Genetic and transcriptomic landscape of colonic diverticulosis.

OBJECTIVE: Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case-control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders. DESIGN: We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders. RESULTS: We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13, with potential causal effects on diverticulosis. Notably, ENTPD7 upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis. CONCLUSION: Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy.

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Strategy for Generating Blinded Evidence for Single-Arm Trials with External Controls Using Expert Review of Home Video.

INTRODUCTION: Neurodegenerative diseases cause developmental delays and loss of milestones in infants and children. However, scalable outcome measures that quantify features meaningful to parents/caregivers (P/CGs) and have regulatory precedence are lacking for assessing the effectiveness of treatments in clinical trials of neurodegenerative disorders. To address this gap, we developed an innovative, blinded strategy for single-arm trials with external controls using expert panel review of home video. METHOD: We identified meaningful, observable, and objective developmental milestones from iterative interviews with P/CGs and clinical experts. Subsequently, we standardized video recording procedures and instructions to ensure consistency in how P/CGs solicited each activity. In practice, videos would be graded by an expert panel blinded to treatment. To ensure blinding and quality control, video recordings from interim time points would be randomly interspersed. We conducted a pilot study and a pretest of grading to test feasibility and improve the final strategy. RESULTS: The five P/CGs participating in the pilot study found the instructions clear, selected activities important and reflective of their children's abilities, and recordings at-home preferrable to in-clinic assessments. The three grading experts found the videos easy to grade and the milestones clinically meaningful. CONCLUSION: Our standardized strategy enables expert panel grading of developmental milestone achievements using at-home recordings, blinded to treatment and post-baseline time points. This rigorous and objective scoring system has broad applicability in various disease contexts, with or without external controls. Moreover, our strategy facilitates flexible, continued data collection and the videos can be archived for future analyses.

A Systematic Review of Epidemiology and Outcomes Associated with Local Surgical and Intersphincteric Ligation Procedures for Complex Cryptoglandular Fistulas.

INTRODUCTION: This systematic literature review (SLR) assessed incidence/prevalence of cryptoglandular fistulas (CCF) and outcomes associated with local surgical and intersphincteric ligation procedures for CCFs. METHODS: Two trained reviewers searched PubMed and Embase for observational studies evaluating the incidence/prevalence of cryptoglandular fistula and clinical outcomes of treatments for CCF after local surgical and intersphincteric ligation procedures for CCF. RESULTS: In total 148 studies met a priori eligibility criteria for all cryptoglandular fistulas and all intervention types. Of those, two assessed incidence/prevalence of cryptoglandular fistulas. Eighteen reported clinical outcomes of surgeries of interest in CCF and were published in the past 5 years. Prevalence was reported as 1.35/10,000 non-Crohn's patients, and 52.6% of non-IBD patients were found to progress from anorectal abscess to fistula over 12 months. Primary healing rates ranged from 57.1% to 100%; recurrence occurred in a range of 4.9-60.7% and failure in 2.8-18.0% of patients. Limited published evidence suggests postoperative fecal incontinence and long-term postoperative pain were rare. Several of the studies were limited by single-center design with small sample sizes and short follow-up durations. DISCUSSION: This SLR summarizes outcomes from specific surgical procedures for the treatment of CCF. Healing rates vary according to procedure and clinical factors. Differences in study design, outcome definition, and length of follow-up prevent direct comparison. Overall, published studies offer a wide range of findings with respect to recurrence. Postsurgical incontinence and long-term postoperative pain were rare in the included studies, but more research is needed to confirm rates of these conditions following CCF treatments. CONCLUSION: Published studies on the epidemiology of CCF are rare and limited. Outcomes of local surgical and intersphincteric ligation procedures show differing success and failure rates, and more research is needed to compare outcomes across various procedures. (PROSPERO; registration number CRD42020177732).

Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

Global epidemiology of factor XI deficiency: A targeted review of the literature and foundation reports.

INTRODUCTION: Hereditary factor XI (FXI) deficiency is a rare coagulation disorder that may result in excessive bleeding requiring intervention to restore haemostasis. AIM: The aim of this review was to report the current knowledge of the worldwide incidence and prevalence of FXI deficiency. METHODS: A targeted PubMed search using terms related to FXI deficiency was conducted to identify studies published from April 2002 through April 2022. A manual search supplemented the electronic search. Studies were eligible for data abstraction if they reported population-based incidence proportions/rates or prevalence proportions for FXI deficiency. RESULTS: The electronic and manual searches returned 253 publications. After applying exclusion criteria, seven publications were included in the analysis, including a global report from the World Federation of Haemophilia (WFH). Six publications provided information on the prevalence of FXI deficiency that included 74 countries and regions. The estimated prevalence of FXI in the WFH report ranged from 0/100,000 in several countries to 55.85/100,000 individuals in the United Kingdom. Prevalence estimates in the PubMed findings ranged from .1 to 246.2/1,000,000 inhabitants with varying methods of case identification and time periods of analysis. One study estimated the incidence of FXI deficiency in Yecla, Spain at 2% of blood donors and .09% of hospital inpatients/outpatients with activated partial thromboplastin time (aPTT) tests. CONCLUSION: FXI deficiency is rare across the world, but additional steps could be taken to improve incidence and prevalence estimation, for example, development of a consistent FXI deficiency definition and incorporating genetic testing into a clinical routine to better identify and characterise cases.

Novel Insights into the Effects of Genetic Variants on Serum Urate Response to an Acute Fructose Challenge: A Pilot Study.

Studies have shown that genetic variations can influence metabolic response to nutrient intake, and that diets rich in fructose contribute to hyperuricemia. In this pilot study, our aim was to determine the variability of serum urate in response to an acute fructose challenge and to investigate if genetic variants would affect this response in young to middle-aged adults who self-reported as Black or White. Fifty-seven participants consumed a fructose-rich beverage after an overnight fast. Blood was drawn at five time points (baseline, 30, 60, 120, and 180 min after consumption). Thirty urate-related single nucleotide polymorphisms (SNPs) were analyzed for their associations with baseline serum urate and its percent changes, using a two-step modeling approach followed by meta-analysis. At baseline, serum urate (mg/dL, mean ± SD) was higher in Whites (5.60 ± 1.01 vs. 5.37 ± 0.96), men (6.17 ± 1.14 vs. 5.24 ± 0.79), and those with obesity (5.69 ± 1.08 vs. 5.42 ± 1.06 vs. 5.34 ± 0.80). Three SNPs were significantly associated with baseline serum urate or its percent changes, and six SNPs were nominally associated with percent changes in serum urate. In summary, our results showed that genetic variants could play a role in short-term urate metabolism.

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Online Learning Approach for Predictive Real-Time Energy Trading in Cloud-RANs.

Constantly changing electricity demand has made variability and uncertainty inherent characteristics of both electric generation and cellular communication systems. This paper develops an online learning algorithm as a prescheduling mechanism to manage the variability and uncertainty to maintain cost-aware and reliable operation in cloud radio access networks (Cloud-RANs). The proposed algorithm employs a combinatorial multi-armed bandit model and minimizes the long-term energy cost at remote radio heads. The algorithm preschedules a set of cost-efficient energy packages to be purchased from an ancillary energy market for the future time slots by learning both from cooperative energy trading at previous time slots and by exploring new energy scheduling strategies at the current time slot. The simulation results confirm a significant performance gain of the proposed scheme in controlling the available power budgets and minimizing the overall energy cost compared with recently proposed approaches for real-time energy resources and energy trading in Cloud-RANs.

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.