bluuebunny/crossref_metadata_2025 huggingface dataset:
Transformed Cell Ratio (TCR): A Novel Parameter for Radiation Dose Estimation in Rapid Premature Chromosome Condensation (PCC) Assay Induced by 0–40 Gy Co-60 Gamma Rays
Authors: Gao Ling , Lu Xue , Liu Meng-Meng , Li Shuang , Liu Qing-Jie
Published: October 2022

Calyculin A-induced premature chromosome condensation (PCC) assay is considered a method for estimating radiation dose. In this study, a novel parameter, the transformed cell ratio (TCR), which is the ratio of irradiated and unirradiated lymphocyte transformation rates in the PCC assay, was suggested for dose estimation since it may be correlated with ionizing radiation dose. Human peripheral lymphocytes were irradiated in vitro with 60Co gamma ray doses of 0, 10, 20, 30, and 40 Gy, stimulated with phytohemagglutinin, and incubated for 3, 6, 12, or 48 h, division-blocked with colcemid, and PCC-induced by calyculin A or addition of extra cyclin-dependent kinase 1/cyclin B (CDK1/cyclinB). Results showed that G1-, S-, G2-, and M-PCC cells appeared in human lymphocyte culture, dose-response curves between the absorbed dose and lymphocyte transformation rate or TCR was fitted. TCR presented the best goodness-of-fit to a linear model (y = 0.0097 X +0.9952, R2 = 0.971, P < 0.05) within 0 to 40 Gy. Observations also suggested that TCR is a potential biological dosimeter for assessing received radiation doses ranging from 0 to 40 Gy during radiation exposure.
Outcomes of very delayed onset chronic postoperative endophthalmitis caused by Cutibacterium acnes including treatment with endolaser photocoagulation
Authors: Mammo Danny A. , Le Phuoc-Hanh , Arepalli Sruthi , Srivastava Sunil K. , Sharma Sumit
Published: October 2022

Introduction:

To the authors' knowledge, these are 2 of the longest reported time periods between cataract surgery and diagnosis of chronic postoperative endophthalmitis. The clinical course and outcomes are discussed.

Patient and Clinical Findings:

2 patients underwent uneventful cataract surgery and presented with recurrent anterior segment inflammation years after the surgery. In the first case, an 88-year-old man presented with granulomatous uveitis in the left eye 4 years after intracapsular cataract extraction and posterior chamber intraocular lens (CE/PC IOL) placement. In the second case, a 79-year-old woman presented with iritis 7 years after CE/PC IOL.

Diagnosis, Intervention, and Outcomes:

Both patients were treated for presumed idiopathic uveitis for years before the diagnosis of chronic endophthalmitis caused by Cutibacterium acnes. 1 case required endolaser photocoagulation to an infectious nidus.

Conclusions:

Chronic postoperative endophthalmitis can present many years after uneventful cataract surgery.
Tachygastria in Preterm Infants
Authors: Ortigoza Eric Brum , Cagle Jackson , Brown Larry Steven , Mansi Sherief , Gosser Sandra Peralez , Montgomery Ashley D. , Foresman Zeri , Boren Monica L. , Pettit Pamela S. , Thompson Tami D. , Vasil Diana M. , Chien Jui‐Hong , Neu Josef , Koh Andrew Young , Sanghavi Rinarani , Mirpuri Julie
Published: October 2022

Objectives:

Tachygastria is a gastric dysrhythmia (>4 to ≤9 cycles per minute, cpm) associated with gastric hypomotility and gastrointestinal disorders. Healthy preterm infants spend more time in tachygastria than adults; however, normative values are not defined. We sought to determine the percent of time preterm infants spend in tachygastria.

Methods:

We conducted a longitudinal, prospective cohort study with weekly electrogastrography (EGG) recordings in 51 preterm <34 weeks’ gestation and 5 term (reference) infants. We calculated percentage recording time in tachygastria (% tachygastria) and determined the mean ± standard deviation (SD) across EGG sessions. Mixed effects model was performed to test weekly variance in % tachygastria and gestational age effect. Successive pre‐ and post‐prandial measurements were obtained to assess reproducibility of % tachygastria. We compared time to achieve full feeds between subjects with % tachygastria within 1 SD from the mean versus % tachygastria >1 SD from mean.

Results:

Three hundred seventy‐six EGG sessions were completed (N = 56). Mean % tachygastria was 40% with SD ±5%. We demonstrated no change in % tachygastria across 9 postnatal weeks (P = 0.70) and no gestational age effect. No difference was demonstrated between successive pre‐ (P = 0.91) and post‐prandial (P = 0.96) % tachygastria. Infants with 35%–45% tachygastria (within 1 SD from mean) had higher gestational age and less time to achieve full feeds than infants with <35% or >45% tachygastria.

Conclusions:

EGG is a reproducible tool to assess % tachygastria in preterm infants. Clinical significance of increased or decreased % tachygastria needs further investigation to validate if 35%–45% tachygastria is safe for feeding.
Budesonide and the Gluten Containing Elimination Diet as Treatments for Non‐responsive Celiac Disease in Children
Authors: Ali Ibrahim Awab , Kenyon Victoria , Fasano Alessio , Leonard Maureen M.
Published: October 2022

Objectives:

Non‐responsive celiac disease (NRCD) is defined as patients having persistent symptoms and enteropathy (Marsh 3 histology) suggestive of active celiac disease (CeD), after following a gluten‐free diet (GFD) for at least 12 months. NRCD is suggested to affect 15% of children with CeD but data are limited and there is no research to date describing treatment of children with this condition. The aim of this study was to describe our center’s approach to identifying and treating NRCD with budesonide and the Gluten Containing Elimination Diet (GCED).

Methods:

We performed a retrospective, single center analysis over a 5‐year period of patients with CD less than 18 years of age (inclusive) who underwent treatment for persistent symptoms and enteropathy despite following a GFD.

Results:

We identified 22 patients with NRCD. Thirteen were treated with the GCED for 3 months with 46% achieving both histological and symptomatic resolution. Nine patients were treated with budesonide (6–9 mg), with 89% achieving both symptomatic and histologic resolution after a median 3‐month treatment course. Further, 67% of patients who responded to the GCED and 100% of patients who responded to budesonide remained in remission for at least 6 months following treatment transition back to exclusive GFD.

Conclusions:

The GCED and budesonide can provide benefit for NRCD. Most patients with NRCD can return to a GFD after 3 months of treatment.
Impact of Dose Reduction of Topical Steroids to Manage Adrenal Insufficiency in Pediatric Eosinophilic Esophagitis
Authors: Nistel Mason , Furuta Glenn T. , Pan Zhaoxing , Hsu Stephanie
Published: October 2022

Objective:

To evaluate the impact of type and dose of swallowed topical steroids (STS) and concurrent steroid therapy on the development and resolution of adrenal insufficiency (AI) in pediatric eosinophilic esophagitis (EoE).

Methods:

We performed a retrospective case-control study of pediatric EoE subjects in a single tertiary care center, who were treated with STS for at least 3 months and diagnosed with AI based on a peak stimulated cortisol level of <18 µg/dL (500 nmol/L). Steroid forms and doses, and endoscopy data were collected at the time of AI diagnosis and AI resolution or the last known evaluation. Steroid formulations were converted to a fluticasone-equivalent dose for analysis.

Results:

Thirty-two EoE subjects with AI were identified, and 20 had AI resolution, including 12 who remained on lower dose STS. Eight of the 32 patients were also treated with extended-release budesonide (ER budesonide), which resulted in a 7-fold higher total daily steroid dose, and thus were analyzed separately. When the 24 cases that were not on ER budesonide were compared to the 81 controls, no difference was found in the STS dose nor total daily steroid dose, although the inhaled steroid dose had marginal significance. Peak eosinophil counts tended to increase when STS doses were decreased, except in subjects on ER budesonide at AI diagnosis.

Conclusion:

Altering the total daily steroid regimen can lead to resolution of AI in patients with EoE, though this may come at the expense of disease control.
Intestinal Ultrasound for the Pediatric Gastroenterologist: A Guide for Inflammatory Bowel Disease Monitoring in Children: Expert Consensus on Behalf of the International Bowel Ultrasound Group (IBUS) Pediatric Committee
Authors: Kellar Amelia , Dolinger Michael , Novak Kerri L. , Chavannes Mallory , Dubinsky Marla , Huynh Hien
Published: October 2022

Crohn disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) often diagnosed in childhood. A strict monitoring strategy can potentially alter the disease course and facilitate early effective treatment before irreversible bowel damage occurs. Serial colonoscopy in children, the gold standard for monitoring, is impractical. Accurate, real-time, noninvasive markers of disease activity are needed. Intestinal ultrasound is an accurate, noninvasive, real-time, point-of-care, cross-sectional imaging tool used to monitor inflammation in pediatric IBD patients in Europe, Canada, and Australia. It is now emerging in a few expert centers in the United States as a safe, non-radiating, inexpensive, bedside tool used by the treating gastroenterologist for real-time decision-making. Unlike the standard biomarkers of pediatric IBD activity, C-reactive protein, and fecal calprotectin, intestinal ultrasound (IUS) facilitates disease localization, characterizes severity, extent, and accurately detects complications. Perhaps most importantly, IUS may enhance shared understanding and ease the burden of treatment decision-making for both the gastroenterologist and the patient. There is a lack of standardization for bedside IUS among pediatric gastroenterologists. The purpose is to outline a standardized approach to pediatric bedside IUS, including basic equipment requirements and technique, patient selection, preparation and positioning, technical considerations and limitations, documentation of mesenteric and luminal features of IBD, characterization of penetrating disease and strictures, and provide a proposed pediatric IUS monitoring algorithm to guide care.
Prevalence and predictors of psychological distress in women diagnosed with breast cancer and women without breast cancer: a prospective study of psychological risk and resilience factors
Authors: Van Noyen Lotte , Markovitz Sabine , Broers Nick J. , Peters Madelon L.
Published: October 2022

Background:

There is some controversy whether psychological distress after breast cancer diagnosis and treatment remains elevated at the long-term follow-up. This study compares the prevalence of psychological distress and anxiety and depressive disorders between patients with breast cancer and women without cancer in a prospective longitudinal design. Moreover, risk and protective factors for psychological distress and anxiety and depressive disorders were compared between the 2 groups.

Methods:

Two hundred fifty-three patients with breast cancer who underwent surgery completed a series of self-report questionnaires immediately after surgery and 18 months later. In addition, 211 female participants without being diagnosed with cancer were assessed at the same time points. Outcomes are psychological distress as measured with the Hospital Anxiety and Depression Scale and possible presence of anxiety and depressive disorders measured with the Patient Health Questionnaire. Trait resilience, optimism, and neuroticism were investigated as protective or risk factors for the development of psychological distress, anxiety, and depression.

Results:

We found that the levels of psychological distress and the prevalence of anxiety and depressive disorders are higher in the breast cancer group both at baseline and at 18 months of follow-up. Trait resilience and optimism were observed to be protective factors, and neuroticism was found to be a risk factor in both the breast cancer group and the comparison group.

Conclusions:

Psychological distress, depression, and anxiety remain elevated in patients with breast cancer over a period of one-and-a-half year. The identified protective and risk factors for these conditions are not unique for patients with breast cancer.
Data Set for the Reporting of Endometrial Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR)
Authors: Matias-Guiu Xavier , Selinger Christina I. , Anderson Lyndal , Buza Natalia , Ellenson Lora H. , Fadare Oluwole , Ganesan Raji , Ip Philip P.C. , Palacios Jose , Parra-Herran Carlos , Raspollini Maria R. , Soslow Robert A. , Werner Henrica M.J. , Lax Sigurd F. , McCluggage W. Glenn
Published: October 2022

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.
Impact and cost-effectiveness of non-governmental organizations on the HIV epidemic in Ukraine among MSM
Authors: Trickey Adam , Walker Josephine G. , Bivegete Sandra , Semchuk Nadiya , Saliuk Tetiana , Varetska Olga , Stone Jack , Vickerman Peter
Published: October 2022

Objective:

Non-governmental organizations (NGOs) in Ukraine have provided HIV testing, treatment, and condom distribution for MSM. HIV prevalence among MSM in Ukraine is 5.6%. We estimated the impact and cost-effectiveness of MSM-targeted NGO activities in Ukraine.

Design:

A mathematical model of HIV transmission among MSM was calibrated to data from Ukraine (2011–2018).

Methods:

The model, designed before the 2022 Russian invasion of Ukraine, evaluated the impact of 2018 status quo coverage levels of 28% of MSM being NGO clients over 2016–2020 and 2021–2030 compared with no NGO activities over these time periods. Impact was measured in HIV incidence and infections averted. We compared the costs and disability adjusted life years (DALYs) for the status quo and a counterfactual scenario (no NGOs 2016–2020, but with NGOs thereafter) until 2030 to estimate the mean incremental cost-effectiveness ratio (cost per DALY averted).

Results:

Without NGO activity over 2016–2020, the HIV incidence in 2021 would have been 44% (95% credibility interval: 36–59%) higher than with status quo levels of NGO activity, with 25% (21–30%) more incident infections occurring over 2016–2020. Continuing with status quo NGO coverage levels will decrease HIV incidence by 41% over 2021–2030, whereas it will increase by 79% (60–120%) with no NGOs over this period and 37% (30–51%) more HIV infections will occur. Compared with if NGO activities had ceased over 2016–2020 (but continued thereafter), the status quo scenario averts 14 918 DALYs over 2016–2030 with a mean incremental cost-effectiveness ratio of US$600.15 per DALY averted.

Conclusion:

MSM-targeted NGOs in Ukraine have prevented considerable HIV infections and are highly cost-effective compared with a willingness-to-pay threshold of 50% of Ukraine's 2018 GDP (US$1548).
Effect of weekly 17-hydroxyprogesterone caproate on small for gestational age among pregnant women with HIV in Zambia
Authors: Conner Madelyn G. , Vwalika Bellington , Freeman Bethany L. , Sebastião Yuri V. , Mabula-Bwalya Chileshe M. , Cole Stephen R. , Stringer Elizabeth M. , Kasaro Margaret P. , Stringer Jeffrey S.A. , Price Joan T.
Published: October 2022

The IPOP trial demonstrated a reduced risk of severe small for gestational age among infants born to women with HIV who received weekly intramuscular 17 alpha-hydroxyprogesterone caproate. This secondary analysis examined the 17P treatment effect in subgroups of maternal BMI, parity, timing of antiretroviral therapy (ART) initiation, and ART regimen. We found that 17P was more effective among nulliparous women, women who started ART before pregnancy, and those taking protease inhibitors.
An International Multicenter Prospective Study Evaluating the Long-term Oncological Impact of Adjuvant Chemotherapy in ypN+ Rectal Cancer
Authors: Denost Quentin , Fleming Christina A. , Burghgraef Thijs , Celerier Bertrand , Geitenbeek Ritchie , Rullier Eric , Tuynman Jurriaan , Consten Esther , Hompes Roel ,   Dutch MIRECA Collaborative Group (Pubmed Citable)
Published: October 2022

Objective:

To assess the oncological benefit of adjuvant chemotherapy (AC) in node positive (ypN+) rectal cancer after neoadjuvant chemoradiotherapy and radical surgery.

Background:

The evidence for AC after total mesorectal excision for locally advanced rectal cancer is conflicting and the net survival benefit is debated.

Methods:

An international multicenter comparative cohort study was performed comparing oncological outcomes in tertiary rectal cancer centers from the Netherlands and France. Patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by total mesorectal excision surgery and with positive lymph nodes on histologic examination (ypN+) were included for analysis. Kaplan-Meier curves were generated to compare disease-free (DFS) and overall survival in AC and non-AC groups.

Results:

Of 1265 patients screened, a total of 239 rectal cancer patients with ypN+ disease were included. Demographic and clinical characteristics were similar in both groups. Higher systemic recurrence rates were observed in the non-AC group compared with those who received AC [32.0% (n=40) vs 17.5% (n=11), respectively, P=0.034]. DFS at 1 and 5 years postoperatively were significantly better in the AC group (92% vs 80% at 1 year; 72% vs 51% at 5 years, P=0.024), whereas no difference in overall survival was observed.

Conclusions:

In this multicenter comparative cohort study, we identified an oncological benefit of AC in both systemic recurrence and DFS in ypN+ rectal cancer patients. From this data, systemic chemotherapy continues to confer oncological benefit in locally advanced ypN+ rectal cancer.
Trends in Stenotrophomonas maltophilia antibiotic resistance rates in the United States Veterans Affairs Health System
Authors: Appaneal Haley J. , Lopes Vrishali V. , LaPlante Kerry L. , Caffrey Aisling R.
Published: October 2022

Introduction.Stenotrophomonas maltophiliais an important multidrug-resistant Gram-negative pathogen. While largely a hospital-acquired pathogen, there have been increasing reports of the pathogen in the community.

Gap Statement. Trends inS. maltophiliaprevalence and resistance rates that include outpatient isolates are unknown.

Aim. We described recent trends in prevalence and resistance ofS. maltophiliain the national Veterans Affairs (VA) Healthcare system.

Methodology. The study identified positiveS. maltophiliaclinical cultures among VA adult patients from 2010 to 2018 across all VA hospitals, long-term care facilities/units, and outpatient settings. AnnualS. maltophiliaresistance rates were evaluated. Multidrug resistant (MDR) was defined as resistance to sulfamethoxazole/trimethoprim (SMX/TMP) and minocycline or levofloxacin. Time trends were assessed with regression analyses to estimate annual average percent changes (AAPC) with 95 % confidence intervals using Joinpoint software.

Results. Over the 9 year study period, 18 285 S.maltophiliacultures were identified (57 % hospital, 3 % long-term care, 40 % outpatient). The most common source ofS. maltophiliacultures were respiratory cultures (34.6 %) followed by urine cultures (30.4 %). In VA hospitals and long-term care facilities, the number ofS. maltophiliacultures decreased significantly (by 5.4% and 8.4 % per year respectively). Overall, 3.1 % of isolates were MDR which remained stable over the study period. Resistance to other antibiotics assessed mostly remained stable, except SMX/TMP resistance decreased significantly by 8.5 % (2010, 15 %; 2018, 6 %) per year in VA hospitals.

Conclusion. While previous work has recognizedS. maltophiliaas primarily a nosocomial pathogen, the present study found that 40 % of cultures collected were among outpatients. Between 2010 and 2018, the number of positiveS. maltophiliacultures decreased significantly in the national VA Healthcare System. Resistance to SMX/TMP decreased over the study period in VA hospitals and now more closely reflects previously reported resistance rates worldwide (0–10 %). MDRS. maltophiliaremained stable and low in the national VA Healthcare System.
Fingerprinting of Mycobacterium tuberculosis isolates by MIRU-VNTR genotyping and detection of isoniazid resistance by real-time PCR
Authors: Gaballah Ahmed , Ghazal Abeer , Almiry Reda , Hussein Somaya , Emad Rasha , El-Sherbini Eglal
Published: October 2022

Introduction.Tuberculosis (TB) is a great public health problem in developing countries such as Egypt. Genotyping ofMycobacterium tuberculosisisolates has a prominent role in the field of TB prevention.

Aim.This study aimed to evaluate real-time PCR using Minor Groove Binder (MGB) probes and to identify circulating lineages/sub-lineages ofM. tuberculosisand their transmission patterns.

Hypothesis.We hypothesize that MIRU-VNTR technique is efficient in identifying circulatingM. tuberculosislineages in Egypt.

Methodology.Fifty sputum specimens positive for acid-fast bacilli were included. Isoniazid (INH) resistance was detected using the 1 % proportion method. Real-time PCR using MGB-probes was used for simultaneous detection of TB infection and INH resistance. Partial sequencing of thekatGgene was used to confirm INH resistance results. A standard 15 Mycobacterial Interspersed Repetitive Unit Variable Number Tandem Repeat (15-MIRU-VNTR) approach was used for genotyping through the MIRU-VNTRplusonline platform.

Results.Only seven specimens showed phenotypic resistance to INH.M. tuberculosiswas detected in all samples, while a mutation in thekatGgene codon 315 was detected only in five samples, which were also phenotypically INH-resistant. Sequencing of thekatGgene showed codon 315 mutation genotypically and phenotypically in the five INH-resistant isolates. Molecular genotyping ofM. tuberculosisisolates revealed that the majority of isolates (26/50, 52 %) belonged to the S family of lineage_4. A low clustering rate (2 %) was observed among our isolates. According to the Hunter-Gaston Discriminatory Index (HGDI), 11 MIRU-VNTR loci were highly or moderately discriminative, while four loci were less polymorphic.

Conclusion.MIRU-VNTR genotyping revealed a low clustering rate with a low recent transmission rate ofM. tuberculosisstrains in Alexandria, Egypt.
Did Risk-based or Age-based Vaccine Prioritization for Covid-19 Save More Lives?
Authors: Smits Joeri , Malik Amyn A. , Elharake Jad A. , Mobarak Ahmed Mushfiq , Omer Saad B.
Published: October 2022

Importance

All U.S. states provided Covid-19 vaccine access to frontline healthcare workers first, but after that, states varied in whether they gave earlier access to the elderly, versus the vulnerable with comorbidities, or school employees or essential workers, reflecting the underlying scientific and policy uncertainty.

Objective

To evaluate if risk-based or age-based prioritization is more effective at reducing reported Covid-19 cases and deaths.

Design

A serial cross-sectional study

Setting

50 U.S. states and Washington D.C.

Participants

60+ years of age, high-risk individuals, K-12 school employees, and essential workers

Main Outcomes and Measures

Hospitalizations and deaths

Results

Seven to nine weeks after 60-year-olds became eligible for a vaccine, there was a statistically significant 40-50% decline in Covid-19 hospitalizations in that state. In contrast, there was no statistically detectable change in hospitalizations in the 7-9 weeks after K-12 employees become eligible for vaccines. Vaccine eligibility of “high-risk adults” and “essential workers” produces effects somewhere in the middle, with reductions in hospitalization of about 25%. There was a large statistically significant decline in death rates (25-38%) 10 to 11 weeks after people aged over 60 became vaccine-eligible. These effects were generally statistically larger than high risk individuals, K-12 school employees, and essential workers.

Conclusions and Relevance

Panel data analysis of weekly variation in Covid-19 health outcomes reveals that prioritizing adults 60+ years of age is associated with the largest reduction in hospitalizations and Covid-19 cases, followed by vaccines for adults with high-risk comorbidities. Vaccinations extended to K-12 school employees and essential workers is associated with the smallest reductions in hospitalizations and deaths.

Key Points

Question

Did Risk-based or Age-based Vaccine Prioritization for Covid-19 Save More Lives?

Findings

Panel data analysis of weekly variation in Covid-19 health outcomes reveals that prioritizing adults 60+ years of age is associated with the largest reduction in hospitalizations and Covid-19 cases, followed by vaccines for adults with high-risk comorbidities. Vaccinations extended to K-12 school employees and essential workers is associated with the smallest reductions in hospitalizations and deaths.

Meaning

Prioritizing adults 60+ years of age can lead to a higher estimated reduction in hospitalizations and deaths, followed by a strategy of prioritizing adults with high-risk comorbidities. Our findings add to the limited evidence for the roadmap for prioritizing use of Covid-19 vaccines, and help address uncertainties about the relative effectiveness of different vaccine strategies.
Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets
Authors: Singhal Pankhuri , Veturi Yogasudha , Dudek Scott M. , Lucas Anastasia , Frase Alex , Schrodi Steven J. , Fasel David , Weng Chunhua , Pendergrass Rion , Schaid Daniel J. , Kullo Iftikhar J. , Dikilitas Ozan , Sleiman Patrick M.A. , Hakonarson Hakon , Moore Jason H. , Williams Scott M. , Ritchie Marylyn D. , Verma Shefali S.
Published: October 2022

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWAS). Standard GWAS are well-powered to interrogate additive models; however, new approaches are required to investigate other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected due to lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWAS excludes detection of sites in LD that may underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for associations between 23 common diseases and 5,625,845 epistatic SNP-SNP pairs (determined by Ohta’sDstatistics) in long-range LD (> 0.25cM). We identified five significant associations across five disease phenotypes that replicated in two large genotype-phenotype datasets (UK Biobank and eMERGE). The genes that were most likely involved in the replicated associations were 1) members of highly conserved gene families with complex roles in multiple pathways, 2) essential genes, and/or 3) associated in the literature with complex traits that display variable expressivity. These results support the highly pleiotropic and conserved nature of variants in long-range under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and may especially be driving factors in conditions with a wide range of phenotypic outcomes.

Significance

Current knowledge of genotype-phenotype relationships is largely contingent on traditional univariate approaches to genomic analysis. Yet substantial evidence supports non-additive modes of inheritance and regulation, such as epistasis, as being abundant across the genome. In this genome-wide study, we probe the biomolecular mechanisms underlying complex human diseases by testing the association of pairwise genetic interactions with disease occurrence in large-scale biobank data. Specifically, we tested intrachromosomal and interchrosomal long-range interactions between regions of the genome in high linkage disequilibrium, these regions are typically excluded from genomic analyses. The results from this study suggest that essential gene, members of highly conserved gene families, and phenotypes with variable expressivity, are particularly enriched with epistatic and pleiotropic activity.
Selective mutism in China: a nationwide survey and case-control study
Authors: Hu Xinwen , Reitman Junhua , Pan Stephen W.
Published: October 2022

Background

Selective mutism (SM) is an anxiety disorder characterized by a consistent failure to speak in particular public settings despite speaking normally in other situations. However, quantitative SM research from China remains scanty at best. In response, this study aimed (1) to describe the sociodemographics and experiences of children and families with SM in China and (2) to identify sociodemographic and environmental correlates of SM in China.

Methods

This case-control mixed-methods study was composed of 172 cases with SM and 179 controls, recruited by online surveys. Multilevel logistic regression was performed to examine the association between potential correlates and SM.

Results

Only 51.2% of SM cases were diagnosed by a professional, and 31.1% of SM cases that received treatment were guided by a professional. Child SM was associated with: having two parents with an introverted personality (Adjusted odds ratio (AOR): 15.05, (95% confidence interval (CI): 5.39 – 42.07), being born to a mothers aged ≥ 35 (AOR 6.44, 95%CI: 1.24-33.43), and having a sibling (AOR 1.92, 95% CI: 1.00 – 3.70). However, child SM was inversely associated with ever receiving bilingual (AOR 0.20, 95% CI 0.10-0.39) education or being enrolled in an international school (AOR 0.12, 95% CI 0.04-0.35).

Conclusions

Findings suggest that many children with SM in China have not received professional treatment or interventions. Hereditary and social environmental factors may be contributing to childhood onset of SM in China. Novel policies such as access to special education resources, SM-training for therapists, and school support are needed to enhance the early detection and treatment of SM in China.
Effects of PM2.5 Air Pollutants on Cardiovascular Health in Ohio: A Secondary Data Analysis
Authors: Finkle Peyton G. , Gillespie Jahasia W. , Piper Brian J.
Published: October 2022

Background

Multiple adverse health outcomes have been linked to air pollution, particularly exposure to particulate matter (PM2.5).

Justification

This research will help to identify the role that socioeconomic and geographical factors have in increased cardiovascular disease and cardiac events due to elevated exposure amounts of PM2.5. Minorities in the United States are more likely to have or die from cardiovascular disease and also are the majority of the occupants in low-income communities with high levels of PM2.5.

Methods

PM2.5pollutant concentrations were measured from 2016 to 2018 and collected by air quality monitoring equipment in Ohio. The cardiovascular disease data on adult residents of Ohio from 2016-2018 was from the National Vital Statistics System (NVSS) and the Centers for Medicare and Medicaid Services Medicare Provider Analysis and Review (MEDPAR). R programming was used to find associations between cardiovascular disease and PM2.5in Ohio. Contingency tables compared the consumption of PM2.5and the rate of heart disease mortality. Heat maps indicated areas where heart disease mortality and PM2.5concentrations were highest.

Results

The average PM2.5concentration in Ohio was determined to be 7.9 μG/m3. The highest PM2.5concentrations were found in Montgomery County, Ohio and the lowest were recorded in Allen County, Ohio. With increased population density, there was also an increase with PM2.5concentrations (P<0.01). The association between cardiovascular disease mortality and PM2.5rates in these counties was nonsignificant (P>0.01). It was also found that 31.8% of counties in Ohio had air monitoring while the remaining 68.2% did not have any form of it.

Conclusion

Knowing the risk of PM2.5levels in any neighborhood could help community members and leaders pick a more appropriate course of action. Reducing air pollutants in these areas may in turn reduce cardiovascular disease in that population, leading to better health outcomes and longevity. This research also identified gaps in air monitoring that assists in prioritizing areas that need immediate remediation.
ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon
Authors: Hartmann Sylvia , Yasmeen Summaira , Jacobs Benjamin M , Denaxas Spiros , Pirmohamed Munir , Gamazon Eric R. , Caulfield Mark J. ,   Genes & Health Research Team, Hemingway Harry , Pietzner Maik , Langenberg Claudia
Published: October 2022

Raynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p<5×10−8). We prioritizedADRA2A(rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p<9.6×10-27) andIRX1(rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p<4.8×10-13) as candidate causal genes through integration of gene expression in disease relevant tissues. We further identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG=-0.21; p-value=2.3×10-3), and systematically highlighted drug repurposing opportunities, like the antidepressant mirtazapine. Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of α2A-adrenoreceptor signalling, encoded atADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.
“It is bad because it limits capacity building here back at home”Genetic and genomic researchers’ perspectives on biological sample sharing in collaborative research
Authors: Kaawa-Mafigiri David , Ekusai- Sebatta Deborah , Munabi Ian , Mwaka Erisa Sabakaki
Published: October 2022

Numerous ethical, legal and social issues arise with biological sample sharing. The study explored the perspectives of genetic/genomic researchers on the sharing of biological samples in international collaborative research. Qualitative in-depth interviews were conducted with 15 researchers. Participants expressed positive attitudes towards biobanking and appreciated the benefits of cross-border sharing of biological samples but noted that this practice had adversely affected local capacity building efforts. There was limited understanding of the ethico-regulatory frameworks governing sample sharing. Researchers emphasized the importance of respecting cultural values in biobanking research. Issues concerning poor governance and inequitable benefit sharing were also raised. There is a need for fair and equitable international collaborations where all researchers are treated with respect and as equal partners.
Using polygenic risk scores for prioritising individuals at greatest need of a CVD risk assessment
Authors: Chung Ryan , Xu Zhe , Arnold Matthew , Ip Samantha , Harrison Hannah , Barrett Jessica , Pennells Lisa , Kim Lois G. , DiAngelantonio Emanuele , Paige Ellie , Ritchie Scott C. , Inouye Michael , Usher-Smith Juliet A. , Wood Angela M.
Published: October 2022

Background

To provide quantitative evidence of the use of polygenic risk scores (PRS) for systematically identifying individuals for invitation for full formal cardiovascular disease (CVD) risk assessment.

Methods

108,685 participants aged 40-69, with measured biomarkers, linked primary care records and genetic data in UK Biobank were used for model derivation and population health modelling. Prioritisation tools using age, PRS for coronary artery disease and stroke, and conventional risk factors for CVD available within longitudinal primary care records were derived using sex-specific Cox models. Rescaling to account for the healthy cohort effect, we modelled the implications of initiating guideline-recommended statin therapy after prioritising individuals for invitation to a formal CVD risk assessment.

Results

1,838 CVD events were observed over median follow up of 8.2 years. If primary care records were used to prioritise individuals for formal risk assessment using age- and sex-specific thresholds corresponding to 5% false negative rates then we would capture 65% and 43% events amongst men and women respectively. The numbers of men and women needed to be screened to prevent one CVD event (NNS) are 74 and 140 respectively. In contrast, adding PRS to both prioritisation and formal assessments, and selecting thresholds to capture the same number of events resulted in a NNS of 60 for men and 90 for women.

Conclusion

The use of PRS together with primary care records to prioritise individuals at highest risk of a CVD event for a formal CVD risk assessment can more efficiently prioritise those who need interventions the most than using primary care records alone. This could lead to better allocation of resources by reducing the number of formal risk assessments in primary care while still preventing the same number CVD events.
Association between cancer and dementia risk in the UK Biobank: evidence of diagnostic bias
Authors: Wang Jingxuan , Buto Peter , Ackley Sarah F. , Kobayashi Lindsay C. , Graff Rebecca E. , Zimmerman Scott C. , Hayes-Larson Eleanor , Mayeda Elizabeth Rose , Asiimwe Stephen B. , Calmasini Camilla , Glymour M. Maria
Published: October 2022

Introduction

Epidemiological studies have identified an inverse association between cancer and dementia. Underlying methodological biases have been postulated, yet no studies have systematically investigated the potential for each source of bias within a single dataset. We used the UK Biobank to compare estimates for the cancer-dementia association using different analytical specifications designed to sequentially address multiple sources of bias, including competing risk of death, selective survival, confounding bias, and diagnostic bias.

Methods

We included 140,959 UK Biobank participants aged ≥55 without dementia before enrollment and with linked primary care data. We used cancer registry data to identify cases of prevalent cancer before UK Biobank enrollment and incident cancer diagnosed after enrollment. We used Cox models to evaluate associations of prevalent and incident cancer with all-cause dementia, Alzheimer’s disease (AD), and vascular dementia. We used time-varying models to evaluate diagnostic bias.

Results

The cohort accumulated 3,310 incident dementia diagnoses over a median of 12.3 years of follow-up. All-site incident cancer was positively associated with all-cause dementia incidence (hazard ratio [HR]=1.15, 95% CI: 1.02-1.29), but prevalent cancer was not (HR=1.04, 95% CI: 0.92-1.17). Results were similar for vascular dementia. AD was not associated with prevalent or incident cancer. Dementia diagnosis was substantially elevated in the first year after cancer diagnosis (HR=1.83, 95% CI: 1.42-2.36), after which the association attenuated to null, suggesting diagnostic bias.

Conclusion

Health care utilization after a cancer diagnosis may increase chance of a dementia diagnosis, creating potential diagnostic bias in electronic health records-based studies.
Global prediction for monkeypox epidemic
Authors: Zhang Li , Huang Jianping , Chen Bin , Zhao Yingjie , Wang Danfen , Yan Wei
Published: October 2022

The monkeypox epidemic has now spread all over the world and has become an epidemic of widespread concern in the international community. Before the emergence of targeted vaccines and specific drugs, it is necessary to numerically simulate and predict the epidemic. In order to better understand and grasp its transmission situation, and put forward some countermeasures accordingly, we predicted and simulated monkeypox transmission and vaccination scenarios using models developed for COVID-19 predictions. The results suggest the monkeypox epidemic will spread to almost all countries in the world by the end of 2022 based on modified SEIR model prediction. The total number of people infected with monkeypox will reach 100,000. The top five countries will be the United States, Brazil, Germany, France and Britain with more than 28000, 20000, 4000, 4500 and 4000 cases respectively. If 30% of the population is vaccinated, the number of infected people will drop by 35%.
Life-course social participation and physical activity in midlife: Longitudinal associations in the 1970 British Cohort Study (BCS70)
Authors: Tsoli Stergiani , Fancourt Daisy , Sullivan Alice , Hamer Mark , Ploubidis George B. , Kawachi Ichiro
Published: October 2022

Background

A hypothesized benefit of social participation is that it encourages people to be more physically active. However, limited evidence exists on the association between social participation over the life-course and physical activity in midlife. We sought to apply a life-course framework to examine the association of social participation and device measured physical activity in midlife in the UK.

Methods

We used the 1970 British Birth Cohort Study (BCS70), which includes all people born in Britain during a single week in 1970. Social participation was assessed at ages 16, 30, 34 and 42. Physical activity was measured by accelerometery at age 46, as mean daily step count and time spent in Moderate to Vigorous Physical Activity (MVPA). The associations of social participation and physical activity were tested using two different life-course models: the sensitive period model and the accumulation model.

Results

Individuals with medium and high participation compared to no social participation over their life-course had higher mean daily step count and MVPA in midlife, supporting the accumulation model. In the sensitive period model, only those that actively participated at age 42 had higher mean daily steps and MVPA compared to those who did not participate.

Conclusion

Our study provides empirical evidence on the importance of sustaining social participation at all ages over the life-course rather than at a particular timepoint of someone’s life. Interventions to promote social participation throughout the life-course could be an avenue to promote physical activity in middle life.
Viral load of SARS-CoV-2 Omicron BA.5 is lower than that of BA.2 despite the higher infectivity of BA.5
Authors: Takatsuki Yuna , Takahashi Yuta , Nakajima Jun , Iwasaki Yumi , Nagano Katsutoshi , Tani-Sassa Chihiro , Yuasa Sonoka , Kanehira Saki , Sonobe Kazunari , Nukui Yoko , Takeuchi Hiroaki , Tanimoto Kousuke , Tanaka Yukie , Kimura Akinori , Ichimura Naoya , Tohda Shuji
Published: October 2022

Sublineage BA.5 of the SARS-CoV-2 Omicron variant rapidly spread and replaced BA.2 in July 2022 in Tokyo. A high viral load can be a possible cause of high transmissibility. Therefore, the copy numbers of SARS-CoV-2 in nasopharyngeal swab samples obtained from all patients visiting the hospital where this research was conducted were measured using quantitative polymerase chain reaction (qPCR). Viral genotypes were determined using PCR-based melting curve analysis. Next, whole-genome sequencing was performed using approximately one-fifth of the samples to verify the viral genotypes determined using PCR. Then, the copy numbers of the BA.1, BA.2, and BA.5 cases were compared. Contrary to expectations, the copy numbers of the BA.5 cases (median 4.7 × 104copies/μL,n= 290) were significantly (p= 0.001) lower than those of BA.2 cases (median 1.1 × 105copies/μL,n= 184). There was no significant difference between the BA.5 and BA.1 cases (median, 3.1 × 104copies/μL;n= 215). The results presented here suggest that the increased infectivity of BA.5 is not caused by higher viral loads, but presumably by other factors such as increased affinity to human cell receptors or immune escape due to its L452R mutation.
Characterising indel diversity in a largeMycobacterium tuberculosisoutbreak – implications for transmission reconstruction
Authors: Sobkowiak Benjamin , Colijn Caroline
Published: October 2022

Genomic sequencing ofMycobacterium tuberculosis (Mtb), the primary aetiological agent of tuberculosis (TB) in humans, has been used to understand transmission dynamics and reconstruct past outbreaks. Putative transmission events between hosts can be predicted by linking cases with low genomic variation between pathogen strains, though typically only variation in single nucleotide polymorphisms (SNPs) is used to calculate divergence. In highly clonalMtbpopulations there can be many strains that appear identical by SNPs, reducing the utility of genomic data to disentangle potential transmission routes in these settings. Small insertions and deletions (indels) are found in high numbers across theMtbgenome and can be an important source of variation to increase the observed diversity in outbreaks. Here, we examine the value of including indels in the transmission reconstruction of a largeMtboutbreak in London, UK, characterised by low levels of SNP diversity between 1998 and 2013. Our results show that including indel polymorphism decreases the number of strains in the outbreak with at least one other identical sequence by 43% compared to using only SNP variation and reduces the size of largest clonal cluster by 53%. Considering both SNPs and indel polymorphisms alters the reconstructed transmission network and decreases likelihood of direct transmission between hosts with variation in indels. This work demonstrates the importance of incorporating indels intoMtbtransmission reconstruction and we provide recommendations for further work to optimise the inclusion of indel diversity in such analyses.