Citations

Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.

AbstractBackgroundPatients presenting to the emergency department (ED) with acute vertigo or dizziness represent a diagnostic challenge. Neuroimaging has variable indications and yield. We aimed to conduct a systematic review and meta‐analysis of the diagnostic test accuracy of neuroimaging for patients presenting with acute vertigo or dizziness.MethodsAn electronic search was designed following patient–intervention–control–outcome (PICO) question—(P) adult patients with acute vertigo or dizziness presenting to the ED; (I) neuroimaging including computed tomography (CT), CT angiography (CTA), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and ultrasound (US); (C) MRI/clinical criterion standard; and (O) central causes (stroke, hemorrhage, tumor, others) versus peripheral causes of symptoms. Articles were assessed in duplicate. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines were followed. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess certainty of evidence in pooled estimates.ResultsWe included studies that reported diagnostic test accuracy. From 6309 titles, 460 articles were retrieved, and 12 were included: noncontrast CT scan—six studies, 771 patients, pooled sensitivity 28.5% (95% confidence interval [CI] 14.4%–48.5%, moderate certainty) and specificity 98.9% (95% CI 93.4%–99.8%, moderate certainty); MRI—five studies, 943 patients, sensitivity 79.8% (95% CI 71.4%–86.2%, high certainty) and specificity 98.8% (95% CI 96.2%–100%, high certainty); CTA—one study, 153 patients, sensitivity 14.3% (95% CI 1.8%–42.8%) and specificity 97.7% (95% CI 93.8%–99.6%), CT had higher sensitivity than CTA (21.4% and 14.3%) for central etiology; MRA—one study, 24 patients, sensitivity 60.0% (95% CI 26.2%–87.8%) and specificity 92.9% (95% CI 66.1%–99.8%); US—three studies, 258 patients, sensitivity ranged from 30% to 53.6%, specificity from 94.9% to 100%.ConclusionsNoncontrast CT has very low sensitivity and MRI will miss approximately one in five patients with stroke if imaging is obtained early after symptom onset. The evidence does not support neuroimaging as the only tool for ruling out stroke and other central causes in patients with acute dizziness or vertigo presenting to the ED.

ObjectiveSome patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID‐19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID‐19 ARDS in this population and to create a simple risk score calculator for use in clinical settings.MethodsData were derived from the COVID‐19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID‐19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier.ResultsThe study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67‐0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%‐83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator.ConclusionWe were able to predict ARDS with good sensitivity using information readily available at COVID‐19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID‐19 disease progression.

Background The Woven EndoBridge (WEB) device is a novel intrasaccular flow disruptor tailored for bifurcation aneurysms. We aim to describe the degree of aneurysm occlusion at the latest follow-up, and the rate of complications of aneurysms treated with the WEB device stratified according to rupture status. Methods Our data were taken from the WorldWideWeb Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups: ruptured and unruptured. We compared clinical and radiologic outcomes of both groups. Propensity score matching (PSM) was done to match according to age, gender, bifurcation, location, prior treatment, neck, height, dome width, daughter sac, incorporated branch, pretreatment antiplatelets, and last imaging follow-up. Results The study included 676 patients with 691 intracranial aneurysms (529 unruptured and 162 ruptured) treated with the WEB device. The PSM analysis had 55 pairs. In both the unmatched (85.8% vs 84.3%, p=0.692) and matched (94.4% vs 83.3%, p=0.066) cohorts there was no significant difference in the adequate occlusion rate at the last follow-up. Likewise, there were no significant differences in both ischemic and hemorrhagic complications between the two groups. There was no documented aneurysm rebleeding after WEB device implantation. Conclusion There was no significant difference in both the radiologic outcomes and complications between unruptured and ruptured aneurysms. Our findings support the feasibility of treatment of ruptured aneurysms with the WEB device.

Objectives Evaluate the associations between patients taking ACE inhibitors and angiotensin receptor blockers (ARBs) and their clinical outcomes after an acute viral respiratory illness (AVRI) due to COVID-19. Design Retrospective cohort. Setting The USA; 2017–2018 influenza season, 2018–2019 influenza season, and 2019–2020 influenza/COVID-19 season. Participants People with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. Main outcome measures Change in hospital admission, intensive care unit (ICU) or coronary care unit (CCU), acute respiratory distress (ARD), ARD syndrome (ARDS) and all-cause mortality, comparing COVID-19 to pre-COVID-19 influenza seasons. Results The cohort included 1 059 474 episodes of AVRI (653 797 filled an ACEi or ARB, and 405 677 other HTN medications). 58.6% were women and 72.9% with age ≥65. The ACEi/ARB cohort saw a larger increase in risk in the COVID-19 influenza season than the other HTN medication cohort for four out of five outcomes, with an additional 1.5 percentage point (pp) increase in risk of an inpatient stay (95% CI 1.2 to 1.9 pp) and of ICU/CCU use (95% CI 0.3 to 2.7 pp) as well as a 0.7 pp (0.1 to 1.2 pp) additional increase in risk of ARD and 0.9 pp (0.4 to 1.3 pp) additional increase in risk of ARDS. There was no statistically significant difference in the absolute risk of death (−0.2 pp, 95% CI −0.4 to 0.1 pp). However, the relative risk of death in 2019/2020 versus 2017/2018 for the ACEi/ARB group was larger (1.40 (1.36 to 1.44)) than for the other HTN medication cohort (1.24 (1.21 to 1.28)). Conclusions People with AVRI using ACEi/ARBs for HTN had a greater increase in poor outcomes during the COVID-19 pandemic than those using other medications to treat HTN. The small absolute magnitude of the differences likely does not support changes in clinical practice.

Purpose To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. Methods Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. Results Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. Conclusion The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

Restrictive cardiomyopathy secondary to cardiac amyloidosis is an underdiagnosed, but treatable, cause of heart failure involving an extracellular deposition of misfolded protein. Hereby, we report a case of female patient with heart failure and nephrotic syndrome. The case underscores the importance of a timely diagnosis.

AbstractBackgroundAn increasing demand of minimally‐invasive aesthetic procedures of the forehead concomitantly leads to higher numbers of adverse events. Adequate application of anatomical knowledge is required to increase safety and efficacy of different minimally‐invasive aesthetic procedures in this anatomical region.ObjectiveTo describe the layered anatomy of the forehead soft tissues with respect to their thicknesses and how they relate to different minimally‐invasive aesthetic treatments.MethodsA total of n = 85 healthy study participants (69 females and 16 males) with a mean age of 40.84 ± 10.9 years and a mean body mass index of 22.65 ± 2.6 kg/m2 were investigated with ultrasound‐based imaging to measure the thickness of different forehead soft tissues.ResultsThe mean overall soft tissue thickness of the forehead was measured to be 4.18 ± 0.7 mm for the entire study population. Increasing BMI values correlated statistically significantly with increasing thickness of all measured forehead soft tissues with exception of the frontalis muscle. On a statistically significant level, males showed thicker forehead soft tissues than females, with exception of the retrofrontalis fat and the frontalis muscle.ConclusionOn basis of the findings obtained in this study, basic treatment principles can be derived and improved for the injection of neuromodulators, hyaluronic acid as well as the application of polydiaxonane (PDO) threads and micro‐focused ultrasound. Precise knowledge and thorough understanding of the layers and soft tissues of the forehead is required to guarantee safe and effective procedures in this aesthetically important facial region.