bluuebunny/crossref_metadata_2025 huggingface dataset:
The uncemented Avenir® stem covered with hydroxyapatite in a septic environment in the revision of an infected total hip arthroplasty : a report on 40 cases
Authors: Mangin Matthieu , Aouzal Zouhair , Leclerc Grégoire , Sergent Anne Pauline , Bouiller Kévin , Patry Isabelle , Garbuio Patrick
Published: September 2022

Does the implantation of an uncemented hydroxyapatite-coated first-line stem in a septic environment during a one-stage total hip arthroplasty revision (THAR) for periprosthetic joint infection on total hip arthroplasty provide good results in terms of healing the infection and osteointegration of the stem ?

We retrospectively reviewed 40 patients operated on for septic THAR with placement of the cementless Avenir® stem - between 2008 and 2018 at the Besançon University Hospital - with a minimum follow-up of 2 years necessary to define cure in the absence of infectious recurrence. Clinical outcome was assessed using the Harris, Oxford and Merle D’Aubigné scores. Osteointegration was analyzed by the Enhg radiographic score.

Mean follow-up was 4.5 years (0-11). Cure of infection was achieved in 35 of 40 (87.5%). The median Harris score was 74/100, Oxford score 45/60, and Merle d’Aubigné score 15/18. Of 37 femoral stems, 36 (97%) had radiographically stable osteointegration. An age of 80 years is a risk factor for failure of septic THAR with implantation of an uncemented stem in one stage. The cementless Avenir® stem has its place in one-stage septic THAR. It gives good results on the healing of the infection and the integration of the stem in the context of femoral bone loss rated Paprosky 1.
Community-based Health Insurance Membership Renewal and Associated Factors among Communities in Addis Ababa, Ethiopia
Authors: Gashaw Walelign Mekonnen , Beyene Kidanemariam G/Michael , Tiruneh Mesafint Abeje
Published: September 2022

Introduction

Utilization of contemporary health services in developing nations has remained low. Ethiopia has introduced community-based health insurance (CBHI) to improve access to health services and reduce out-of-pocket payments. However, high dropout and low enrolment rates hamper implementation of CBHI scheme. This study aimed to assess CBHI membership renewal and associated factors among communities in Addis Ababa.

Methods

Community-based cross-sectional mixed study design was employed among 626 CBHI members and ten key informants in Addis Ababa from July 05 to August 30, 2021. Multi-stage sampling technique was used to select study participants, and purposive sampling technique was used to select key informants. Quantitative data was collected using structured interviewer administered questionnaire and analyzed using SPSS version 23.0, whereas semi-structured questionnaire was used for in-depth interviews. Binary logistic regression and thematic analysis were employed for quantitative and qualitative data respectively.

Results

Membership renewal of the community was 67.3%. Family size (AOR=2.54; 95%CI: 1.26-5.12), knowledge (AOR=1.87; 95%CI: 1.05-3.32), years of enrollment (AOR=2.22; 95%CI: 1.39-3.54), enrollment fee contributor (AOR=9.16; 95%CI: 5.29-15.82), benefit packages (AOR=1.99; 95%CI: 1.18-3.35), trust in CBHI scheme (AOR=3.53; 95%CI: 2.12-5.86), training (AOR=1.81; 95%CI 1.01-3.21), chronic illness (AOR=6.82; 95%CI: 3.80-12.24) and having children under five (AOR=1.98; 95%CI: 1.27-3.10) were significantly associated with CBHI membership renewal. Low level of awareness, limited benefit packages, unaffordable premium, poor quality health services, and shortage of supplies were determinant factors for CBHI membership renewal.

Conclusion

CBHI membership renewal was low. Family size, knowledge, years of enrollment, enrollment fee contributor, benefits packages, trust in CBHI scheme, training, chronic illness and having children under five were significantly associated with CBHI membership renewal. In addition, there are correctable gaps in community awareness, benefit packages, affordable premiums, quality health services, and availability of supplies. Hence, necessary measures at all levels must be taken to reduce dropouts from membership.
Head-to head comparison of anterior nares and nasopharyngeal swabs for SARS-CoV-2 antigen detection in a community drive-through test centre in the UK
Authors: Byrne Rachel L , Aljayyoussi Ghaith , Kontogianni Konstantina , Clerkin Karina , McIntyre Mathew , Wardale Jahanara , Williams Christopher T ,   CONDOR steering group, Body Richard , Adams Emily R , de Vos Margaretha , Escadafal Camille , Cubas Atienzar Ana I
Published: September 2022

Objective

To conduct a head-to-head diagnostic accuracy evaluation of professionally taken anterior nares (AN) and nasopharyngeal (NP) swabs for SARS-CoV-2 antigen detection using rapid diagnostic tests (Ag-RDT).

Methods

NP swabs for SARS-CoV-2 reverse transcription quantitative polymerase chain reaction (RT-qPCR) testing and paired AN and NP swabs for the antigen detection were collected from symptomatic participants enrolled at a community drive-through COVID-19 test centre in Liverpool. Two Ag-RDT brands were evaluated: Sure-Status (PMC, India) and Biocredit (RapiGEN, South Korea). The visual read out of the Ag-RDT test band was quantitative scored and the 50% and 95% limit of detection (LoD) of both Ag-RDT brands using AN and NP swabs was calculated using a probabilistic logistic regression model.

Results

A total of 604 participants were recruited of which 241 (40.3%) were SARS-CoV-2 positive by RT-qPCR. Sensitivity and specificity of AN swabs was equivalent to the obtained with NP swabs: 83.2% (75.2-89.4%) and 98.8% (96.5-99.6%) utilising NP swabs and 84.0% (76.2-90.1%) and 99.2% (97.0-99.8%) with AN swabs for Sure-Status and; 81.2% (73.1-87.7%) and 99.0% (94.7-86.5%) with NP swabs and 79.5% (71.3-86.3%) and 100% (96.5-100%) with AN swabs for Biocredit. The agreement of the AN and NP swabs was high for both brands with an inter-rater relatability (κ) of 0.918 and 0.833 for Sure-Status and Biocredit, respectively. The overall 50% LoD and 95% LoD was 0.9-2.4 × 104and 3.0-3.2 × 108RNA copies/mL for NP swabs and 0.3-1.1 × 105and 0.7-7.9 × 107RNA copies/mL and for AN swabs with no significant difference on LoD for any of the swabs types or test brands. Quantitative read-out of test line intensity was more often higher when using NP swabs with significantly higher scores for both Ag-RDT brands.

Conclusions

the diagnostic accuracy of the two SARS-CoV-2 Ag-RDTs brands evaluated in this study was equivalent using AN swabs than NP swabs. However, test line intensity was lower when using AN swabs which could influence negatively the interpretation of the Ag-RDT results for lay users. Studies on Ag-RDT self-interpretation using AN and NP swabs are needed to ensure accurate test use in the wider community.
Associations Between Maternal Risk Factors and Intrinsic Placental and Fetal Brain Functional Properties in Congenital Heart Disease
Authors: Rajagopalan Vidya , Schmithorst Vanessa , El-Ali Alex , Reynolds William , Lee Vincent , Wallace Julia , Wienberg Jaqueline , Johnson Jennifer , Votava-Smith Jodie , Adibi Jennifer , Panigrahy Ashok
Published: September 2022

Background

The relationship between maternal risk factors (MRFs) (particularly pre-gravid obesity, diabetes, and hypertension) and congenital heart disease (CHD) to placental and fetal brain outcomes is poorly understood. Here, we tested the hypothesis that MRF and CHD would be associated with reduced intrinsic placental and fetal brain function using a novel non-invasive technique.

Methods

Pregnant participants with and without MRF and fetal CHD were prospectively recruited and underwent feto-placental MRI. Using intrinsic properties of blood oxygen level dependent imaging (BOLD) we quantified spatiotemporal variance of placenta and fetal brain. MRFs and CHD were correlated with functional characteristics of the placenta and fetal brain.

Results

Co- morbid MRF (hypertension, diabetes, and obesity) reduced spatiotemporal functional variance of placenta and fetal brain (p < 0.05). CHD predicted reduced fetal brain temporal variance compared to controls (p<0.05). Interaction of MRF and CHD status was associated with reduced intrinsic pBOLD temporal variance (p=0.047). There were no significant interactions of MRFs and CHD status on either temporal or spatial variance of intrinsic brain BOLD.

Conclusion

MRF and CHD reduced functional characteristic of placenta and brain in fetuses. MRF modification and management during pregnancy may have the potential to not only provide additional risk stratification but may also improve neurodevelopmental outcomes.
Persistence of a SARS-CoV-2 variant with a frameshifting deletion for the duration of a major outbreak
Authors: Foster Charles S.P. , Bull Rowena A. , Tedla Nicodemus , Santiago Fernando , Agapiou David , Adhikari Anurag , Walker Gregory J. , Shrestha Lok Bahadur , van Hal Sebastiaan J. , Kim Ki Wook , Rawlinson William D.
Published: September 2022

Australia experienced widespread COVID-19 outbreaks from infection with the SARS-CoV-2 Delta variant between June 2021 and February 2022. Whole-genome sequencing of virus from an early case revealed a sub-consensus level of sequencing reads supporting a 17-nucleotide frameshift-inducing deletion in ORF7a that truncated the peptide sequence. The variant rapidly became represented at the consensus level (Delta-ORF7aΔ17del) in most of the outbreak cases in Australia. Retrospective analysis of ORF7a deletions in all GISAID clade GK Delta genomes showed that of 4,018,216 genomes, 134,751 (∼3.35%) possessed a deletion in ORF7a, with the ORF7aΔ17del mutation by far the most common. Approximately 99.05% of Delta-ORF7aΔ17del genomes on GISAID originated from the Australian Delta outbreak, and comprised 87% of genomes in the outbreak. In vitro comparison of lineages in cell culture showed a significantly greater proportion of cells were infected with Delta-ORF7aΔ17del than with a contemporaneous Delta variant without ORF7aΔ17del (Delta-ORF7aintact), and the proportion was also measurably higher than an early SARS-CoV-2 strain (A.2.2). These results showed that Delta-ORF7aΔ17del potentially has a slight growth advantage compared to Delta-ORF7aintact. Delta-ORF7aΔ17del viruses still produced ORF7a protein, but significantly less than A.2.2, in a different cellular distribution with a more diffuse expression throughout the cytoplasm of infected cells. These data suggest that the proliferation of Delta-ORF7aΔ17del genomes during the Australian Delta outbreak was likely not a result of an intrinsic benefit of the ORF7aΔ17del mutation, but rather a chance founder effect. Nonetheless, the abundance of different ORF7a deletions in genomes worldwide suggests these have some benefit to virus transmission.

IMPORTANCE

Deletions in the ORF7a region of SARS-CoV-2 have been noted since early in the COVID-19 pandemic, but are generally reported as transient mutations that are quickly lost in the population. Consequently, ORF7a deletions are considered disadvantageous to the virus through possible loss-of-function effects. In constrast to these earlier reports, we present the first report of a SARS-CoV-2 variant with an ORF7a deletion that dominated for the entirety of a protracted outbreak, and found no associated fitness disadvantage or advantage in cell culture. The relatively common rise and fall of ORF7a deletion variants over time likely represent chance founder events followed by proliferation until a more fit variant(s) is introduced to the population. Our global clade-level survey of ORF7a deletions will be a useful resource for future studies into this gene region.
Multicentre accuracy trial of FUJIFILM SILVAMP TB LAM test in people with HIV reveals lot variability
Authors: Székely Rita , Sossen Bianca , Mukoka Madalo , Muyoyeta Monde , Nakabugo Elizabeth , Hella Jerry , Van Nguyen Hung , Ubolyam Sasiwimol , Chikamatsu Kinuyo , Macé Aurélien , Vermeulen Marcia , Centner Chad M , Nyangu Sarah , Sanjase Nsala , Sasamalo Mohamed , Dinh Huong Thi , Ngo The Anh , Manosuthi Weerawat , Jirajariyavej Supunnee , Mitarai Satoshi , Nguyen Nhung Viet , Avihingsanon Anchalee , Reither Klaus , Nakiyingi Lydia , Kerkhoff Andrew D. , MacPherson Peter , Meintjes Graeme , Denkinger Claudia M , Ruhwald Morten ,   FujiLAM Study Consortium
Published: September 2022

Rationale

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis.

Objectives

This prospective trial in seven high tuberculosis burden countries set out to evaluate the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatient and outpatient people living with HIV.

Methods

Diagnostic performance of FujiLAM at point of care was assessed among adult people with HIV against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard including available non-study test results, and a composite reference standard including clinical evaluation.

Measurements and Main Results

Of 1624 participants enrolled, 294 (18·0%) were classified as TB positive by eMRS. Median age was 40 years, median CD4 cell count was 372 cells/ul, 52% were female and 78% were taking antiretroviral therapy at enrollment. Overall FujiLAM sensitivity was 54·8% (95% CI: 49·1–60·4), and overall specificity was 85·1% (83·1–86·9), against the extended mycobacterial reference standard. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%–38·0%) to 83·3% (43·6%–97·0%), and 75·0 (65·0%–82·9%) to 96·5 (92·1%–98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study.

Conclusions

Lot variability limited interpretation of FujiLAM test performance. Although the results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics.
Knowledge, Attitude and Practice (KAP) study on COVID-19 among the general population of Nepal
Authors: Shrestha Salina , Malla Rabin , Shrestha Sadhana , Singh Pallavi , Sherchand Jeevan B.
Published: September 2022

The COVID-19 pandemic has become one of the global health challenges in the current context. In Nepal, the first confirmed case was reported on 23 January 2020, and since then it has resulted in several negative impacts including economic disruption and deterioration of physical and mental health. In such a pandemic, it is indispensable to understand the knowledge and behavioral patterns of the general population regarding COVID-19. Therefore, our study aimed to assess the knowledge, attitude and practice on COVID-19, among the general population and its relationship with socio-demographic conditions.

The questionnaire survey was conducted to collect data from eight districts of Nepal which included Kathmandu, Bhaktapur, Lalitpur, Morang, Sunsari, Rupandehi, Chitwan, and Kaski. Descriptive statistics, parametric and non-parametric statistical tests, and a logistic regression model were used for analysis. The study showed that 93.3% of respondents had knowledge of overall preventive practice whereas only 32% had knowledge of overall symptoms of COVID-19. Regarding attitude, only 14.3% believed that they will get rid of COVID-19 soon. The preventive practice was reduced after lockdown compared to that during lockdown. The respondents with white-collar occupations, high-income, and unmarried were good at KAP. Similarly, highly educated and those residing in urban areas had good knowledge and practice.

The study findings will help in the development of targeted programs to improve the knowledge, attitude, practice of the general population on COVID-19, which is of paramount importance to deal with the existing pandemic and also such possible future waves of the pandemic.
Increased Levels of N-Lactoylphenylalanine After Exercise are Related to Adipose Tissue Loss During Endurance Training in Humans With Overweight and Obesity
Authors: Hoene Miriam , Zhao Xinjie , Machann Jürgen , Birkenfeld Andreas L. , Heni Martin , Peter Andreas , Niess Andreas , Moller Anja , Lehmann Rainer , Xu Guowang , Weigert Cora
Published: September 2022

Objective

The exercise-inducible metabolite N-Lactoylphenylalanine (Lac-Phe) has recently been shown to reduce food intake and adipose tissue mass in mice. We addressed whether Lac-Phe could have a similar function in humans.

Methods

Sedentary subjects with overweight and obesity completed an 8-week supervised endurance exercise intervention (n=22). Before and after the intervention, blood plasma levels of Lac-Phe were determined by UHPLC-MS in the resting state and immediately after an acute endurance exercise test. Adipose tissue and muscle volume were quantified by MRI.

Results

Acute exercise caused a pronounced increase in Lac-Phe, both before and after the intervention. Higher levels of Lac-Phe after acute exercise were associated with a greater reduction in abdominal subcutaneous and, to a lower degree, visceral adipose tissue during the intervention.

Conclusions

Lac-Phe produced during physical activity could boost weight loss in humans with obesity and overweight, possibly by transmitting or enhancing the appetite-suppressing effects of lactate. Exercise-induced Lac-Phe could be employed to predict and, potentially, improve the effectiveness of lifestyle interventions in subjects with overweight and obesity.

Trial Registration

Clinicaltrials.gov

NCT03151590

22 May 2017

https://clinicaltrials.gov/ct2/show/NCT03151590
The aerobiology of SARS-CoV-2 in UK hospitals and the impact of aerosol generating procedures
Authors: Gould Susan , Byrne Rachel L , Edwards Thomas , Aljayyoussi Ghaith , Wooding Dominic , Buist Kate , Kontogianni Konstantina , Bennett Allan , Atkinson Barry , Moore Ginny , Dunning Jake , Todd Stacy , Hoyle Marie-Claire , Turtle Lance , Solomon Tom , Fitzgerald Richard , Beadsworth Mike , Garner Paul , Adams Emily R , Fletcher Tom
Published: September 2022

Background

SARS-CoV-2 nosocomial transmission to patients and healthcare workers (HCWs) has occurred throughout the COVID-19 pandemic. Aerosol generating procedures (AGPs) seemed particularly risky, and policies have restricted their use in all settings. We examined the prevalence of aerosolized SARS-CoV-2 in the rooms of COVID-19 patients requiring AGP or supplemental oxygen compared to those on room air.

Methods

Samples were collected prospectively near to adults hospitalised with COVID-19 at two tertiary care hospitals in the UK from November 2020 – October 2021. The Sartorius MD8 AirPort air sampler was used to collect air samples at a minimum distance of 1.5 meters from patients. RT-qPCR was used following overnight incubation of membranes in culture media and extraction.

Results

We collected 219 samples from patients’ rooms: individuals on room air (n=67), receiving oxygen (n=65) or AGP (n=67). Of these, 54 (24.6%) samples were positive for SARS-CoV-2 viral RNA. The highest prevalence was identified in the air around patients receiving oxygen (32.3%, n=21, CI95% 22.2 to 44.3%) with AGP and room air recording prevalence of (20.7%, n=18, CI95% 14.1 – 33.7%) and (22.3%, n=15, CI95% 13.5 – 30.4%) respectively. We did not detect a significant difference in the observed frequency of viral RNA between interventions.

Interpretation

SARS-CoV-2 viral RNA was detected in the air of hospital rooms of COVID-19 patients, and AGPs did not appear to impact the likelihood of viral RNA. Enhanced respiratory protection and appropriate infection prevention and control measures are required to be fully and carefully implemented for all COVID-19 patients to reduce risk of aerosol transmission.
Changes in presentation, treatment, and survival of patients with hepatocellular carcinoma in Damietta, Egypt, 2007-2019: a retrospective monocentric cohort study
Authors: Jean Kévin , Tawheed Ahmed , Luong Nguye Liem Binh , Heikal Tarek , Eldaly Usama , Elhadidy Neven , Elghaieb Ahmed , Aboudonia Ahmed , Tondeur Laura , Dublineau Amélie , Fontanet Arnaud , El-Kassas Mohamed
Published: September 2022

Context

We aimed to assess temporal changes in the presentation and survival of patients with hepatocellular carcinoma (HCC) in the northern Egypt region, one of the regions reporting the highest incidence of the disease globally.

Method

We conducted a monocentric retrospective study. Patients presenting at the Damietta Oncology referral center between 2007 and 2019 with a diagnosed HCC were eligible. Individual, clinical and tumor characteristics at HCC diagnosis, including the Barcelona Clinic Liver Cancer (BCLC) staging, were retrieved from medical files and patients’ final vital status was ascertained by combining various data sources. Patients were divided into 2 groups based on diagnosis period: pre- and post-2014. Survival was analysed based on Kaplan-Meier curves and differences in restricted mean survival time (RMST).

Results

Data from 5,097 patients (among 5,210 eligible, 97.8%) wereere analyzed. We observed a significant trend toward HCC diagnosed at earlier stage in the post- vs. pre-2014 period (BCLC stage 0/A or B: 37.2% vs. 27.1%, p<10−3). Overall patient’s survival after the HCC diagnosis was poor, with a median of 8.1 months. The BCLC staging system performed well in predicting survival (median survival for patients diagnosed with BCLC stage 0/A, B, C, and D: 28, 25, 7, and 4 months, respectively, p<10−3). Despite a trend toward HCC diagnosed at earlier stages, we did not observe a significant improvement in survival over time. Overall, treatments offered in this medical center were in line with international guidelines, and 16.1% of the patients who received a curative treatment had an improved survival (30.7 months in median). However, HCC recurrence was frequent among patients cured for HCC, with a median time to recurrence of 22 months.

Conclusion

Overall survival after HCC diagnosis in Egypt remains poor but is significantly improved by curative therapy. Despite a trend toward earlier diagnosis of HCC, we did not observe a general improvement in survival over time, which remains to be clearly understood.
The association between heterosexual anal intercourse and HIV acquisition in three prospective cohorts of women
Authors: Silhol Romain , Nordsletten Ashley , Maheu-Giroux Mathieu , Elmes Jocelyn , Staunton Roisin , Owen Branwen , Shacklett Barbara , McGowan Ian , Feliciano Kailazarid Gomez , van der Straten Ariane , Eller Leigh Anne , Robb Merlin , Marrazzo Jeanne , Dimitrov Dobromir , Boily Marie-Claude
Published: September 2022

Receptive anal intercourse (RAI) may substantially increase HIV acquisition risk per sex act compared to receptive vaginal intercourse (RVI). To understand how levels of RAI change over time and evaluate the impact of exposure definitions for RAI on HIV incidence, we analysed three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline 16.0% (RV 217), 17.5% (VOICE) of women reported RAI in the past 3 months and 27.3% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. Hazard ratios, adjusted for potential confounders (aHR), indicate that reporting RAI at baseline increased HIV incidence in the three cohorts: 1.1 (95% Confidence interval: 0.8-1.5) for VOICE, aHR of 3.3 (1.6-6.8) for RV 217, and 1.9 (0.6-6) for HVTN 907. Using time-varying exposure definition slightly increased the estimated association for VOICE (aHR=1.2; 0.9-1.6), however reporting >30% RAI sex acts during VOICE follow-up was not associated with higher HIV incidence (aHR=0.7 (0.4-1.1)). Women who always reported RAI during follow-up where also at increased HIV acquisition risk. Overall, we found that precisely estimating RAI and HIV association after multiple RVI/RAI exposures is sensitive to RAI exposure definitions and may be influenced by measurement errors.
Rapid emergence of extensively drug-resistant Shigella sonnei in France
Authors: Lefèvre Sophie , Njamkepo Elisabeth , Feldman Sarah , Ruckly Corinne , Carle Isabelle , Lejay-Collin Monique , Fabre Laëtitia , Yassine Iman , Frezal Lise , de la Gandara Maria Pardos , Fontanet Arnaud , Weill François-Xavier
Published: September 2022

Shigella sonnei, the main cause of bacillary dysentery in high-income countries, has become increasingly resistant to antibiotics. We monitored the antimicrobial susceptibility of 7,121 S. sonnei isolates collected in France between 2005 and 2021. We identified a dramatic increase in the proportion of extensively drug-resistant (XDR) isolates (i.e., simultaneously resistant to ciprofloxacin, third-generation cephalosporins and azithromycin), to 22.3% of all S. sonnei isolates in 2021. Our genomic analysis identified 13 different clusters of XDR isolates descended from a ciprofloxacin-resistant sublineage originating from South Asia. The 164 XDR isolates detected were resistant to azithromycin, principally through a pKSR100-like plasmid, and to third-generation cephalosporins through various genes and plasmids. This rapid emergence of XDR S. sonnei in different transmission networks, particularly among men who have sex with men, is a matter of concern, and good laboratory-based surveillance of Shigella infections will be crucial for informed decision-making and appropriate public health action.
lincRNA RP24-315D19.10 promotes endometrial decidualization via upregulation of hnRNPA2B1
Authors: Tan Liping , Gao Rufei , Chen Xuemei , Geng Yanqing , Yin Xin , Chuan Peng , Mu Xinyi , Su Yan , Zhang Yan , Li Fangfang , He Junlin
Published: September 2022

Sufficient decidualization is necessary to maintain successful pregnancy. The physiological function and underlying molecular mechanisms of intergenic long non-coding RNA (lincRNAs) in this process remain largely unknown. Herein, we identified a lincRNA, RP24-315D19.10, which is highly expressed during mouse decidualization during early pregnancy, by performing RNA-sequencing (RNA-seq) analysis and weighted gene co-expression network analysis (WGCNA). Detailed cell and molecular assays revealed that lincRNA RP24-315D19.10 knockdown blocked decidualization in primary mouse endometrial stromal cells (mESCs), suggesting that RP24-315D19.10 is a promoting factor for decidualization. Mechanistically, cytoplasmic RP24-315D19.10 directly interacted with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and upregulated its protein level. Moreover, we found that hnRNPA2B1 is involved in the regulation of decidualization through loss- and gain-of-function studiesin vitro. Clinically, patients diagnosed with spontaneous miscarriage were found to have lower hnRNPA2B1 levels than healthy individuals, suggesting that RP24-315D19.10-regulated hnRNPA2B1 may participate in the development and progression of early spontaneous abortion. Our study indicates that RP24-315D19.10 enhances endometrial decidualization in a hnRNPA2B1-dependent manner, providing further insights into this physiological process.
The Phenotype-Genotype Reference Map: Improving biobank data science through replication
Authors: Bastarache Lisa , Delozier Sarah , Pandit Anita , He Jing , Lewis Adam , Annis Aubrey C , LeFaive Jonathon , Denny Joshua C. , Carroll Robert J. , Hughey Jacob J. , Zawistowski Matthew , Peterson Josh F.
Published: September 2022

Population-scale biobanks linked to electronic health record data provide vast opportunity to extend our knowledge of human genetics. While biobanks have already proven their value to research, data quality remains an important concern. Here we introduce the phenotype-genotype reference map (PGRM), a set of 5,879 genetic associations from 523 GWAS publications that can be used for high-throughput replication experiments in biobank data. We tested the PGRM on five ancestry-specific cohorts drawn from four established, independent biobanks and found evidence of robust replications across a wide array of phenotypes. We defined simple replication measures and show how these can be applied to any EHR-linked biobank to detect data corruption and to empirically assess parameters for phenome-wide studies. Finally, we used the PGRM to determine factors associated with reproducibility of GWAS results.
MRI-based computational model generation for cerebral perfusion simulations in health and ischaemic stroke
Authors: Józsa T. I. , Petr J. , Barkhof F. , Payne S. J. , Mutsaerts H. J. M. M.
Published: September 2022

Cerebral perfusion models were found to be promising research tools to predict the impact of acute ischaemic stroke and related treatments on cerebral blood flow (CBF) linked to patients’ functional outcome. To provide insights relevant to clinical trials, perfusion simulations need to become suitable for group-level investigations, but computational studies to date have been limited to a few patient-specific cases. This study set out to overcome issues related to automated parameter inference, that restrict the sample size of perfusion simulations, by integrating neuroimaging data. Seventy-five brain models were generated using measurements from a cohort of 75 healthy elderly individuals to model resting-state CBF distributions. Computational perfusion model geometries were adjusted using healthy reference subjects’ T1-weighted MRI. Haemodynamic model parameters were determined from CBF measurements corresponding to arterial spin labelling perfusion MRI. Thereafter, perfusion simulations were conducted for 150 acute ischaemic stroke cases by simulating an occlusion and cessation of blood flow in the left and right middle cerebral arteries. The anatomical (geometrical) fitness of the brain models was evaluated by comparing the simulated grey and white matter (GM and WM) volumes to measurements in healthy reference subjects. Statistically significant, strong positive correlations were found in both cases (GM: Pearson’s r 0.74, P-value< 0.001; WM: Pearson’s r 0.84, P-value< 0.001). Haemodynamic parameter tuning was verified by comparing total volumetric blood flow rate to the brain in reference subjects and simulations resulting in Pearson’s r 0.89, and P-value< 0.001. In acute ischaemic stroke cases, the simulated infarct volume using a perfusion-based proxy was 197±25 ml. Computational results showed excellent agreement with anatomical and haemodynamic literature data corresponding to T1-weighted, T2-weighted, and phase-contrast MRI measurements both in healthy scenarios and in acute ischaemic stroke cases. Simulation results represented solely worst-case stroke scenarios with large infarcts because compensatory mechanisms, e.g. collaterals, were neglected. The established computational brain model generation framework provides a foundation for population-level cerebral perfusion simulations and for in silico clinical stroke trials which could assist in medical device and drug development.
Strategies and Techniques for Quality Control and Semantic Enrichment with Multimodal Data: A Case Study in Colorectal Cancer with eHDPrep
Authors: Toner Tom M , Miller Paul , Forster Thorsten , Coleman Helen G , Overton Ian M
Published: September 2022

Abstract

Background

Integration of data from multiple domains can greatly enhance the quality and applicability of knowledge generated in analysis workflows. However, working with health data is challenging, requiring careful preparation in order to support meaningful interpretation and robust results. Ontologies encapsulate relationships between variables that can enrich the semantic content of health datasets to enhance interpretability and inform downstream analyses.

Findings

We developed an R package for electronic Health Data preparation ‘eHDPrep’, demonstrated upon a multi-modal colorectal cancer dataset (n=661 patients, n=155 variables; Colo-661). eHDPrep offers user-friendly methods for quality control, including internal consistency checking and redundancy removal with information-theoretic variable merging. Semantic enrichment functionality is provided, enabling generation of new informative ‘meta-variables’ according to ontological common ancestry between variables, demonstrated with SNOMED CT and the Gene Ontology in the current study. eHDPrep also facilitates numerical encoding, variable extraction from free-text, completeness analysis and user review of modifications to the dataset.

Conclusion

eHDPrep provides effective tools to assess and enhance data quality, laying the foundation for robust performance and interpretability in downstream analyses. Application to a multi-modal colorectal cancer dataset resulted in improved data quality, structuring, and robust encoding, as well as enhanced semantic information. We make eHDPrep available as an R package from CRAN [[URL will go here]].
Exploring high-quality microbial genomes by assembling short-reads with long-range connectivity
Authors: Zhang Zhenmiao , Xiao Jin , Wang Hongbo , Yang Chao , Huang Yufen , Yue Zhen , Chen Yang , Han Lijuan , Yin Kejing , Lyu Aiping , Fang Xiaodong , Zhang Lu
Published: September 2022

Despite long-read sequencing enables to generate complete genomes of unculturable microbes, its high cost hinders its widespread application in large cohorts. An alternative method is to assemble short-reads with long-range connectivity, which can be a cost-effective way to generate high-quality microbial genomes. We developed Pangaea to improve metagenome assembly using short-reads with physical or virtual barcodes. It adopts a deep-learning-based binning algorithm to assemble the co-barcoded reads with similar sequence contexts and abundances to improve assemblies of high- and medium-abundance microbes. Pangaea also leverages a multi-thresholding reassembly strategy to refine assembly for low-abundance microbes. We benchmarked Pangaea with linked-reads and a combination of short- and long-reads from mock communities and human gut metagenomes. Pangaea achieved significantly higher contig continuity as well as more near-complete metagenome-assembled genomes (NCMAGs) than the existing assemblers. Pangaea was also observed to generate three complete and circular NCMAGs on the human gut microbiomes.
Temporal enzymatic treatment to enhance the remodelling of multiple cartilage microtissues into a structurally organised tissue
Authors: Burdis Ross , Gallostra Xavier Barceló , Kelly Daniel J.
Published: September 2022

Scaffold-free tissue engineering strategies aim to recapitulate key aspects of normal developmental processes as a means of generating highly biomimetic grafts. Cartilage and fibrocartilaginous tissues have successfully been engineered by bringing together large numbers of cells, cellular aggregates or microtissues and allowing them to self-assemble or self-organize into a functional graft. Despite the promise of such approaches, considerable challenges still remain, such as engineering scaled-up tissues with predefined geometries, ensuring robust fusion between adjacent cellular aggregates or microtissues, and directing the (re)modelling of such biological building blocks into a unified scaled-up graft with hierarchical matrix organisation mimetic of the native tissue. In this study, we first demonstrate the benefits of engineering cartilage via the fusion of multiple cartilage microtissues compared to conventional scaffold-free approaches where (millions of) individual cells are allowed to aggregate and generate a cartilaginous graft. Key advantages include the engineering of a tissue with a richer extracellular matrix, a more hyaline-like cartilage phenotype and a final graft which better matched the intended geometry. A major drawback associated with this approach is that individual microtissues did not completely (re)model and remnants of their initial architectures where still evident throughout the macrotissue. In an attempt to address this limitation, the enzyme chondroitinase ABC (cABC) was employed to accelerate structural (re)modelling of the engineered tissue. Temporal enzymatic treatment supported robust fusion between adjacent microtissues, enhanced microtissue (re)modelling and supported the development of a more biomimetic tissue with a zonally organised collagen architecture. Additionally, we observed that cABC treatment modulated matrix composition (rebalancing the collagen:glycosaminoglycans ratio), tissue phenotype, and to a lesser extent, tissue mechanics. Ultimately, this work demonstrates that microtissue self-organisation is an effective method for engineering scaled-up cartilage grafts with a pre-defined geometry and near-native levels of ECM accumulation. Importantly we have demonstrated that key limitations associated with tissue engineering using multiple cellular aggregates, microtissues or organoids can be alleviated by temporal enzymatic treatment during graft development.
Maternal provisioning of an obligate symbiont
Authors: Carrier Tyler J. , Schmittmann Lara , Jung Sabrina , Pita Lucía , Hentschel Ute
Published: September 2022

Vertical transmission of microbial symbionts is interpreted as all offspring within a clutch being provided a similar number of symbionts irrespective of reproductive output (fecundity). This interpretation, however, stems primarily from oviparous insects and, thus, has yet to consider other major reproductive strategies. We used the viviparous spongeHalichondria paniceaand its obligate symbiont “CandidatusHalichondribacter symbioticus” to test the hypothesis that offspring receive quantitatively similar numbers of its obligate symbiont. This quantitative strategy of vertical transmission was not observed. Instead, we find thatH. paniceahas a maternal pool of ‘Ca. H. symbioticus’ that is partitioned proportionally to reproductive output and allometrically by offspring size. Moreover, ‘Ca. H. symbioticus’ could not be experimentally reduced in larvae by antibiotics, while the total bacterial community could be depleted. The ability to undergo metamorphosis was unaffected by this perturbation. Together, this demonstrates that the obligate symbiont ‘Ca. H. symbioticus’ is maternally provisioned and, thus, provides an additional strategy for how microbes can be vertically transmitted.
Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis
Authors: Nakajima-Takagi Yaeko , Oshima Motohiko , Takano Junichiro , Koide Shuhei , Itokawa Naoki , Uemura Shun , Yamashita Masayuki , Andoh Shohei , Aoyama Kazumasa , Isshiki Yusuke , Shinoda Daisuke , Saraya Atsunori , Arai Fumio , Yamaguchi Kiyoshi , Furukawa Yoichi , Koseki Haruhiko , Ikawa Tomokatsu , Iwama Atsushi
Published: September 2022

Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.
Spinal VGLUT3 lineage neurons drive visceral mechanical allodynia but not visceromotor reflexes
Authors: Qi Lu , Lin Shing-Hong , Ma Qiufu
Published: September 2022

Visceral pain is among the most prevalent and bothersome forms of chronic pain, but their transmission in the spinal cord is still poorly understood. Here we used a focal colorectal distention (fCRD) method to drive visceromotor responses (VMRs) plus affective pain-indicative aversive learning. We first found that spinal CCK neurons were necessary for noxious fCRD to drive both VMRs and aversion. We next showed that spinal VGLUT3 neurons mediate affective visceral allodynia, whose ablation caused loss of aversion evoked by low-intensity fCRD in mice with gastrointestinal (GI) inflammation or spinal circuit disinhibition. Importantly, these neurons are dispensable for driving VMRs. Anatomically, VGLUT3 neurons send projection to the parabrachial nuclei, whose photoactivation sufficiently generated aversion in mice with GI inflammation. Our studies suggest the presence of different spinal substrates that transmit nociceptive versus affective dimensions of visceral sensory information.
Small RNAs activate Salmonella pathogenicity island 1 by modulating mRNA stability through the hilD mRNA 3′ UTR
Authors: Abdulla Sabrina Z. , Kim Kyungsub , Azam Muhammad S. , Golubeva Yekaterina A. , Cakar Fatih , Slauch James M. , Vanderpool Carin K.
Published: September 2022

Salmonella enterica serovar Typhimurium is an enteric pathogen associated with food-borne disease. Salmonella invades the intestinal epithelium using a type three secretion system encoded in Salmonella pathogenicity Island 1 (SPI-1). SPI-1 genes are tightly regulated by a complex feed-forward loop to ensure proper spatial and temporal expression. Most regulatory input is integrated at HilD, through control of hilD mRNA translation or HilD protein activity. The hilD mRNA possesses a 310-nucleotide 3′ untranslated region (UTR) that influences HilD and SPI-1 expression, and this regulation is dependent on Hfq and RNase E, cofactors known to mediate small RNA (sRNA) activities. Thus, we hypothesized that the hilD mRNA 3′ UTR is a target for sRNAs. Here we show that the sRNAs, SdsR and Spot 42 regulate SPI-1 by targeting different regions of the hilD mRNA 3′ UTR. Regulatory activities of these sRNAs depend on Hfq and RNase E, in agreement with previous roles found for both at the hilD 3′ UTR. We show that SdsR and RNase E are responsible for the accumulation of variable fragments of the hilD mRNA 3′ UTR. Collectively, this work suggests that these sRNAs targeting the hilD mRNA 3′ UTR regulate hilD mRNA levels by interfering with RNase E-dependent mRNA degradation. Our work provides novel insights into mechanisms of sRNA regulation at bacterial mRNA 3′ UTRs and adds to our knowledge of post-transcriptional regulation of the SPI-1 complex feed-forward loop.

Importance

Salmonella are prominent food-borne pathogens, infecting millions of people a year. To express virulence genes at the correct time and place in the host, Salmonella uses a complex regulatory network that senses environmental conditions. Known for their role in allowing quick responses to stress and virulence conditions, we investigate the role of small RNAs in facilitating precise expression of these genes. We provide evidence that the 3′ untranslated region of the hilD mRNA, encoding a key virulence regulator, is a target for small RNAs and the ribonuclease RNase E. The small RNAs play a role in stabilizing hilD mRNA to allow proper expression of Salmonella virulence genes in the host.
Pre-existing immunity to influenza viruses through infection and/or vaccination leads to viral mutational signatures associated with unique immune responses during a subsequent infection
Authors: Rioux Melissa L. , Ge Anni , Yourkowski Anthony , Francis Magen E. , McNeil Mara , Selim Alaa , Xue Bei , Darbellay Joseph , Kelvin Alyson A.
Published: September 2022

Our biggest challenge to reducing the burden of seasonal influenza is the constant antigen drift of circulating influenza viruses which then evades the protection of pre-existing immunity. Continual viral infection and influenza vaccination creates a layered immune history in people, however, how host preimmunity interacts with an antigenically divergent virus exposure is poorly understood. Here we investigated the influence of host immune histories on influenza viral mutations. Immune backgrounds were devised in mice similar to what is experienced in people: naive; previously infected (A/FM/1/1947); previously vaccinated (Sanofi quadrivalent vaccine); and previously infected and then vaccinated. Mice were challenged with the heterologous H1N1 strain A/Mexico/4108/2009 to assess protection, viral mutation, and host responses in respect to each immune background by RNAseq. Viral sequences were analyzed for antigenic changes using DiscoTope 2.0 and Immune Epitope Database (IEDB) Analysis Resource NetMHCpan EL 4.1 servers. The mock infected-vaccinated group consistently had the greatest number of viral mutations seen across several viral proteins, HA, NA, NP, and PB1 which was associated with strong antiviral responses and moderate T cell and B cell responses. In contrast, the preimmune-vaccinated mice were not associated with variant emergence and the host profiles were characterized by minimal antiviral immunity but strong T cell, B cell, and NK cell responses. This work suggests that the infection and vaccination history of the host dictates the capacity for viral mutation at infection through immune pressure. These results are important for developing next generation vaccination strategies.

Importance

Influenza is a continual public health problem. Due to constant virus circulation and vaccination efforts, people have complex influenza immune histories which may impact the outcome of future infections and vaccinations. How immune histories influence the emergence of new variants and the immune pressure stimulated at exposure is poorly understood. Our study addressed this knowledge gap by utilizing mice that are preimmune to influenza viruses and analyzing host responses as well as viral mutations associated with changes in antigenicity. Importantly, we found previous vaccination induced immune responses with moderate adaptive immunity and strong antiviral immunity which was associated with increased mutations in the influenza virus. Interestingly, animals that were previously infected with a heterologous virus and also vaccinated had robust adaptive responses with little to no antiviral induction which was associated with no emergence of viral variants. These results are important for the design of next generation influenza vaccines.