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OBJECTIVE Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models, yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n = 296) from the Vienna Transdanube Aging study, a prospective community-based cohort study. Participants were followed up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n = 90) was used to validate our findings. RESULTS Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to hemoglobin A1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. CONCLUSIONS We found a set of circulating lncRNAs that independently portends incident type 2 diabetes in older adults years before disease onset.

Damages to the ear are very diverse and can depend on the type of inherited metabolic diseases (IMD). Indeed, IMDs can affect all parts of the auditory system, from the outer ear to the central auditory process. We have identified 219 IMDs associated with various types of ear involvement which we classified into five groups according to the lesion site of the auditory system: congenital external ear abnormalities, acquired external ear abnormalities, middle ear involvement, inner ear or retrocochlear involvement, and unspecified hearing loss. This represents the ninth issue in a series of educational summaries providing a comprehensive and updated list of metabolic differential diagnoses according to system involvement.

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Metabolic myopathies are characterized by the deficiency or dysfunction of essential metabolites or fuels to generate energy for muscle contraction; they most commonly manifest with neuromuscular symptoms due to impaired muscle development or functioning. We have summarized associations of signs and symptoms in 358 inherited metabolic diseases presenting with myopathies. This represents the tenth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.

Diabetes mellitus is one of the most frequent diseases in the general population. Electrical stimulation is a treatment modality based on the transmission of electrical pulses into the body that has been widely used for improving wound healing and for managing acute and chronic pain. Here, we discuss recent advancements in electroceuticals and haptic/smart devices for quality of life and present in which patients and how electrical stimulation may prove to be useful for the treatment of diabetes-related complications.

Type 2 diabetes is a common manifestation of metabolic dysfunction due to obesity and constitutes a major burden for modern health care systems, in concert with the alarming rise in obesity worldwide. In recent years, several successful pharmacotherapies improving glucose metabolism have emerged and some of these also promote weight loss, thus, ameliorating insulin resistance. However, the progressive nature of type 2 diabetes is not halted by these new anti-diabetic pharmacotherapies. Therefore, novel therapies promoting weight loss further and delaying diabetes progression are needed. Amylin, a beta cell hormone, has satiating properties and also delays gastric emptying and inhibits postprandial glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the six amylin receptors, which share the core component with the calcitonin receptor. Calcitonin, derived from thyroid C cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating calcium. However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce the gastric emptying rate and promote satiation. Preclinical trials with agents targeting the calcitonin receptor and the amylin receptors, show improvements in several parameters of glucose metabolism including insulin sensitivity and some of these agents are currently undergoing clinical trials. Here, we review the physiological and pharmacological effects of amylin and calcitonin and discuss the future potential of amylin and calcitonin-based treatments for patients with type 2 diabetes and obesity.

Background & aims: Total parenteral nutrition (TPN) causes gut atrophy, dysbiosis and leakage of the gut barrier. This study aimed to characterize the gut microbiome in response to different TPNs and tested the hypothesis whether increased gut permeability in TPN would lead to changes in the circulating bacterial DNA (“blood microbiome”). Methods: Male C57BL/6J mice were randomly allocated to the following groups for seven days (1) chow-fed control (C) without jugular vein catheter (JVC, n=6) (2) chow-fed with JVC and infusion of saline (S) (n = 6) (3) Intralipid-based TPN (n-6:n-3 ratio 7:1) (IL, n = 6) (4) Omegaven-based TPN (n-6:n-3 ratio 1:8) (OV, n = 6). Blood was collected by cardiac puncture and feces (stool pellet) were collected from the colon. Blood and stool samples were analyzed by 16S rRNA gene sequencing. Results: TPN administration was associated with a compositional shift in the gut microbial community that involved the expansion of Bacteroidota along with a decrease in gut bacteria belonging to the Firmicutes phylum as compared to chow-fed mice. Gram-negative Verrucomicrobiota and Proteobacteria were also increased in the gut microbiome of mice receiving TPN. Gammaproteobacteria, namely Burkholderiales, were specifically increased in Intralipid-based TPN. On the other hand, Proteobacteria and Actinobacteriota were the dominant taxa in blood samples. The families Comamonadaceae and Burkholderiaceae (both from Burkholderiales order) were increased in the “blood microbiome” of mice with indwelling JVC when compared with chow-fed mice without JVC. The increase in Burkholderiaceae was more pronounced in Intralipid-based TPN. Conclusions: Profound changes in the gut microbiome of mice subjected to TPN occurred, which were not reflected in the “blood microbiome” suggesting that the gut and “blood microbiome” represent two rather distinct separate microbiotic compartments. The parenteral provision of n-3 fatty acids appears to protect against proinflammatory bacteria in the gut and against the increased presence of JVC-associated bacteria as measured by circulating bacterial DNA. ISSN:2405-4577

Aims: We assess the incidence and economic burden of severe and non-severe hypoglycemia in insulin-treated diabetes type 1 and 2 patients in Switzerland. Methods: We developed a health economic model to assess the incidence of hypoglycemia, the subsequent medical costs, and the production losses in insulin-treated diabetes patients. The model distinguishes between severity of hypoglycemia, type of diabetes, and type of medical care. We used survey data, health statistics, and health care utilization data extracted from primary studies. Results: The number of hypoglycemic events in 2017 was estimated at 1.3 million in type 1 diabetes patients and at 0.7 million in insulin-treated type 2 diabetes patients. The subsequent medical costs amount to 38 million Swiss Francs (CHF), 61 % of which occur in type 2 diabetes. Outpatient visits dominate costs in both types of diabetes. Total production losses due to hypoglycemia amount to CHF 11 million. Almost 80 % of medical costs and 39 % of production losses are due to non-severe hypoglycemia. Conclusions: Hypoglycemia leads to substantial socio-economic burden in Switzerland. Greater attention to non-severe hypoglycemic events and to severe hypoglycemia in type 2 diabetes could have a major impact on reducing this burden.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.

Background By means of a structured nutritional support intervention, EFFORT showed a risk reduction for adverse events in medical in-patients. We were interested in the prognostic and therapeutic potential of an untargeted proteomics approach to understand response to nutritional support, risk of 30-day mortality, and distinct patterns in severity of malnutrition risk as assessed by the Nutritional Risk screening (NRS 2002), respectively. Methods From 2,088 patients, we randomly took 120 blood samples drawn before treatment initiation on day 1 after hospital admission. Cases were selected by treatment allocation (nutritional support vs. usual nutrition), NRS 2002, and mortality at 30 days, but not on disease type. We measured proteins by untargeted liquid chromatography mass spectrometry (LC-MS/MS). Results We found 242 distinct proteins in 120 patients of which 81 (67.5%) survived until day 30. Between group analysis revealed a slight difference between the treatment groups in patients with a NRS 3, but not in those with a higher NRS. C-statistic between non-survivors and survivors at day 30 ranged from 0.60 (95% confidence interval 0.34–0.78) for a combination of 3 proteins/predictors to 0.65 (95% CI 0.53–0.78) for a combination of 32 proteins/predictors. In nutritional support non-survivors, pathway analysis found significant enrichment in pathways for signal transduction, platelet function, immune system regulation, extracellular matrix organization, and integrin cell surface interactions compared to survivors. Conclusion Within this pilot study using an untargeted proteomics approach, there was only little prognostic and therapeutic potential of proteomics for phenotyping the risk of malnutrition and response to nutritional therapy. The small sample size and high heterogeneity of our population regarding comorbidity burden calls for more targeted approaches in more homogenous populations to understand the true potential of proteomics for individualizing nutritional care. Trial registration This is a pre-planned secondary analysis of the EFFORT trial (ClinicalTrials.gov NCT02517476)., Clinical Nutrition ESPEN, 48, ISSN:2405-4577

Bariatric techniques for bypass surgery evolve constantly. Switching from one well-established protocol to another in a running surgical teaching program is challenging. We analyzed clinical and financial outcomes at a single bariatric center transitioning from circular to an augmented linear bypass protocol.Between 2011 and 2018, 454 patients were included in this retrospective study. The circular bypass protocol (CIRC; n = 177) was used between 2011 and 2012. Between 2013 and 2015 the transition occurred. Thereafter, the augmented linear protocol (aLIN; n = 277) was primarily utilized.Overall, the mean preoperative BMI dropped from 42.2 to 29.6 kg/mThis study shows improved clinical and financial outcomes after a gradual transition from a circular stapling protocol to an augmented linear stapling protocol in proximal gastric bypass surgery.

Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. (c) 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression. We examined putative biomarkers of neuropathy in blood and tissue and quantified levels of small fiber neuropathy, looking for associations between lowered 1-deoxySL and phenotypes. Toxic 1-deoxySLs were suppressed long-term in plasma and various tissue including the sciatic nerve, which is particularly targeted in DN. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease. However, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Hyperglycemia and dyslipidemia persisted during our study, and high levels of glutathione were seen in the spinal cord. Our results demonstrate that despite significant functional improvements, l-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia, that persist despite 1-deoxySL reduction.

The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Considering the limited efficacy and toxicity of this treatment, new strategies are required. Trabectedin is a marine-derivated antitumoral agent that inhibits oncogenic transcription. We have already demonstrated trabectedin cytotoxic activity at sub-nanomolar concentrations in ACC cells. Here, we expanded the investigation of trabectedin effect on ACC preclinical models, evaluating whether trabectedin could affect ACC cells’ invasiveness and metastasis formation. NCI-H295R, MUC-1, and TVBF-7 cell lines were used. Cell tumor xenografts in Danio rerio embryos were performed. The tumor mass areas and the number of embryos with metastasis were evaluated. The in vitro invasiveness of cells was evaluated. Effects of trabectedin of MMP2, TIMP1, and TIMP2 were evaluated at gene level qRT-PCR. MMP2 secreted in the cell medium was evaluated by Western blot and by zymography. Xenograft experiments demonstrated that trabectedin significantly reduced the tumor area in each ACC cell model and metastasis formation in embryos injected with metastasis-derived cell lines. Trabectedin treatment reduced the invasiveness of ACC cells across the matrix, which was greater at baseline for the metastatic models. In metastatic cell models, protein analysis demonstrated a reduction of MMP2 secretion and activity in the culture medium after treatment. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic features of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients.

Hypokalemia plays a central role for case finding, course, treatment decision, and prognosis of patients with primary aldosteronism. However, to date there is a lack of high-level evidence about the incidence of primary aldosteronism in hypokalemic patients. The IPAHK+study is an epidemiological, cross-sectional, monocentric study to provide evidence on the incidence of PA in a hypokalemic population. The aim of the current analysis was to describe the baseline characteristics of the first 100 patients eligible for study inclusion. The recruitment of patients with hypokalemia (≤3 mmol/l) is carried out continuously on a referral-basis by the central laboratory of the University Hospital Zurich through an automated suitability testing and data delivery system. The careful evaluation of the first 100 reported patients was based on the available reporting system. Out of 28 140 screened patients, 222 (0.79%) were identified with a serum potassium value of≤3 mmol/l (mean 2.89±0.02 mmol/l). Mean potassium levels were slightly lower in non-hypertensive subjects compared to hypertensive subjects (mean difference 0.07 mmol/l, p=0.033), while no significant difference was found between the sexes and patients with and without the diagnosis of primary aldosteronism, atrial fibrillation, or the use of diuretics. The incidence of PA was 4% in the total population studied and 7.5% in the subgroup of hypertensive patients. In conclusion, the continuous enrollment of patients from the IPHAK+hypokalemia registry into the IPAHK+trial will provide evidence about the actual incidence of primary aldosteronism in a hypokalemic outpatient population.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus statement on the management of type 1 diabetes in adults. The writing group has considered the rapid development of new treatments and technologies and addressed the following topics: diagnosis, aims of management, schedule of care, diabetes self-management education and support, glucose monitoring, insulin therapy, hypoglycaemia, behavioural considerations, psychosocial care, diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special populations, inpatient management and future perspectives. Although we discuss the schedule for follow-up examinations and testing, we have not included the evaluation and treatment of the chronic microvascular and macrovascular complications of diabetes as these are well-reviewed and discussed elsewhere. The writing group was aware of both national and international guidance on type 1 diabetes and did not seek to replicate this but rather aimed to highlight the major areas that healthcare professionals should consider when managing adults with type 1 diabetes. Though evidence-based where possible, the recommendations in the report represent the consensus opinion of the authors. [Figure not available: see fulltext.]

Aims/hypothesis Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation. Methods We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2–20 years), subclinical inflammation (high-sensitivity C-reactive protein 2–10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro. Results Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 μl−1, p = 0.005) and aspirin (266.0 ± 212.7 vs 201.7 ± 162.7 μl−1, p = 0.021). PMPs of rivaroxaban-treated participants stimulated HUVEC proliferation in vitro compared with aspirin. Rivaroxaban was associated with a higher number of bleeding events. Conclusions/interpretation Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding. Trial registration: ClinicalTrials.gov NCT02164578. Funding The study was supported by a research grant from Bayer Vital AG, Germany. Graphical abstract

It is unclear whether testosterone replacement therapy (TRT) in adolescent boys, affected by a range of endocrine diseases that may be associated with hypogonadism, is particularly common. The aim of this study was to assess the contemporary practice of TRT in boys included in the I-DSD Registry. All participating centres in the I-DSD Registry that had boys between 10 and 18 years of age and with a condition that could be associated with hypogonadism were invited to provide further information in 2019. Information on 162 boys was collected from 15 centres that had a median (range) number of 6 boys per centre (1.35). Of these, 30 (19%) from 9 centres were receiving TRT and the median (range) age at the start was 12.6 years (10.8–16.2), with 6 boys (20%) starting at

Testosterone has been hypothesized to promote sexual motivation and behavior. However, experimental evidence in healthy humans is sparse and rarely establishes causality. The present study investigated how testosterone affects delay of gratification for sexual rewards. We administered a single dose of testosterone to healthy young males in a double-blind, placebo-controlled, between-participant design (N = 140). Participants underwent a sexual delay discounting task, in which they made a choice between a variable larger-later option (i.e., waiting longer to view a sexual picture for a longer duration) and a smaller-sooner option (i.e., waiting for a fixed shorter period of time to view the same picture for a shorter duration). We found that testosterone administration increased preference for the smaller-sooner option and induced steeper discounting for the delayed option. These findings provide direct experimental evidence that rapid testosterone elevations increase impulsivity for sexual rewards and represent an important step towards a better understanding of the neuroendocrine basis of sexual motivation in humans.

Context Menopause has been associated with adverse cardiovascular disease (CVD) risk profile, yet it is unclear whether the changes in CVD risk factors differ by reproductive stage independently of underlying ageing trajectories. Design The CoLaus study is a prospective population-based cohort study in Lausanne, Switzerland. Patients We used data from women at baseline and follow-up (mean: 5.6 ± 0.5 years) from 2003 to 2012 who did not use hormone therapy. We classified women into (i) premenopausal, (ii) menopausal transition, (iii) early (≤5 years) and (iv) late (>5 years) postmenopausal by comparing their menstruation status at baseline and follow-up. Measurements We measured fasting lipids, glucose and cardiovascular inflammatory markers. We used repeated measures (linear mixed models) for longitudinal analysis, using premenopausal women as a reference category. We adjusted analyses for age, medications and lifestyle factors. Results We used the data from 1710 women aged 35–75 years. Longitudinal analysis showed that the changes in CVD risk factors were not different in the other three menopausal categories compared to premenopausal women. When age was used as a predictor variable and adjusted for menopause status, most CVD risk factors increased, while interleukin-6 and interleukin-1β decreased with advancing age. Conclusion The current study suggests that women have a worsening cardiovascular risk profile as they age, and although menopausal women may have higher levels of cardiovascular risk factors compared to premenopausal women at any given time, the 5-year changes in cardiovascular risk factors may not depend on the reproductive stage., + ID der Publikation: unilu_64234 + Sprache: Englisch + Letzte Aktualisierung: 2023-07-07 09:54:37

Objective Cortisol measurements are essential for the interpretation of adrenal venous samplings (AVS) in primary aldosteronism (PA). Cortisol cosecretion may influence AVS indices. We aimed to investigate whether cortisol cosecretion affects non-adrenocorticotrophic hormone (ACTH)-stimulated AVS results. Design Retrospective cohort study at a tertiary referral center. Methods We analyzed 278 PA patients who underwent non-ACTH-stimulated AVS and had undergone at least a 1-mg dexamethasone suppression test (DST). Subsets underwent additional late-night salivary cortisol (LSC) and/or 24-h urinary free cortisol (UFC) measurements. Patients were studied from 2013 to 2020 with follow-up data of 6 months following adrenalectomy or mineralocorticoid antagonist therapy initiation. We analyzed AVS parameters including adrenal vein aldosterone/cortisol ratios, selectivity, lateralization (LI) and contralateral suppression indices and post-operative ACTH-stimulation. We classified outcomes according to the primary aldosteronism surgical outcome (PASO) criteria. Results Among the patients, 18.9% had a pathological DST result (1.9–5 µg/dL: n = 44 (15.8%); >5 µg/dL: n = 8 (2.9%)). Comparison of AVS results stratified according to the 1-mg DST (≤1.8 vs >1.8 µg/dL: P = 0.499; ≤1.8 vs 1.8 ≤ 5 vs >5 µg/dL: P = 0.811) showed no difference. Lateralized cases with post DST serum cortisol values > 5 µg/dL had lower LI (≤1.8 µg/dL: 11.11 (5.36; 26.76) vs 1.9–5 µg/dL: 11.76 (4.9; 31.88) vs >5 µg/dL: 2.58 (1.67; 3.3); P = 0.008). PASO outcome was not different according to cortisol cosecretion. Conclusions Marked cortisol cosecretion has the potential to influence non-ACTH-stimulated AVS results. While this could result in falsely classified lateralized cases as bilateral, further analysis of substitutes for cortisol are required to unmask effects on clinical outcome.

Hair concentrations of cortisol, cortisone, and testosterone are non-invasive measures of cumulative steroid hormone levels. Use of contraceptives co-varies with levels of cortisol and cortisone in women's hair. It is unclear, however, how different contraceptive methods (i.e., that differ in their steroid hormone composition) affect corticosteroid and testosterone hair levels. The current study examines associations of contraceptives with hair steroid hormone concentrations in females from the community (N = 464, M = 20.6 years old, age range = 19–22). Self-reported contraceptives were first categorized as combined estrogen-progestin or progestin-only, and then analyzed individually in follow-up analyses. Multiple regressions adjusting for body mass index (BMI) and hair characteristics revealed that levels of hair cortisol, cortisone, and testosterone were significantly lower in women who used combined estrogen-progestin methods than in women who did not use hormonal contraception (βcortisol(log) = −0.29; βcortisone(log) = −0.28; βtestosterone(log) = −0.36), showing moderate to large effect sizes (d = 0.64, d = 0.71, and d = 0.81, respectively). Concentrations of hair cortisol were lower in women who used progestin-only contraceptives (β = −0.49) compared to no contraceptive use, with a large effect size (d = 1.67). Follow-up analyses revealed that the association of the three steroid hormones with estrogen-progestin methods was strongest for the combined oral “micro-pill.” Future studies of hair steroid hormones should take into account the specific type of contraceptive used, as this may affect study results., Comprehensive Psychoneuroendocrinology, 12

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) have a synergistic effect on cardiovascular disease (CVD). We investigated the association of changes in hepatic steatosis and advanced hepatic fibrosis with risk of CVD and mortality in new-onset T2DM.Using the Korean National Health Insurance dataset, we included 120,256 patients with new-onset T2DM. Hepatic steatosis and advanced hepatic fibrosis were determined using the fatty liver index (FLI) and BARD score. According to the changes of the two scores over two years, patients were divided into four groups and analyzed for development of myocardial infarction (MI), stroke, heart failure (HF), and mortality.Incident hepatic steatosis was associated with increased development of stroke, HF, and mortality compared with non-NAFLD (all p 0.05). Regression and persistent hepatic steatosis were associated with increased risk of MI, stroke, HF, and mortality compared with non-NAFLD (all p 0.05). Persistent advanced hepatic fibrosis was associated with increased risk of stroke, HF, and mortality (all p 0.05).) Compared with persistent hepatic fibrosis, regression of hepatic fibrosis was associated with decreased risk of stroke, HF, and mortality (all p 0.05).Changes in FLI or BARD score were associated with CVD and mortality in new-onset T2DM.

The early detection of inflammation and infection is important to prevent irreversible lung damage in cystic fibrosis. Novel and non-invasive monitoring tools would be of high benefit for the quality of life of patients. Our group previously detected over 100 exhaled mass-to-charge (m/z) features, using on-line secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS), which distinguish children with cystic fibrosis from healthy controls. The aim of this study was to annotate as many m/z features as possible with putative chemical structures. Compound identification was performed by applying a rigorous workflow, which included the analysis of on-line MS2 spectra and a literature comparison. A total of 49 discriminatory exhaled compounds were putatively identified. A group of compounds including glycolic acid, glyceric acid and xanthine were elevated in the cystic fibrosis group. A large group of acylcarnitines and aldehydes were found to be decreased in cystic fibrosis. The proposed compound identification workflow was used to identify signatures of volatile organic compounds that discriminate children with cystic fibrosis from healthy controls, which is the first step for future non-invasive and personalized applications.

Prolactin (Prl) and growth hormone (Gh) as well as insulin-like growth factor 1 (Igf1) are involved in the physiological adaptation of fish to varying salinities. The Igfs have been also ascribed other physiological roles during development, growth, reproduction and immune regulation. However, the main emphasis in the investigation of osmoregulatory responses has been the endocrine, liver-derived Igf1 route and local regulation within the liver and osmoregulatory organs. Few studies have focused on the impact of salinity alterations on the Gh/Igf-system within the neuroendocrine and immune systems and particularly in a salinity-tolerant species, such as the blackchin tilapia Sarotherodon melanotheron. This species is tolerant to hypersalinity and saline variations, but it is confronted by severe climate changes in the Saloum inverse estuary. Here we investigated bidirectional effects of increased salinity followed by its decrease on the gene regulation of prl, gh, igf1, igf2, Gh receptor and the tumor-necrosis factor a. A mixed population of sexually mature 14-month old blackchin tilapia adapted to freshwater were first exposed to seawater for one week and then to fresh water for another week. Brain, pituitary, head kidney and spleen were excised at 4 h, 1, 2, 3 and 7 days after both exposures and revealed differential expression patterns. This investigation should give us a better understanding of the role of the Gh/Igf system within the neuroendocrine and immune organs and the impact of bidirectional saline challenges on fish osmoregulation in non-osmoregulatory organs, notably the complex orchestration of growth factors and cytokines.

Pheochromocytomas (PCCs) are rare but potentially lethal tumors that arise from the adrenal medulla. The clinical suspicion and diagnosis of PCC can be challenging due to the non-specific nature of signs and symptoms. In many patients, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could lead to long-term symptoms including fatigue, headaches, and cognitive dysfunction. Here, we present the case of a patient incidentally diagnosed with an adrenal mass that proved to be a PCC after imaging was performed due to persisting complaints after coronavirus disease 2019 (COVID-19) infection. A 37-year-old male patient was referred to our center because of a right-sided inhomogeneous adrenal mass, incidentally found during a computed tomographic scan of the thorax performed due to cough and dyspnea that persisted after COVID-19 infection. Other complaints that were present prior to COVID-19 infection included profuse sweating, dizziness, exhaustion with chronic fatigue, and concentration difficulties. The patient had no history of hypertension, his blood pressure was normal, and the 24-h ambulatory blood pressure monitoring confirmed normotension but with the absence of nocturnal dipping. Plasma normetanephrine was 5.7-fold above the upper limit (UL) of reference intervals (738 pg/ml, UL = 129 pg/ml), whereas plasma metanephrine and methoxytyramine were normal at 30 pg/ml (UL = 84 pg/ml) and

Background: Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the tyrosine catabolic pathway. Since HT1 patients are treated with NTBC, outcome improved and life expectancy greatly increased. However extensive neurocognitive and behavioural problems have been described, which might be related to treatment with NTBC, the biochemical changes induced by NTBC, or metabolites accumulating due to the enzymatic defect characterizing the disease.Objective: To study the possible pathophysiological mechanisms of brain dysfunction in HT1, we assessed blood and brain LNAA, and brain monoamine neurotransmitter metabolite levels in relation to behavioural and cognitive performance of HT1 mice.Design: C57BL/6 littermates were divided in three different experimental groups: HT1, heterozygous and wild-type mice (n = 10; 5 male). All groups were treated with NTBC and underwent cognitive and behavioural testing. One week after behavioural testing, blood and brain material were collected to measure amino acid profiles and brain monoaminergic neurotransmitter levels.Results: Irrespective of the genetic background, NTBC treatment resulted in a clear increase in brain tyrosine levels, whereas all other brain LNAA levels tended to be lower than their reference values. Despite these changes in blood and brain biochemistry, no significant differences in brain monoamine neurotransmitter (metabolites) were found and all mice showed normal behaviour and learning and memory.Conclusion: Despite the biochemical changes, NTBC and genotype of the mice were not associated with poorer behavioural and cognitive function of the mice. Further research involving dietary treatment of FAH−/− are warranted to investigate whether this reveals the cognitive impairments that have been seen in treated HT1 patients.

Context Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. Objective This work aims to characterize the genetic associations and biochemical profile of mild IIH. Methods This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. Results The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. Conclusion The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.

Tetrahydrobiopterin (BH4) deficiency is caused by genetic variants in the three genes involved in de novo cofactor biosynthesis, GTP cyclohydrolase I (GTPCH/GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), sepiapterin reductase (SR/SPR), and the two genes involved in cofactor recycling, carbinolamine-4α-dehydratase (PCD/PCBD1) and dihydropteridine reductase (DHPR/QDPR). Dysfunction in BH4 metabolism leads to reduced cofactor levels and may result in systemic hyperphenylalaninemia and/or neurological sequelae due to secondary deficiency in monoamine neurotransmitters in the central nervous system. More than 1100 patients with BH4 deficiency and 800 different allelic variants distributed throughout the individual genes are tabulated in database of pediatric neurotransmitter disorders PNDdb. Here we provide an update on the molecular-genetic analysis and structural considerations of these variants, including the clinical courses of the genotypes. From a total of 324 alleles, 11 are associated with the autosomal recessive form of GTPCH deficiency presenting with hyperphenylalaninemia (HPA) and neurotransmitter deficiency, 295 GCH1 variant alleles are detected in the dominant form of L-dopa-responsive dystonia (DRD or Segawa disease) while phenotypes of 18 alleles remained undefined. Autosomal recessive variants observed in the PTS (199 variants), PCBD1 (32 variants), and QDPR (141 variants) genes lead to HPA concomitant with central monoamine neurotransmitter deficiency, while SPR deficiency (104 variants) presents without hyperphenylalaninemia. The clinical impact of reported variants is essential for genetic counseling and important for development of precision medicine.

The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future., Studies have shown that the three pathways of regulated necrosis, namely necroptosis, pyroptosis and ferroptosis, can be therapeutically targeted. This Perspective summarizes existing data on the newly characterized cell death pathways in endocrine disorders.

Background Whereas the dietary intake of industrial trans fatty acids (iTFA) has been specifically associated with inflammation, cardiovascular disease, and type 2 diabetes, understanding the impact of dietary fats on human health remains challenging owing to their complex composition and individual effects of their lipid components on metabolism. The aim of this study is to profile the composition of blood, measured by the fatty acid (FAs) profile and untargeted metabolome of serum and the transcriptome of blood cells, in order to identify molecular signatures that discriminate dietary fat intakes. Methods In a parallel study, the molecular effects of consuming dairy fat containing ruminant TFA (rTFA) or margarine containing iTFA were investigated. Healthy volunteers (n = 42; 45–69 y) were randomly assigned to diets containing margarine without TFA as major source of fat (wTFA control group with 0.4 g TFA per 100 g margarine), margarine with iTFA (iTFA group with 4.1 g TFA per 100 g margarine), or butter with rTFA (rTFA group with 6.3 g TFA per 100 g butter) for 4 weeks. The amounts of test products were individually selected so that fat intake contributed to 30–33% of energy requirements and TFA in the rTFA and iTFA groups contributed to up to 2% of energy intake. Changes in fasting blood values of lipid profiles (GC with flame-ionization detection), metabolome profiles (LC-MS, GC-MS), and gene expression (microarray) were measured. Results Eighteen FAs, as well as 242 additional features measured by LC-MS (185) and GC-MS (54) showed significantly different responses to the diets (PFDR-adjusted trans vaccenic acid), and margarines, i.e. TFA containing (E)-octadec-9-enoic acid (C18:1 t9; elaidic acid) were reflected in the significantly different serum levels of TFAs measured after the dietary interventions. Conclusions The untargeted serum metabolome differentiates margarine from butter intake although the identification of the discriminating features remains a bottleneck. The targeted serum FA profile provides detailed information on specific molecules differentiating not only butter from margarine intake but also diets with different content of iTFAs in margarine. Trial registration ClinicalTrials.gov NCT00933322.

Facial mimicry and emotion recognition are two socio-cognitive abilities involved in adaptive socio-emotional behavior, promoting affiliation and the establishment of social bonds. The mu-opioid receptor (MOR) system plays a key role in affiliation and social bonding. However, it remains unclear whether MORs are involved in the categorization and spontaneous mimicry of emotional facial expressions. Using a randomized, placebo-controlled, double-blind, between-subjects design, we investigated in 82 healthy female volunteers the effects of the specific MOR agonist morphine on the recognition accuracy of emotional faces (happiness, anger, fear), and on their facial mimicry (measured with electromyography). Frequentist statistics did not reveal any significant effects of drug administration on facial mimicry or emotion recognition abilities. However, post hoc Bayesian analyses provided support for an effect of morphine on facial mimicry of fearful facial expressions. Specifically, compared to placebo, morphine reduced mimicry of fear, as shown by lower activity of the frontalis muscle. Bayesian analyses also provided support for the absence of a drug effect on mimicry of happy and angry facial expressions, which were assessed with the zygomaticus major and corrugator supercilii muscles, as well as on emotion recognition accuracy. These findings suggest that MOR activity is involved in automatic facial responses to fearful stimuli, but not in their identification. Overall, the current results, together with the previously reported small effects of opioid compounds, suggest a relatively marginal role of the MOR system in emotion simulation and perception., Psychoneuroendocrinology, 142

The coronavirus disease 2019 (COVID-19) pandemic is currently one of the major health concerns worldwide accounting for many deaths and posing a great social and economic burden. Early activation of adrenal hormone secretion is pivotal to surviving systemic microbial infections. In addition, clinical studies demonstrated that glucocorticoids might also be beneficial in reducing disease progression and life deterioration in certain patients with COVID-19. Recent studies demonstrated that SARS-CoV-2 might target the adrenal glands, raising the possibility that at least some COVID-19 complications may be associated with adrenal dysfunction. Whether SARS-CoV-2 infection might cause adrenal dysfunction remains unknown. Histopathological examinations provided evidence that SARS-CoV-2 infection might indeed cause certain structural damage to the adrenal glands, especially concerning its vascular system. However, since no widespread cellular damage to cortical cells was observed, it is less likely that those changes could lead to an immediate adrenal crisis. This assumption is supported by the limited number of studies reporting rather adequate cortisol levels in patients with acute COVID-19. Those studies, however, could not exclude a potential late-onset or milder form of adrenal insufficiency. Although structural damage to adrenal glands is a rarely reported complication of COVID-19, some patients might develop a critical illness-related corticosteroid insufficiency (CIRCI), or iatrogenic adrenal insufficiency resulting from prolonged treatment with synthetic glucocorticoids. In this mini-review article, we aimed at describing and discussing factors involved in the adrenal gland function and possible dysfunction during COVID-19.

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9–79.1), range 50.0–96.6 yr; 574 women, median age 65.5 yr (58.1–75.4), range 50.1–94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2–13.2) and 10.9(6.3–11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00–2.37; 1.90, 1.18–3.05; 2.15, 1.26–3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34–5.29) and adjusted (2.03, 1.01–4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07–2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74–2.22). No other differences were observed. In men, lower dose (0

Major advancements are expected in medicine and healthcare in the 21st century- "Digital Age", mainly due to the application of data technologies and artificial intelligence into healthcare. In this perspective article we share a short story depicting the future Cushings' Disease patient and the postulated diagnostic and management approaches. In the discussion, we explain the advances in recent times which makes this future state plausible. We postulate that endocrinology care will be completely reinvented in the Digital Age. Ministry of Health (MOH) Published version RD is supported by Ministry of Health, Clinician Scientist Award (MOH-000014).

Tetrahydrobiopterin (BH4) is a cofactor that participates in the biogenesis reactions of a variety of biomolecules, including l‐tyrosine, l‐3,4‐dihydroxyphenylalanine, 5‐hydroxytryptophan, nitric oxide, and glycerol. Dihydropteridine reductase (DHPR, EC 1.5.1.34) is an enzyme involved in the BH4 regeneration. DHPR deficiency (DHPRD) is an autosomal recessive disorder, leading to severe and progressive neurological manifestations, which cannot be exclusively controlled by l‐phenylalanine (l‐Phe) restricted diet. In fact, the supplementation of neurotransmitter precursors is more decisive in the disease management, and the administration of sapropterin dihydrochloride may also provide positive effects. From the best of our knowledge, there is limited information regarding DHPRD in the past 5 years in the literature. Here, we describe the medical journey of the first patient to have DHPRD confirmed by molecular diagnostic methods in Brazil. The patient presented with two pathogenic variants of the quinoid dihydropteridine reductase (QDPR) gene—which codes for the DHPR protein, one containing the in trans missense mutation c.515C>T (pPro172Leu) in exon 5 and the other containing the same type of mutation in the exon 7 (c.635T>C [p.Phe212Ser]). The authors discuss their experience with sapropterin dihydrochloride for the treatment of DHPRD in this case report.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited autosomal recessive disorder of biogenic amine metabolism. Diagnosis requires analysis of neurotransmitter metabolites in cerebrospinal fluid, AADC enzyme activity analysis, or molecular analysis of the DDC gene. 3-O-methyldopa (3-OMD) is a key screening biomarker for AADC deficiency.We describe a rapid method for 3-OMD determination in dried blood spots (DBS) using flow-injection analysis tandem mass spectrometry with NeoBase™ 2 reagents andWithin-day and between-day precision determined with quality control samples demonstrated coefficients of variation15%. 3-OMD concentrations in 1000 healthy newborns revealed a mean of 1.33 μmol/L (SD ± 0.56, range 0.61-3.05 μmol/L), 100 non-AADC control subjects (age 7 days - 1 year) showed a mean of 1.19 μmol/L (SD ± 0.35-2.00 μmol/L), and 81 patients receiving oral L-Dopa had a mean 3-OMD concentration of 14.90 μmol/L (SD ± 14.18, range 0.4-80.3 μmol/L). A patient with confirmed AADC was retrospectively analyzed and correctly identified (3-OMD 10.51 μmol/L). In April 2020, we started a pilot project for identifying AADC deficiency in DBSs routinely submitted to the expanded newborn screening program. 3-OMD concentrations were measured in 21,867 samples; no patients with AADC deficiency were identified. One newborn had a high 3-OMD concentration due to maternal L-Dopa treatment.We demonstrated a rapid new method to identify AADC deficiency using reagents and equipment already widely used in newborn screening programs. Although our study is limited, introduction of our method in expanded neonatal screening is feasible and could facilitate deployment of screening, allowing for early diagnosis that is important for effective treatment.

AIMS To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy. MATERIALS AND METHODS We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change. RESULTS The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (β = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (β = 0.31%, P

ContextIdentification of patients with endocrine forms of hypertension (EHT) (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL], and Cushing syndrome [CS]) provides the basis to implement individualized therapeutic strategies. Targeted metabolomics (TM) have revealed promising results in profiling cardiovascular diseases and endocrine conditions associated with hypertension.ObjectiveUse TM to identify distinct metabolic patterns between primary hypertension (PHT) and EHT and test its discriminating ability.MethodsRetrospective analyses of PHT and EHT patients from a European multicenter study (ENSAT-HT). TM was performed on stored blood samples using liquid chromatography mass spectrometry. To identify discriminating metabolites a “classical approach” (CA) (performing a series of univariate and multivariate analyses) and a “machine learning approach” (MLA) (using random forest) were used.The study included 282 adult patients (52% female; mean age 49 years) with proven PHT (n = 59) and EHT (n = 223 with 40 CS, 107 PA, and 76 PPGL), respectively.ResultsFrom 155 metabolites eligible for statistical analyses, 31 were identified discriminating between PHT and EHT using the CA and 27 using the MLA, of which 16 metabolites (C9, C16, C16:1, C18:1, C18:2, arginine, aspartate, glutamate, ornithine, spermidine, lysoPCaC16:0, lysoPCaC20:4, lysoPCaC24:0, PCaeC42:0, SM C18:1, SM C20:2) were found by both approaches. The receiver operating characteristic curve built on the top 15 metabolites from the CA provided an area under the curve (AUC) of 0.86, which was similar to the performance of the 15 metabolites from MLA (AUC 0.83).ConclusionTM identifies distinct metabolic pattern between PHT and EHT providing promising discriminating performance.

The present pilot study investigated the effect of Teriparatide 1–34 rh-PTH (TPT) in young women diagnosed with anorexia nervosa (AN), and markedly compromised Bone Mineral Density (BMD). Patients were included who had (i) very low BMD (defined as Z-Score T-Score Z-Score T-Score

Over the past century, since the discovery of insulin, the therapeutic offer for diabetes has grown exponentially, in particular for type 2 diabetes (T2D). However, the drugs in the diabetes pipeline are even more promising because of their impressive antihyperglycemic effects coupled with remarkable weight loss. An ideal medication for T2D should target not only hyperglycemia but also insulin resistance and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the new class of GLP1 and gastric inhibitory polypeptide dual RAs counteract 2 of these metabolic defects of T2D, hyperglycemia and obesity, with stunning results that are similar to the effects of metabolic surgery. An important role of antidiabetic medications is to reduce the risk and improve the outcome of cardiovascular diseases, including coronary artery disease and heart failure with reduced or preserved ejection fraction, as well as diabetic nephropathy, as shown by SGLT2 inhibitors. This review summarizes the main drugs currently under development for the treatment of type 1 diabetes and T2D, highlighting their strengths and side effects.

PurposeTo establish and evaluate the diagnostic accuracy of volumetric bone mineral density (vBMD) threshold values at different spinal levels, derived from opportunistic quantitative computed tomography (QCT), for the prediction of incident vertebral fractures (VF).Materials and MethodsIn this case-control study, 35 incident VF cases (23 women, 12 men; mean age: 67 years) and 70 sex- and age-matched controls were included, based on routine multi detector CT (MDCT) scans of the thoracolumbar spine. Trabecular vBMD was measured from routine baseline CT scans of the thoracolumbar spine using an automated pipeline including vertebral segmentation, asynchronous calibration for HU-to-vBMD conversion, and correction of intravenous contrast medium (https://anduin.bonescreen.de). Threshold values at T1-L5 were calculated for the optimal operating point according to the Youden index and for fixed sensitivities (60 – 85%) in receiver operating characteristic (ROC) curves.ResultsvBMD at each single level of the thoracolumbar spine was significantly associated with incident VFs (odds ratio per SD decrease [OR], 95% confidence interval [CI] at T1-T4: 3.28, 1.66–6.49; at T5-T8: 3.28, 1.72–6.26; at T9-T12: 3.37, 1.78–6.36; and at L1-L4: 3.98, 1.97–8.06), independent of adjustment for age, sex, and prevalent VF. AUC showed no significant difference between vertebral levels and was highest at the thoracolumbar junction (AUC = 0.75, 95%-CI = 0.63 - 0.85 for T11-L2). Optimal threshold values increased from lumbar (L1-L4: 52.0 mg/cm³) to upper thoracic spine (T1-T4: 69.3 mg/cm³). At T11-L2, T12-L3 and L1-L4, a threshold of 80.0 mg/cm³ showed sensitivities of 85 - 88%, and specificities of 41 - 49%. To achieve comparable sensitivity (85%) at more superior spinal levels, resulting thresholds were higher: 114.1 mg/cm³ (T1-T4), 92.0 mg/cm³ (T5-T8), 88.2 mg/cm³ (T9-T12).ConclusionsAt all levels of the thoracolumbar spine, lower vBMD was associated with incident VFs in an elderly, predominantly oncologic patient population. Automated opportunistic osteoporosis screening of vBMD along the entire thoracolumbar spine allows for risk assessment of imminent VFs. We propose level-specific vBMD threshold at the thoracolumbar spine to identify individuals at high fracture risk.