Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis.

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme. A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested. These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis.

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) have an increased risk for severe COVID-19 disease and mortality. The goal of this study was to determine the efficacy of COVID-19 vaccine in patients with CLL. We evaluated humoral immune responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine in patients with CLL and compared responses with those obtained in age-matched healthy control subjects. Patients received 2 vaccine doses, 21 days apart, and antibody titers were measured by using the Elecsys Anti-SARS-CoV-2 S assay after administration of the second dose. In a total of 167 patients with CLL, the antibody response rate was 39.5%. A comparison between 52 patients with CLL and 52 sex- and aged-matched healthy control subjects revealed a significantly reduced response rate among patients (52% vs 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). The response rate was highest in patients who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients and 16.0% in patients under treatment at the time of vaccination. In patients treated with either Bruton's tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, response rates were considerably low (16.0% and 13.6%). None of the patients exposed to anti-CD20 antibodies <12 months before vaccination responded. In a multivariate analysis, the independent predictors of response were younger age, female sex, lack of currently active treatment, immunoglobulin G levels ≥550 mg/dL, and immunoglobulin M levels ≥40 mg/dL. In conclusion, antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in patients with CLL is markedly impaired and affected by disease activity and treatment. This trial was registered at www.clinicaltrials.gov as #NCT04746092.

Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in adolescents with rheumatic diseases treated with immunomodulatory medications.

OBJECTIVES: Adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) could be at risk for disease flare secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or to withholding anti-inflammatory therapy. While vaccination can protect against coronavirus disease 2019 (COVID-19), safety and immunogenicity data regarding anti-SARS-CoV-2 vaccines among adolescents with AIIRDs are limited. This international, prospective, multicentre study evaluated the safety and immunogenicity of the BNT162b2 anti-SARS-CoV-2 vaccine among adolescents and young adults with juvenile-onset AIIRDs, 80% of whom are on chronic immunomodulatory therapy. METHODS: Vaccine side effects, disease activity and short-term efficacy were evaluated after 3 months in 91 patients. Anti-spike S1/S2 IgG antibody levels were evaluated in 37 patients and 22 controls 2-9 weeks after the second dose. RESULTS: A total of 91 patients and 40 healthy controls were included. The safety profile was good, with 96.7% (n = 88) of patients reporting mild or no side effects and no change in disease activity. However, three patients had transient acute symptoms: two following the first vaccination (renal failure and pulmonary haemorrhage) and one following the second dose (mild lupus flare vs viral infection). The seropositivity rate was 97.3% in the AIIRD group compared with 100% among controls. However, anti-S1/S2 antibody titres were significantly lower in the AIIRD group compared with controls [242 (s.d. 136.4) vs 387.8 (57.3) BAU/ml, respectively; P < 0.0001]. No cases of COVID-19 were documented during the 3 month follow-up. CONCLUSION: Vaccination of juvenile-onset AIIRD patients demonstrated good short-term safety and efficacy and a high seropositivity rate but lower anti-S1/S2 antibody titres compared with healthy controls. These results should encourage vaccination of adolescents with juvenile-onset AIIRDs, even while on immunomodulation.

Impaired aldosterone response to ACTH without hypoaldosteronism: An unrecognized secretory pattern in search of clinical implications.

CONTEXT: Aldosterone has been recently characterized as a 'stress hormone'. Stress per se elicits a sizable rise in aldosterone secretion, which could be replicated by the administration of a low dose (0.03-1 µg, IV) of adrenocorticotropic hormone (ACTH). Whether or not the aldosterone response to ACTH could be selectively impaired, that is, in association with intact cortisol response, is presently unknown. OBJECTIVE: To determine whether or not the aldosterone response to low dose of ACTH is impaired in subjects referred to assess the hypothalamic-pituitary-adrenal axis (HPA). DESIGN: Retrospective analysis. SETTING: Outpatient referral endocrine day care centre. PATIENTS: One hundred and ninety-five consecutive subjects who underwent the low dose (1 µg) ACTH test, in whom decreased cortisol reserve was suspected due to former/present glucocorticoid excess, pituitary disease or/and unexplained weakness. MAIN OUTCOME MEASURES: The outcome was the detection of lack of aldosterone response, defined as a rise <111 pmol/l. RESULTS: In all, 46/195 subjects had subnormal aldosterone response as compared with 52/195 subjects showing diminished cortisol response. Nine subjects had combined deficient aldosterone and cortisol response. In the 37 subjects with isolated subnormal aldosterone response common associations were the use of exogenous glucocorticoids, mostly prednisone (n = 16); former Cushing disease (n = 2); nonfunctioning pituitary adenoma (n = 8); hypothyroidism (n = 11); the use of statins (n = 11), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 6), sex steroids in transgenders and orthostatic hypotension (n = 3). Twenty-seven percent (25/93) of the subjects with recent exposure to glucocorticoids had impaired aldosterone response to ACTH. CONCLUSION: Blunted aldosterone response to ACTH in the absence of hypoaldosteronism was seen in ~27% of subjects referred for HPA assessment using the low dose 1 µg ACTH test. Exposure to glucocorticoid excess was often linked to this impairment, independent of the cortisol response to ACTH.

Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study.

INTRODUCTION: Vaccination represents a cornerstone in mastering the COVID-19 pandemic. Data on immunogenicity and safety of messenger RNA (mRNA) vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) are limited. METHODS: A multicentre observational study evaluated the immunogenicity and safety of the two-dose regimen BNT162b2 mRNA vaccine in adult patients with AIIRD (n=686) compared with the general population (n=121). Serum IgG antibody levels against SARS-CoV-2 spike S1/S2 proteins were measured 2-6 weeks after the second vaccine dose. Seropositivity was defined as IgG ≥15 binding antibody units (BAU)/mL. Vaccination efficacy, safety, and disease activity were assessed within 6 weeks after the second vaccine dose. RESULTS: Following vaccination, the seropositivity rate and S1/S2 IgG levels were significantly lower among patients with AIIRD versus controls (86% (n=590) vs 100%, p<0.0001 and 132.9±91.7 vs 218.6±82.06 BAU/mL, p<0.0001, respectively). Risk factors for reduced immunogenicity included older age and treatment with glucocorticoids, rituximab, mycophenolate mofetil (MMF), and abatacept. Rituximab was the main cause of a seronegative response (39% seropositivity). There were no postvaccination symptomatic cases of COVID-19 among patients with AIIRD and one mild case in the control group. Major adverse events in patients with AIIRD included death (n=2) several weeks after the second vaccine dose, non-disseminated herpes zoster (n=6), uveitis (n=2), and pericarditis (n=1). Postvaccination disease activity remained stable in the majority of patients. CONCLUSION: mRNA BNTb262 vaccine was immunogenic in the majority of patients with AIIRD, with an acceptable safety profile. Treatment with glucocorticoids, rituximab, MMF, and abatacept was associated with a significantly reduced BNT162b2-induced immunogenicity.

Improving blood glucose level predictability using machine learning.

This study was designed to improve blood glucose level predictability and future hypoglycemic and hyperglycemic event alerts through a novel patient-specific supervised-machine-learning (SML) analysis of glucose level based on a continuous-glucose-monitoring system (CGM) that needs no human intervention, and minimises false-positive alerts. The CGM data over 7 to 50 non-consecutive days from 11 type-1 diabetic patients aged 18 to 39 with a mean HbA1C of 7.5% ± 1.2% were analysed using four SML models. The algorithm was constructed to choose the best-fit model for each patient. Several statistical parameters were calculated to aggregate the magnitudes of the prediction errors. The personalised solutions provided by the algorithm were effective in predicting glucose levels 30 minutes after the last measurement. The average root-mean-square-error was 20.48 mg/dL and the average absolute-mean-error was 15.36 mg/dL when the best-fit model was selected for each patient. Using the best-fit-model, the true-positive-hypoglycemia-prediction-rate was 64%, whereas the false-positive- rate was 4.0%, and the false-negative-rate was 0.015%. Similar results were found even when only CGM samples below 70 were considered. The true-positive-hyperglycemia-prediction-rate was 61%. State-of-the-art SML tools are effective in predicting the glucose level values of patients with type-1diabetes and notifying these patients of future hypoglycemic and hyperglycemic events, thus improving glycemic control. The algorithm can be used to improve the calculation of the basal insulin rate and bolus insulin, and suitable for a closed loop "artificial pancreas" system. The algorithm provides a personalised medical solution that can successfully identify the best-fit method for each patient.

Higher C-peptide levels and glucose requirements may identify neonates with transient hyperinsulinism hypoglycemia who will benefit from diazoxide treatment.

The aim of the study was to characterize factors that may serve as clinical tools to identify neonates with transient neonatal hyperinsulinism hypoglycemia (HH) who may benefit from diazoxide treatment. This retrospective study included 141 neonates with transient HH (93 males) of whom 34 (24%) were treated with diazoxide. Diazoxide treatment was started at median age of 13 days (range 5-35) and discontinued at median age of 42 days (range 14-224). The maximal dose was 7.1 ± 2.3 mg/kg/day. Diazoxide-treated neonates required a higher glucose infusion rate (GIR) compared with non-treated neonates (16.6 ± 3.4 vs. 10.4 ± 4.0 mg/kg/min, respectively, P < .01), had a longer duration of intravenous fluids (15.9 ± 9.3 vs. 7.8 ± 6.5 days, P < .01), a longer hospitalization (32.8 ± 22.7 vs. 20.4 ± 13.4 days, P < .01), a longer duration of carbohydrate supplementation (38.9 ± 40.4 vs. 17.8 ± 21.4 days, P < .01), and higher mean C-peptide levels on "critical sample" (1.4 ± 0.9 vs. 0.8 ± 0.5 ng/ml, P < .01). Their insulin levels also tended to be higher (3.5 ± 2.9 vs. 2.2 ± 3.8 µU/ml, P = .07). A stepwise logistic regression model revealed that significant predictors of prolonged HH were maximal GIRs (odds ratio (OR) 1.56, 95%; confidence interval (CI) 1.3-1.88, P < .001) and C-peptide levels (OR 3.57, 95%; CI 1.3-12.1, P = .005).Conclusion: Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.What is Known:• Neonates with transient hyperinsulinism usually do not require treatment beyond glucose supplementation due to its self-limited clinical course, but some may benefit from diazoxide treatment.What is New:• Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.• The incidence of prolonged neonatal HH is higher than the currently accepted figures.

Increase of body mass index and waist circumference predicts development of metabolic syndrome criteria in apparently healthy individuals with 2 and 5 years follow-up.

BACKGROUND: The metabolic syndrome (MetS) is associated with overweight and abdominal obesity. Our aim was to use longitudinal measurements to provide clinically relevant information on the relative influence of changes in body mass index (BMI), waist circumference (WC), and weekly physical exercise duration on the development of each of the MetS components. METHODS: We analyzed data collected at the Tel-Aviv Medical Center Inflammation Survey (TAMCIS). Apparently healthy individuals with two consecutive visits that were not treated for any metabolic criteria were included in this study. We analyzed the influence of changes in BMI, WC, and time engaged in physical exercise on the change in each of the components of the metabolic syndrome using linear regressions. RESULTS: Included were 7532 individuals (5431 men, 2101 women) with 2 years follow-up. Participants who gained two BMI points, had the mean number of criteria increase from 1.07 to 1.52, while participants who lost two BMI points, decreased from 1.64 to 1.16. A long-term analysis over 5 years showed similar results. Furthermore, an increase in WC was independently associated with increased severity of each of the other components, when controlling for increase in BMI. Increase in weekly exercise duration had a small but statistically significant favorable effect on blood triglycerides and HDL levels, but not on blood pressure or HbA1C. CONCLUSIONS: Changes in BMI and WC are highly associative with the likelihood and severity of the MetS independently of the baseline levels, suggesting that obese individuals can substantially improve their MetS prognosis by losing both body weight and abdominal fat.

Metabolic syndrome is associated to high-sensitivity cardiac troponin T elevation.

INTRODUCTION: Metabolic syndrome (MetS) and high-sensitivity cardiac troponin T (hs-TnT) are associated with higher risk for cardiovascular diseases (CVD). Our aim was to assess the relation between hs-TnT elevation and MetS in a general population sample. MATERIALS AND METHODS: Individuals participating in an annual health survey program between 2010 and 2016 were included in the study. Blood samples including hs-TnT levels were collected. The study population was divided into three groups based on hs-TnT levels - undetectable (<5 ng/L), intermediate (5-14 ng/L) and elevated (>14 ng/L). RESULTS: A total of 5994 subjects were included in the study, the mean age was 48.5 and 4336 (72%) were males. Compared with subjects with undetectable hs-TnT the prevalence of MetS was higher in those with detectable and elevated levels - 392 (10%) vs. 270 (15%) and 51 (33%), respectively (p < 0.001). In a multivariate model adjusted for age, gender and multiple co-morbidities, the number of MetS components and presence of MetS were significantly associated with an increased risk for detectable hs-TnT levels (OR = 1.02 {for each component}; 95% CI [1.00-1.05], p = 0.04) and (OR = 1.13; 95% CI [1.07-1.2], p < 0.001) respectively. Only the waist, glucose and hypertension components of the MetS were significantly associated with elevated troponin. CONCLUSIONS: The MetS and its distinct components have a cumulative impact on hs-TnT levels in apparently healthy subjects.

Total serum cholinesterase activity predicts hemodynamic changes during exercise and associates with cardiac troponin detection in a sex-dependent manner.

BACKGROUND: Imbalanced autonomic nervous system (ANS) activity is associated with poor cardiovascular outcome. However, clinically validated biomarkers to assess parasympathetic function are not yet available. We sought to evaluate parasympathetic dysfunction by measuring serum cholinesterase activity and to determine its relationship to high sensitive cardiac troponin T (hs-cTnT) as well as traditional non-invasive parameters of ANS function during exercise in apparently healthy individuals. METHODS: We enrolled 1526 individuals (mean age 49 ± 11 yr., 75% men) from the Tel Aviv Medical Center Inflammation Survey (TAMCIS). We used the acetylcholine (ACh) analog acetylthiocholine (ATCh) as a substrate that is hydrolyzed by both ACh degrading enzymes and reflects the total serum capacity for acetylcholine hydrolysis, referred to as cholinergic status (CS). All subjects performed a cardiac stress test reviewed on the spot by a cardiologist and multiple physiological and metabolic parameters including hs-cTnT were measured. RESULTS: CS values at rest predicted multiple exercise-hemodynamic changes. Heart rate recovery after exercise was inversely correlated to CS values (p < 0.01 and p = 0.03 for women and men respectively), and a hypertensive reaction during exercise was associated with elevated CS levels in women. Most importantly, women with detectable hs-cTnT (> 5 ng/L) presented with elevated CS levels compared to women with undetectable levels; 1423 ± 272.5 vs 1347 ± 297.9 (p = 0.02). An opposite trend was observed in men. Metabolic dysfunction parameters were also associated with CS elevation in both men and women. CONCLUSIONS: Parasympathetic dysfunction assessed by total serum cholinesterase activity predicts hemodynamic changes during exercise. CS is also associated with hs-cTnT detection in women and inversely so in men. Future studies to assess the potential clinical use of this new sex-specific biomarker in cardiovascular disease risk stratification are warranted.

Elevated high-sensitive troponin T in negative stress test individuals.

BACKGROUND: The exercise ECG stress test (EST) is still the first step of work-up in intermediate risk patients in many clinical scenarios. High-sensitive cardiac troponin T (hs-cTnT) elevation is related to future cardiovascular events in the general population and in patients with ischaemic heart disease. The relation between these 2 tests is not well described. MATERIALS AND METHODS: A total of 2780 participants from the Tel-Aviv Medical Center Inflammation Survey cohort (mean age 49 years, 79% men) were analysed. Multiple physiologic and metabolic parameters including hs-cTnT were collected. All participants completed an EST manually reviewed by a cardiologist. RESULTS: A positive EST was documented in 224 subjects (8%). The majority (91%) of participants with hs-cTnT levels of 5-14 ng/L had a negative EST as well as 89.3% of subjects with levels >14 ng/L. The proportion of subjects with a positive EST and detectable hs-cTnT levels (>5 ng/L) was not significantly greater compared to those with a negative EST (53.1% vs 46.2%, respectively, P = .09). CONCLUSION: Among subjects referred for EST as part of an annual health survey, we found no significant association between EST results to hs-cTnT detection.

Pancreatic Beta-Cell Proliferation Induced by Estradiol-17ß is Foxo1 Dependent.

Estradiol-17ß (E2) and the Foxo1 transcription factor have each been implicated in the regulation of ß-cell proliferation. Interaction between Foxo1and estrogen receptor alpha (ERα), effecting cell cycle, has been demonstrated in breast cancer cells, but has not been studied thus far in ß-cells. Using human islets and the INS1-E ß-cell line, this study investigated the contribution of Foxo1 to E2-mediated ß-cell replication. Foxo1 expression was knocked down in INS1-E cells using siRNA and Foxo1 activity was inhibited in human islets with a specific Foxo1 inhibitor (AS1842856). Cells were treated with E2 and the ERα agonist PPT and evaluated for proliferation by 3[H]-thymidine incorporation and for transcriptional activity through the estrogen response element by the luciferase assay. As Foxo1 activity is regulated by post-translational modifications, the effect of E2 on phosphorylation was also assessed. In INS1-E cells, knock down of Foxo1 abrogated the proliferative response to E2 and PPT. In human islets, inhibition of Foxo1 abrogated E2-mediated proliferation and attenuated the response to PPT. Foxo1 knock down and inhibition reduced activity through the estrogen response element by 25% (p<0.05) and 50% (p<0.01) respectively, in INS1-E cells. E2 increased Foxo1 phosphorylation in a time dependent manner in INS1-E and human islets (p<0.01, p<0.05, respectively). These findings suggest that Foxo1 is involved in E2-mediated proliferation in INS1-E cells and human islets. This may have implications vis-à-vis variations in circulating endogenous E2 concentrations in diabetes.

GENDER DETERMINES SERUM FREE CORTISOL: HIGHER LEVELS IN MEN.

OBJECTIVE: Because only the free fraction of serum cortisol can readily access glucocorticoid receptors, we investigated whether or not a gender-related difference in serum free cortisol (FC) exists in the basal and adrenocorticotropic hormone (ACTH)-stimulated state. METHODS: Serum total cortisol (TC) and FC were measured in 323 subjects (175 men; 148 women). Additionally, the low-dose 1-µg ACTH test was performed in 56 subjects (30 women, 26 men). Subjects were healthy volunteers, recruited in a preventive medicine screening program and an outpatient clinic. RESULTS: Overall, basal serum TC and FC level were ~18 and ~33%, respectively, higher in men than in women (TC, 14.5 ± 0.33 µg/dL vs. 12.3 ± 0.33 µg/dL; P<.0001; FC, 0.68 ± 0.02 µg/dL vs. 0.51 ± 0.02 µg/dL; P<.0001). The higher FC in men relative to women was apparent across a wide age range (17 to 86 years) and persisted after adjustment for age and body mass index. The FC fraction (%FC, out of TC) was concordantly higher in men (5.4 ± 0.09% vs. 4.8 ± 0.3%; P = .046). FC was not related to the estimated menopausal status (women age below and above 47, 50, or 53 years). ACTH-stimulated FC levels were significantly higher in men compared to women, as reflected by the area under the response curve (49.4 ± 3.4 µg × min vs. 39.6 ± 2.2 µg × min; P = .0014). CONCLUSION: Gender is an unrecognized determinant of serum FC in humans. The possibility of lifelong exposure to the higher bioactive fraction of cortisol under basal conditions or daily stress involving ACTH stimulation should be further investigated in the context of gender-related phenotypic features such as "android" (visceral) fat deposition and longevity. ABBREVIATIONS: ACTH = adrenocorticotropic hormone BMI = body mass index CBG = cortisol-binding globulin FC = free cortisol HPA = hypothalamic-pituitary-adrenal TC = total cortisol.

Polyethylene glycol thyroid-stimulating hormone (PEG-TSH) testing in the management of pediatric thyroid dysfunction.

PURPOSE: The polyethylene glycol (PEG) methodology is used for investigating incongruities in laboratory assays, such as thyroid-stimulating hormone (TSH) measurements. The aim of the study is to investigate the practical application of PEG-TSH testing in cases of discrepancies between elevated TSH and normal free thyroxine (FT4) levels. METHODS: A real-life observational study conducted in a tertiary medical center. The hospital's electronic database was queried for TSH tests performed in pediatric patients between 2015 and 2023. Of those, PEG-TSH were identified. Patients' clinical and biochemical characteristics and PEG-TSH-guided management were assessed. RESULTS: In total, 2949 TSH tests were performed in 891 children and adolescents for various indications. Among them were 61 (2.1%) PEG-TSH results, mean age 7.1 ± 5.3 years, of 38 patients (4.3%), comprised of 16 with congenital hypothyroidism, 16 with subclinical hypothyroidism, and 6 with Hashimoto thyroiditis. Both the TSH and the PEG-TSH levels of patients with congenital hypothyroidism were higher than those of the other two groups (P = 0.021 and P = 0.009, respectively), with no group differences in FT4 levels. Spearman's correlation analysis revealed a strong association between TSH and PEG-TSH levels: r = 0.871, P < 0.001. In nearly one-half of the cases, clinical decisions made by clinicians (decreasing the dose or not initiating L-thyroxine treatment) were affected by the PEG-TSH results. CONCLUSION: Our findings support PEG-TSH testing for determining appropriate TSH levels and avoid unnecessary thyroid hormone treatment among children and adolescents. We propose the suitability of managing their clinical condition based upon age-appropriate clinical parameters and FT4 levels when their PEG-TSH levels are within the normal range.

Metabolically Healthy Obesity Is a Misnomer: Components of the Metabolic Syndrome Linearly Increase with BMI as a Function of Age and Gender.

OBJECTIVES: We aimed to examine the relationships between body mass index (BMI) and metabolic syndrome (MS) components as a function of age and gender across weight categories. METHODS: This cross-sectional study included 19,328 subjects who participated in a health-screening program. We analyzed 14,093 apparently healthy subjects with a BMI ≥ 18.5 kg/m2 (ranging from 18.5 to 46 kg/m2). RESULTS: At a BMI of 18.5 kg/m2, 16% of subjects had one or more MS components (MS ≥ 1). The number of MS components increased linearly with BMI. The most prevalent components for MS1-4 were hypertension (in men) and increased waist circumference (in women). Among 6391 non-obese subjects with MS = 0, there was a linear increase in blood pressure, glucose, and triglycerides, as well as a decline in high-density lipoprotein cholesterol, as BMI increased. In 2087 subjects with a BMI ≥ 30 kg/m2, a true normometabolic state (MS = 0) was observed in only 7.5%, declining to less than 1% at a BMI ≥ 36 kg/m2 (ATP criteria). Women were metabolically protected relative to men between the ages of 30 and 50 years. CONCLUSIONS: (A) MS components increase linearly with BMI from the lowest normal BMI and continue to increase with age and BMI; (B) metabolically healthy obesity is rare in subjects with a high BMI and declines with age; (C) hypertension is the most common component in men; and (D) in women, MS components are seen at older ages than in men for the same BMI. Metabolic health declines with age and BMI in nearly all subjects with obesity.

Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study.

Purpose: Chronic gender-affirming hormone therapy (GAHT) with sublingual estradiol (SLE) has not been studied. We aimed to compare GAHT with SLE only, to combined oral (CO) estradiol and cyproterone acetate, in treatment-naive trans women. Methods: Twenty-two trans women enrolled into either the CO arm or the SLE-only arm (0.5 mg four times daily) in this 6-month prospective study. Anthropometric and laboratory variables were collected at baseline and 3 and 6 months. At the study beginning and end, body composition was measured by dual-energy X-ray absorptiometry and bioelectrical impedance, and gender dysphoria, sexual desire, and function were assessed by validated questionnaires. Results: Subjects in the SLE were older, 26.3±5.8 years versus 20.1±2.3 years, p=0.006. All anthropometric, body composition, and laboratory variables were identical at baseline. Although dysphoria appeared greater, and sexual function lower at baseline in the CO group, this canceled out after age adjustment. Both treatments induced similar biochemical and hormonal changes. Creatinine, hemoglobin and cholesterol decreased significantly, while testosterone was suppressed to the same level in both groups: 3.22 [1.47-5.0] nmol/L in the SLE group and 2.41 [0.55-8.5] nmol/L in the CO, p=0.65. Significant changes in body composition toward a more feminine body were noted in both groups. Dysphoria did not significantly improve in either group, while sexual desire and function decreased at six months in both, p<0.001. Conclusions: Both treatments achieved similar clinical changes. At this stage, SLE, which repeatedly induces alarming excursions of serum estradiol throughout the day, appears to offer no advantage over the CO approach.

Alcohol Drinks Induce Acute Lowering in Circulating l-Arginine in Obese and Type 2 Diabetic Subjects.

Since low serum l-arginine (Arg) and high asymmetric dimethylarginine (ADMA) can predict microvascular complications in type 2 diabetes mellitus (T2DM), we tested whether Arg and ADMA are affected by diet and physical activity in overweight/obese and T2DM subjects. We tested the effects on serum Arg and ADMA of single loads of dextrose, protein, fat, or alcohol (∼300 calories each); one episode of physical exercise; and 12 weeks of standard lifestyle modification (dietary and physical activity counseling). Alcohol drink was followed by ∼30% lowering in Arg. Arg and ADMA increased after a protein load but remained stable after glucose or fat load or 30 min of treadmill walk. Following 12 weeks of lifestyle modification, ADMA declined only in subjects achieving weight loss >5%. In conclusion, alcohol is a previously unrecognized acute suppressor of serum Arg. Lifestyle modification lowers ADMA in subjects who achieve weight loss >5%. Clinical Trial Registration Number: NCT04406402.

Whole blood analysis for medical diagnostics by GC-MS with Cold EI.

This study covers a new method and related instrumentation for whole blood analysis for medical diagnostics. Two-µL whole blood samples were collected using "minimal invasive" diabetes lancet and placed on a thin glass rod mounted on a newly designed BloodProbe. The BloodProbe with the whole blood sample was inserted directly into a ChromatoProbe mounted on the GC inlet, and thus, no sample preparation was involved. The analysis was performed within 10 min using a GC-MS with Cold EI that is based on interfacing GC and MS with supersonic molecular beams (SMB) along with electron ionization of vibrationally cold sample compounds in the SMB (hence the name Cold EI). Our blood analysis revealed several observations: (1) Detailed mass chromatograms were generated with full range of all the nonpolar lipids in blood including fatty acids, cholesterol, cholesteryl esters, vitamin E, monoglycerides, diglycerides, and triglycerides. (2) The analysis of whole blood was found to be as informative as the conventional clinical analysis of blood serum. (3) Cholesteryl esters were more sensitive than free cholesterol alone to the effect of diet of obese people. (4) Major enhancement of several fatty acid methyl esters was found in the blood of a cancer patient with liver dysfunction. (5) Vitamin E as both α- and ß-tocopherol was found with person-dependent ratio of these two compounds. (6) Elemental sulfur S8 was identified in blood. (7) Several drugs and other compounds were found and need further study of their correlation to medical issues.

Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns.

BACKGROUND: The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging. RESULTS: Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the inter-personal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age. CONCLUSIONS: Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.

The depletion of skeletal muscle satellite cells with age is concomitant with reduced capacity of single progenitors to produce reserve progeny.

Satellite cells are myogenic progenitors that reside on the myofiber surface and support skeletal muscle repair. We used mice in which satellite cells were detected by GFP expression driven by nestin gene regulatory elements to define age-related changes in both numbers of satellite cells that occupy hindlimb myofibers and their individual performance. We demonstrate a reduction in satellite cells per myofiber with age that is more prominent in females compared to males. Satellite cell loss also persists with age in myostatin-null mice regardless of increased muscle mass. Immunofluorescent analysis of isolated myofibers from nestin-GFP/Myf5(nLacZ/+) mice reveals a decline with age in the number of satellite cells that express detectable levels of betagal. Nestin-GFP expression typically diminishes in primary cultures of satellite cells as myogenic progeny proliferate and differentiate, but GFP subsequently reappears in the Pax7(+) reserve population. Clonal analysis of sorted GFP(+) satellite cells from hindlimb muscles shows heterogeneity in the extent of cell density and myotube formation among colonies. Reserve cells emerge primarily within high-density colonies, and the number of clones that produce reserve cells is reduced with age. Thus, satellite cell depletion with age could be attributed to a reduced capacity to generate a reserve population.