both alone and incorporated into regression models – in discriminating between groups. Results The best parameter discriminating between GCK-MODY and T1D was a multivariable model comprising glycated hemoglobin (HbA1c), fasting plasma glucose, age at diagnosis, hypertension, microvascular complications, previous diabetic ketoacidosis, and family history of diabetes. This model had a ROC-AUC value of 0.980 (95% confidence interval [CI] 0.974-0.985) and positive (PPV) and negative (NPV) predictive values of 43.74% and 100%, respectively. The best model discriminating between GCK and NoVar included HbA1c, age at diagnosis, hypertension, and triglycerides and had a ROC-AUC value of 0.850 (95% CI 0.783-0.916), PPV of 88.36%, and NPV of 97.7%; however, this model was not significantly different from the others. A novel GCK variant was also described in one individual with MODY (7-44192948-T-C, p.Ser54Gly), which showed evidence of pathogenicity on in silico prediction tools. Conclusions This study identified a highly accurate (98%) composite model for differentiating GCK-MODY and T1D. This model may help clinicians select patients for genetic evaluation of monogenic diabetes, enabling them to implement correct treatment without overusing limited resources.

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ABSTRACT Objective Sulfonylureas have been used to improve performance in strength sports. However, this hypothetical effect has not been proven. We examined the ergogenic acute effect of gliclazide on resistance training performance and muscle recovery. Subjects and methods We conducted a double-blind, randomized, crossover pilot study with 10 healthy resistance-trained adults (29.3 ± 4.4 years), nonusers of anabolic steroids. The participants were randomized to two exercise sessions. In the first session, five participants received placebo and the other five received gliclazide modified release, both administered 8 hours before the session. Session two was performed in a crossover fashion a week later. The volume load was calculated as the maximum number of repetitions of four sets multiplied by load (65% 1-RM). Blood samples were collected before and after exercise, as well as 24 hours and 48 hours after exercise for measurement of creatine kinase (CK-MM) and lactate dehydrogenase (LDH) activity. Blood glucose was measured with a glucometer before, during, and after the exercise sessions. Results Gliclazide did not enhance volume load for bench press (placebo: 2,698.0 ± 923.0 kg; gliclazide: 2,675.0 ± 1,088.0 kg; p = 0.073) or leg press (placebo: 10,866.0 ± 2,671.0 kg; gliclazide: 10,817.0 ± 2,888.0 kg; p = 0.135). However, CK-MM (-27.7%; p = 0.034) and LDH (-21.1%; p = 0.021) activities were decreased with gliclazide 48 hours after exercise. There was also a decrease in blood glucose in the gliclazide compared with the placebo session (p = 0.018). Conclusion Gliclazide did not enhance performance in a single resistance training session, but promoted faster muscle recovery. The decrease in blood glucose post-exercise with gliclazide was an undesirable effect that could lead to long-term glucose metabolism disorders. Registered in ClinicalTrials.gov under number NCT04443777.

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ABSTRACT Objective Subcentimeter papillary thyroid carcinoma (sPTC), also known as papillary thyroid microcarcinoma, is associated with a good prognosis and low mortality risk. However, some sPTCs exhibit biologically aggressive characteristics. The aim of this study was to identify factors affecting the prognosis and aggressiveness of sPTC by considering the demographic characteristics of patients with sPTC and the pathologic characteristics of the tumors. Subjects and methods The study included 255 patients aged ≥ 18 years who were operated on at Ondokuz Mayis University, Faculty of Medicine (Samsun, Turkey) between June 2008 and December 2021. All patients had histopathologic confirmation of sPTC (≤10 mm) and underwent regular follow-up for at least 36 months. Results The tumors had a mean size of 5 mm (0.1-10 mm) and were multifocal in 53.7% of patients. Capsular invasion was observed in 9% of patients. Vascular invasion, lymphatic invasion, and extrathyroidal invasion were present in 2%, 5.5%, and 0.8% of patients, respectively. Metastatic cervical lymph nodes were observed in 9.4% of patients. On multivariate logistic regression analysis, tumor size (odds ratio [OR] 1.380, 95% confidence interval [CI] 1.106-1.722, p = 0.004) and sex (OR 4.233, 95% CI 1.355-13.226, p = 0.013) were the main predictive factors influencing lymph node metastasis. Tumors > 5 mm, compared with tumors ≤ 5 mm, had higher rates of multifocality (p = 0.009), parenchymal invasion (p = 0.008), calcifications (p = 0.001), microscopic lymphatic invasion (p = 0.002), and presence of metastatic lymph nodes (p < 0.001). Conclusion The findings of this study highlight important factors to consider in making decisions about prophylactic central compartment neck dissection in patients with sPTCs, particularly those with clinically node-negative tumors.

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ABSTRACT Objective Thyroid hormones are known to affect the biosynthesis and degradation of antioxidant compounds, suggesting a possible link between hypothyroidism and oxidative stress. However, there is no clear consensus in the literature regarding this association. The aim of this study was to evaluate oxidative stress markers (extracellular thiol-disulfide homeostasis and intracellular glutathione homeostasis) in patients with hypothyroidism due to autoimmune (Hashimoto’s thyroiditis) or nonautoimmune thyroid disease rendered euthyroid after levothyroxine replacement. Subjects and methods The study included 116 patients admitted to the Taksim Training and Research Hospital (Istanbul, Türkiye). Of these, 50 had hypothyroidism due to Hashimoto’s thyroiditis (HT group), 30 had nonautoimmune hypothyroidism (NAIH group), and 36 were healthy controls (control group). All participants were women. Extracellular thiol-disulfide homeostasis and intracellular glutathione homeostasis tests were assessed as oxidative stress markers. Results Thiol-disulfide homeostasis in both HT and NAIH groups was shifted toward the oxidative spectrum. Compared with the control group, the HT and NAIH groups had lower levels of native (p < 0.001 and p = 0.001, respectively) and total (p = 0.002 and p = 0.012, respectively) thiol, as well as a lower native thiol/total thiol ratio (p < 0.001 for both). The HT group also had higher disulfide levels than the control group (p = 0.027). Reduced glutathione (GSH) and oxidized glutathione (GSSG) values were comparable across all three groups, but the HT and NAIH groups had higher GSSG/GSH (p < 0.001 for both) and GSSG/(GSH+GSSG) ratios (p = 0.003 and p = 0.005, respectively), along with lower GSH/(GSH+GSSG) ratio (p = 0.001 and p = 0.002, respectively) than the control group. Conclusion Levothyroxine replacement was ineffective in ameliorating oxidative stress in patients with hypothyroidism due to Hashimoto’s thyroiditis or nonautoimmune causes, as extracellular thiol-disulfide homeostasis was notably altered in these patients compared with healthy controls. The findings of this study suggest that oxidative stress remains a prevailing issue in patients with autoimmune or nonautoimmune hypothyroidism even after euthyroidism is restored.

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ABSTRACT Objective To analyze in silico the evidence of molecular mimicry between human beta-cell autoantigens and cow’s milk proteins as a potential type 1 diabetes mellitus (T1DM) trigger. Materials and methods The in silico analysis was performed using bioinformatics tools to compare the amino acid sequences of cow’s milk proteins (bovine serum albumin [BSA] and beta-lactoglobulin [BLG]) and human beta-cell autoantigens (glutamic acid decarboxylase-65 [GAD-65], insulin, and zinc transporter 8 [ZnT8]). The structural and functional characteristics of the proteins were analyzed to identify potential molecular mimicry mechanisms. Results The results of the in silico analysis showed significant sequence similarity between BSA/BLG and GAD-65/human insulin/ZnT8, ranging from 19.64% to 27.27%. The cow’s milk proteins evaluated shared structural features with the beta-cell antigens selected for comparison, indicating a potential for molecular mimicry between these proteins. Conclusion The findings of this study provide further evidence for a potential role of cow’s milk proteins in triggering T1DM. The in silico analysis suggests that molecular mimicry mechanisms between cow’s milk proteins and human beta-cell antigens may contribute to the autoimmune response leading to T1DM.

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ABSTRACT Objective To investigate the prognostic significance of thyroid hormone profile in patients hospitalized for decompensated cirrhosis. Subjects and methods Prospective cohort study that included 119 subjects. All subjects were evaluated at admission and followed for 90 days. TSH, fT3, fT4 were measured within 24 hours of hospitalization. Results Higher fT4 and lower fT3 levels were observed among Child-Pugh C patients as compared to Child-Pugh A and B, and in those with acute-on-chronic liver failure (ACLF). Lower fT3/fT4 ratio was observed in those with ascites, infections, ACLF, and in Child-Pugh C. Ninety-day mortality was 26.9% and it was independently associated with higher Model for End-stage Liver Disease (MELD) and TSH, and lower fT3/fT4 ratio in multivariate analysis. A new prognostic model including MELD, TSH and fT3/fT4 ratio was devised. The areas under the receiver operating characteristic curves for MELD, fT3/fT4 ratio, TSH (μIU/mL), and the new model for predicting 90-day mortality were 0.847 ± 0.041, 0.841 ± 0.039, 0.658 ± 0.062, and 0.899 ± 0.031, respectively. The 90-day survival was 31.6% in patients with values of the predictive model ≥ -0.77 and 93.5% for values < -0.77 (P < 0.001). Conclusions Thyroid hormone profile was strongly associated with worse outcomes in patients with cirrhosis and might represent promising prognostic tools that can be incorporated in clinical practice.

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ABSTRACT Objectives Individuals with congenital isolated growth hormone deficiency (IGHD) in Northeastern Brazil have a normal lifespan with a prolonged healthspan. We hypothesize that their increased healthspan is accompanied by a reduced cognitive decline during aging. We have recently shown that these individuals have a similar total cognitive function and better attention and executive function than controls. These data were obtained using a Portuguese version of the Literacy Independent Cognitive Assessment (LICA) instrument, whose translation to facilitate cognitive research in Portuguese-speaking countries is described here. Subjects and methods In the first stage, a psychologist and a psychiatrist translated the LICA instrument from English into Portuguese, and an English teacher proofread the translation. The second stage included its synthesis and cultural adaptation, carried out by Brazilian authors, and changes in some words and images. The third stage involved an evaluation round with two referees (independent psychologists). The fourth stage involved a back translation of the instrument, which demonstrated > 95% agreement with the original version. The fifth stage included a study to verify the understanding of the questionnaire by responders. In the sixth stage, an endocrinologist and a psychiatrist approved the final Portuguese version of the instrument, which was then administered to 15 individuals with IGHD and 15 controls older than 50 years. Results The LICA instrument was applied 59 times (5 times in the pilot study, 24 in the variability studies, and 30 in the experimental step). The interobserver and intraobserver variabilities were 99% and 96%, respectively. Cronbach’s alpha was 0.76, indicating good reliability. The mean (± standard deviation) duration of the application was 39 ± 8.6 and 48.5 ± 5.8 minutes in literate and illiterate individuals, respectively. Conclusion The Portuguese version of the LICA instrument was valuable for the cognitive assessment of individuals with Itabaianinha syndrome.

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ABSTRACT Objective: Pituitary stalk thickening (PST) is a rare condition in pediatric patients. Data on PST in Latin American pediatric populations are scarce. The aim of this study was to characterize a comprehensive cohort of pediatric patients diagnosed with PST in Chile between 2020 and 2022. Subjects and methods: Retrospective review of medical records from 2020 to 2022 of patients under 18 years old diagnosed with PST, defined as a pituitary stalk width ≥ 3 mm at the pituitary insertion and/or ≥ 4 mm at the optic chiasm. A literature review was also performed to compare the identified cases with previously published ones. Results: Nine patients with PST were identified. Their mean age at diagnosis was 10.36 years (range 2.4-17 years). The patients’ main manifestations were polydipsia and polyuria (100%) and poor growth (77.8%). Eight patients had germ cell tumors, while one patient had Langerhans cell histiocytosis. At the time of diagnosis, all patients had arginine vasopressin (AVP) deficiency, along with a deficiency in at least one anterior pituitary hormone. Germ cell tumor markers were negative in all patients. A biopsy-confirmed diagnosis was obtained in all cases. Four patients required a second biopsy. The frequency of PST due to germ cell tumors was four patients/year during the study period, which is twice the expected frequency in Chile. Conclusion: This study, characterizing the largest cohort of pediatric patients with PST in Latin America, found germ cell tumors to be the main etiology of this condition. It is important to focus diagnostic procedures on obtaining a correct diagnosis and promptly initiating appropriate treatment in patients with PST. Regional cooperation is essential for gathering data from larger cohorts to enhance our understanding of pediatric PST and improve patient outcomes.

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ABSTRACT Objective: To evaluate the association between subclinical hypothyroidism and hepatic steatosis and fibrosis using the noninvasive diagnostic methods transient hepatic elastography (TE) and controlled attenuation parameter (CAP) in patients with subclinical hypothyroidism. Subjects and methods: This was a cross-sectional study including women with confirmed spontaneous subclinical hypothyroidism and an age- and body mass index (BMI)-matched control group without thyroid disease or circulating antithyroperoxidase (anti-TPO) antibodies. Exclusion criteria were age > 65 years, thyroid-stimulating hormone (TSH) > 10.0 mIUI/L, BMI ≥ 35 kg/m2, diabetes, or other chronic liver diseases. Liver stiffness was classified according to TE values (in kPa) and ranged from absence of fibrosis (F0) to advanced fibrosis (F3). Hepatic steatosis was classified according to CAP values (in dB/m) and ranged from low-grade (S1) to advanced (S3) steatosis. Results: Of 68 women enrolled, 27 were included in the subclinical hypothyroidism group and 41 in the control group. Advanced steatosis (S3) was more frequent in the subclinical hypothyroidism group (25.9% versus 7.3%, respectively, p = 0.034). Circulating anti-TPO was an independent factor associated with advanced steatosis (odds ratio 9.5, 95% confidence interval 1.3–68.3). In multiple linear regression analysis, TE values (which evaluated fibrosis) correlated negatively with free thyroxine levels. Conclusion: The results of this study strengthen the hypothesis that hepatic steatosis is associated with autoimmune (positive anti-TPO) subclinical hypothyroidism, independently from BMI. However, subclinical hypothyroidism alone does not appear to be associated with a significantly increased risk of hepatic fibrosis.

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ABSTRACT Objective Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by metabolic, reproductive, and psychological manifestations. Growth and differentiation factor 15 (GDF-15) is a cytokine associated with metabolic and inflammatory disorders. Metformin is commonly used for the treatment of PCOS. We investigated the relationship between GDF-15 levels and PCOS, the effect of metformin on GDF-15 levels, and potential biologic pathways related to GDF-15. Subjects and methods The study included 35 women with PCOS and 32 women without PCOS (controls). Both groups were compared in terms of GDF-15 levels. Additional analysis was conducted on samples from 22 women with PCOS who were treated with either metformin (n = 7) or placebo (n = 15), retrieved from a previous randomized, controlled trial. Levels of GDF-15 were measured using MILLIPLEX. The biologic pathways related to GDF-15 were evaluated using the databases STRING, SIGNOR, and Pathway Commons. The statistical analysis was conducted using the software SPSS. Results Levels of GDF-15 were higher in the PCOS group compared with the non-PCOS group (p = 0.039). Among women with PCOS, GDF-15 levels were higher in those treated with metformin compared with placebo (p = 0.007). The proteins related to GDF-15 overlapped between the databases, and a significant interaction was found between GDF-15 and proteins related to PCOS and its complications, including those related to estrogen response, oxidative stress, ovarian infertility, interleukin (IL)-18, IL-4, the ratio of advanced glycation end products to their receptor (AGE/RAGE), leptin, transforming growth factor beta (TGF-β), adipogenesis, and insulin. Conclusion The findings of the present study suggest a relationship between GDF-15 and PCOS and a potential increase in GDF-15 levels with metformin treatment. An additional finding was that GDF-15 could be involved in biologic pathways related to PCOS complications.

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ABSTRACT Objective This study aimed to assess vitamin D deficiency in a cohort of healthy young adults using the novel inflammatory parameters neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), monocyte-to-high-density lipoprotein (HDL) cholesterol ratio (MHR), and uric acid-to-HDL cholesterol ratio (UHR). Subjects and methods The study included 1,190 participants, with demographic and laboratory data retrieved retrospectively from our institution’s database. The inclusion criteria were ages 22-35 years; absence of acute, subacute, or chronic diseases; no regular medication use; and laboratory values within specified reference ranges. The exclusion criteria were pregnancy, diagnosis of malignancy, and laboratory measurements indicating infection. Participants were categorized into four groups based on vitamin D levels for comparative analysis of study parameters. Correlation analyses were conducted between these parameters and 25-hydroxyvitamin D levels, followed by receiver-operating characteristic analyses to determine the parameters’ sensitivity and specificity in detecting vitamin D deficiency. Additionally, regression analyses were performed to identify potential risk factors for vitamin D deficiency. Results Subjects in Groups A1 and A2 exhibited higher MHR and UHR than those in Groups A3 and A4 (p < 0.001). Both MHR and UHR correlated negatively with vitamin D levels (r = -0.377 and r = -0.363, respectively; p < 0.001). The area under the curve for MHR was 0.766 (95% confidence interval [CI] 0.739-0.794), with a 79% sensitivity and 61% specificity for identification of vitamin D deficiency. Increased MHR and UHR were independent risk factors for vitamin D deficiency (β = 0.219, odds ratio 1.244 95% CI 1.178-1.315, and β = 2.202, odds ratio 1.224, 95% CI 1.150-1.303). Conclusions Both MHR and UHR can be useful in predicting vitamin D deficiency in healthy young adults and may serve as valuable screening tools.

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ABSTRACT Objective: This study was designed to investigate the possible effect of the insulin receptor substrate 1 (IRS1) gene rs1801276 polymorphism on the risk of nonalcoholic fatty liver disease (NAFLD). Subjects and methods: The rs1801276 polymorphism was investigated in 127 controls and 123 biopsy-proven NAFLD patients using PCR-RFLP. Results: No deviation from Hardy-Weinberg equilibrium was discovered for the rs1801276 variant of IRS1 in either NAFLD patients or controls (P>0.05). The distribution of different rs1801276 genotypes and alleles showed significant variations between controls and NAFLD patients. In comparison to rs1801276 ‘CC’ genotype, the "GG+GC" genotype occurred less frequently in NAFLD patients than in controls, which also persisted after adjustment for confounding factors (P = 0.041, OR = 0.60, 95% CI = 0.45-0.93). In comparison with the IRS1 rs1801276 "C" allele, the "G" allele was significantly less prevalent in NAFLD patients than in controls (P = 0.045, OR = 0.69, 95% CI = 0.58-0.91). Conclusions: For the first time, we reported a significant association between the IRS1 rs1801276 polymorphism and biopsy-proven NAFLD. More studies are required to further elucidate the contribution of the IRS1 gene to NAFLD susceptibility.

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ABSTRACT Objective: To describe the secondary outcomes (weight loss, waist circumference [WC], and glycolipid profile) of a previous randomized controlled trial designed to investigate the impact of a high-protein, low-glycemic-index (GI) diet on lean body mass in late postmenopausal women. Subjects and methods: A total of 26 healthy women aged ≥ 65 years and with a mean body mass index (BMI) of 26.1 ± 3.5 kg/m2 were randomly assigned to follow a low-GI diet (GI < 55) with protein consumption at the current recommended dietary allowance (RDA, 0.8 g/kg body weight) or twice the RDA (2RDA, 1.6 g/kg body weight). Changes in body weight, BMI, WC, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol, and triglycerides were assessed at 3- and 6-month of follow-up in all participants. An intention-to-treat analysis was performed using a linear mixed model. Results: Weight loss (mean change -1.7 kg, 95% confidence interval [CI] -2.8 to -0.5 kg, p = 0.004) was observed at 6 months, with no significant difference between the RDA and 2RDA groups. An overall significant WC decrease was observed at 6 months in all participants (mean change -3.8 cm, 95% CI -5.5 to -2.1 cm, p < 0.001), with no differences between groups. The glycolipid profile remained unchanged after 6 months of dietary intervention. Conclusion: Increasing protein intake did not lead to greater weight loss or reduction in WC in a sample of healthy postmenopausal women following a low-GI diet for 6 months.

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ABSTRACT Objective Determining the etiology of hyperprolactinemia is fundamental for selecting the most appropriate treatment strategy. The aim of this study was to evaluate the usefulness and accuracy of prolactin levels in predicting the etiology of nonphysiological hyperprolactinemia. Subjects and methods In this retrospective study, we reviewed medical records of patients with nonphysiological hyperprolactinemia seen at two neuroendocrine reference centers located in Recife, Brazil, from January 2000 to December 2019. Results The study included 770 patients aged 12-73 years (65% female). The three most frequent etiologies of hyperprolactinemia were prolactinomas (n = 263; 34.2%), drug-induced hyperprolactinemia (n = 160; 20.8%), and macroprolactinemia (n = 120; 15.6%). The highest mean prolactin levels were observed in cases of prolactinomas and idiopathic hyperprolactinemia. Most patients with hyperprolactinemia due to other etiologies had prolactin levels < 100 ng/mL, but these levels were also found in 16.5% of patients with microproplactinomas and in 20% of those with idiopathic hyperprolactinemia. Likewise, prolactin levels largely overlapped among patients with microprolactinomas, macroprolactinemia, and drug-induced hyperprolactinemia. Notably, prolactin levels > 250 ng/mL enabled a clear distinction between the etiologies of macroprolactinoma and nonfunctioning pituitary adenoma. Moreover, prolactin levels > 500 ng/mL were highly suggestive of macroprolactinomas, although they were also found in very few patients (<2%) with microprolactinomas or drug-induced hyperprolactinemia. Conclusion Despite considerable overlap in prolactin levels among the different etiologies of hyperprolactinemia, values > 250 ng/mL allowed a clear distinction between macroprolactinomas and nonfunctioning pituitary adenomas. Furthermore, prolactin levels > 500 ng/mL were almost exclusively found in patients with prolactinomas.

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ABSTRACT Objective: Bariatric surgery has several benefits, including sustainable weight loss and improvement or resolution of metabolic comorbidities. However, despite initially successful weight loss, weight regain occurs during long-term follow-up, and many patients are unable to reach or maintain their target weight goals. Liraglutide is a therapy for obesity aimed at preventing weight regain. Materials and methods: This retrospective, observational, single-arm, pre-post study was performed to analyze the relative change in body weight among patients receiving liraglutide after bariatric surgery in a real-world setting in Chile. Results: Treatment with liraglutide at a median dose of 1.2 mg was associated with a mean weight loss from baseline to 3, 6, 12, 24, and 36 months of 5%, 7.7%, 7.6%, 5.8%, and 5.1%, respectively. The mean body mass index reduction was 14.8% at 36 months. Dropout rates were consistent with those of usual obesity treatments. Overall, 70% of the patients were receiving other weight-loss drugs. Liraglutide was well tolerated, but cost barriers led to several patients interrupting its use. Conclusion: Liraglutide is an effective and safe treatment for weight reduction after bariatric surgery in patients receiving routine clinical care in Chile.

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ABSTRACT Objectives: To assess the molecular profile of follicular cell-derived thyroid carcinomas (FCDTCs) and correlate the identified mutations with the clinical and pathological features of the affected patients. Materials and methods: Cross-sectional study of tumor samples from 100 adult patients diagnosed with FCDTC between 2010 and 2019. The patients’ clinical and pathological data were collected. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumors using the ReliaPrep FFPE gDNA Miniprep System. Genotyping of target genomic regions (KRAS, NRAS, BRAF, EGFR, and PIK3CA) was performed using the AmpliSeq panel, while sequencing was performed on the iSeq 100 platform. Results: The patients’ mean age was 39 years. In all, 82% of the tumors were classic papillary thyroid carcinomas. Overall, 54 (54%) tumor samples yielded satisfactory results on next-generation sequencing (NGS), of which 31 harbored mutations. BRAF gene mutations were the most frequent, with the BRAFV600E mutation present in 10 tumors. Seven tumors had BRAFNON-V600E mutations not previously described in FCDTCs (G464E, G464R, G466E, S467L, G469E, G596D, and the T599Ifs*10 deletion) but described in other types of cancer (i.e., skin/melanoma, lung, colorectal, and others). One tumor had a previously reported BRAFA598V mutation. EGFR gene mutations were found in 16 (29%) and KRAS or NRAS alterations in 8 (14%) of the 54 tumors analyzed. Conclusion: We described herein seven non-hotspot/novel variants in the BRAF gene, highlighting their potential role in expanding our understanding of FCDTC genetics.

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ABSTRACT Thyroid nodules are a very common finding and have a malignancy rate of 7%-15%. Some malignant nodules have an indolent behavior and may not affect mortality if left untreated. Active surveillance (AS) is a strategy to prevent overtreatment in patients with papillary thyroid microcarcinomas (PTMCs). This review was conducted to evaluate the status of AS for low-risk PTMC in Latin America, including cultural and logistical challenges, disease progression data, and financial viability. We searched PubMed (MEDLINE), SciELO, LILACS, and Web of Science for articles published after 2014 and enrolling adult Latin American patients. Articles cited in the selected studies were also retrieved. We analyzed the AS protocols, technical or logistical challenges, patient adherence, reasons for AS interruption, surgical conversion rates, duration of AS, and disease progression during AS in our region. Three articles were included in the analysis, all of which considered AS a viable option and reported tumor progression and outcomes similar to those reported in other countries. Neck ultrasound and serum levels of thyroglobulin, thyroid-stimulating hormone (TSH), thyroxine (T4), and antithyroglobulin antibodies were included in the follow-up. No cases of new distant metastases were reported, and the outcomes were favorable when surgery was required. Anxiety was the main reason for AS interruption. We conclude that AS can be an acceptable approach and is safe and effective in Latin America, although more prospective studies are needed to consolidate this strategy in our region. Adequate infrastructure, follow-up, and patient education, as well as multidisciplinary healthcare teams trained in conducting AS must be ensured for successful results.

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ABSTRACT Objective: Considering the rarity and clinical and molecular diversity of Wolfram syndrome (WS), the objective of this study was to identify patients with a clinical presentation suggestive of WS following up at a single Brazilian diabetes service and analyze their clinical and molecular characteristics. Subjects and methods: The study included all patients with a clinical presentation of WS following up between 1991 and 2022 with early-onset diabetes mellitus and other WS signs and symptoms. A retrospective analysis was conducted, including patients’ age, sex, consanguinity, age at symptom onset, diagnosis of diabetes mellitus, optic atrophy, diabetes insipidus, neurological and psychiatric disorders, hearing loss, urinary disorders, hypogonadism, and WFS1 molecular analysis. Results: Eight patients were identified, all of whom were diagnosed with diabetes mellitus at an average age of 3.7 years. Optic atrophy, diabetes insipidus, and hearing loss were common, while psychiatric and neurological alterations were observed in some cases. Genetic analysis revealed pathogenic variants in homozygosity or compound heterozygosity. The most frequent variant was p. Val412Serfs29, present in five of the seven families. Conclusions: This study represents the second-largest Brazilian sample of WS and is the first cohort from a single center in Southeast Brazil. The patients had an early, severe, and complete clinical presentation. The genetic variants identified were consistent with previous literature descriptions. The variant p. Val412Serfs29 was particularly common in this cohort, highlighting its relevance in the region.

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ABSTRACT Objective: Patients with pediatric differentiated thyroid carcinoma (DTC) treated with radioiodine (RAI) therapy may experience long-term side effects, such as gonadal dysfunction. Therefore, it is crucial to understand the impact of this therapy on ovarian reserve and future pregnancy rates. Subjects and methods: Retrospective analysis of 64 female DTC survivors of childbearing age to assess the risk of infertility due to RAI performed before the age of 19 years. Results: Thirty-two out of the 64 DTC survivors had a history of at least one pregnancy during follow-up. No significant differences were observed between the cumulative RAI activity, treatment regimens (multiple versus single RAI treatment), age at first treatment, or presence of lymph node or distant metastases. Notably, the group without a history of pregnancy had a younger age at the time of diagnosis and larger tumors. Age at first pregnancy was slightly higher than that in the general population, but no increase in negative maternal or fetal outcomes was observed. Conclusions: The results of this study show little observational evidence suggesting important adverse effects of RAI on fertility or pregnancy outcomes among female survivors of childhood DTC. Still, studies including larger populations are warranted.

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ABSTRACT Objective: Fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) index are relatively simple and reliable noninvasive markers of insulin resistance (IR). Given the relevance of correctly diagnosing IR, we emphasize the importance of establishing reliable reference intervals (RIs) for these markers. This study aimed to determine the RIs of fasting insulin and HOMA-IR index in adults living in Rio de Janeiro and, secondarily, to verify potential RI differences between sexes. Subjects and methods: Serum insulin levels of 146,497 individuals (ages 20-60 years) who underwent blood sampling in the state of Rio de Janeiro were obtained retrospectively through access to an extensive laboratory database. Insulin was measured using the electrochemiluminescence immunoassay method. After applying exclusion criteria, 21,684 individuals (18,576 [86%] women) were included. The RIs were estimated using a computational mining approach that integrates a selection of R packages. Results: The 95% RIs in women and men and in the overall population were, respectively, 2.54-13.30 μU/mL (15.3-80.12 pmol/L), 2.43-11.89 μU/mL (14.6-71.7 pmol/L), and 2.52-13.14 μU/mL (15.2-79.2 pmol/L) for fasting insulin levels and 0.39-2.86, 0.38-2.81, and 0.39-2.86 for HOMA-IR values. Despite significant differences in insulin levels and HOMA-IR index between men and women, the use of sex-specific RIs was not justified. Conclusion: The RIs of fasting insulin levels and HOMA-IR values found in the overall population can be applied to both sexes. Thus, for our population, we suggest the RIs of 2.52-13.14 μU/mL (15.1-78.8 pmol/L) for fasting insulin and 0.39-2.86 for the HOMA-IR index.

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ABSTRACT Objective This study aimed to evaluate the association of detectable C-peptide levels with various continuous glucose monitoring (CGM) metrics and diabetes complications in patients with type 1 diabetes mellitus (T1DM). Subjects and methods Retrospective, descriptive study of 112 patients with T1DM undergoing intensive insulin therapy, categorized according to fasting C-peptide level into undetectable (<0.05 ng/mL) and detectable (≥0.05 ng/mL) groups. Results The patients’ median age at diagnosis was 22 (12-34) years and the median T1DM duration was 18.5 (12-29) years. Patients with detectable versus undetectable C-peptide levels were older (27.5 [16.5-38.5] versus 17.5 [9.8-28.8] years, respectively, p = 0.002) and had shorter disease duration (14 [9-24] versus 20 [14-32] years, respectively, p = 0.004). After adjustment for covariates (sex, disease duration, body mass index, and use of continuous subcutaneous insulin infusion), detectable C-peptide level was associated with lower time above range (TAR; aβ -11.03, p = 0.002), glucose management indicator (GMI, aβ -0.55, p = 0.024), and average glucose (aβ -14.48, p = 0.045) and HbA1c (aβ -0.41, p = 0.035) levels. Patients with detectable versus those with undetectable C-peptide level had significantly higher time in range (TIR) before (β = 7.13, p = 0.044) and after (aβ = 11.42, p = 0.001) adjustments. Detectable C-peptide level was not associated with lower time below range (TBR), coefficient of variation (CV), or prevalence of chronic microvascular and macrovascular complications. Conclusions Persistent C-peptide secretion in patients with T1DM was associated with significantly better metabolic control reflected by different glucose metrics, namely, TIR, TAR, GMI, and HbA1c.

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ABSTRACT Objective This pilot study investigated whether single nucleotide polymorphisms (SNP) in the NOX5 gene (NADPH oxidase 5) are associated with the type 2 diabetes (T2D) risk. Subjects and methods A total of 1579 patients with T2D and 1627 age- and sex-matched healthy subjects were recruited for this study. Genotyping of common SNPs, namely rs35672233, rs3743093, rs2036343, rs311886, and rs438866, was performed using the MassArray-4 system. Results SNP rs35672233 was associated with an increased risk of T2D (OR = 1.67, 95% CI 1.29-2.17, FDR = 0.003). The H3 haplotype (rs35672233T-rs3743093G-rs2036343A-rs311886C-rs438866C) increased T2D risk (OR = 1.65, 95% CI 1.27-2.13, FDR = 0.001). The rs35672233 polymorphism and H3 haplotype were found to have an association with T2D risk only in subjects with a body mass index greater than 25 kg/m2 (FDR < 0.01). Environmental risk factors, such as chronic psycho-emotional stress, sedentary lifestyle, high-calorie diet and SNP rs35672233 were jointly associated with T2D susceptibility. A haplotype comprising the allele rs35672233-C and conferring protection against T2D, was associated with elevated levels of antioxidants such as total glutathione and uric acid, as well as reduced levels of two-hour postprandial glucose in the plasma of patients. The NOX5 polymorphisms showed no associations with diabetic complications. Conclusion The present study is the first to establish associations between polymorphisms in NOX5 and the risk of type 2 diabetes mellitus, and provides a new line of evidence for the crucial role of oxidative stress-related genes in disease susceptibility.

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ABSTRACT Objective: To investigate the association between the long noncoding RNAs (lncRNAs) maternally expressed gene 3 (MEG3) rs7158663 polymorphism and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Subjects and methods: The study included 628 patients with T2DM and DR ("case group," including 283 with proliferative DR [PDR] and 345 with nonproliferative DR [NPDR]), and 381 patients with T2DM but no DR ("control group"). The diagnosis of DR was established using indirect ophthalmoscopy. The rs7158663 A/G polymorphism was genotyped using real-time polymerase chain reaction (PCR) with TaqMan probes. Results: Patients with DR, compared with those without DR, had lower frequencies of both the G/G genotype (17.5% and 23.6%, respectively, p = 0.044) and the G allele (p = 0.017). When only patients with PDR were compared with controls, the G/G genotype was associated with increased protection against PDR after adjustment (odds ratio 0.551, 95% confidence interval 0.314–0.966, p = 0.038). This association also remained in the dominant (p = 0.036) and additive (p = 0.031) genetic models. Conclusion: This study reveals, for the first time, that the G/G genotype of the lncRNA MEG3 rs7158663 single-nucleotide polymorphism is associated with a protective effect against advanced-stage DR in patients with T2DM. Additional studies are warranted to validate this finding.

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ABSTRACT Objective: This study analyzed systemic inflammatory changes reflected by hematologic and biochemical indices in patients with hyperparathyroidism (PHPT) after parathyroidectomy. Materials and methods: Retrospective study of 70 patients who underwent curative parathyroidectomy for PHPT treatment. Data on clinical presentation, biochemical assays, imaging studies, and postoperative outcomes were collected. Systemic inflammation was quantified using different indices, including the triglyceride-glucose (TyG) index, Fibrosis-4 (FIB-4) score, systemic immune-inflammation index (SII), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), platelet-to-lymphocyte ratio (PLR), and platelet distribution width (PDW). Results: Significant pre-surgical to post-surgical decreases were observed in serum levels of mean normalized calcium (11 ± 0.65 mg/dL and 9.1 ± 0.42 mg/dL, respectively, p = 0.001) and parathyroid hormone (PTH) (235.5 ± 132.9 and 78.1 ± 60.5 ng/L, respectively, p = 0.001). The inflammatory indices changed substantially, with decreases in SII (from 564.8 ± 257.5 to 516.6 ± 201.1, p = 0.001) and PLR (from 143.0 ± 46.2 to 133.6 ± 38.6, p = 0.001). Additionally, PDW decreased from 52.8 ± 8.2% to 47.5 ± 9.3% (p = 0.001) and MHR increased from 7.19 ± 3.06 to 7.81 ± 3.13 (p = 0.001). No significant changes occurred in other inflammatory markers, including the TyG index (p = 0.431) and FIB-4 score (p = 0.401). Logistic regression analysis identified PDW (odds ratio [OR] 0.920, 95% confidence interval [CI] 0.879-0.963, p = 0.001) and PLR (OR 0.991, 95% CI 0.983-1, p = 0.042) as significant predictors of inflammation. Conclusions: Successful parathyroidectomy in patients with PHPT reduces systemic inflammation, as evidenced by decreased PDW and PLR. Our results indicate the importance of integrating PDW and PLR in the postoperative assessment of PHPT for monitoring inflammatory activity.

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ABSTRACT Objective We examined the accuracy of novel anthropometric indices in predicting the progression of prediabetes to diabetes. Subjects and methods This study was performed on the pre-diabetic sub-population from Isfahan Cohort Study (ICS). Participants were followed up from 2001 to 2013. During every 5-year follow-up survey, patients’ data regarding the incidence and time of incidence of diabetes were recorded. We evaluated the association between the risk of developing diabetes and novel anthropometric indices including: visceral adiposity index (VAI), lipid accumulation products (LAP), deep abdominal adipose tissue (DAAT), abdominal volume index (AVI), A body shape index (ABSI), body roundness index (BRI) and weight-adjusted waist index (WWI). We categorized the indices into two groups according to the median value of each index in the population. We used Cox regression analysis to obtain hazard ratios (HR) using the first group as the reference category and used receiver operating characteristics (ROC) curve analysis for comparing the predictive performance of the indices. Results From 215 included subjects, 79 developed diabetes during the 13-year follow-up. AVI, LAP, BRI, and VAI indicated statistically significant HR in crude and adjusted regression models. LAP had the greatest association with the development of diabetes HR = 2.18 (1.36-3.50) in multivariable analysis. ROC curve analysis indicated that LAP has the greatest predictive performance among indices (area under the curve = 0.627). Conclusion Regardless of baseline confounding variables, prediabetic patients with a higher LAP index may be at significantly higher risk for developing diabetes.

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ABSTRACT Objective Sex differences in lipid metabolism associated with prevalent small dense (S-) low-density lipoprotein (LDL) cholesterol particles are not elucidated. An LDL to apolipoprotein B (ApoB) ratio < 1.2 can estimate how prevalent S-LDL particles are and, thus, reflect cardiovascular risk. The aim of this study was to evaluate the sex distribution of LDL/ApoB ratio among patients with type 2 diabetes (DM) and to assess, in both sexes, the correlations between key lipid parameters and LDL/ApoB < 1.2. Subjects and methods The study included 190 Caucasian participants (mean age 51.8 ± 6.4 years) with DM (DM group) or without DM (control group) divided into subgroups according to sex. The participants were examined for levels of several lipid parameters, selected lipid-related oxidative stress markers, and estimated S-LDL prevalence. Results An LDL/ApoB < 1.2 (p < 0.05) was observed in 67% of male and female patients with DM. Although triglyceride levels did not differ between men and women, women had higher levels of total cholesterol (p < 0.05) and LDL cholesterol (p < 0.01) than men. Among women with LDL/ApoB < 1.2, strong correlations were observed between values of lipid hydroperoxides (LOOH) and atherogenic index of plasma (p < 0.005) and between levels of triglycerides and LOOH (p < 0.005) and ApoB (p < 0.0001). Conclusions The findings indicate that women with LDL/ApoB < 1.2 tend to have a higher cardiovascular risk than men. Additionally, LDL/ApoB < 1.2 can be a surrogate marker for estimating the S-LDL prevalence in individuals with potentially increased cardiovascular risk.

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ABSTRACT Objective: To determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in men with spinal cord injury (SCI) and to identify the independent factors associated with steatosis. Subjects and methods: This is a cross-sectional study. Inclusion criteria were males over 18 years of age with chronic traumatic SCI enrolled in a rehabilitation programme. A multivariable logistic regression model was constructed using a stepwise variable selection procedure. Results: After exclusion criteria, 160 participants were included. The prevalence of MASLD was 19%. Men with hepatic steatosis were older, had a higher prevalence of hypogonadism, obesity and diabetes mellitus. Additionally, they exhibited significantly higher levels of ALT, AST and GGT. The mean time since the SCI was 7.8 years in those with steatosis and 4.3 years in those without. Multiple logistic regression analysis revealed age (p < 0.001 OR: 1.07), time since SCI (p = 0.025, OR: 1.11) and total testosterone ≤ 300 ng/dL (p = 0.036, OR: 3.35) as significant independent variables associated with steatosis. Conclusion: Our findings suggest a prevalence of MASLD in men with SCI similar to that of the general population. Independent factors associated with steatosis were age, time since injury and total testosterone. Notably, individuals with testosterone levels ≤ 300 ng/dL were 3.35 times more likely to have steatosis compared to those with higher testosterone levels.

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ABSTRACT Objective: The pan-immune-inflammation value (PIV) is a novel inflammatory biomarker for evaluating inflammatory status in patients with cancer. The aim of this study was to evaluate the prognostic value of PIV in patients with differentiated thyroid cancers (DTCs). Subjects and methods: The study included 376 patients with DTC who underwent curative resection. The PIV was calculated using the formula (neutrophils × monocytes × platelets)/lymphocytes. The TNM stages 3-4 were considered advanced. Patients were also categorized into low-, intermediate-, and high-risk groups according to the American Thyroid Association (ATA) risk classification system. Demographic, laboratory, and clinicopathological data were obtained from the patients’ files. The predictive value of PIV on TNM advanced stage, ATA high-risk category, and distant metastases was evaluated using receiver operating characteristic (ROC) curve analysis. Results: The optimal PIV values for predicting TNM advanced stage, ATA high-risk category, and distant metastases were, respectively, 331.62 (area under the curve [AUC] 0.730, sensitivity 66.7%, specificity 64.8%), 365.52 (AUC 0.822, sensitivity 79.5%, specificity 76.9%), and 357.65 (AUC 0.774, sensitivity 75.2%, specificity 72%). On regression analysis, PIV ≥ 365.52 (odds ratio [OR] 29.150, 95% confidence interval [CI] 8.148-104.290, p < 0.001) and PIV ≥ 357.65 (OR 7.224, 95% CI 1.700-30.693, p = 0.007) emerged as independent risk factors for ATA high-risk category and distant metastases, respectively. Conclusion: Among patients with DTC, PIV is an independent risk factor for distant metastases and ATA high-risk category. While this finding must be supported by more comprehensive studies, PIV has the potential to be used as a prognostic biomarker in these patients.

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ABSTRACT Objective: The study objectives were to characterize adult patients with XLH treated at a referral center, assess their physical function and the impact of X-linked hypophosphatemia (XLH) on their quality of life, and estimate their adherence to conventional treatment. Subjects and methods: Observational, retrospective study of patients with XLH from a referral center in Argentina, based on demographic and clinical data, complementary methods, and validated questionnaires (WOMAC, PROMIS, and SF-36). Results: Sixteen patients (age: 40.3 ± 13.2 years; female: 87.2%) were included. All patients had clinical and/or radiological skeletal manifestations (lower limb malformations and/or pseudofractures). The prevalence of clinical fractures was 60%. Hearing loss was the most frequent extraskeletal finding (67%). The WOMAC score was 47.8 ± 26 (62.5% of patients had ≥ 40 points). The PROMIS score was 23-33 (43% of patients) and ≥ 34 in 14% of patients. Except for emotional function, the median scores of the SF-36 domains were below 50 points. Only 20% of patients had good adherence to conventional treatment. Conclusions: Adult patients with XLH have numerous unmet needs, with frequent bone and extraskeletal complications. Physical function and quality of life scores were poor. Adherence to conventional treatment was unsatisfactory. Long-term studies are required to characterize these patients and confirm the efficacy and safety of continuous treatment, such as anti-fibroblast growth factor-23 monoclonal antibodies.

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ABSTRACT Objective: This study investigated the acute effects of cocoa flavanol (CF) supplementation on glucose homeostasis, aerobic performance, and lactate concentration in rats with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and normoglycemia (NORM). Materials and methods: The study included 28 male Wistar rats (220-290 g). Induction of T1DM (n = 8) was achieved through intraperitoneal injection of streptozotocin, while T2DM (n = 10) was induced using an ad libitum high-fat diet combined with a fructose-rich beverage. The rats in the NORM group (n = 10) received a standard diet for 30 days. Two experiments were conducted: (1) T1DM rats performed two successive 30-minute treadmill runs below the anaerobic threshold and (2) T2DM and NORM rats underwent two incremental maximal treadmill running tests, both after CF or placebo supplementation. Blood glucose concentrations were measured from pre-exercise to 60 minutes post-exercise. Results: Glycemic reduction at 60 minutes post-exercise was significantly potentiated by CF compared with placebo supplementation in T1DM, T2DM, and normoglycemic rats (p < 0.05 for all). In T2DM rats, CF induced a glycemic response comparable to the NORM placebo-supplemented condition. These effects of CF persisted despite variations in aerobic performance or lactate concentration after incremental exercise. Conclusion: Supplementation with CF prior to physical exercise elicited a pronounced post-aerobic exercise glycemic reduction. This represents a promising strategy for mitigating the duration of hyperglycemia exposure after physical exercise.

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ABSTRACT Objective: This study aims to explore the association between dietary antioxidant index (DAI) and type 2 diabetes (T2D) in the Iranian population. Subjects and methods: The present cross-sectional study comprised 4,241 participants aged from 35 to 70. A food frequency questionnaire (FFQ) was used to assess dietary intake. The DAI score was determined using Wright's method, which quantifies the antioxidant content of the diet. Logistic and linear regression analyses were used to determine the link between DAI and T2D after adjusting for confounding variables. Results: Negative associations were found between T2D with total score of DAI (OR = 0.67, CI95%: 0.55-0.81, P = 0.001) and DAI score of zinc (OR = 0.53, CI95%: 0.40-0.72, P = 0.001), manganese (OR = 0.77, CI95%: 0.68-0.88, P = 0.001), and selenium (OR = 0.88, CI95%: 0.78-0.98, P = 0.010) after adjustments for age, sex, BMI, education level, marital status, occupation, physical activity, and calorie intake. Conclusion: These results indicate the significance of an antioxidant-rich diet in preventing T2D and its complications. Nevertheless, additional investigation is required to validate these findings and explore the fundamental mechanisms of the association of T2D and dietary antioxidants.

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ABSTRACT Objective: To investigate the association of the rs741301 polymorphism in the ELMO1 gene with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Materials and methods: This study analyzed 350 patients with T2DM and DR (cases) and 234 patients with T2DM without this complication but with more than 10 years of diabetes mellitus (DM) (controls). DR was diagnosed by indirect fundoscopy. Genotyping was performed by allelic discrimination real-time PCR. Results: The frequency of the C/C genotype of the rs741301 polymorphism in the ELMO1 gene was 26.9% in cases and 17.9% in controls (P = 0.011). After adjustment for covariables, the C/C genotype was associated with an increased risk of DR [odds ratio (OR) = 1.805, 95%CI 1.101–2.961; P = 0.019]. This association remained significant in dominant and additive inheritance models after adjustment for the same variables [OR = 1.597, 95%CI 1.089-2.343; P = 0.017; and OR = 1.818, 95%CI 1.099-3.007; P = 0.020]. Conclusion: This study demonstrated an association between the presence of the C allele of the ELMO1 rs741301 polymorphism and an increased risk of DR in patients with T2DM from Southern Brazil.

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ABSTRACT Objective: To evaluate the rates of permanent hypoparathyroidism based on demographic variables, patient comorbidities, clinical staging of the disease, surgery performed, and severity of transient hypoparathyroidism. Subjects and methods: This is a retrospective cohort study with patients who underwent total thyroidectomy with or without neck dissection between January 2014 and December 2021. Results: 5,671 patients were analyzed, 966 (17%) presented transient hypoparathyroidism and 106 (1.8%) developed permanent hypoparathyroidism. The logistic regression model analyzing the cohort of patients with transient hypoparathyroidism demonstrates that the number of dissected lymph nodes from the central compartment, immediate postoperative PTH levels, the necessity of postoperative intravenous (IV) calcium supplementation and the duration of IV calcium supplementation are significant predictors. When applied to the original dataset, this model presents a NPV of 1.0000 and a PPV of 0.9594 with an overall accuracy of 0.9624. Conclusion: The incidence of permanent hypoparathyroidism was closely associated with the extent of level VI dissection, particularly regarding the number of lymph nodes removed and whether the dissection was bilateral. Furthermore, the severity of post-operative hypocalcemia was demonstrated by the decrease in PTH levels, as well as the need for and duration of intravenous calcium supplementation.

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ABSTRACT Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis and reduce fragility fractures. Its beneficial effects on bone tissue have been consolidated in the literature for the last decades. They have a high affinity for bone hydroxyapatite crystals, and most bisphosphonates remain on the bone surface for a long period of time. Benefits of long-term use of BPs: Large and important trials (Fracture Intervention Trial Long-term Extension and Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial) with extended use of alendronate (up to 10 years) and zoledronate (up to 6 years) evidenced significant gain of bone mineral density (BMD) and vertebral fracture risk reduction. Risks of long-term use of BPs: The extended use of antiresorptive therapy has drawn attention to two extremely rare, although severe, adverse events. That is, atypical femoral fracture and medication-related osteonecrosis of the jaw are more common in patients with high cumulative doses and longer duration of therapy. BPs have demonstrated safety and effectiveness throughout the years and evidenced increased BMD and reduced fracture risks, resulting in reduced morbimortality, and improved quality of life. These benefits overweight the risks of rare adverse events.

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ABSTRACT FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.

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ABSTRACT Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.

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ABSTRACT Nonketotic hyperglycemia may occur as a cause of chorea in patients with chronic decompensated diabetes. Because it is rare and consequently poorly studied, diagnosis and treatment can be delayed. Therefore, our objective was to summarize clinical and radiological features, as well as treatments performed, from previously reported cases to facilitate adequate management in clinical practice. We searched MEDLINE/PubMed, EMBASE, Cochrane, CINAHL, Web of Science, Scopus, and LILACS databases for studies published before April 23, 2021. We included case reports and case series of adults (aged ≥ 18 years) that described hyperglycemic chorea with measurement of glycated hemoglobin (HbA1c) and cranial magnetic resonance imaging (MRI). Studies were excluded if participants were pregnant women, aged < 18 years, and had no description of chorea and/or physical examination. We found 121 studies that met the inclusion criteria, for a total of 214 cases. The majority of the included studies were published in Asia (67.3%). Most patients were women (65.3%) aged > 65 years (67.3%). Almost all patients had decompensated diabetes upon arrival at the emergency department (97.2%). The most common MRI finding was abnormalities of the basal ganglia (89.2%). There was no difference in patient recovery between treatment with insulin alone and in combination with other medications. Although rare, hyperglycemic chorea is a reversible cause of this syndrome; therefore, hyperglycemia should always be considered in these cases.

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ABSTRACT The aim of this study was to assess the efficacy and safety of hybrid closed-loop (HCL) systems for insulin delivery in children and adolescents with type 1 diabetes (T1D). We searched Embase, PubMed, and Cochrane Library for randomized controlled trials (RCTs) published until March 2023 comparing the HCL therapy with control therapies for children and adolescents with T1D. We computed weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) with 95% confidence intervals (CIs) for binary endpoints. Four RCTs and 501 patients were included, of whom 323 were randomized to HCL therapy. Compared with control therapies, HCL significantly improved the period during which glucose level was 70-180 mg/dL (WMD 10.89%, 95% CI 8.22-13.56%) and the number of participants with glycated hemoglobin (HbA1c) level < 7% (RR 2.61, 95% CI 1.29-5.28). Also, HCL significantly reduced the time during which glucose level was > 180 mg/dL (WMD -10.46%, 95% CI -13.99 to -6.93%) and the mean levels of glucose (WMD -16.67 mg/dL, 95% CI -22.25 to -11.09 mg/dL) and HbA1c (WMD -0.50%, 95% CI -0.68 to -0.31). There were no significant differences between therapies regarding time during which glucose level was < 70 mg/dL or <54 mg/dL or number of episodes of ketoacidosis, hyperglycemia, and hypoglycemia. In this meta-analysis, HCL compared with control therapies was associated with improved time in range and HbA1c control in children and adolescents with T1D and a similar profile of side effects. These findings support the efficacy of HCL in the treatment of T1D in this population.

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ABSTRACT Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.

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ABSTRACT Muscle weakness has been associated to insulin resistance and metabolic syndrome in the general population. However, it is still unclear whether this association is maintained in older adults. This study investigated correlations between low handgrip strength (HGS) and metabolic syndrome, or some of its components, in older adults through a systematic review of the literature. Searches were conducted in the Virtual Health Library Regional Portal, Scopus, Cochrane, Embase, MEDLINE/PubMed, SciELO, and Web of Science databases for relevant studies investigating muscle weakness (measured by hand dynamometer) and metabolic syndrome or its components in older adult populations, published up to September 2023. From the 2050 references initially identified, 20 studies, comprising a total of 31,264 older adults of both genders, completely met the inclusion/exclusion criteria. Eighteen studies showed that lower HGS was associated with metabolic syndrome or some of its risk factors, such as abdominal obesity, hyperglycemia, insulin resistance, dyslipidemia, or high blood pressure. Two studies found that older men with high blood pressure had increased HGS. Most studies included in this systematic review revealed a significant correlation between reduced HGS and metabolic syndrome or some of its components, especially abdominal obesity and insulin resistance. We conclude that below-average HGS can be associated with metabolic syndrome in older adults.

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ABSTRACT Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: −1.46, 95% confidence interval [CI]: −1.76 to −1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.

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ABSTRACT The incidence of thyroid cancer is increasing globally, but mortality rates have remained steady. Many patients with thyroid cancer have low-risk, nonmetastatic intrathyroidal tumors smaller than 2 cm. Active surveillance has shown benefits in these patients, but the adoption of this approach remains below standard in Latin America. The purpose of this article is to identify ways to improve the incorporation of active surveillance into clinical practice for patients with low-risk thyroid carcinoma in Latin America, taking into consideration cultural and geographic factors. Current recommendations include three steps involving patient participation. The first step, which consists of the initial clinical examination, has eight factors requiring special attention. Anxiety must be managed while considering individual, disease-related, cognitive, and environmental aspects. Terms like "overdiagnosis", "incidentaloma," and "overtreatment" must be explained to the patient. Implementing precise terminology contributes to adequate disease perception, substantially reducing stress and anxiety. Clarifying the nonprogressive nature of thyroid cancer helps dispel myths surrounding the disease. The second step includes advice about procedures and guidelines for patients who choose active surveillance. Flexible monitoring techniques should be implemented, with regular check-ins scheduled based on patient needs. Reasons for adjusting treatment must be clearly communicated to the patient, and changes in preference regarding active surveillance should be considered in advance. The third step includes assistance during follow-up. Patients must be educated about ultrasound results and receive surgical indications from specialized physicians. The effectiveness of active surveillance can be reinforced by explaining to the patients the dynamics of changes in nodule size using clear and concise visual aids.

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ABSTRACT Obesity is a prevalent chronic disease. The management of extreme obesity – i.e., body mass index (BMI) ≥ 50 kg/m2 or obesity class IV and V – is still far from ideal. Individuals with extreme obesity have a high risk of surgical complications, mortality, comorbidities, and reduced weight loss following bariatric surgery. Although lifestyle changes and anti-obesity medications are recommended for all patients with extreme obesity as adjuvants to weight loss, these measures are less effective than bariatric surgery. As a first step, sleeve gastrectomy or an inpatient very-low-calorie diet should be incentivized to enhance weight loss before definitive surgery. Although malabsorptive procedures lead to greater weight loss, they are associated with an increased risk of early complications and malnutrition. Nonstandard techniques employed in clinical trial protocols, such as transit bipartition, may be performed as they maintain a weight loss potency comparable to that of the classic duodenal switch but with fewer nutritional problems. Anatomical causes should be investigated in patients with postoperative suboptimal clinical response or recurrent weight gain. In these cases, the initiation of anti-obesity drugs, endoscopic therapies, or a conversion procedure might be recommended. More studies are needed to address the specific population of patients with extreme obesity, as their outcomes are expected to be distinct from those of patients with lower BMI.

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ABSTRACT The poor diet quality in line with the rising prevalence of noncommunicable chronic diseases, coupled with the substantial deficit in nutritional education within medical training programs, has precipitated the emergence of Culinary Medicine as an evolving discipline. Culinary Medicine fuses the art of home cooking with the sciences of human nutrition, psychology, gastronomy, and medicine to promote health and well-being. This comprehensive narrative review explores the diverse facets of Culinary Medicine, elucidating its historical evolution, theoretical foundations, educational initiatives in Brazil and worldwide, and its practical implementation in clinical contexts. By integrating evidence-based nutrition knowledge with culinary skills, behavior change tools, and well-established principles of healthy dietary practices, Culinary Medicine arrives to empower individuals – physicians and patients – to make informed dietary choices and enhance their overall health outcomes. Moreover, this review contemplates the roles of physicians in providing dietary guidance within the Culinary Medicine paradigm and the challenges associated with incorporating Culinary Medicine as a complementary facet of conventional medical care and medical education.

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ABSTRACT The aim of this study is to assess the effects of once-daily oral orforglipron on weight and metabolic markers in adult patients. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched until February 2024 for randomized controlled trials (RCTs) comparing orforglipron versus placebo or other anti-obesity medications in adult patients. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) or risk differences for binary endpoints were computed, with 95% confidence intervals (CIs). Heterogeneity and risk of bias were assessed with I2 statistics and Rob-2, respectively. Statistical analyses were performed using R, version 4.2.2. A total of four studies were included, comprising 815 patients, of whom 620 (76.1%) were prescribed orforglipron. Compared with placebo, orforglipron reduced body weight (WMD -6.14 kg, 95% CI -9.62 to -2.66 kg), body mass index (WMD -2.87 kg/m2, 95% CI -4.65 to -1.10 kg/m2), and waist circumference (WMD -5.32 cm, 95% CI -9.13 to -1.51 cm). More patients treated with orforglipron than placebo achieved a weight loss of ≥ 5% (RR 3.31, 95% CI 2.23-4.93), ≥ 10% (RR 5.24, 95% CI 2.07-13.31), and ≥ 15% (RR 9.53, 95% CI 1.26-71.89). The most common adverse events were related to the gastrointestinal tract. In this meta-analysis, the use of once-daily oral orforglipron by adult patients was associated with a significant decrease in body weight, as compared with placebo, with an increase in non-severe gastrointestinal adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-daily oral orforglipron over the long term.

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SUMMARY Denosumab is a potent antiresorptive medication, commonly used in the treatment of osteoporosis, as well as in a variety of other diseases. Potential adverse rebound effects after its cessation include a loss in bone mineral density and an increased risk of osteoporotic fractures. Hypercalcemia is a less frequently reported rebound phenomenon after denosumab discontinuation, that may pose a diagnostic challenge to physicians as a rare non-parathyroid hormone (PTH) dependent cause of hypercalcemia. In our case, a 47-year-old male presented with rebound hypercalcemia after denosumab cessation during follow-up after surgical treatment for parathyroid carcinoma. This non-PTH-dependent hypercalcemia resolved after re-initiation of denosumab. We performed a systematic literature review on rebound hypercalcemia after denosumab cessation and identified 52 individual patient cases. Children appear to be more prone to developing rebound hypercalcemia, which could be attributed to their higher baseline bone turnover, underlying conditions, or denosumab dosage regimens. In most cases, patients initially presented with acute and often severe symptoms of hypercalcemia that occur from 1.75 to 9 months after denosumab cessation (4 to 9 months in adults). Most effective treatment approaches to sufficiently decrease serum calcium levels were bisphosphonates or re-administration of denosumab. A watch and wait strategy may be sufficient in asymptomatic cases, which are less common and probably underdiagnosed. Subsequent antiresorptive treatment after denosumab cessation, which is a common practice in osteoporosis treatment, may reduce the risk of rebound hypercalcemia. As denosumab is a frequently used drug in patients with advanced malignant diseases and rebound hypercalcemia with low PTH levels may raise the suspicion for skeletal metastases, awareness of this rebound effect may be for particular relevance in such settings.

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ABSTRACT Type 1 diabetes (TID) is a chronic disease caused by autoimmune destruction of pancreatic β-cells, that progresses in three stages: 1) stage 1: β-cell autoimmunity + normoglycemia; 2) stage 2: β-cell autoimmunity + mild dysglycemia; 3) stage 3: symptomatic disease + hyperglycemia. Interventions to prevent or cure T1D in the various stages of the disease have been pursued and may target the prevention of the destruction of β cells, regression of insulitis, preservation or recovery of β cells residual mass. Some therapies show promising results that might change the natural history and the approach to patients with T1D in the next few years. Teplizumab, a humanized monoclonal antibody that binds to CD3, was recently approved in the USA to delay Stage 3 T1D in individuals ≥ 8 years of age. Other non-cellular immunomodulatory therapies, both antigen-specific and non-specific, have shown interesting results either in patients with stage 2 or recent onset stage 3 T1D. Cell therapies such as non-myeloablative transplantation of autologous hematopoietic stem cells, mesenchymal stem cells, and tolerogenic dendritic cells have been also studied in these individuals, aiming immunomodulation. Stem cell-derived islet replacement therapy is promising for patients with long-standing T1D, especially with asymptomatic hypoglycemia not resolved by technology. This review aimed to provide updated information on the main immunomodulatory agents and cell therapy options for type 1 diabetes.

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ABSTRACT The global increase in life expectancy has led to a concomitant rise in diagnoses of sarcopenia. At the same time, the epidemic levels of obesity have given rise to the emergence of a complex condition known as sarcopenic obesity. Characterized by the simultaneous presence of loss of muscle mass and strength along with obesity or excess body fat, sarcopenic obesity represents a concerning health condition. Contrary to prevailing assumptions, sarcopenic obesity is not exclusive to older adults, as it may also manifest in individuals with obesity and chronic diseases and in those who undergo rapid weight loss. This juxtaposition of fat accumulation and muscle depletion epitomizes a harmful combination, especially in healthy adults. A precise definition of sarcopenic obesity and an understanding of how different body composition components affect functional parameters, comorbidities, and mortality rates are crucial for grasping the full extent and significance of this condition. Despite its multifaceted nature, sarcopenic obesity is often undiagnosed and undertreated, posing a considerable challenge to healthcare systems worldwide. In this review, we explore the intricate interplay of factors contributing to the development and consequences of sarcopenic obesity and discuss newly proposed diagnostic guidelines aimed at improved screening. Enhancing awareness and understanding of sarcopenic obesity is imperative for addressing its growing prevalence and mitigating its adverse health effects.

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ABSTRACT The aim of this review is to comprehensively assess the association between a gluten-free diet (GFD) and metabolic control of type 1 diabetes mellitus (T1DM) in children and adolescents with T1DM and with T1DM plus coeliac disease (CD). PubMed, Embase, Cochrane Library, and Web of Science were searched until June 19, 2023. Primary outcomes were hemoglobin A1c (HbA1c), insulin dose, insulin dose adjusted A1c (IDAA1c), blood glucose (B-glu) at 90 min during Mixed Meal Tolerance Test (MMTT), C-peptide area under the curve (AUC), and C-peptide. Seven studies involving 355 T1DM patients were included. Three studies involving 141 patients compared a GFD to a standard diet in children and adolescents with T1DM without CD. Additionally, two studies with 164 patients examined the same diet comparison in those with T1DM and concurrent CD. A comparison between T1DM with CD and T1DM alone, using a GFD, was conducted in two studies encompassing 50 patients. Patients with T1DM alone had similar HbA1c [pooled weighted mean difference (WMD) = −0.5, 95% confidence interval (CI): −1.0 to 0.1, P = 0.079] and IDAA1c (pooled WMD = −0.4, 95%CI: −0.9 to 0.1, P = 0.095) levels after a GFD and a standard diet. In children and adolescents with T1DM and CD, a GFD was associated with a significantly lower HbA1c compared with a standard diet (pooled WMD = −0.64, 95%CI: −1.22 to −0.05, P = 0.034). Insulin dose was significantly lower in T1DM combined with CD patients having a GFD vs a standard diet (pooled WMD = −0.34, 95%CI: −0.66 to −0.03, P = 0.032). Our study suggests that a GFD may offer significant benefits for children and adolescents with both T1DM and CD over a standard diet. While the evidence indicates improved glycemic control with a GFD, the quality of this evidence is low, highlighting the need for rigorous, randomized trials to confirm these preliminary findings. In the interim, enhancing dietary awareness and providing tailored nutritional guidance could be pivotal for optimizing glucose management in this patient population.

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ABSTRACT Hyperprolactinemia is a frequent cause of menstrual irregularity, galactorrhea, hypogonadism, and infertility. The most common etiologies of hyperprolactinemia can be classified as physiological, pharmacological, and pathological. Among pathological conditions, it is essential to distinguish prolactinomas from other tumors and pituitary lesions presenting with hyperprolactinemia due to pituitary stalk disconnection. Proper investigation considering clinical data, laboratory tests, and, if necessary, imaging evaluation, is important to identify the correct cause of hyperprolactinemia and manage the patient properly. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and medication-induced hyperprolactinemia in women.

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ABSTRACT Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.

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ABSTRACT There is increasing interest in ultrasound-guided ablation treatments for thyroid diseases, including benign and malignant ones. Surgeons, radiologists, and endocrinologists carry out these treatments, and various organizations within these specialties have recently released multiple international consensus statements and clinical practice standards. The aim of the present consensus statement is to provide guidance, cohesion, and standardization of best practices for thermal ablation procedures of thyroid nodules. The statement includes the indications for these procedures, preprocedural evaluations, technical aspects of the procedures, posttreatment care, follow-up, complications, and training recommendations. This document was written by a panel of specialists from the Brazilian Society of Interventional Radiology and Endovascular Surgery (SOBRICE), the Brazilian Society of Head and Neck Surgery (SBCCP), and the Brazilian Society of Endocrinology and Metabolism (SBEM). The statement does not aim to provide criteria for assessing the capability of specialists to perform the procedure. Instead, it aims to promote the standardization of best practices to reduce potential adverse outcomes. Additionally, it strives to enhance the delivery of high-quality care and the widespread adoption of these technologies on a national level. The recommendations collectively serve as a guidebook for applying best practices in thyroid ablation.

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ABSTRACT Pharmacological treatment of obesity is passing through many changes in the last decades; different agents have been approved, and newer options are leaning towards higher efficacy and a more favourable safety profile; however, medications approved for a longer time are still available and useful for many patients. This document is an 2024 Update Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM), with the aim of reviewing all the approved medications for the management of obesity in Brazil (sibutramine, orlistat, liraglutide, semaglutide and bupropion/naltrexone fixed dose), with the addition of tirzepatide, that is approved in other countries and likely approved soon in Brazil. The review is focused on efficacy, safety profile and the impact of drugs (based on existing studies) on different comorbidities.

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ABSTRACT Objective: The study aims to explore the relationship between lipoprotein lipase (LPL) variants and hyperlipidemic acute pancreatitis (HLAP) in the southeastern Chinese population. Subjects and methods: In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the LPL gene were sequenced. The correlations between variants and phenotypes were also analysed. Results: The rate of rare LPL variants in the HLAP group is 14.81% (8 of 54), higher than in controls. Among the detected four variants (rs3735959, rs371282890, rs761886494 and rs761265900), the most common variant was rs371282890. Further analysis demonstrated that subjects with rs371282890 "GC" genotype had a 2.843-fold higher risk for HLAP (odds ratio [OR]: 2.843, 95% confidence interval [CI]: 1.119-7.225, p = 0.028) than subjects with the "CC" genotype. After adjusting for sex, the association remained significant (adjusted OR: 3.083, 95% CI: 1.208-7.869, p = 0.018). Subjects with rs371282890 "GC" genotype also exhibited significantly elevated total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels in all the participants and the HLAP group (p < 0.05). Conclusion: Detecting rare variants in LPL might be valuable for identifying higher-risk patients with HLAP and guiding future individualised therapeutic strategies.

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ABSTRACT Objective To identify predictors of mental health disorders and self-care worsening in patients with diabetes through 15 months of COVID-19 pandemic. Subjects and methods Prospective study following patients with type 1 and type 2 diabetes during the COVID-19 pandemic in Southern Brazil. Participants were evaluated through phone calls in two moments: first three months of the outbreak, and 15 months later. The outcomes were the assessment of worsening in mental health disorders (increase ≥ 10% in the total score of the Self-Report Questionnaire), the assessment of emotional distress related to diabetes (increase ≥ 10% in the total score of the Brazilian version of the Problem Areas in Diabetes), and worsening in self-care parameters (reduction ≥ 3 points in the Self-Care Inventory-Revised). Logistic regression models were used to determine the odds ratio (OR) and their respective confidence intervals. Point-biserial correlation coefficients (rpb) were used to measure the relationship between the variation in scores and patient characteristics. Results In total, 150 adults were enrolled (54.6 ± 13.9 years old, 58.7% female, 85.9% white), out of which 118 remained during follow up. After 18 months, 34,7% of them (52.2 ± 14.8 years old, 53.7% female, 87.5% white) worsened mental health scores. An increase in mental health disorders was experienced by patients with lower middle-income [OR 4.2 (1.2-15.0)], and those who reported greater difficulty managing diabetes [OR 3.2 (1.4-7.1); rpb 0.32, P < 0.01]. In contrast, those who perceived an improvement in diabetes control showed a reduction in their mental health scores [OR 0.3 (0.1-0.8)]. For self-care, there was a score worsening in patients with longer duration of diabetes [OR 1.1 (1.0-1.1)] and in those using insulin [OR 8.3 (1.7-41.4); rpb 0.23, P = 0.01]. Conversely, those who followed the social distancing guidance had an improvement in self-care [OR 0.4 (0.1-0.9); rpb 0.18, P = 0.05]. Conclusion Some clinical and socioeconomic characteristics may be suitable for identifying patients at higher risk of mental health and self-care worsening, signaling who needs to be monitored more closely during crisis situations.

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ABSTRACT Introduction: Providing widespread access to thyroidectomies while consolidating services in high-volume centers is a significant challenge in healthcare. In this context, from a national perspective, we aimed to analyze the impact of the COVID-19 pandemic on the institutional case volumes of thyroid surgery in Brazil. Material and methods: We analyzed retrospective thyroidectomy data from the Department of Informatics of the Unified Health System (Datasus), stratifying institutions into low-volume, intermediate-volume, and high-volume centers (<10, 10-100, and >100 thyroidectomies/year, respectively). We assessed the differences in absolute numbers and percentages of thyroidectomies performed during the pandemic years (2020-2022) compared with the pre-pandemic year (2019). Differences in the proportion of institutions based on case volumes from 2019 to 2022 were assessed using Cochran's Q test. Results and discussion: In 2019, 556 Brazilian institutions performed 15,331 thyroidectomies. Of these, 46.4% were categorized as low-volume, 48.4% as intermediate-volume, and 5.2% as high-volume institutions, accounting for 5.5%, 61.4%, and 33.1% of the thyroidectomies, respectively. Compared with 2019, the volume of thyroidectomies was lower by 41.2% in 2020, 37.0% in 2021, and 12.8% in 2022. When analyzing the proportions of institutions that maintained their pre-pandemic case volume in the first pandemic year, the intermediate and high-volume institutions experienced reductions of 34.9% (p < 0.001) and 58.6% (p < 0.001), respectively, while low-volume institutions presented a 4.3% reduction (p = 0.081). Conclusion: The COVID-19 pandemic disrupted the landscape of thyroidectomies in Brazil, particularly affecting intermediate-volume and high-volume institutions, while low-volume institutions showed greater resilience.

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SUMMARY Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

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SUMMARY Calcitonin (CT) is a diagnostic and follow-up marker of medullary thyroid carcinoma. Heterophile antibodies (HAbs) may interfere during immunometric assay measurements and result in falsely high CT levels and different markers. A 50-year-old female patient was referred to our institution for elevated CT levels (3,199 pg/mL [0-11,5]). Physical examination and thyroid ultrasonography show no thyroid nodules. Because of the discrepancy between the clinical picture and the laboratory results, various markers and hormones were examined to determine whether there was any interference in the immunometric assay. Thyroglobulin (Tg) and Adrenocorticotropic hormone (ACTH) levels were also found inaccurately elevated. After precipitation with polyethylene glycol, CT, Tg, and ACTH levels markedly decreased, showing macro-aggregates. Also, serial dilutions showed non-linearity in plasma concentrations. Additionally, CT samples were pretreated with a heterophilic blocking tube before measuring, and the CT level decreased to < 0.1 pg/mL, suggesting a HAb presence. Immunoassay interference should be considered when conflicting laboratory data are observed. This may help reduce the amount of unnecessary laboratory and imaging studies and prevent patients from complex diagnostic procedures.

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SUMMARY Mutations in the insulin receptor (INSR) gene may present with variable clinical phenotypes. We report herein a novel heterozygous INSR mutation in an adolescent girl with type A insulin resistance syndrome and her mother. The index case was a 12-year-old girl without obesity who presented with excessive hair growth, especially in the chest and back area, and hyperpigmentation on the back of the neck (acanthosis nigricans). Acanthosis nigricans was first observed at the age of 11 years. On physical examination, the patient had acanthosis nigricans and hypertrichosis with no acne. Systolic and diastolic blood pressure measurement was within the normal range for age and sex. Laboratory tests revealed fasting hyperglycemia, fasting and postprandial hyperinsulinemia, elevated HbA1c level, and biochemical hyperandrogenemia. Fasting plasma lipids were normal. A diagnosis of type A insulin resistance syndrome was considered, and INSR gene mutation analysis was performed. Next-generation sequence analysis was performed with the use of primers containing exon/exon-intron junctions in the INSR gene, and a novel heterozygous c.3486_3503delGAGAAACTGCATGGTCGC/p. Arg1163_Ala1168del change was detected in exon 19 of the INSR gene. In segregation analysis, the same variant was detected in the patient's mother, who had a milder clinical phenotype. We reported a novel, heterozygous, p. Arg1163_Ala1168del mutation in exon 19 of the INSR gene in a patient with type A insulin resistance syndrome, expanding the mutation database. The same mutation was associated with variable phenotypical severity in two subjects within the same family.

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SUMMARY Brugada syndrome (BrS) is an inherited disorder that can cause ventricular fibrillation and sudden cardiac death in individuals with otherwise structurally normal hearts. Several provoking factors are known to potentially unmask or exacerbate a typical Brugada ECG pattern in predisposed subjects. Hypothyroidism has been suggested as one of these triggers, but the exact mechanisms underlying this relationship remain poorly understood. Moreover, the severity of thyroid dysfunction beyond which a Brugada-type ECG alteration might be triggered is still unclear. We report the case of a 33-year-old male who displayed a Brugada type 1 ECG pattern and was diagnosed with severe hypothyroidism (TSH > 100 mU/L with undetectable levels of fT4 and fT3). Hormonal replacement therapy with levothyroxine was initiated at increasing doses; serial biochemical and ECG controls were performed, initially every 3 weeks up to 15 weeks and afterward every 3 months. The regression of typical Brugada ECG waveforms could be seen at an early stage, when the patient was still taking a low dose of levothyroxine (37.5 µg/day, i.e., one-fourth of his final requirements of 150 µg/day), and laboratory tests still showed a marked alteration of thyroid hormonal parameters. Hypothyroidism may act as a trigger for Brugada-type ECG abnormalities, but a very severe alteration of the hormonal parameters is necessary to prompt these alterations. In our case, the initiation of replacement therapy with levothyroxine rapidly reversed the ECG modifications, even at a low subtherapeutic dose.

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SUMMARY Treating hypothyroidism can be challenging in patients with malabsorption, as they require a higher daily dose of oral levothyroxine (L-T4). Oral L-T4 absorption occurs mainly in the jejunum and the ileum and is affected by gastric acidity. As a result, absorption can be impaired by bariatric surgery. This paper presents a case of myxedema in a young man who had previously undergone biliopancreatic diversion. He was referred to the Emergency Department with deteriorated mental state, hypotension, bradycardia and hypothermia. Laboratory tests revealed severe hypothyroidism and hypokalaemia. The clinical and biochemical profile of the patient suggested myxedema coma. The tablet-based L-T4 therapy was replaced with intravenous (iv) L-T4, oral liquid L-T4 and oral liothyronine (L-T3) and inotropic agents and supportive care were also administered, resulting in a gradual improvement in clinical condition. The patient reported taking L-T4 tablets as prescribed before hospitalization. In patients with malabsorption, impaired L-T4 absorption may lead to severe forms of hypothyroidism. This case outlines the need for more frequent monitoring of serum Thyroid Stimulating Hormone in patients submitted to bariatric surgery and suggests the benefit of using liquid L-T4 in the place of tablets in cases of malabsorption.

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SUMMARY Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening – two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.

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SUMMARY Thyroglobulin (Tg) levels are important to predict recurrence in differentiated thyroid cancer patients. However, false-positive results can hence the request of unnecessary tests and treatments. We reported two cases of interference in thyroglobulin measurement and the workup to investigate them. Both patients achieved an excellent response to therapy after total thyroidectomy and one patient had also received radioiodine treatment. During the follow-up, Tg levels increased and there was no evidence of recurrent disease in the imaging studies. The Tg levels by the Access platform were positive but the results by Elecsys platform and LC-MS/MS were undetectable, leading to the hypothesis of heterophile antibodies (HAbs) interference. The possibility of HAbs interference must be considered when the Tg levels do not fit in the clinical picture. The measurement of Tg by another immunoassay or by LC-MS/MS may be useful in these situations.

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SUMMARY Thyroid storm is a rare but well-known life-threatening complication that occurs due to acute exacerbation of thyrotoxicosis with the increased levels of circulating thyroid hormones. Reports of metabolic encephalopathy associated with thyroid storm are scarce. We describe the case of a 23-year-old male patient with no previous history of abnormal thyroid function who had consumed excessive amounts of alcohol before disease onset. The patient was found unconscious and febrile on a roadside by a passerby and was admitted to our hospital's emergency department. His primary clinical presentation included hyperthermia (40.8 °C), nodal tachycardia (180 beats/min), seizures, coma, and hypoglycemia (2.18 mmol/L). The hypoglycemia was quickly corrected after admission, but his level of consciousness showed no improvement. With aggressive screening, the patient was found to have severe thyroid dysfunction (T3 = 6.67 nmol/L, T4 = 252.00 nmol/L, free T3 = 29.20 pmol/L, free T4 = 65.30 pmol/L, and TSH = 0.001 μIU/mL). After medical treatment, plasmapheresis, hemofiltration, and hemoperfusion, the patient showed substantial improvement in thyroid hormone levels and stabilization of vital signs, but the impaired consciousness and seizures persisted. Multiple computed tomography scans revealed brain abnormalities. Magnetic resonance imaging performed after tracheal extubation revealed bilateral frontal lobe lesions. We reported a case of metabolic encephalopathy in a patient with life-threatening thyroid storm and bilateral frontal lobe lesions. Hypoglycemia may have been involved in the development of encephalopathy in our patient. Health care providers should consider thyroid storm in the differential diagnosis of hyperthermia, seizures, and coma. Early plasmapheresis, hemofiltration, and hemoperfusion can lower T4 levels and improve prognosis in patients with thyroid storm and encephalopathy.

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SUMMARY Hypopituitarism is a rare clinical condition that can present as a partial or complete absence of pituitary hormones. Hypopituitarism is most commonly caused by a sellar or parasellar mass, particularly a tumor, and the gold standard for its differential diagnosis is magnetic resonance imaging (MRI). Intrasellar aneurysm is an unusual cause of hypopituitarism. Indeed, about 0.17% of all cases of hypopituitarism are due to intrasellar aneurysms. We report the case of a 72-year-old man who was admitted to the hospital due to gastrointestinal symptoms and malnourishment. Due to persistent hyponatremia and spontaneous hypoglycemia in laboratory findings, the examination of the hypothalamic-pituitary-adrenal axis was eventually initiated, and the patient was later diagnosed with an unruptured aneurysm of the ophthalmic segment of the right internal carotid artery with sellar extension as a cause of panhypopituitarism. A combined endovascular treatment was performed with stent-assisted coil embolization of the aneurysm, and the patient was prescribed oral hormonal therapy. At the 1-year follow-up visit, no improvement in pituitary function was observed, and a pituitary MRI showed complete aneurysm occlusion and partial empty sella with significantly decreased pituitary volume. Aneurysms of the internal carotid artery are rare and may be associated with hypopituitarism and delayed diagnosis due to their unusual clinical presentation. Endovascular procedures, such as coil embolization of the aneurysm, could be the treatment of choice in these patients. Persistent hypopituitarism may occur even after successful treatment of the aneurysm.

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SUMMARY Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephrotic-range proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and to nephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

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SUMMARY Hemangioblastomas associated with von Hippel-Lindau (VHL) disease are frequently multiple and recur during prolonged follow-up. Currently, no systemic treatment is available for these tumors. Recent studies have shown the expression of somatostatin receptors in these types of hemangioblastomas. Notably, increased somatostatin receptor expression in a tumor, as determined by peptide-receptor radionuclide imaging, is a predictive factor of response to treatment with somatostatin analogs and peptide-receptor radionuclide therapy. The aim of this study was to describe the case of a patient with increased expression of somatostatin receptors in a suprasellar hemangioblastoma associated with VHL disease and conduct a literature review on somatostatin receptor expression in patients with VHL-associated hemangioblastomas. We describe herein the case of a 51-year-old man with VHL disease who had a suprasellar hemangioblastoma detected on magnetic resonance imaging. Peptide-receptor radionuclide imaging using gallium-68-DOTATOC (68Ga-DOTATOC) identified increased expression of somatostatin receptors in the suprasellar hemangioblastoma, along with multiple pancreatic neuroendocrine tumors and bilateral pheochromocytomas. The patient was treated for 1 year with lanreotide, a somatostatin analog. A repeat 68Ga-DOTATOC 1 year after starting lanreotide revealed decreased radiotracer uptake by the hemangioblastoma, consistent with a metabolic response. The presence of somatostatin receptors in hemangioblastomas associated with VHL disease is a novel finding. The decreased expression of these receptors after treatment with a somatostatin analog, as described in the present case, positions the somatostatin receptor as a new target for novel diagnostic, therapeutic, and follow-up opportunities in patients with VHL disease.

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SUMMARY Familial partial lipodystrophy (FPLD) is a very rare genetic disease characterized by insulin resistance due to a loss of subcutaneous fat from the extremities together with a progressive storage of fat around the face and neck and inside the abdomen. In over 50% of cases, molecular genetic testing reveals pathogenic variants in two nuclear genes, LMNA and PPARG. The case reported here refers to a woman phenotypically diagnosed with FPLD, who presented with diabetes and multiple cervical lipomatosis and in whom no variant had been found in the nuclear genes classically associated with this syndrome that could explain her phenotype. Genetic sequencing using a target panel containing 48 nuclear genes related to monogenic diabetes plus the whole mitochondrial genome revealed the mitochondrial variant m.A8344G in 84.1% heteroplasmy. Following molecular diagnosis, her phenotype was expanded with the recognition of additional clinical characteristics: mild sensorineural hearing loss, proximal myopathy, fatigue, cognitive impairment, sensory ataxia, cardiac abnormalities and, finally, muscle biopsy findings compatible with mitochondrial disease. Therefore, careful and detailed phenotypic and genotypic reanalysis proved crucial in improving molecular diagnosis in FPLD.

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SUMMARY Aldosterone-secreting adrenocortical carcinomas (ACCs) are rare and usually present as large tumors. The only potentially curative treatment for ACC is surgical resection. However, surgery may be unfeasible in some patients who have multiple comorbidities or decline the procedure. We describe herein the case of a 44-year-old man with aldosterone-secreting ACC who declined surgery because of religious convictions. As a Jehovah’s Witness, the patient was concerned about requiring blood transfusion during surgery. Treatment with mitotane was started but interrupted due to hepatotoxicity. Subsequently, the patient was successfully treated with stereotactic ablative radiotherapy (SABR). After SABR, the patient had progressive improvement of pain, reduction in antihypertensive drugs, control of blood pressure and hypokalemia, normalization of serum aldosterone and renin levels, and reduction in tumor size and weight. To our knowledge, this is the first report of a patient with a pure aldosterone-secreting ACC who received SABR. The patient’s response was substantial, showing that SABR could be considered as an alternative local treatment for aldosterone-secreting ACCs when surgery is unfeasible.

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SUMMARY Malignant mesenchymal thyroid tumors are one of the rarest types of thyroid cancer. Clinically, these tumors present as a rapidly growing thyroid mass. Due to their rarity and nonspecific findings, they are not the first conditions that come to mind during differential diagnosis. We report herein the case of an 87-year-old woman presenting with a rapidly growing thyroid mass in whom the differential diagnosis of anaplastic cancer was challenging. Following work up, the patient was diagnosed with primary fibrosarcoma of the thyroid, a rare type of malignant mesenchymal thyroid tumor. Because she declined surgery and her clinical condition was unsuitable for chemotherapy, she was treated with palliative radiotherapy. Primary thyroid fibrosarcoma is a rare cause of thyroid cancer and should be considered in the differential diagnosis of rapidly growing thyroid masses.

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SUMMARY Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic diabetes characterized by onset at a young age and an autosomal dominant mode of inheritance. Notably, MODY accounts for 2%-5% of all diabetes cases, and its distinction from types 1 (T1DM) and 2 (T2DM) diabetes mellitus is often challenging. We report herein the cases of two girls and a boy who presented initially with diabetic ketoacidosis. In view of the strong family history of diabetes in all three of them, the diagnosis of MODY was considered and confirmed by molecular testing. The patient in Case 1 (a 10-year-old girl) had a variation in the HNF1A gene (MODY 3). The patient in Case 2 (a 13-year-old girl) had a variation in the HNF1B gene (MODY 5) and was also clinically diagnosed with HNF1B MODY due to short stature, abnormal renal function, renal cysts, unicornuate uterus, and diabetic ketoacidosis at presentation. The patient in Case 3 (a 14-year-old boy) had a variation in the KCNJ11 gene (MODY 13) and presented with diabetic ketoacidosis; after initially being treated as having T1DM, he developed progressive weight gain, acanthosis nigricans, and decreased requirement of insulin. The patients in Cases 1 and 3 were subsequently treated with oral sulfonylureas and insulin was gradually tapered and interrupted, resulting in drastic improvement in glucose control. The patient in Case 2 remained on insulin, as this is the appropriate management for MODY 5. This case series demonstrates that atypical cases of MODY with ketoacidosis do occur, underscoring the potential for this complication within the phenotypic spectrum of MODY. In patients with atypical presentations, a thorough family history taking may reveal the diagnosis of MODY.

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SUMMARY Euglycemic diabetic ketoacidosis (DKA) is a rare complication of diabetes mellitus (DM) characterized by metabolic acidosis, ketosis, and blood glucose levels < 250 mg/dL. The prevalence of euglycemic DKA is increasing with the popularity of ketogenic (low-carbohydrate) diets. We present herein the case of a patient with newly diagnosed type 1 DM who developed euglycemic DKA following a ketogenic diet. A 22-year-old woman presented to the emergency department with malaise, fatigue, nausea, and vomiting. She had no family history of DM. She had consulted her primary care physician 2 weeks before due to hair loss, numbness, and tingling sensation in her fingertips. Her fasting blood glucose was 205 mg/dL at that time. Reluctant to use medication to control her blood glucose levels, she started a ketogenic diet. On admission, she was conscious, oriented, cooperative, and tachycardic. Her body mass index was 17.6 kg/m2. Laboratory tests showed fasting blood glucose of 86 mg/dL, glycated hemoglobin of 10.3%, and elevated insulin levels. Ketone levels in urine and blood were high, indicating ketosis. High anion-gap metabolic acidosis was detected, with a pH of 7.10 and serum bicarbonate level of 12 mEq/L. A diagnosis of new-onset DM and euglycemic DKA was established. She was treated with a modified DKA protocol that included intravenous dextrose-containing serum as fluid therapy, and intravenous insulin infusion was delayed until blood glucose levels increased above 250 mg/dL. The development of euglycemic DKA in our patient was attributed to severe carbohydrate restriction. This case underscores the importance of considering dietary risk factors, particularly ketogenic diets, in the management of DM.

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SUMMARY We present the case of a young adult who had lethargy and significant weight loss for the three weeks before his death. The history of the present illness suggested a prodrome of several weeks, with progressive weakness indicating an advancing metabolic decompensation. To our knowledge, this is the first study performed on human brain tissue with type 1 diabetes (T1D) and likely diabetic ketoacidosis (DKA) before treatment. We studied neuroinflammatory markers in an insulin-deficient state without treatment compared with those found in a treated patient with T1D/DKA of similar age and race who died shortly after treatment. The frontal cortex and hippocampus were stained for tight junction proteins, RAGE, NLRP3, and HMGB1. Other markers that can disrupt the blood-brain barrier, such as IL-17, IL-6, IL-1β, GFAP, and IL-10 were also tested. This case study reveals that neuroinflammatory markers are expressed in the DKA brain at a lower level before treatment than those found to be expressed in the brain after treatment. These findings suggest that in DKA, dehydration minimizes inflammation which could be exacerbated with fluids promoting neuroinflammation and cognitive deficits. These findings require further studies and could identify therapeutic targets to reduce the progression of neuroinflammation and brain edema.

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SUMMARY The main diagnostic dilemma in normocalcemic hyperparathyroidism is differentiating this condition from secondary hyperparathyroidism and other causes of elevated parathyroid hormone (PTH) levels in eucalcemic patients, including potential assay interferences. Despite the analytical sensitivity of immunoassays, they may lack adequate accuracy due to several analytical interferences, such as the presence of heterophilic antibodies. Immunoassays for PTH measurement use the immunometric "sandwich" technique, and only a few cases of interference with this assay have been reported to date. We describe herein two patients in whom PTH immunoassay interference was demonstrated. Both patients presented high serum PTH levels, measured using a second-generation Roche electrochemiluminescence assay (ECLIA; Elecsys Roche, Germany), and normocalcemia. When immunoassay interference was suspected, PTH measurements were repeated using a different analytical platform, the 1-84 PTH third-generation Roche Elecsys ECLIA, resulting in normal levels. We subsequently performed serial dilutions using normal mouse serum with the second-generation ECLIA and found no linearity, indicating the presence of interference in both patients. Immunoassay interference may lead to misinterpretation of a patient's results by the laboratory and incorrect treatment planning by the attending physician. Despite its rarity, the presence of interferences in the PTH immunoassay resulting in falsely high PTH levels should be considered when the laboratory result does not match the patient's clinical presentation, thus preventing erroneous diagnoses and unnecessary therapeutic procedures.

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SUMMARY Long COVID is defined by the occurrence of signs, symptoms, and conditions that develop after COVID-19 and may affect several organs and systems. Arginine-vasopressin deficiency (AVP-D; central diabetes insipidus) is a very rare complication of COVID-19 and SARS-CoV-2 immunization. Case reports, original studies, and reviews on AVP-D and long COVID published until February 2024 were retrieved from PubMed. A 47-year-old man presented with polydipsia, polyuria, memory loss, and mental fog 8 weeks after an episode of mild COVID-19. His past personal and family medical history were unremarkable. Biochemical evaluation was relevant for low urine osmolality and a 24-hour urine volume of 10,350 mL. Basal anterior pituitary evaluation was normal. A water deprivation test was started and interrupted after 2 hours due to the development of hypernatremia, high serum osmolality, and low urine osmolality. Urine osmolality significantly increased after intranasal desmopressin 20 μg. Contrast-enhanced pituitary MRI was suggestive of infundibulo-neurohypophysitis. Further biochemical, genetic, and imaging tests excluded secondary AVP-D causes. The patient was subsequently started on oral desmopressin, showing prompt response. After a follow-up of 20 months, he remained well-controlled with isolated AVP-D. Although molecular and histologic confirmation of SARS-CoV-2 infundibulo-neurohypophysitis could not be investigated, a strong temporal relationship and the absence of an alternative diagnosis rendered plausible the inclusion of AVP-D in the myriad of long COVID manifestations. Further studies with patients recovered from COVID-19 are necessary for a better understanding of the epidemiology, pathophysiology, and clinical course of this very rare endocrine condition.