bluuebunny/crossref_metadata_2025 huggingface dataset:
Scar Perception: A Comparison of African American and White Self-identified Patients
Authors: Garg Stuti P. , Hassan Abbas M. , Patel Anooj , Koko Deima , Varghese Jeffrey , Ellis Marco F. , Kim John Y.S. , Galiano Robert D.
Published: May 2022

Background:

Scars can have significant morbidity and negatively impact psychological, functional, and cosmetic outcomes as well as the overall quality-of-life, especially among ethnic minorities. The objective of this study was to evaluate African American and White patients’ perception of their scars’ impact on symptoms, appearance, psychosocial health, career, and sexual well-being, using validated assessment tools.

Method:

A total of 675 abdominoplasty and breast surgery patients from four providers completed the SCAR-Q, and Career/Sexual Well-Being scales via phone or email. A higher score on both assessments indicates a more positive patient perception.

Results:

Of the 675 respondents, 77.0% were White, and 23.0% were African American. White patients scored significantly higher on the SCAR-Q (232 ± 79 versus 203 ± 116), appearance (66 ± 26 versus 55 ± 29), and Career/Sexual Well-Being (16 ± 2 versus 15 ± 5) scales than African American patients (P < 0.001, P < 0.001, P < 0.001, respectively). There was no significant correlation between duration after surgery and symptoms or appearance scores for African American patients (P = 0.11, P = 0.37). There was no significant correlation between patient age and SCAR-Q score or time after surgery and psychosocial scores.

Conclusions:

African American patients are more likely to have lower perceptions of their scarring appearance, symptoms, psychosocial impact, career impact, and sexual well-being impact than White patients. Scar appearance and symptoms are less likely to improve over time for African American patients. This study highlights the need to address patient ethnicity when considering further follow-up, counseling, or other measures to enhance scar perception.
Acute Bilateral Vision Loss Following Unilateral Optic Nerve Sheath Fenestration
Authors: Levergood Nicholas , Park Ji Kwan , Campbell Benjamin , Lee Hui Bae Harold
Published: May 2022

Optic nerve sheath fenestration (ONSF) is a surgical technique commonly and effectively employed in the treatment of recalcitrant, vision-threatening papilledema. Unilateral blindness, a known risk of unilateral ONSF widely cited with 1%–2% incidence. In this case, a 58-year-old patient who presented symptomatic with bilateral hemorrhagic papilledema unresponsive to medical therapy underwent uneventful unilateral ONSF via standard superomedial eyelid crease incision. The patient presented postoperatively with severe bilateral vision loss. Workup revealed widespread metastatic malignant disease involving the optic chiasm and optic nerve sheath.
5-Fluorouracil With Microneedling Modulates Wound Healing in a Murine Model: An Immunohistochemical Analysis of Mechanism and Dose Efficacy
Authors: Homer Natalie A. , Hanafy Mahmoud S. , Baer Susan C. , Watson Alison H. , Somogyi Marie , Shore John W. , Blaydon Sean , Durairaj Vikram D. , Cui Zhengrong , Nakra Tanuj
Published: May 2022

Purpose:

The purpose of this study is to assess the dose-dependent immunohistopathological effects of intradermal microneedle-delivered 5-fluorouracil (5-FU) for postincisional wound healing in a murine model.

Methods:

A prospective experimental study was performed. Twelve hairless mice were randomized into 4 treatment groups for postincisional wound treatment: microneedling with topical saline, or microneeding with topically-applied 5-FU at concentrations of 25 mg/ml, 50 mg/ml, or 100 mg/ml. Two surgical wounds were created on each animal. Combination wound treatments were performed on postoperative days 14 and 28, and cutaneous biopsies were obtained on day 56. Specimens were analyzed by a dermatopathologist, blinded to the treatment group, for collagen thickness, lymphocytic infiltration, histiocytic response, sub-epidermal basement membrane zone thickness, and myofibroblast density.

Results:

Histopathologic evaluation showed increased collagen thickness, lymphocyte infiltration, and granuloma density in the groups undergoing microneedling treatment with 5-FU, compared to saline. Immunohistochemical analysis revealed a trend toward thicker basement membranes with higher concentrations of 5-FU used, reaching statistical significance between controls and those treated with 100 mg/ml 5-FU (p = 0.0493). A trend toward decreasing myofibroblast density with increasing doses of 5-FU was noted. No postincisional or treatment complications were observed.

Conclusions:

Our results demonstrate that microneedling is an effective topical subepithelial drug delivery system, and further suggest a beneficial dose-dependent immunomodulatory effect of 5-FU on intermediate wound healing when used in combination with microneedling. We recommend a 5-FU dose at the mid-range 50 mg/ml concentration to simultaneously maximize efficacy and minimize complication risk.
Randomized controlled trial of the significance of combined use with Ninjin’yoeito in CapeOX + Bmab therapy for patients with unresectable advanced/recurrent colorectal cancer
Authors: Motoo Yoshiharu , Shinozaki Katsunori , Takagi Tsuyoshi , Ito Shingo , Fujita Hideto , Munemoto Yoshinori , Yoshida Naohisa , Baba Eishi , Shindo Yoshiaki , Nishiuchi Takamasa , Miura Masatomo , Morita Satoshi , Tsuji Akihito
Published: May 2022

Background:

This randomized controlled trial is aimed at clarifying the benefit of an extract of ninjin’yoeito (NYT, traditional Japanese herbal medicine, Kampo) when combined with capecitabine plus oxaliplatin (CapeOX) plus bevacizumab (Bmab) in 150 patients with metastatic or recurrent colorectal cancer with special reference to nutritional status.

Methods/Design:

Patients with unresectable, metastatic, or recurrent colorectal cancer who plan to receive CapeOX + Bmab will be recruited. Of these patients, those who provide written informed consent will be randomly allocated to the NYT group (NYT + CapeOX + Bmab) or the control group (CapeOX + Bmab). The co-primary endpoints will be nutritional status, evaluated with CONtrolling NUTritional Status scores, and severe non-hematological adverse events, assessed using the Common Terminology Criteria for Adverse Events v5.0. The secondary endpoints will include the interaction between NYT and capecitabine; quality of life evaluated using the European Organization for Research and Treatment of Cancer-QLQ-C30; relative dose intensity of oxaliplatin, capecitabine, and bevacizumab; and plasma levels of phosphorylated neurofilament heavy chain. The two groups will include 75 patients each, and the patient recruitment period is January 1st, 2020 to December 31st, 2022.

Discussion:

This trial evaluates the efficacy and safety of NYT in the maintenance of a better nutritional status and fewer adverse events during the standard chemotherapeutic regimen of CapeOX + Bmab administered to patients with advanced or recurrent colorectal cancer. The potential implications include that NYT could be a strong supportive therapy in patients with colorectal cancer receiving chemotherapy.

Trial registration number:

This study was registered in the Japan Registry of Clinical Trials (registration number: jRCTs041190071) on October 2, 2019.
CD133 increases oxidative glucose metabolism of HT29 cancer cells by mitochondrial uncoupling and its inhibition enhances reactive oxygen species-inducing therapy
Authors: Lee Jin Hee , Lee Eun Ji , Park Jin Won , Kim Mina , Jung Kyung-Ho , Cho Young Seok , Lee Kyung-Han
Published: May 2022

Objective

A better understanding of the metabolic phenotype of stem-like cancer cells could provide targets to help overcome chemoresistance. In this study, we hypothesized that colon cancer cells with the stem cell feature of CD133 expression have increased proton leakage that influences glucose metabolism and offers protection against reactive oxygen species (ROS)-inducing treatment.

Methods and Results

In HT29 colon cancer cells, 18F-fluorodeoxyglucose (FDG) uptake was increased by CD133 selection and decreased by CD133 silencing. In CD133(+) cells, greater 18F-FDG uptake was accompanied by increased oxygen consumption rate (OCR) and reduced mitochondrial membrane potential and mitochondrial ROS, indicating increased proton leakage. The uncoupling protein inhibitor genipin reversed the increased 18F-FDG uptake and greater OCR of CD133(+) cells. The ROS-inducing drug, piperlongumine, suppressed CD133(−) cell survival by stimulating mitochondrial ROS generation but was unable to influence CD133(+) cells when used alone. However, cotreatment of CD133(+) cells with genipin and piperlongumine efficiently stimulated mitochondrial ROS for an enhanced antitumor effect with substantially reduced CD133 expression.

Conclusion

These results demonstrate that mitochondrial uncoupling is a metabolic feature of CD133(+) colon cancer cells that provides protection against piperlongumine therapy by suppressing mitochondrial ROS generation. Hence, combining genipin with ROS-inducing treatment may be an effective strategy to reverse the metabolic feature and eliminate stem-like colon cancer cells.
Geospatial Analysis of Social Determinants of Health Identifies Neighborhood Hot Spots Associated With Pediatric Intensive Care Use for Acute Respiratory Failure Requiring Mechanical Ventilation*
Authors: Najjar Nadine , Opolka Cydney , Fitzpatrick Anne M. , Grunwell Jocelyn R.
Published: May 2022

OBJECTIVES:

Poverty, racial bias, and disparities are linked to adverse health outcomes for children in the United States. The social vulnerability and child opportunity indices are composite measures of the social, economic, education, health, and environmental qualities that affect human health for every U.S. census tract. Composite measures of social vulnerability and child opportunity were compared for neighborhood hot spots, where PICU admissions for acute respiratory failure requiring invasive mechanical ventilation were at the 90th percentile or greater per 1,000 children, versus non-hot spots.

DESIGN:

Population-based ecological study.

SETTING:

Two urban free-standing children’s hospital PICUs consisting of a 36-bed quaternary academic and a 56-bed tertiary community center, in Atlanta, GA.

PATIENTS:

Mechanically ventilated children who were 17 years of age or younger with a geocodable Georgia residential address admitted to a PICU for at least 1 day.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Residential addresses were geocoded and spatially joined to census tracts. Composite measures of social vulnerability and childhood opportunity, PICU readmission rates, and hospital length of stay were compared between neighborhood hot spots versus non-hot spots. There were 340 of 3,514 children (9.7%) who lived within a hot spot. Hot spots were associated with a higher (worse) composite social vulnerability index ranking, reflecting differences in socioeconomic status, household composition and disability, and housing type and transportation. Hot spots also had a lower (worse) composite childhood opportunity index percentile ranking, reflecting differences in the education, health and environment, and social and economic domains. Higher social vulnerability and lower childhood opportunity were not associated with readmission rates but were associated with longer total median duration of hospital days per 1,000 children in a census tract.

CONCLUSIONS:

Social determinants of health identified by geospatial analyses are associated with acute respiratory failure requiring invasive mechanical ventilation in critically ill children. Interventions addressing the neighborhood social vulnerability and child opportunity are needed to decrease disparities in intensive care admissions for acute respiratory failure requiring mechanical ventilation.
The National Disaster Medical System and military combat readiness: A scoping review
Authors: Lee Clark J. , Allard Rhonda J. , Adeniji Adeteju A. , Quintanilla Norma , Kirsch Thomas D.
Published: May 2022

A scoping review was conducted to describe the history of the National Disaster Medical System (NDMS) in the context of US military medical preparedness for a large-scale overseas military conflict. National Disaster Medical System civilian hospitals would serve as backups to military treatment facilities if both US Department of Defense and US Department of Veterans Affairs hospitals reached capacity during such a conflict. Systematic searches were used to identify published works discussing the NDMS in the scientific and gray literature. Results were limited to publicly available unclassified English language works from 1978 to January 2022; no other restrictions were placed on the types of published works. Full-text reviews were conducted on identified works (except student papers and dissertations) to determine the extent to which they addressed NDMS definitive care. Data charting was performed on a final set of papers to assess how these works addressed NDMS definitive care. The search identified 54 works published between 1984 and 2022. More than half of the publications were simple descriptions of the NDMS (n = 30 [56%]), and most were published in academic or professional journals (n = 38 [70%]). Only nine constituted original research. There were recurrent criticisms of and recommendations for improving the definitive care component of the NDMS. The lack of published literature on NDMS definitive care supports the assertion that the present-day NDMS may lack the capacity and military-civilian interoperability necessary to manage the casualties resulting from a large-scale overseas military conflict.
Reclassification of Brevibacterium frigoritolerans as Peribacillus frigoritolerans comb. nov. based on phylogenomics and multiple molecular synapomorphies
Authors: Montecillo Jake Adolf V. , Bae Hanhong
Published: May 2022

The taxonomic assignment ofBrevibacterium frigoritoleranstogether with the in-house environmental isolate EB93 was reassessed in this study using phylogenetic and phylogenomic approaches, and the detection of multiple molecular synapomorphies. Results from the reconstructed phylogenetic trees based on the 16S rRNA gene sequences, the concatenated protein sequences ofGyrA-GyrB-RpoB-RpoC, and the whole-genome sequences revealed the consistent exclusion ofB. frigoritoleransand the environmental isolate EB93 from the cluster formed by the type strains of the genusBrevibacterium. In addition,B. frigoritoleransand the environmental isolate EB93 were both observed to form a clade together with the type strains of the genusPeribacillus. The results from the analysis of the digital DNA–DNA hybridization, average nucleotide identity, average amino acid identity and the difference in the G+C content also corroborated with the phylogenetic inference, and thatB. frigoritoleransand the environmental isolate EB93 were of the same species. Furthermore, the presence of the molecular synapomorphies in the protein sequences noted in the description of the genusPeribacilluswere also observed inB. frigoritolerans, further strengthening its taxonomic affiliation in the genus. Based on the evidence from the multiple lines of analyses, we propose the reclassification ofBrevibacterium frigoritoleransas a member of the genusPeribacillusand assume the namePeribacillus frigoritoleranscomb. nov. (type strain DSM 8801T=ATCC 25097T=CCUG 43489T=CIP 67.20T=JCM 11681T).
Estimating the distribution of COVID-19-susceptible, -recovered, and -vaccinated individuals in Germany up to April 2022
Authors: Maier Benjamin F. , Rose Annika H. , Burdinski Angelique , Klamser Pascal , Neuhauser Hannelore , Wichmann Ole , Schaade Lars , Wieler Lothar H. , Brockmann Dirk
Published: May 2022

After having affected the population for two years, the COVID-19 pandemic has reached a phase where a considerable number of people in Germany have been either infected with a SARS-CoV-2 variant, vaccinated, or both. Yet the full extent to which the population has been in contact with either virus or vaccine remains elusive, particularly on a regional level, because (a) infection counts suffer from under-reporting, and (b) the overlap between the vaccinated and recovered subpopulations is unknown. Since previous infection, vaccination, or especially a combination of both reduce the risk of severe disease, a high share of individuals with SARS-CoV-2 immunity lowers the probability of severe outbreaks that could potentially overburden the public health system once again, given that emerging variants do not escape this reduction in susceptibility. Here, we estimate the share of immunologically naïve individuals by age group for each of the 16 German federal states by integrating an infectious disease model based on weekly incidences of SARS-CoV-2 infections in the national surveillance system and vaccine uptake, as well as assumptions regarding under-ascertainment. We estimate a median share of 7.0% of individuals in the German population have neither been in contact with vaccine nor any variant as of March 31, 2022 (quartile range [3.6%– 9.8%]). For the adult population at higher risk of severe disease, this figure is reduced to 3.5% [1.3%–5.5%] for ages 18–59 and 4.3% [2.7%–5.8%] for ages 60 and above. However, estimates vary between German states mostly due to heterogeneous vaccine uptake. Excluding Omicron infections from the analysis, 16.1% [14.0%–17.8%] of the population in Germany, across all ages, are estimated to be immunologically naïve, highlighting the large impact the Omicron wave had until the beginning of spring in 2022.
Ribavirin antiviral combination therapy in COVID 19, a single-center experience
Authors: Singh Budha O , Chikara Gaurav , Panda Prasan Kumar , Bahurupi Yogesh Arvind , Saha Sarama , Pai Venkatesh S.
Published: May 2022

Background

COVID 19 infection has a similar clinical spectrum of disease presentation such as SARS and MERS in the past. These led to the assumption of the possibility to treat COVID 19 infection with antivirals which had been used to treat SARS and MERS.

Methods

A retrospective analysis was done on the data of SEV COVID Trial in symptomatic adult patients of COVID 19 infection with objectives to explore whether ribavirin antiviral combinations reduces the need of both noninvasive and invasive ventilators in treatment of COVID 19 infections.

Results

The patients were categorized as “Cohort A” consisting of 40 patients and “Cohort B” of 61 patients as Cohort A being the group of patients who received the standard therapy and Cohort B the group of patients who received the ribavirin combination therapy.

Conclusion

The study concluded that there was no statistically significant difference in regard to the need of noninvasive ventilation and invasive ventilation and also the development of multi-organ dysfunction in between the two Cohorts. Also, with progress of time, the proportion of patients with single organ dysfunctions in the two cohorts showed gradual recovery without any statistically significant differences.
Log-order improved in trans hammerhead ribozyme turnover rates: reevaluating therapeutic space for small catalytic RNAs
Authors: Myers Jason M. , Sullivan Jack M.
Published: May 2022

We discovered an enhanced functionality hammerhead ribozyme (EhhRz), designed to act in trans against human rod opsin (RHO) mRNA, with turnover activity >300 nM min−1 under substrate-excess conditions and physiological Mg2+ levels (1 mM). We developed a real-time moderate-throughput fluorescence quantitative hhRz kinetic assay, which is linear with substrate and product moles and supported by gel-based measures. The EhhRz targets a CUC↓ cleavage site in a substrate with no predicted secondary/tertiary structure and demonstrates classic Michaelis-Menten turnover behavior when the substrate is in 10-fold excess (Vmax/Km up to 1.60 × 108 min−1 M−1), which is comparable to RNase A. EhhRzs show cooperative titration with a Kd of 0.73 ± 0.02 mM at cellular Mg2+ concentrations and a Hill coefficient of 1.73 ± 0.07. The upstream EhhRz antisense flank (bound to a downstream substrate flank) interacts with stem-loop II, and examinations of different variants revealed that a U7 residue in the downstream flank of the substrate is not essential for enhanced activity. Under single-turnover conditions with substrate pre-annealed to enzyme, reaction rates exceeded 1,000 min−1. These findings show that RNA catalysis approaches the efficiency of the ribosome and suggests EhhRz in trans is a druggable nucleic acid therapeutic.
Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
Authors: Castilla-Vallmanya Laura , Centeno-Pla Mónica , Serrano Mercedes , Franco-Valls Héctor , Martínez-Cabrera Raúl , Prat-Planas Aina , Rojano Elena , Ranea Juan A. G. , Seoane Pedro , Oliva Clara , Paredes-Fuentes Abraham J. , Artuch Rafael , Grinberg Daniel , Rabionet Raquel , Balcells Susanna , Urreizti Roser
Published: May 2022

Background

Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels.

Methods

We performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ1-40), and performed targeted metabolomic and transcriptomic profiles in SYS patients’ fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein.

Results

Functional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients.

Conclusion

A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.

Key Messages

MAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients’ fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here.
Adherence trajectory as an on-treatment risk indicator among drug-resistant TB patients in the Philippines
Authors: Huddart S , Geocaniga-Gaviola DM , Crowder R , Lim AR , Lopez E , Valdez CL , Berger CA , Destura Raul , Kato-Maeda M , Cattamanchi A , Garfin AMC
Published: May 2022

Introduction

High levels of treatment adherence are critical for achieving optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.

Methods

We conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.

Results

Of 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%) extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n=483), a moderate adherence group (n=93) and a low adherence group (n=20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90 - 6.12) and final (aOR 2.71, 95% 1.73 - 4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9 % vs. 65.4 % correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).

Conclusions

Adherence patterns are strongly predictive of patient treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns.
A Statistical Definition of Epidemic Waves
Authors: Kriston Levente
Published: May 2022

The timely identification of expected surges of cases during infectious disease epidemics is essential for allocating resources and preparing interventions. This study describes a simple way to evaluate whether an epidemic wave is likely to be present based on daily new case count data. The proposed measure compares two models that assume exponential or linear dynamics, respectively. Technically, the output of two regression analyses is used to approximate a Bayes factor, which quantifies the support for the exponential over the linear model and can be used for epidemic wave detection. The trajectory of the coronavirus epidemic in three countries is analyzed and discussed for illustration. The proposed measure detects epidemic waves at an early stage, which are otherwise visible only by inspecting the development of case count data retrospectively. In addition to informing public health decision making, the outlined approach may serve as a starting point for scientific discussions on epidemic waves.
Changes in English medication safety indicators throughout the COVID-19 pandemic: a federated analysis of 57 million patients’ primary care records in situ using OpenSAFELY
Authors: Fisher Louis , Hopcroft Lisa E. M. , Rodgers Sarah , Barrett James , Oliver Kerry , Avery Anthony J. , Evans Dai , Curtis Helen , Croker Richard , Macdonald Orla , Morley Jessica , Mehrkar Amir , Bacon Seb , Davy Simon , Dillingham Iain , Evans David , Hickman George , Inglesby Peter , Morton Caroline E. , Smith Becky , Ward Tom , Hulme William , Green Amelia , Massey Jon , Walker Alex J. , Bates Chris , Cockburn Jonathan , Parry John , Hester Frank , Harper Sam , O’Hanlon Shaun , Eavis Alex , Jarvis Richard , Avramov Dima , Griffiths Paul , Fowles Aaron , Parkes Nasreen , Goldacre Ben , MacKenna Brian
Published: May 2022

Objective

To describe the impact of the COVID-19 pandemic on safe prescribing, using the PINCER prescribing indicators; to implement complex prescribing indicators at national scale using GP data.

Design

Population based cohort study, with the approval of NHS England using the OpenSAFELY platform.

Setting

Electronic health record data from 56.8 million NHS patients’ general practice records.

Participants

All NHS patients registered at a GP practice using TPP or EMIS computer systems and recorded as at risk of at least one potentially hazardous PINCER indicator between September 2019 and September 2021.

Main outcome measure

Monthly trends and between-practice variation for compliance with 13 PINCER measures between September 2019 and September 2021.

Results

The indicators were successfully implemented across GP data in OpenSAFELY. Hazardous prescribing remained largely unchanged during the COVID-19 pandemic, with only small reductions in achievement of the PINCER indicators. There were transient delays in blood test monitoring for some medications, particularly ACE inhibitors. All indicators exhibited substantial recovery by September 2021. We identified 1,813,058 patients at risk of at least one hazardous prescribing event.

Conclusion

Good performance was maintained during the COVID-19 pandemic across a diverse range of widely evaluated measures of safe prescribing.

Summary box

WHAT IS ALREADY KNOWN ON THIS TOPIC

Primary care services were substantially disrupted by the COVID-19 pandemic.

Disruption to safe prescribing during the pandemic has not previously been evaluated.

PINCER is a nationally adopted programme of activities that aims to identify and correct hazardous prescribing in GP practices, by conducting manual audit on subgroups of practices.

WHAT THIS STUDY ADDS

For the first time, we were able to successfully generate data on PINCER indicators for almost the whole population of England, in a single analysis.

Our study is the most comprehensive assessment of medication safety during the COVID-19 pandemic in England, covering 95% of the population using well-validated measures.

Good performance was maintained across many PINCER indicators throughout the pandemic.

Delays in delivering some medication-related blood test monitoring were evident though considerable recovery was made by the end of the study period.
DeepPheWAS: an R package for phenotype generation and association analysis for phenome-wide association studies
Authors: Packer R , Williams AT , Hennah W , Eisenberg MT , Fawcett KA , Pearson W , Guyatt A , Edris A , Hollox EJ , Rao BS , Bratty JR , Wain LV , Dudbridge F , Tobin MD
Published: May 2022

DeepPheWAS is an R package for phenome wide association studies that creates clinically-curated composite phenotypes, and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression, and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes.

Availability and Implementation

The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS.

Contact

richard.packer@leicester.ac.uk

Supplementary information

Supplementary methods and results are available at Bioinformatics online.
Routine Saliva Testing for SARS-CoV-2 in Children: Partnering with Childcare Centers in the Greater New Haven Community
Authors: Rayack Erica J. , Askari Hibah Mahwish , Zirinsky Elissa , Lapidus Sarah , Sheikha Hassan , Peno Chikondi , Kazemi Yasaman , Yolda-Carr Devyn , Liu Chen , Grubaugh Nathan D. , Ko Albert I. , Wyllie Anne L. , Spatz Erica S. , Oliveira Carlos R. , Bei Amy K.
Published: May 2022

Background

While considerable attention was placed on SARS-CoV-2 testing and surveillance programs in the K-12 setting, younger age groups in childcare centers were largely overlooked. Childcare facilities are vital to communities, allowing parents/guardians to remain at work and providing safe environments for both children and staff. Therefore, early in the COVID-19 pandemic, we established a PCR-based COVID-19 surveillance program in childcare facilities, testing children and staff with the goal of collecting actionable public health data and aiding communities in the progressive resumption of standard operations and ways of life. In this study we describe the development of a weekly saliva testing program and provide early results from our experience implementing this in childcare centers.

Methods

We enrolled children (aged 6 months to 7 years) and staff at 8 childcare facilities and trained participants in saliva collection using video chat technology. Weekly surveys were sent out to assess exposures, symptoms, and vaccination status changes. Participants submitted weekly saliva samples at school. Samples were transported to a partnering clinical laboratory for RT-PCR testing using SalivaDirect and results were uploaded to each participant’s online patient portal within 24 hours.

Results

This study fostered a cooperative partnership with participating childcare centers, parents/guardians, and staff with the goal of mitigating COVID-19 transmission in childcare centers. Age-related challenges in saliva collection were overcome by working with parents/guardians to conceptualize new collection strategies and by offering parents/guardians continued virtual guidance and support.

Conclusion

SARS-CoV-2 screening and routine testing programs have focused less on the childcare population, resulting in knowledge gaps in this critical age group, especially as many are still ineligible for vaccination. SalivaDirect testing for SARS-CoV-2 provides a feasible method of asymptomatic screening and symptomatic testing for children and childcare center staff. Given the relative aversion to nasal swabs in the childcare age group, especially as a routine surveillance tool, an at-home saliva collection method provides an attractive alternative. Results can be shared rapidly electronically through participants’ private medical chart portals, and video chat technology allows for discussion and instruction between investigators and participants.
Impact of COVID-19 non-pharmaceutical interventions on pneumococcal carriage prevalence and density in Vietnam
Authors: Nation Monica Larissa , Manna Sam , Tran Hau Phuc , Nguyen Cattram Duong , Vy Le Thi Tuong , Uyen Doan Y , Phuong Tran Linh , Dai Vo Thi Trang , Ortika Belinda Daniela , Wee-Hee Ashleigh Christina , Beissbarth Jemima , Hinds Jason , Bright Kathryn , Smith-Vaughan Heidi , Nguyen Thuong Vu , Mulholland Kim , Temple Beth , Satzke Catherine
Published: May 2022

Non-pharmaceutical interventions (NPIs) implemented to contain SARS-CoV-2 have decreased invasive pneumococcal disease. We undertook an observational study to evaluate the impact of NPIs on pneumococcal carriage and density, drivers of transmission and disease, during the COVID-19 pandemic in Ho Chi Minh City, Vietnam. While NPIs did not significantly impact pneumococcal carriage, mean capsular pneumococcal density decreased by up to 91.5% (1.07 log10genome equivalents/mL, 95% Confidence Interval: 0.74-1.41) after NPI introduction compared with the pre-COVID-19 period. As higher pneumococcal density is a risk factor for disease, the observed decline provides a plausible mechanism for the reductions in invasive pneumococcal disease.
Clinical prediction models for treatment outcome in newly-diagnosed epilepsy: Protocol for a systematic review
Authors: Ratcliffe Corey , Marson Anthony , Keller Simon S. , Bonnett Laura J.
Published: May 2022

Epilepsy, characterised by a predisposition towards unprovoked seizures, is one of the most common neurological disorders globally. Whilst 60-70% of individuals diagnosed with epilepsy will gain seizure control through anti-seizure medication, the mechanisms underlying seizure persistence are unclear. Intractability can significantly degrade a patient’s quality of life amongst other things; the use of predictive modelling of epilepsy outcomes in deciding on treatment therefore offers a tangible benefit to the patient. Early indicators of pharmacoresistance may discourage certain treatment options, and save time in what has been indicated to be a critical stage for newly-diagnosed epilepsy. Primarily, this paper aims to evaluate existing predictive models to identify demographic, clinical, physiological (e.g. EEG), and neuroimaging (e.g. MRI) factors that may be predictive of treatment outcomes in newly-diagnosed epilepsy. Two electronic databases, MEDLINE and EMBASE, will be searched with terms related to prognosis in newly-diagnosed epilepsy, and identified studies will be included for review if they have combined at least two demographic, clinical, neuroimaging, and/or physiological factors to predict treatment outcome in people with newly-diagnosed epilepsy. Papers will be screened by two independent reviewers via titles, abstracts and then full text against the inclusion criteria for eligibility. Data will be extracted by reviewers using standardised forms, assessed for risk of bias using the PROBAST tool and synthesised narratively. If considered appropriate the authors will carry out a meta-analysis on the available data.

Prospero registration number

– CRD42022329936
Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom
Authors: Zöllner Julia , Finer Sarah , Linton Kenneth J. ,   Genes and Health Research Team, van Heel David A. , Williamson Catherine , Dixon Peter H.
Published: May 2022

Objectives

This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people in the United Kingdom as they are an understudied genetic ancestry group with disproportionate disease burden.

Methods

Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by low/mid whole exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency <5%. Variants were filtered and annotated. Rare variant burden analysis was conducted. Variants associated with a phenotype or predicted to be likely pathogenic (LP) underwent protein structure and modelling analysis in silico.

Results

Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and unique to this cohort and not previously reported in the GnomAD database. Of those novel variants, 22 were considered LP and 9 pathogenic. We identified variants in volunteers with gallstone disease (n=31), intrahepatic cholestasis of pregnancy (ICP, n=16), cholangiocarcinoma and cirrhosis (n=2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased inABCB11. A total of 73 variants were assessed for impact at the protein level. Protein modelling demonstrated variants that appeared to likely cause significant structural damage.

Conclusions

This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.

WHAT IS KNOWN

Cholestatic liver diseases encompass a broad range of conditions.

Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease.

Genetic and environmental factors contribute to the aetiology of cholestatic disease.

South Asian populations are disproportionally affected.

WHAT IS NEW HERE

Exome sequencing analysis in a British Pakistani and Bangladeshi population discovered new genetic mutations.

Pathogenic variants were identified that increase risk of cholestatic liver disease.

Novel variants that contribute to ICP were identified.
Variability of Tissue Mechanical Response in Sus Domesticus Porcine Models from in vivo to ex vivo Conditions
Authors: Malik Faizan A. , Drahos Bradley A. , Safdari Amer , Mazzeo Mark V. , Norfleet Jack E. , Sweet Robert M. , Kowalewski Timothy M.
Published: May 2022

Healthcare simulators have been demonstrated to be a valuable resource for training several technical and nontechnical skills. A gap in the fidelity of tissues has been acknowledged as a barrier to application for current simulators; especially for interventional procedures. Inaccurate or unrealistic mechanical response of a simulated tissue to a given surgical tool motion may result in negative training transfer and/or prevents the “suspension of disbelief” necessary for a trainee to engage in the activity. Thus, where it is relevant to training outcomes, there should be an effort to create healthcare simulators with simulated tissue mechanical responses that match or represent those of biological tissues. Historically, this data is most often gathered from preserved (post mortem) tissue; however, there is a concern that the mechanical properties of preserved tissue, that lacks blood flow, may lack adequate accuracy to provide the necessary training efficacy of simulators. This work explores the effect of the “state” of the tissue testing status on liver and peritoneal tissue by using a customized handheld grasper to measure the mechanical responses of representative porcine (Sus domesticus) tissues in N=5 animals across five test conditions: in vivo, postmortem (in-situ), ex vivo (immediately removed from fresh porcine cadaver), post-refrigeration, and post-freeze-thaw cycle spanning up to 72 hours after death. No statistically significant difference was observed in the mechanical responses due to grasping between in vivo and post-freeze conditions for porcine liver and peritoneum tissue samples (p = 0.05 for derived stiffness at grasping force values F = 5N and 6.5N). Furthermore, variance between in vivo and post-thaw conditions within each animal, was comparable to the variance of the in vivo condition between animals. Thus, the use of thawed, preserved tissue for the further study and emulation of mechanical perturbation of the liver and peritoneum can be considered.
Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa
Authors: Fatumo Segun , Mugisha Joseph , Soremekun Opeyemi S , Kalungi Allan , Mayanja Richard , Kintu Christopher , Makanga Ronald , Kakande Ayoub , Abaasa Andrew , Asiki Gershim , Kalyesubula Robert , Newton Robert , Nyirenda Moffat , Sandhu Manj S. , Kaleebu Pontiano
Published: May 2022

The Uganda Genome Resource (UGR) is a well characterised genomic database, with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC) - a population-based open cohort study established in 1989 by the Medical Research Council (MRC) UK in collaboration with the Uganda Virus Research Institute (UVRI).

In 2011, UGR was launched with genotype data on ∼5000 and whole genome sequence data on ∼2000 Ugandan individuals from 9 ethno-linguistic groups. Leveraging other available platforms at the MRC Uganda such as Biorepository centre for sample storage, Clinical Diagnostic Laboratory Service (CDLS) for sample diagnostic testing, sequencing platform for DNA extraction, Uganda Medical informatics Unit (UMIC) for large-scale data analysis, GPC for additional sample collection, UGR is strategically poised to expand and generate scientific discoveries.

Here, we describe UGR and highlight the important genetic findings thus far including how UGR is providing opportunities to: (1) discover novel disease susceptibility genetic loci; (2) refine association signals at new and existing loci; (3) develop and test Polygenic Risk Score (PRS) to determine individual’s disease risk; 4) assess how some risk factors including infectious diseases are causally related to non-communicable diseases (NCDs) in Africa; (5) develop research capacity for genomics in Africa; and (6) enhance African participation in the global genomics research arena. Leveraging established research infrastructure, expertise, local genomic leadership, global collaboration and strategic funding, we anticipate that UGR can develop further to a comparable level of European and Asian large-scale genomic initiatives.
Reduced motor unit discharge rates in gastrocnemius lateralis, but not in gastrocnemius medialis or soleus, in runners with Achilles tendinopathy
Authors: Fernandes Gabriel L. , Orssatto Lucas B. R. , Sakugawa Raphael L. , Trajano Gabriel S.
Published: May 2022

Objectives

Deficits in muscle performance could be a consequence of a reduced ability of a motor neuron to increase the rate in which it discharges. This study aimed to investigate motor unit (MU) discharge properties of each Triceps surae muscle (TS), and TS torque steadiness during submaximal intensities in runners with Achilles tendinopathy (AT).

Methods

We recruited runners with (n=12) and without (n=13) mid-portion AT. MU discharge rate was analysed for each of the TS muscles, using High-Density surface electromyography during 10 and 20% isometric plantar flexor contractions.

Results

MU mean discharge rate was lower in the Gastrocnemius lateralis (GL) in AT compared to controls. In AT, GL MU mean discharge rate did not increase as torque increased from 10% peak torque, 8.24pps (95%CI: 7.08 to 9.41) to 20%, 8.52pps (7.41 to 9.63, p=0.540); however, in controls, MU discharge rate increased as torque increased from 10%, 8.39pps (7.25 to 9.53) to 20%, 10.07pps (8.89 to 11.25, p<0.001). There were no between-group difference in Gastrocnemius medialis (GM) or Soleus (SOL) MU discharge rates. We found no between-groups differences in coefficient of variation of MU discharge rate in any of the TS muscles nor in TS torque steadiness.

Conclusion

Our data demonstrates that runners with AT may have a reduced neural drive to GL, failing to increase MU discharge rate to adjust for the increase in torque demand. Further research is needed to understand how interventions focusing on increasing neural drive to GL would affect muscle function in runners with AT.
Substance abuse and the risk of severe COVID-19: Mendelian randomization confirms the causal role of opioids but hints a negative causal effect for cannabinoids
Authors: Jabalameli M.Reza , Zhang Zhengdong D
Published: May 2022

Since the start of the COVID-19 global pandemic, our understanding of the underlying disease mechanism and factors associated with the disease severity has dramatically increased. A recent report investigated the relationship between substance use disorders (SUD) and the risk of severe COVID-19 in the United States and concluded that the risk of hospitalization and death due to COVID-19 is directly correlated with substance abuse, including opioid use disorder (OUD) and cannabis use disorder (CUD). While we found this analysis fascinating, we believe this observation may be biased due to comorbidities (such as hypertension, diabetes, and cardiovascular disease) confounding the direct impact of SUD on severe COVID-19 illness. To objectively answer this question, we sought to investigate the causal relationship between substance abuse and medication-taking history (as a proxy trait for comorbidities) with the risk of COVID-19 adverse outcomes. Our Mendelian randomization analysis confirms the causal relationship between SUD and severe COVID-19 illness but hints at a negative causal effect for cannabinoids. Given that a great deal of COVID-19 mortality is attributed to disturbed immune regulation, the possible modulatory impact of cannabinoids in alleviating cytokine storms merits further investigation.