Localization of the corticotropin-releasing hormone receptor gene on mouse Chromosome 11

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47014/1/335_2004_Article_BF00350896.pd

A comparison of covered vs bare expandable stents for the treatment of aortoiliac occlusive disease

ObjectiveThis trial was conducted to determine if covered stents offer a patency advantage over bare-metal stents in the treatment of aortoiliac arterial occlusive disease.MethodsThe Covered Versus Balloon Expandable Stent Trial (COBEST), a prospective, multicenter, randomized controlled trial, was performed involving 168 iliac arteries in 125 patients with severe aortoiliac occlusive disease who were randomly assigned to receive a covered balloon-expandable stent or bare-metal stent. Patient demographic data, clinical signs and symptoms, TransAtlantic Inter-Society Consensus (TASC) classification, and preprocedure and postprocedure ankle-brachial index measurements were recorded. The primary end points included freedom from binary restenosis and stent occlusion of the treated area, as determined by ultrasound imaging or quantitative visual angiography, or both. Postprocedural follow-up was at 1, 6, 12, and 18 months.ResultsAortoiliac lesions treated with a covered stent were significantly more likely to remain free from binary restenosis than those that were treated with a bare-metal stent (hazard ratio [HR], 0.35; 95% confidence interval (CI), 0.15-0.82; P = .02). Freedom from occlusion was also higher in lesions treated with covered stents than in those treated with a bare-metal stent (HR, 0.28; 95% CI, 0.07-1.09); however, this did not reach statistical significance (P = .07). Subgroup analyses demonstrated a significant difference in freedom from binary restenosis for covered stents in TASC C and D lesions compared with a bare stent (HR, 0.136; 95% CI, 0.042-0.442). This difference was not demonstrated for TASC B lesions (HR, 0.748; 95% CI, 0.235-2.386).ConclusionsCOBEST demonstrates covered and bare-metal stents produce similar and acceptable results for TASC B lesions. However, covered stents perform better for TASC C and D lesions than bare stents in longer-term patency and clinical outcome

Dual energy X-ray absorptiometry compared with anthropometry in relation to cardio-metabolic risk factors in a young adult population: Is the ‘Gold Standard’ tarnished?

Background and Aims: Assessment of adiposity using dual energy x-ray absorptiometry (DXA) has been considered more advantageous in comparison to anthropometryfor predicting cardio-metabolic risk in the older population, by virtue of its ability to distinguish total and regional fat. Nonetheless, there is increasing uncertainty regarding the relative superiority of DXA and little comparative data exist in young adults. This study aimed to identify which measure of adiposity determined by either DXA or anthropometry is optimal within a range of cardio-metabolic risk factors in young adults. Methods and Results: 1138 adults aged 20 years were assessed by DXA and standard anthropometry from the Western Australian Pregnancy Cohort (Raine) Study. Cross-sectional linear regression analyses were performed. Waist to height ratio was superior to any DXA measure with HDL-C. BMI was the superior model in relation to blood pressure than any DXA measure. Midriff fat mass (DXA) and waist circumference were comparable in relation to glucose. For all the other cardio-metabolic variables, anthropometricand DXA measures were comparable. DXA midriff fat mass compared with BMI or waist hip ratio was the superior measure for triglycerides, insulin and HOMA-IR. Conclusion: Although midriff fat mass (measured by DXA) was the superior measure with insulin sensitivity and triglycerides, the anthropometricmeasures were better or equal with various DXA measures for majority of the cardio-metabolic risk factors. Our findings suggest, clinical anthropometry is generally as useful as DXA in the evaluation of the individual cardio-metabolic risk factors in young adults

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults

BACKGROUND: The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. RESULTS: The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. CONCLUSIONS: As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required

Serum 25-hydroxyvitamin D concentrations and cardiometabolic risk factors in adolescents and young adults

Evidence associating serum 25-hydroxyvitamin D (25(OH)D) concentrations and cardiometabolic risk factors is inconsistent and studies have largely been conducted in adult populations. We examined the prospective associations between serum 25(OH)D concentrations and cardiometabolic risk factors from adolescence to young adulthood in the West Australian Pregnancy Cohort (Raine) Study. Serum 25(OH)D concentrations, BMI, homoeostasis model assessment for insulin resistance (HOMA-IR), TAG, HDL-cholesterol and systolic blood pressure (SBP) were measured at the 17-year (n 1015) and 20-year (n 1117) follow-ups. Hierarchical linear mixed models with maximum likelihood estimation were used to investigate associations between serum 25(OH)D concentrations and cardiometabolic risk factors, accounting for potential confounders. In males and females, respectively, mean serum 25(OH)D concentrations were 73·6 (sd 28·2) and 75·4 (sd 25·9) nmol/l at 17 years and 70·0 (sd 24·2) and 74·3 (sd 26·2) nmol/l at 20 years. Deseasonalised serum 25(OH)D3 concentrations were inversely associated with BMI (coefficient -0·01; 95 % CI -0·03, -0·003; P=0·014). No change over time was detected in the association for males; for females, the inverse association was stronger at 20 years compared with 17 years. Serum 25(OH)D concentrations were inversely associated with log-HOMA-IR (coefficient -0·002; 95 % CI -0·003, -0·001; P<0·001) and positively associated with log-TAG in females (coefficient 0·002; 95 % CI 0·0008, 0·004; P=0·003). These associations did not vary over time. There were no significant associations between serum 25(OH)D concentrations and HDL-cholesterol or SBP. Clinical trials in those with insufficient vitamin D status may be warranted to determine any beneficial effect of vitamin D supplementation on insulin resistance, while monitoring for any deleterious effect on TAG

Serum 25-hydroxyvitamin D concentrations and cardiometabolic risk factors in adolescents and young adults

Evidence associating serum 25-hydroxyvitamin D (25(OH)D) concentrations and cardiometabolic risk factors is inconsistent and studies have largely been conducted in adult populations. We examined the prospective associations between serum 25(OH)D concentrations and cardiometabolic risk factors from adolescence to young adulthood in the West Australian Pregnancy Cohort (Raine) Study. Serum 25(OH)D concentrations, BMI, homoeostasis model assessment for insulin resistance (HOMA-IR), TAG, HDL-cholesterol and systolic blood pressure (SBP) were measured at the 17-year (n 1015) and 20-year (n 1117) follow-ups. Hierarchical linear mixed models with maximum likelihood estimation were used to investigate associations between serum 25(OH)D concentrations and cardiometabolic risk factors, accounting for potential confounders. In males and females, respectively, mean serum 25(OH)D concentrations were 73·6 (sd 28·2) and 75·4 (sd 25·9) nmol/l at 17 years and 70·0 (sd 24·2) and 74·3 (sd 26·2) nmol/l at 20 years. Deseasonalised serum 25(OH)D3 concentrations were inversely associated with BMI (coefficient -0·01; 95 % CI -0·03, -0·003; P=0·014). No change over time was detected in the association for males; for females, the inverse association was stronger at 20 years compared with 17 years. Serum 25(OH)D concentrations were inversely associated with log-HOMA-IR (coefficient -0·002; 95 % CI -0·003, -0·001; P<0·001) and positively associated with log-TAG in females (coefficient 0·002; 95 % CI 0·0008, 0·004; P=0·003). These associations did not vary over time. There were no significant associations between serum 25(OH)D concentrations and HDL-cholesterol or SBP. Clinical trials in those with insufficient vitamin D status may be warranted to determine any beneficial effect of vitamin D supplementation on insulin resistance, while monitoring for any deleterious effect on TAG

Incidence of Resident Mistreatment in the Learning Environment Across Three Institutions

Introduction: Mistreatment in the learning environment is associated with negative outcomes for trainees. While the Association of American Medical Colleges (AAMC) annual Graduation Questionnaire (GQ) has collected medical student reports of mistreatment for a decade, there is not a similar nationally benchmarked survey for residents. The objective of this study is to explore the prevalence of resident experiences with mistreatment. Methods: Residents at three academic institutions were surveyed using questions similar to the GQ in 2018. Quantitative data were analyzed based on frequency and Mann-Whitney U tests to detect gender differences. Results: Nine hundred ninety-six of 2682 residents (37.1%) responded to the survey. Thirty-nine percent of residents reported experiencing at least one incident of mistreatment. The highest reported incidents were public humiliation (23.7%) and subject to offensive sexist remarks/comments (16.0%). Female residents indicated experiencing significantly more incidents of: public embarrassment, public humiliation, offensive sexist remarks, lower evaluations based on gender, denied opportunities for training or rewards, and unwanted sexual advances. Faculty were the most frequent instigators of mistreatment (66.4%). Of trainees who reported experiencing mistreatment, less than one-quarter reported the behavior. Conclusion: Mistreatment in the academic learning environment is a concern in residency programs. There is increased frequency among female residents

Aged PROP1 Deficient Dwarf Mice Maintain ACTH Production

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1null (Prop1-/-) and the Ames dwarf (Prop1df/df) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication