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KCNQ1/Kv7, a low-voltage-gated K+ channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca2+ flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca2+ channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and β-cell survival in hereditary diabetes pathology.

Patients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.

Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15s direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Obesity, a condition of excess adiposity usually defined by a BMI > 30, can have profound effects on both metabolism and immunity, connecting the condition with a broad range of diseases, including cancer and negative outcomes. Obesity and cancer have been associated with increased incidence, progression, and poorer outcomes of multiple cancer types in part due to the pro-inflammatory state that arises. Surprisingly, obesity has also recently been demonstrated in both preclinical models and clinical outcomes to be associated with improved response to immune checkpoint inhibition (ICI). These observations have laid the foundation for what has been termed the obesity paradox. The mechanisms underlying these augmented immunotherapy responses are still unclear given the pleiotropic effects obesity exerts on cells and tissues. Other important variables such as age and sex are being examined as further affecting the obesity effect. Sex-linked factors exert significant influences on obesity biology, metabolism as well as differential effects of different immune cell-types. Age can be another confounding factor contributing to the effects on both sex-linked changes, immune status, and obesity. This review aims to revisit the current body of literature describing the immune and metabolic changes mediated by obesity, the role of obesity on cancer immunotherapy, and to highlight questions on how sex-linked differences may influence obesity and immunotherapy outcome.

Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushings syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushings syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.

Hypothalamic obesity (HO) is defined as abnormal weight gain resulting in severe persistent obesity due to physical, tumor‐ and/or treatment‐related damage to the hypothalamus. HO epidemiology is poorly understood. We developed a database algorithm supporting the standardized identification of tumor/treatment‐related HO (TTR‐HO) patients. The algorithm is used to estimate incidence rates of TTR‐HO patients in the German healthcare context from a representative claims database (n = 5.42 million) covering 2010–2020. Patients were identified based on surgery/radiotherapy procedures and HO‐associated tumor diagnoses (n = 3976). HO was defined by incident obesity and validated based on incident diabetes insipidus diagnoses and desmopressin prescription within a 12‐month period after surgery/radiotherapy. Uncertainty due to algorithm definitions is explored in sensitivity analyses. Estimated annual incidence of TTR‐HO in Germany is between 0.7 and 1.7 cases per 1,000,000 persons (2019 prevalence: n = 1262 patients). With observed cases in all age groups, two HO‐incidence peaks are identified: children/young adults aged 10–24 years and adults aged 40–44 years. Most frequent HO‐validated tumor diagnoses are benign sellar/suprasellar tumors (6.1/1,000,000 persons over 9 years), including tumors of the craniopharyngeal duct (1.3/1,000,000), neoplasms of the pituitary gland (4.1/1,000,000), and nonspecific brain tumors of endocrine glands (2.4/1,000,000). This is the first real‐world database analysis of TTR‐HO epidemiology, refining current estimates of HO epidemiology and early patient identification. A more comprehensive characterization of patients with HO as well as a better understanding of clinical implications will be crucial in developing optimal treatment strategies to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions Management of idiopathic intracranial hypertension (IIH) is complex requiring multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges for healthcare professionals and patients. Thus, an interdisciplinary integrated outpatient clinic for IIH (comprising neurology, neuroophthalmology, neuroradiology, neurosurgery and endocrinology) was established with central coordination and a one‐stop concept. Here, the aim was to evaluate the effects of this one‐stop concept on objective clinical outcome.In a retrospective cohort study, the one‐stop era with integrated care (IC) (1 July 2021 to 31 December 2022) was compared to a reference group receiving standard care (SC) (1 July 2018 to 31 December 2019) regarding visual impairment/worsening and headache improvement/freedom 6 months after diagnosis. Multivariate binary logistic regression models were used to adjust for confounders.Baseline characteristics of the IC group (n = 85) and SC group (n = 81) were comparable (female 90.6% vs. 90.1%; mean age 33.6 vs. 32.8 years; median body mass index 31.8 vs. 33.0; median cerebrospinal fluid opening pressure 32 vs. 34 cmH2O; at diagnosis, visual impairment was present in 71.8% vs. 69.1% and chronic headache in 55.3% vs. 56.8% in IC vs. SC). IC was associated with a higher likelihood of achieving both headache improvement (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.52–4.33, p < 0.001) and headache freedom (OR 1.75, 95% CI 1.11–3.09, p = 0.031). Regarding the risk of visual impairment and visual worsening IC was superior numerically but not statistically significantly (OR 0.87, 95% CI 0.69–1.16, p = 0.231, and OR 0.67, 95% CI 0.41–1.25, p = 0.354).Interdisciplinary integrated care of IIH is favourably associated with headache outcomes and potentially also visual outcomes. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Caregiver diabetes distress (DD) consists of feeling overwhelmed, sad, and/or concerned; one‐third of parents of youth with type 1 diabetes (T1D) report severe distress up to 4 years after T1D diagnosis. PAID‐PR (Problem Areas in Diabetes Survey—Parent Revised) assesses DD primarily in research settings; however, less is known about its clinical utility. We aimed to identify the feasibility of implementing PAID‐PR screening at a diverse, academic US paediatric diabetes center during routine clinic follow‐up visits through quality improvement methodologies.The PAID‐PR was intended to be offered in English to caregivers at all paediatric T1D appointments, by the front desk during appointment check‐in, or through REDCap prior to telehealth appointments or at local sites to all eligible caregivers. Adult psychosocial resources were provided to all, regardless of score. Forms were scored after appointments; scores ≥80 were referred to Diabetes Psychology providers for follow‐up.A total of 391 caregivers completed the PAID‐PR, though only half of eligible caregivers received it in person. Response rates were highest in person (90%), compared to REDCap (25%). In total, 27% (n = 107) scored ≥56 (DD). Of those with DD, 21% (n = 23) scored ≥80 and were referred to psychology. Demographics are reported in Table 1. PAID‐PR score was positively correlated to A1c (p = 0.038) and inversely to child age (p = 0.014).Clinic caregiver DD screening was implemented with higher response rates in person; however, expanding in‐person screening to all eligible caregivers is necessary. Furthermore, since the PAID‐PR was in English, some caregivers with DD were likely missed. Future directions include screening in additional languages. [ABSTRACT FROM AUTHOR]

Background: Thyroid nodules are unusual in children, but when present, they carry a higher risk for malignancy, as compared to adults. Several guidelines have been created to address the risk stratification for malignancy of thyroid nodules in adults, but none has been completely validated in children. A few authors have proposed lowering the size threshold to the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS™) management guidelines to decrease missed carcinomas at presentation in children; however, little information is known regarding their accuracy. Objective: To assess the performance of proposed modifications of the ACR TI-RADS™ size criteria to guide management decisions in pediatric thyroid nodules and to assess the associated increase in number of fine needle aspiration (FNA) and follow-up exams. Materials and methods: This is a retrospective study of children under 18 years old who underwent ultrasound assessment of a thyroid nodule at a tertiary care pediatric institution between January 2006 and August 2021. The largest dimension, maximum ACR TI-RADS™ score, and final thyroid nodules' diagnoses were documented. The course of action based on the adult ACR TI-RADS™ and after modifying the size threshold for management recommendations was documented and compared. Statistics included descriptive analysis, weighted Kappa statistics, sensitivity, specificity, accuracy, and positive/negative predictive values of the ACR TI-RADS™ presented with 95% confidence intervals (CI) using either Clopper–Pearson or standard logit methods. Results: Of 116 nodules, 18 (15.5%) were malignant. Most malignant nodules (94.4%, n = 17) were ACR TI-RADS™ 4 and ACR TI-RADS™ 5 categories. Based on the adult ACR TI-RADS™ criteria, 24 (24.5%) benign and 15 (83.3%) malignant nodules would have undergone FNA; 14 (14.3%) benign and 3 (16.7%) malignant nodules would have been followed up; and 60 (61.2%) benign and none of malignant nodules would have been dismissed. Three (16.7%) malignant nodules would not have been recommended FNA at presentation, delaying their diagnoses. By lowering the size-threshold criteria of the ACR TI-RADS™ guidelines, no malignancy would have been missed at presentation, but this also resulted in a higher number of FNA from 24 (24.5%) to 36 (36.7%) and follow-up ultrasound exams from 14 (14.3%) to 62 (63.3%). Conclusion: Applying potential modifications to the ACR TI-RADS™ guideline lowering the size threshold criteria of the thyroid nodule to guide management decisions for pediatric thyroid nodules can lead to early detection of malignant nodules in children, but at the cost of a significantly increased number of biopsies or ultrasound exams. Further tailoring of the guideline with larger multicentric studies is needed, before warranting its acceptance and general use in the pediatric population. [ABSTRACT FROM AUTHOR]

The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs as intercellular messengers. However, we know little about the miRNA profile of EVs secreted by adipocytes during postnatal development. Here, we defined the miRNA cargo of EVs secreted by mouse adipocytes in two distinct phases of development: on postnatal day 6, when adipocytes are lipolytic and thermogenic, and on postnatal day 56, when adipocytes have active lipogenesis. EVs were collected from cell culture supernatants, and their miRNA profile was defined by small RNA sequencing. The most abundant miRNA of mouse adipocyte-derived EVs was mmu-miR-148a-3p. Adipocyte EVs on postnatal day 6 were hallmarked with mmu-miR-98-5p, and some miRNAs were specific to this developmental stage, such as mmu-miR-466i-5p and 12 novel miRNAs. Adipocytes on postnatal day 56 secreted mmu-miR-365-3p, and 16 miRNAs were specific to this developmental stage. The miRNA cargo of adipocyte EVs targeted gene networks of cell proliferation, insulin signaling, interferon response, thermogenesis, and lipogenesis. We provided here a database of miRNAs secreted by developing mouse adipocytes, which may be a tool for further studies on the regulation of gene networks that control mouse adipocyte development. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of formal reproductive endocrinology and infertility (REI) consultation in fertility preservation counseling in a pediatric/adolescent oncology patient population. Methods: Retrospective chart review was performed at an academic adult hospital from 2021 to 2022. Pre- and postpubertal patients admitted to the pediatric/adolescent oncology service with cancer diagnoses and imminent gonadotoxic chemotherapy plans were included. Baseline characteristics were collected, including patient age, sex, race, language, insurance, and cancer diagnosis. Primary outcomes were formal REI consultation and fertility preservation election. Results: Nineteen of 58 eligible patients received a formal REI consultation. Patients were more likely to elect fertility preservation if they received a consult. Females were more likely to receive a consult than males and more likely to elect fertility preservation. Patients of age ≥16 years were more likely to receive consultation than younger patients. However, all patients of age <16 years who received a consult elected fertility preservation. There was no difference in consultation based on race, language, or insurance. Thirteen of 19 patients who received an REI consultation elected fertility preservation. Ten of 11 female elections were ovarian suppression, an unproven method of fertility preservation. The two male elections were semen cryopreservation. Conclusion: Underutilization of formal REI consults and a relative lack of proven fertility preservation elections may shed light on a need for increased fertility preservation awareness among young oncology patients and the providers who care for them. A streamlined process that automates formal REI consultation for all eligible patients may maximize the potential for comprehensive counseling and improve patient participation in fertility preservation. [ABSTRACT FROM AUTHOR]

When facing challenges, vertebrates activate a hormonal stress response that can dramatically alter behaviour and physiology. Although this response can be costly, conceptual models suggest that it can also recalibrate the stress response system, priming more effective responses to future challenges. Little is known about whether this process occurs in wild animals, particularly in adulthood, and if so, how information about prior experience with stressors is encoded. One potential mechanism is hormonally mediated changes in DNA methylation. We simulated the spikes in corticosterone that accompany a stress response using non‐invasive dosing in tree swallows (Tachycineta bicolor) and monitored the phenotypic effects 1 year later. In a subset of individuals, we characterized DNA methylation using reduced representation bisulfite sequencing shortly after treatment and a year later. The year after treatment, experimental females had stronger negative feedback and initiated breeding earlier—traits that are associated with stress resilience and reproductive performance in our population—and higher baseline corticosterone. We also found that natural variation in corticosterone predicted patterns of DNA methylation. Finally, corticosterone treatment influenced methylation on short (1–2 weeks) and long (1 year) time scales; however, these changes did not have clear links to functional regulation of the stress response. Taken together, our results are consistent with corticosterone‐induced priming of future stress resilience and support DNA methylation as a potential mechanism, but more work is needed to demonstrate functional consequences. Uncovering the mechanisms linking experience with the response to future challenges has implications for understanding the drivers of stress resilience. [ABSTRACT FROM AUTHOR]

Background: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy. Methods: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy. Results: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m² lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo. Conclusions: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.) [ABSTRACT FROM AUTHOR]

Background: Whether intensive glucose control reduces mortality in critically ill patients remains uncertain. Patient-level meta-analyses can provide more precise estimates of treatment effects than are currently available. Methods: We pooled individual patient data from randomized trials investigating intensive glucose control in critically ill adults. The primary outcome was in-hospital mortality. Secondary outcomes included survival to 90 days and time to live cessation of treatment with vasopressors or inotropes, mechanical ventilation, and newly commenced renal replacement. Severe hypoglycemia was a safety outcome. Results: Of 38 eligible trials (n=29,537 participants), 20 (n=14,171 participants) provided individual patient data including in-hospital mortality status for 7059 and 7049 participants allocated to intensive and conventional glucose control, respectively. Of these 1930 (27.3%) and 1891 (26.8%) individuals assigned to intensive and conventional control, respectively, died (risk ratio, 1.02; 95% confidence interval [CI], 0.96 to 1.07; P=0.52; moderate certainty). There was no apparent heterogeneity of treatment effect on in-hospital mortality in any examined subgroups. Intensive glucose control increased the risk of severe hypoglycemia (risk ratio, 3.38; 95% CI, 2.99 to 3.83; P<0.0001). Conclusions: Intensive glucose control was not associated with reduced mortality risk but increased the risk of severe hypoglycemia. We did not identify a subgroup of patients in whom intensive glucose control was beneficial. (Funded by the Australian National Health and Medical Research Council and others; PROSPERO number CRD42021278869.) [ABSTRACT FROM AUTHOR]

A retrospective review of gender-affirming hormone therapy was conducted in 101 transgender boys followed in the pediatric endocrine clinic. Eighty-seven percent were postmenarchal at the initial visit. Of the 44% prescribed gonadotropin-releasing hormone analogs (GnRHas), insurance coverage was denied in 34% and an average of 4.5 months elapsed before treatment could be started in the remainder. Patients prescribed GnRHas were younger than those who were not, 13.7±2.1 versus 15.5±2.0 years, p<0.001. Continued menstrual bleeding was reported by patients receiving testosterone alone at doses ranging from 50 to 200 mg every 2 weeks. [ABSTRACT FROM AUTHOR]

A key goal of the field of endocrinology has been to understand the hormonal mechanisms that drive social behavior and influence reactions to others, such as oxytocin. However, it has sometimes been challenging to understand which aspects and influences of hormonal action are conserved and common among mammalian species, and which effects differ based on features of these species, such as social system. This challenge has been exacerbated by a focus on a relatively small number of traditional model species. In this review, we first demonstrate the benefits of using non-traditional models for the study of hormones, with a focus on oxytocin as a case study in adding species with diverse social systems. We then expand our discussion to explore differing effects of oxytocin (and its response to behavior) within a species, with a particular focus on relationship context and social environment among primate species. Finally, we suggest key areas for future exploration of oxytocin's action centrally and peripherally, and how non-traditional models can be an important resource for understanding the breadth of oxytocin's potential effects. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs), pervasive organic compounds stemming from combustion processes and industrial activities, have raised significant concerns due to their ubiquitous presence in the environment and potential impact on human health. This review provides a comprehensive overview of the physiological effects of PAHs on diverse human body systems. Extensively studied for their respiratory toxicity, inhalation exposure to PAHs is associated with asthma, bronchitis, and impaired lung function. Moreover, certain PAHs are identified as carcinogens, heightening the risk of lung cancer. The cardiovascular system is also vulnerable to PAH exposure, as evidence suggests their contribution to oxidative stress, inflammation, and endothelial dysfunction, pivotal in cardiovascular disease development. PAHs exhibit endocrine-disrupting properties, influencing hormone levels and disrupting reproductive health, correlating with fertility issues, adverse birth outcomes, and developmental abnormalities. Understanding PAH-induced toxicity mechanisms is crucial for developing mitigation strategies. PAHs can directly interact with cellular components, modulate gene expression, induce oxidative stress, and cause DNA damage, leading to cellular dysfunction and apoptosis. This review underscores the ongoing need for research to fully elucidate the physiological effects of PAH exposure on human health. By synthesizing current knowledge, it aims to raise awareness of potential health risks associated with PAHs and stress the importance of preventive measures to reduce exposure. Ultimately, a comprehensive understanding of PAH-induced physiological impacts will inform the development of effective interventions and policies to safeguard human health in environments where PAH contamination is prevalent. [ABSTRACT FROM AUTHOR]

Background: Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. Objective: This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. Methods: We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. Results: We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (b=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (b=-0.127), showed an indirect effect on infertility mediated by SUA (b=- 0.0187; 95% CI, -0.041 to -0.003; P=0.046). Conclusion: Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms. [ABSTRACT FROM AUTHOR]

Background: Anti‐Müllerian hormone (AMH) holds potential as a biomarker for assessing the superovulation (SO) response in cattle. Nonetheless, there exists scant information regarding this aspect in the literature concerning dairy heifers. Given this gap, our objective is to explore the viability of AMH as an indicator for gauging the SO response specifically in Holstein heifers. Furthermore, our aim encompasses examining the variations in AMH levels within the same individuals before and after undergoing SO. Methods: The study included 41 Holstein heifers. All heifers were superovulated and blood samples were taken both before and after the SO protocol. Results: The findings revealed that the mean values of serum AMH concentrations before and after SO were 0.122 ng/mL (0.093–0.248 ng/mL) and 0.119 ng/mL (0.084–0.170 ng/mL), respectively. AMH concentrations in heifers were stratified into low (<0.106 ng/mL), medium (0.107–0.126 ng/mL) and high (>0.127 ng/mL) categories both before and after SO. Conclusions: There was no significant correlation between AMH levels in the heifers both before and after SO treatment with the number of follicles, corpora lutea, total embryos collected or embryos transferred (p > 0.05). Furthermore, this study showed that serum AMH concentrations in Holstein heifers did not change after SO treatment. In this study, as AMH levels in Holstein heifers were in a narrow range, a relationship between AMH and SO response could not be determined. In future studies, we believe that it would be more useful to plan more studies in Holstein donor heifers, taking into account the number of animals and AMH levels. [ABSTRACT FROM AUTHOR]

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To understand the long-term negative physical and psychosocial consequences of precocious puberty • To learn about central precocious puberty (CPP), the more prevalent form of precocious puberty • To familiarise yourself with the factors to consider when deciding whether to treat CPP. Precocious puberty is defined as the onset of puberty before the age of eight years in girls and before the age of nine years in boys. It is associated with negative physical health consequences in the long term and can also have negative psychosocial effects, particularly in adolescence. Central precocious puberty (CPP), which is caused by the early activation of the hypothalamic-pituitary-gonadal axis, is the more prevalent form of precocious puberty. This article explains CPP and its signs, assessment, diagnosis and treatment. It also discusses the factors to consider when deciding whether or not to treat it, stressing the importance of a shared decision-making process that children and parents should be involved in. Precocious puberty must be diagnosed and managed by specialists, but all children’s nurses need a broad understanding of the condition so that they can refer children as early as possible and reassure and advise families. [ABSTRACT FROM AUTHOR]

From the mid-seventeenth century, resorption of a testicular "ferment" and resorption of some part of the semen constituted reputable accounts of secondary sexual characteristics. Only in the early twentieth century was the latter, "recrementitious secretion" theory, explicitly considered superseded by one of internal secretion, an advance ushering in the hormone era. A reconstruction of these proto-endocrinological concepts is offered onward from the first, 1490 print edition of Galen's On Semen. Early modern physicians picking up from Galen deliberated widely on the medium and pathway of male and female testicular influences on "the entire body," including the mind, causing "femininity" and "masculinity" in physical, mental–temperamental, and behavioral terms. A switch is discernible from "heat and strength" (Galen) to blood-borne "virility" or testicular vapor (such as proposed in 1564 by Tomás Rodrigues da Veiga), to iatrochemical postulations of a "seminal ferment" (suggested in the late 1650s, perhaps independently, by Thomas Willis at Oxford and Lambert van Velthuysen in Utrecht), finally to a "seminal recrement" or "reabsorbed semen" concept soon after (emergent in the posthumous work of Giovanni Alfonso Borelli, among others). During the late eighteenth century, mounting controversy surrounded both the very idea of that concept and the involved anatomical pathways, informed by multiple experiments. [ABSTRACT FROM AUTHOR]

Background: CD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression. Methods: We conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose. Results: Sixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were -0.17% (95% CI, -0.60 to 0.26%) for HbA1c and -0.06 U/kg/day (95% CI, -0.14 to 0.02) for daily insulin dose. Conclusions: In this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.) [ABSTRACT FROM AUTHOR]

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Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy. [ABSTRACT FROM AUTHOR]

The article explores the use of Mendelian Randomisation (MR) studies in endocrinology research and raises concerns about the proliferation of redundant and low-quality studies in the field. It emphasizes the need for rigorous evaluation and careful interpretation in MR studies, as well as the importance of clear justification and strong associations between genetic variants and exposures. The authors express concern about the impact of these redundant studies on the integrity of scientific literature and highlight the efforts of the journal, Frontiers in Endocrinology, to promote valuable and rigorous research. [Extracted from the article]

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo‐pituitary disorders, whether organic or functional. [ABSTRACT FROM AUTHOR]

Background: Individuals facing socioeconomic hardship experience higher than average rates of chronic disease, such as diabetes, with less access to evidence-based treatment. One solution to address these inequities is a team-based care (TBC) model, defined as one in which at least two providers work collaboratively with a patient and their caregiver(s) to make healthcare decisions. This paper seeks to describe the implementation of a TBC model within a safety-net healthcare setting and determine the extent to which it can be an effective, patient-centered approach to treating individuals with diabetes. Methods: Semi-structured interviews were conducted with staff (n = 15) and patients (n = 18). Clinical data were extracted from the electronic medical record of patients (n = 1,599) seen at a safety-net health system in Chicago, Illinois, United States. The mixed methods study was guided by implementation science and participatory research principles. Staff interviews were 60 min and covered patient care activities, work flow, perceived patient experience, and facilitators/barriers to care coordination. Patient interviews were 60 min and covered satisfaction, attitudes about diabetes management, quality of life, and technology. Patient interviews were co-analyzed by research staff and members of a patient advisory committee. Clinical data were collected at an index visit, two years prior and at one-year follow up (n = 1,599). Results: Four themes emerged from the interviews: (1) patients perceived the TBC model to be patient centered and of high quality; (2) technology can be an innovative tool, but barriers exist; (3) diabetes management is a complex process; and (4) staff communication enhances care coordination, but misinterpreting roles reduces care coordination. From pre-enrollment to the follow-up period, we found a statistically significant increase in missed visits, decrease in hemoglobin A1c (HbA1c), decrease in body mass index, and decrease in the percent of patients with high blood pressure. We found that each medical visit during the follow-up period was associated with an HbA1c decrease of 0.26 points. Conclusions: A TBC model is a patient-centered approach to providing care to patients with complex health needs, such as diabetes, patients were satisfied with the care they were receiving, and the model was associated with an improvement in clinical outcomes. [ABSTRACT FROM AUTHOR]

Thyroid hormones, thyroxin (T4) and the biologically active triiodothyronine (T3), play important roles in liver metabolic regulation, including fatty acid biosynthesis, beta-oxidation, and cholesterol homeostasis. These functions position TH signaling as a potential target for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated T3 levels in the circulation are associated with increased hepatic lipid turnover, which is also under the control of the circadian clock system. In this study, we developed a cell system to study the impact of hepatocyte circadian rhythms on the metabolic response to T3 treatment under control and steatotic conditions. Synchronized AML-12 circadian reporter hepatocytes were treated with T3 at different circadian phases and metabolic conditions. T3 treatment increased metabolic activity in a dose-independent fashion and had no significant effect on circadian rhythms in AML-12 cells. T3 had marked time-of-treatment-dependent effects on metabolic transcript expression. Steatosis induction altered metabolic transcript expression in AML-12 cells. In this condition, the circadian rhythm period was lengthened, and this effect was independent of T3. Under steatotic conditions, T3 had marked time-of-treatment dependent effects on metabolic transcript expression, which differed from those observed under control conditions. These findings reveal a time-of-day-dependent response of hepatocytes to T3, which is further modulated by the metabolic state. Our data suggest that time has a strong influence on liver TH action, which might be considered when treating MASLD. [ABSTRACT FROM AUTHOR]

The current study examined the effects of official chess competition on salivary cortisol and mood swings in adolescent girls. Fourteen girl competitive chess players participated in the 5-day Swiss chess tournament held in nine heavy and light rounds. The tournament was performed at 9:00 a.m. (first, third, fifth, seventh, and ninth rounds) and 3:00 p.m. (second, fourth, sixth, and eighth rounds). Salivary cortisol and mood was measured before the tournament, before and after the second, fourth, sixth, and eighth rounds, and following the tournament (10 samples). The resting levels of salivary cortisol had considerably greater values on the first, second, third, and fourth competition days compared to 1 week before the competition (P = 0.001). The post-competition cortisol concentration was significantly higher on the second and third days than before the competition (P = 0.001). Winners had considerably higher levels of salivary cortisol compared to losers (P = 0.001). There was a significant increase in total mode disturbance (P = 0.001), anger (P = 0.009), and tension (P = 0.045) following heavy rounds (second and third day) compared to the values before the competition. At the same time, the Scores of vigor decreased significantly (P = 0.001). The findings of the present study showed participating in the official chess competition increased salivary cortisol and caused negative alterations in mood components associated with the difficulty and outcome of the match, indicating the psychological stress. Hence, psychological interventions can be used for psychological recovery of competitive chess players after the competition. [ABSTRACT FROM AUTHOR]

Thyroid hormones influence multiple systems, but most often the impact on the cardiovascular system is what brings the patient to the emergency department. Basedow's disease, an autoimmune condition, is one of the most common causes of hyperthyroidism. The purpose of this presentation is to raise attention to an extracardiac cause that can lead to cardiac failure. A 55-year-old woman presented to our cardiology service with rapid palpitations, shortness of breath on small efforts, and extreme fatigue. The electrocardiogram revealed sinus tachycardia with a heart rate of 144 beats per min. Paraclinical investigations and a multidisciplinary team consultation led to a diagnosis of thyrotoxicosis due to Basedow's disease. Following the initiation of cardiological and endocrinological treatments, the patient's condition improved. Although hyperthyroidism is an extracardiac cause, it brought the patient to the cardiology emergency service for heart failure symptoms. The key to achieving a correct diagnosis and determining an optimal treatment lies in the multidisciplinary approach of pathology. [ABSTRACT FROM AUTHOR]

Objective: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. Design, Participants, Measurements: Thirty‐seven individuals with CAH and 33 age‐ and sex‐matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24‐h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. Results: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA‐IR): 2.7 vs. 1.9, p = 0.018), prolonged E‐wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self‐reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. Conclusion: A sex‐specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self‐reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits. [ABSTRACT FROM AUTHOR]

Summary: Anti‐Müllerian hormone (AMH) is commonly used as a marker of ovarian reserve. Although obesity is associated with decreased fertility, the relationship between body mass index (BMI) and AMH remains uncertain, hindering the accurate interpretation of AMH. We sought to assess the relationship between serum AMH and BMI in patients with and without polycystic ovarian syndrome (PCOS). This study analysed 500 patients at a single centre between 2020 and 2021. Patients were divided into cohorts: those with BMI <40 kg/m2 and those with BMI >40 kg/m2. Patients with and without PCOS were included. Chi‐square tests, Fisher's exact tests, multiple linear regression analysis and independent t‐tests were performed as appropriate. In the general study population, serum AMH was not significantly different in the BMI >40 kg/m2 group compared to the BMI <40 kg/m2 group (4.3 ± 5.6 vs. 4.3 ± 5.6, p =.35). Patient ages between these two groups differed, with an average age of 35.4 ± 5.4 years in the BMI <40 kg/m2 group and 33.7 ± 5.4 years in the BMI <40 kg/m2 group (p =.031). Our multivariate regression analysis, which adjusted for age, demonstrated a significant interaction effect between BMI and PCOS diagnosis, indicating that the relationship between BMI and AMH is dependent on PCOS status (β = −.03, 95% confidence interval [CI]: −0.05, 0.00, p =.044). In patients without PCOS, we found a non‐significant relationship between AMH and BMI (β =.00, 95% CI −0.01, 0.01, p =.7); however, in patients with PCOS, AMH significantly decreased as BMI increased (β = −.03, 95% CI −0.06, 0.00, p =.034). BMI has an inverse association with AMH levels in patients with PCOS, indicating a need for future research to determine if that interaction represents a clinically significant negative effect on reproductive function. [ABSTRACT FROM AUTHOR]

Endocrine physiology is a complex subject for students. Game-based learning (GBL) and case-based learning (CBL) are active methodologies that are widely used because of their potential for motivation and greater proximity to the reality of modern students. We evaluated the effectiveness of GBL and CBL among veterinary medicine students compared with a control group using peer tutoring. Students (n = 106) from two institutions volunteered to participate in this study. The participants were submitted to a pretest questionnaire and subsequently were divided into three paired groups by their performance on the pretest exam: 1) traditional class + peer tutoring, 2) traditional class + GBL, and 3) traditional class + CBL. After the students completed the activities, their performance was once again evaluated by applying a new test with the same initial 10 questions and another set of 10 different questions. The students' perceptions and satisfaction with the methodologies and learning strategies were assessed. Anxiety was assessed with the State-Trait Anxiety Inventory before and after the conventional class and after the active methodologies. The GBL group significantly improved their correct answers compared with the baseline (P < 0.05), with no significant difference from CBL and peer tutoring. Anxiety levels did not differ regardless of the time of evaluation or the teaching methodology applied. GBL promoted a greater perception of the stimulus for self-study and problem-solving ability and contributed to the development of group dynamics compared with the group who received CBL (P < 0.05). In conclusion, GBL showed better results than peer tutoring and CBL. NEW & NOTEWORTHY: We compared the supplementary use of game-based learning, case-based learning, and peer tutoring in the study of endocrine physiology by veterinary students and observed a slight advantage for game-based learning over the other two methodologies. The game was developed by the authors and is an unprecedented tool that can prove useful to improve knowledge acquisition in students of veterinary medicine. Thus, game-based learning is an effective supplementary teaching strategy. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of young ‘MODY’ type 6 is a rare form of monogenic diabetes caused by mutations in neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and body mass index (BMI) at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting BG (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m² ). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m² and a normal oral glucose tolerance test. Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals. [ABSTRACT FROM AUTHOR]

Maturity onset diabetes of the young (MODY) is characterized by noninsulin-dependent diabetes diagnosed before the age of 25 years with an autosomal dominant inheritance. Rare mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that resembles MODY. About half of patients diagnosed with MODY type 5 due to HNF1B variants, carry a whole gene deletion, known as 17q12 deletion syndrome. 17q12 deletion syndrome is a rare chromosomal anomaly and is typified by deletion of more than 15 genes, including HNF1B resulting in kidney abnormalities and renal cysts, a diabetes syndrome and neurodevelopmental or neuropsychiatric disorders. A 12-year-old girl was referred after high blood sugar was detected in the hospital where she presented with polyuria and polydipsia, which had persisted for one month. Her serum magnesium (Mg) level was low at 1.5 mg/dL (normal value 1.6-2.6) and glycated hemoglobin was 14% (normal value 3.6-5.8) concurrent with a c-peptide of 1.54 ng/mL (normal value 0.8-4). MODY5 was suspected but the NGS gene panel (ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEURODD1, PAX4, PDX1, RFX6, ZFP57, GLIS3, FOXP3, NEUROG3, G6PC2) did not identify any abnormality. During follow-up, her serum Mg remained low (1.2 mg/ dL) together with elevated urinary Mg excretion at 172.5 mg/day. An HNF1B variant was again suspected in a patient with chronic hypomagnesemia with normal basal C peptide level. Abdominal computed tomography and magnetic resonance imaging revealed a 43 mm diameter, cystic lesion in the head of the pancreas, with agenesis of the pancreatic neck, trunk and tail. Genetic testing using a microarray analysis was subsequently performed and a heterozygous deletion at 17q12, including HNF1B, was detected. In case of clinical suspicion of HNF1B variants, further genetic examination using other techniques such as MLPA and CGH array may be required to detect the variant. This is because deletions and duplications may not be detected using next generation screening panel techniques. [ABSTRACT FROM AUTHOR]

In endocrinology, the types and quantity of digital data are increasing rapidly. Computing capabilities are also developing at an incredible rate, as illustrated by the recent expansion in the use of popular generative artificial intelligence (AI) applications. Numerous diagnostic and therapeutic devices using AI have already entered routine endocrine practice, and developments in this field are expected to continue to accelerate. Endocrinologists will need to be supported in managing AI applications. Beyond technological training, interdisciplinary vision is needed to encompass the ethical and legal aspects of AI, to manage the profound impact of AI on patient/provider relationships, and to maintain an optimal balance between human input and AI in endocrinology. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) holds the promise of addressing many of the numerous challenges healthcare faces, which include a growing burden of illness, an increase in chronic health conditions and disabilities due to aging and epidemiological changes, higher demand for health services, overworked and burned-out clinicians, greater societal expectations, and rising health expenditures. While technological advancements in processing power, memory, storage, and the abundance of data have empowered computers to handle increasingly complex tasks with remarkable success, AI introduces a variety of meaningful risks and challenges. Among these are issues related to accuracy and reliability, bias and equity, errors and accountability, transparency, misuse, and privacy of data. As AI systems continue to rapidly integrate into healthcare settings, it is crucial to recognize the inherent risks they bring. These risks demand careful consideration to ensure the responsible and safe deployment of AI in healthcare. [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

Abstract/Introduction: Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively1–4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population5–9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such asFGF21, ADIPOQ, GCGandIL6showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liverPCSK9) as well as genes encoding enzymes producing metabolites (adiposePNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource asGene-DerivedCorrelationsAcrossTissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.

Background Both Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are classified as autoimmune thyroid diseases (AITDs). It has been hypothesized that changes in the thyroid-stimulating hormone receptor (TSHR) gene may contribute to the development of these conditions. This study aimed to analyze the correlation between the TSHR rs179247 gene polymorphism and susceptibility to AITD. Methods We conducted a thorough search of the Google Scholar, Scopus, Medline, and Cochrane Library databases up until March 2, 2024, utilizing a combination of relevant keywords. This review examines data on the association between TSHR rs179247 and susceptibility to AITD. Random-effect models were employed to assess the odds ratio (OR), and the findings are presented along with their respective 95% confidence intervals (CIs). Results The meta-analysis included 12 studies. All genetic models of the TSHR rs179247 gene polymorphism were associated with an increased risk of developing GD. Specifically, the associations were observed in the dominant model (OR, 1.65; P

Diabetic ketoalkalosis (DKALK) is a rare but significant variant of diabetic emergencies, characterized by metabolic alkalosis rather than the typical acidosis seen in diabetic ketoacidosis (DKA). Despite its clinical importance, DKALK often goes unrecognized due to limited literature on its presentation and biochemical variables. This work examines the pathophysiology, clinical presentation, diagnostic challenges, management strategies, and implications for clinical practice of DKALK, drawing insights from case studies and research gaps in the field. Notable case studies underscore the diagnostic challenges and emphasize the importance of tailored management strategies for DKALK. Risk assessment involves recognizing predisposing factors such as severe vomiting, alcohol abuse, or concomitant diuretic use. Timely recognition and intervention are essential to prevent potentially life-threatening complications associated with DKALK. Continued research efforts are warranted to refine diagnostic criteria, optimize therapeutic approaches, and enhance early recognition of DKALK, ultimately improving patient outcomes in this challenging clinical scenario.

Abstract Background Type I and type II diabetes mellitus (DM) patients have a higher prevalence of cardiovascular diseases, as well as a higher mortality risk of cardiovascular diseases and interventions. This study provides an update on the impact of DM on clinical outcomes, including mortality, complications and reinterventions, using data on percutaneous and surgical cardiac interventions in the Netherlands. Methods This is a retrospective, nearby nationwide study using real-world observational data registered by the Netherlands Heart Registration (NHR) between 2015 and 2020. Patients treated for combined or isolated coronary artery disease (CAD) and aortic valve disease (AVD) were studied. Bivariate analyses and multivariate logistic regression models were used to evaluate the association between DM and clinical outcomes both unadjusted and adjusted for baseline characteristics. Results 241,360 patients underwent the following interventions; percutaneous coronary intervention(N = 177,556), coronary artery bypass grafting(N = 39,069), transcatheter aortic valve implantation(N = 11,819), aortic valve replacement(N = 8,028) and combined CABG and AVR(N = 4,888). The incidence of DM type I and II was 21.1%, 26.7%, 17.8%, 27.6% and 27% respectively. For all procedures, there are statistically significant differences between patients living with and without diabetes, adjusted for baseline characteristics, at the expense of patients with diabetes for 30-days mortality after PCI (OR = 1.68; p

Abstract Background Individuals facing socioeconomic hardship experience higher than average rates of chronic disease, such as diabetes, with less access to evidence-based treatment. One solution to address these inequities is a team-based care (TBC) model, defined as one in which at least two providers work collaboratively with a patient and their caregiver(s) to make healthcare decisions. This paper seeks to describe the implementation of a TBC model within a safety-net healthcare setting and determine the extent to which it can be an effective, patient-centered approach to treating individuals with diabetes. Methods Semi-structured interviews were conducted with staff (n = 15) and patients (n = 18). Clinical data were extracted from the electronic medical record of patients (n = 1,599) seen at a safety-net health system in Chicago, Illinois, United States. The mixed methods study was guided by implementation science and participatory research principles. Staff interviews were 60 min and covered patient care activities, work flow, perceived patient experience, and facilitators/barriers to care coordination. Patient interviews were 60 min and covered satisfaction, attitudes about diabetes management, quality of life, and technology. Patient interviews were co-analyzed by research staff and members of a patient advisory committee. Clinical data were collected at an index visit, two years prior and at one-year follow up (n = 1,599). Results Four themes emerged from the interviews: (1) patients perceived the TBC model to be patient centered and of high quality; (2) technology can be an innovative tool, but barriers exist; (3) diabetes management is a complex process; and (4) staff communication enhances care coordination, but misinterpreting roles reduces care coordination. From pre-enrollment to the follow-up period, we found a statistically significant increase in missed visits, decrease in hemoglobin A1c (HbA1c), decrease in body mass index, and decrease in the percent of patients with high blood pressure. We found that each medical visit during the follow-up period was associated with an HbA1c decrease of 0.26 points. Conclusions A TBC model is a patient-centered approach to providing care to patients with complex health needs, such as diabetes, patients were satisfied with the care they were receiving, and the model was associated with an improvement in clinical outcomes.

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

Sturge-Weber syndrome (SWS) is a rare congenital disorder marked by facial port-wine birthmarks, neurological impairments, and ocular anomalies. Our case report describes a 20-year-old man with SWS who presented with right-sided weakness, slurred speech, and oral dyskinesia. Laboratory studies demonstrated elevated prolactin levels, and imaging confirmed a pituitary macroadenoma. While not well-documented, the association between SWS and pituitary macroadenomas is emerging based on current evidence. The potential link may involve embryological, genetic, or hormonal factors influencing the simultaneous development of these conditions. This case highlights the need for a thorough evaluation in patients with SWS, incorporating both neuroimaging and endocrine assessments to manage associated complications effectively. Further research is necessary to investigate the link between SWS and pituitary tumors. Establishing evidence-based guidelines for the screening and management of these patients will improve outcomes and provide a standardized approach to care.