Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

Nephropathy is among the most frequent complications of diabetes and the leading cause of end-stage renal disease. Despite the success of novel drugs in animal models, the majority of the subsequent clinical trials employing those drugs targeting diabetic nephropathy failed. This lack of translational value may in part be due to an inadequate comparability of human disease and animal models that often capture only a few aspects of disease. Here we overcome this limitation by developing a multimolecular noninvasive humanized readout of diabetic nephropathy based on urinary peptidomics. The disease-modified urinary peptides of 2 type 2 diabetic nephropathy mouse models were identified and compared with previously validated urinary peptide markers of diabetic nephropathy in humans to generate a classifier composed of 21 ortholog peptides. This classifier predicted the response to disease and treatment with inhibitors of the renin-angiotensin system in mice. The humanized classifier was significantly correlated with glomerular lesions. Using a human type 2 diabetic validation cohort of 207 patients, the classifier also distinguished between patients with and without diabetic nephropathy, and their response to renin-angiotensin system inhibition. Thus, a combination of multiple molecular features common to both human and murine disease could provide a significant change in translational drug discovery research in type 2 diabetic nephropathy

5 years DKMS Chile: approach, results and impact of the first unrelated stem cell donor center in Chile

IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed worldwide to treat blood cancer and other life-threatening blood disorders. As successful transplantation requires an HLA-compatible donor, unrelated donor centers and registries have been established worldwide to identify donors for patients without a family match. Ethnic minorities are underrepresented in large donor registries. Matching probabilities are higher when donors and patients share the same ethnic background, making it desirable to increase the diversity of the global donor pool by recruiting donors in new regions. Here, we report the establishment and the first 5 years of operation of the first unrelated stem cell donor center in Chile, a high-income country in South America with a population of over 19 million.MethodsWe used online and in-person donor recruitment practices through patient appeals and donor drives in companies, universities, the armed forces, and public services. After confirmatory typing donors were subjected to medical work-up and cleared for donation.ResultsWe recruited almost 170,000 donors in 5 years. There were 1,488 requests received for confirmatory typing and donor availability checks, of which 333 resulted in medical work-up, leading to 194 stem cell collections. Products were shipped to Chile (48.5%) and abroad. Even when the COVID-19 pandemic challenged our activities, the number of donors recruited and shipped stem cell products remained steady. In Chile there was an almost 8-fold increase in unrelated donor transplantation activity from 16 procedures in 2016–2018 to 124 procedures in 2019–2021, mainly for pediatric patients following the center’s establishment. We estimate that 49.6% of Chilean patients would find at least one matched unrelated donor in the global DKMS donor pool.DiscussionEstablishing a DKMS donor center in Chile has significantly increased donor availability for Chilean patients and contributed to an increase of unrelated donor stem cell transplant activity

Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity

textabstractBackground: To examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum. Methods: In this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1-5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia. Results: Fifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor. Conclusion: Higher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Dilatation and curettage fails to detect most focal lesions in the uterine cavity in women with postmenopausal bleeding

OBJECTIVE: To determine the prevalence of focally growing lesions in the uterine cavity in women with postmenopausal bleeding and endometrium > or = 5 mm and the extent to which such lesions can be correctly diagnosed by D&C. METHODS: In a prospective study, 105 women with postmenopausal bleeding and endometrium > or = 5 mm at transvaginal ultrasound examination underwent diagnostic hysteroscopy, D&C and hysteroscopic resection of any focally growing lesion still left in the uterine cavity after D&C. Twenty-four women also underwent hysterectomy. If the histological diagnosis differed between specimens from the same patient, the most relevant diagnosis was considered the final one. RESULTS: Eighty percent (84/105) of the women had pathology in the uterine cavity, and 98% (82/84) of the pathological lesions manifested a focal growth pattern at hysteroscopy. In 87% of the women with focal lesions in the uterine cavity, the whole or parts of the lesion remained in situ after D&C. D&C missed 58% (25/43) of polyps, 50% (5/10) of hyperplasias, 60% (3/5) of complex atypical hyperplasias, and 11% (2/19) of endometrial cancers. The agreement between the D&C diagnosis and the final diagnosis was excellent (94%) in women without focally growing lesions at hysteroscopy. CONCLUSION: If there are focal lesions in the uterine cavity, hysteroscopy with endometrial resection is superior to D&C for obtaining a representative endometrial sample in women with postmenopausal bleeding and endometrium > or = 5 mm

Transvaginal sonography, saline contrast sonohysterography and hysteroscopy for the investigation of women with postmenopausal bleeding and endometrium > 5 mm

OBJECTIVES: To determine the ability of transvaginal ultrasound, with or without saline infusion, to detect focally growing lesions in the uterine cavity in women with postmenopausal bleeding and endometrium > 5 mm, and to determine the accuracy of conventional ultrasound, saline contrast sonohysterography and diagnostic hysteroscopy under general anesthesia to diagnose endometrial polyps, submucous myomas and uterine malignancy. DESIGN: In a prospective study, 105 women with postmenopausal bleeding and endometrium > 5 mm underwent conventional ultrasound examination and saline contrast sonohysterography. Diagnostic and operative hysteroscopy under general anesthesia was then performed. The presence of focally growing lesions and the type of lesion (endometrial polyp, submucous myoma, malignancy or unclear focal lesion) were noted at ultrasound examination and at hysteroscopy. RESULTS: There was almost perfect agreement (96%) between saline contrast sonohysterography and hysteroscopy in the diagnosis of focally growing lesions. Saline contrast sonohysterography and hysteroscopy both had a sensitivity of approximately 80% with regard to diagnosing endometrial polyps (false-positive rates of 24% and 6%, respectively), whereas conventional ultrasound missed half of the polyps (sensitivity, 49%; false-positive rate, 19%). Hysteroscopy was superior to both saline contrast sonohysterography and conventional ultrasound with regard to discriminating between benign and malignant lesions (sensitivity, 84%, 44%, and 60%; false-positive rate, 15%, 6% and 10%, respectively). The risk of malignancy was increased seven-fold (odds ratio, 7.3; 95% confidence interval, 1.9-27.8) in women with distension difficulties at saline contrast sonohysterography, and two thirds of the women with a poorly distensible uterine cavity had a malignant diagnosis. CONCLUSION: Saline contrast sonohysterography is as good as hysteroscopy at detecting focally growing lesions in the uterine cavity in women with postmenopausal bleeding. However, neither hysteroscopy nor saline contrast sonohysterography can reliably discriminate between benign and malignant focal lesions. Distension difficulties at saline contrast sonohysterography should raise a suspicion of malignancy