bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial/Ethnic Disparities in Health Care Setting Choice for Adults Seeking Severe Acute Respiratory Syndrome Coronavirus 2 Testing
Authors: Sparling Alica , Walls Morgan , Mayfield Carlene A. , Priem Jennifer S. , Durham Jason , Hetherington Timothy , Taylor Yhenneko J.
Published: November 2021

Objectives:

Equitable access to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing is important for reducing disparities. We sought to examine differences in the health care setting choice for SARS-CoV-2 testing by race/ethnicity and insurance. Options included traditional health care settings and mobile testing units (MTUs) targeting communities experiencing disproportionately high coronavirus disease 2019 (COVID-19) rates.

Methods:

We conducted a retrospective, observational study among patients in a large health system in the Southeastern US. Descriptive statistics and multinomial logistic regression analyses were employed to evaluate associations between patient characteristics and health care setting choice for SARS-CoV-2 testing, defined as: (1) outpatient (OP) care; (2) emergency department (ED); (3) urgent care (UC); and (4) MTUs. Patient characteristics included race/ethnicity, insurance, and the existence of an established relationship with the health care system.

Results:

Our analytic sample included 105,386 adult patients tested for SARS-CoV-2. Overall, 55% of patients sought care at OP, 24% at ED, 12% at UC, and 9% at MTU. The sample was 58% White, 24% Black, 11% Hispanic, and 8% other race/ethnicity. Black patients had a higher likelihood of getting tested through the ED compared with White patients. Hispanic patients had the highest likelihood of testing at MTUs. Patients without a primary care provider had a higher relative risk of being tested through the ED and MTUs versus OP.

Conclusions:

Disparities by race/ethnicity were present in health care setting choice for SARS-CoV-2 testing. Health care systems may consider implementing mobile care delivery models to reach vulnerable populations. Our findings support the need for systemic change to increase primary care and health care access beyond short-term pandemic solutions.
Decreased Racial and Ethnic Disparities in Emergency Department Wait Time in the United States
Authors: Abdulai Abubakar-Sadiq B. , Mukhtar Fahad , Ehrlich Michael
Published: November 2021

Background:

Previous data over an extended period indicated that Black and Hispanic patients waited significantly longer than their White counterparts to see a qualified practitioner in US emergency departments (EDs).

Objective:

The objective of this study was to assess recent trends and sources of racial and ethnic disparities in patient wait time to see a qualified practitioner in US EDs.

Data Sources:

Publicly available ED subsample of the National Hospital Ambulatory Medical Care Survey (NHAMCS), 2003–2017.

Research Design:

A retrospective cross-sectional analysis of a nationally representative sample of visits to US EDs from 2003 to 2017. Joinpoint statistical analysis and survey-weighted regression were used to assess changes in ED wait time by race/ethnic group over time.

Principal Findings:

For non-Hispanic White patients, median ED wait time increased annually by 1.3 minutes from 2003 through 2008, decreased by 3.0 minutes from 2008 through 2012, and decreased by 1.7 minutes from 2012 to 2017. For non-Hispanic Black patients, median wait time increased annually by 2.0 minutes from 2003 through 2008, decreased by 3.8 minutes from 2008 through 2015, and remained fairly unchanged from 2015 through 2017. For Hispanic patients, the trend in median wait time remained statistically unchanged from 2003 through 2009. It decreased by annually by 4.7 minutes from 2009 to 2012 and by 1.5 minutes from 2012 through 2017. By the end of 2017, median ED wait time decreased to under 20 minutes across all 3 groups.

Conclusions:

Over time, ED wait times decreased to under 20 minutes across all racial and ethnic groups between 2003 and 2017. Observed disparities were largely the result of where minority populations accessed care and disappeared over time.
Family Practices in Transforming Clinical Practice Initiative Showed No Changes in Medicare Costs or Utilization
Authors: Dai Mingliang , Chung Yoonkyung , Peterson Lars E. , Petterson Stephen , Phillips Robert L.
Published: November 2021

Background:

The Centers for Medicare and Medicaid Services proposed that the Transforming Clinical Practice Initiative (TCPI) would improve health outcomes for patients, reduce utilization of institutional services, and generate significant savings for payers by the end of September 2019.

Objective:

The objective of this study was to investigate whether participation in TCPI’s Practice Transformation Networks (PTNs) was associated with improved cost and utilization outcomes for Medicare patients of family medicine–based practices in the first 2 years, that is, 2016–2017, of the Initiative.

Study Design:

A quasi-experimental design with a longitudinal cohort of family medicine–based practices and a propensity-matched comparison sample.

Subjects:

A total of 761 PTN practices and 3451 non-PTN practices.

Measures:

To measure practice-level patient outcomes, we attributed patients to practice based on the plurality of office visits. We obtained Medicare claims from 2011 to 2017 to assess PTN participation effects for Medicare Part A and B costs, hospital admission, and emergency department visit rates using a Difference-in-Differences design, adjusting for baseline characteristics.

Results:

The differences in Medicare Part A and B costs (−1.71%, P=0.25), annual rates of hospitalization (−0.59%, P=0.12) and emergency department visit (−0.29%, P=0.46) were not significantly lower among PTN practices (N=761) than among propensity score–matched non-PTN practices (N=3541).

Conclusions:

TCPI’s transforming efforts, such as the outcomes examined in the study, might need a longer time frame to manifest and require evaluation after the full 4-year participation period. The indistinguishable effect of PTN participation may also be attributed to the fact that non-PTN practices might have participated in other initiatives that changed their care and curbed health care utilization and costs consequently.
Postmortem Interval Estimation With Corneal Endothelial Cell Density
Authors: Özsoy Sait , Kaya Burak , Balandiz Hüseyin , Akyol Mesut , Özge Gökhan , Özmen Mehmet Cüneyt , Uysal Betül Seher
Published: November 2021

Objectives

In the neonatal period, healthy people have the highest corneal endothelial cell density (CECD) (5000–7000 cells/mm2). Corneal endothelial cell density declines with age in adults (2500–3000 cells/mm2) and continues to decline in the postmortem period. We measured CECD in cases with different postmortem interval (PMI) and investigated its association with PMI.

Methods

A total of 555 corneas harvested from 285 cases with a known time of death were examined using a specular microscope.

Results

Postmortem corneal removal time ranged between 10 and 1395 minutes. The CECD averages were 2653 for right cornea and 2678 cells/mm2 for left cornea. An inverse but nonlinear relationship was found between age and CECD. In both men and women, there was an inverse and weak correlation between age and CECD (ρ = −0.282; P < 0.001; ρ = −0.264; P < 0.001, respectively). There was no significant relationship between postmortem corneal removal time and CECD (ρ = 0.049; P = 0.421; ρ = 0.011; P = 0.855 for right and left corneas, respectively). The highest decline in time dependent CECD was detected between the 480th and 540th minutes at −7.2%.

Conclusions

We found no significant decrease in CECD numbers according to PMI or cause of death. Experimental studies on cases with known and standardized antemortem CECD values will provide essential results in estimating PMI.
Solitary Fibrous Tumors of the Female Genital Tract
Authors: Devins Kyle M. , Young Robert H. , Croce Sabrina , Burandt Eike , Bennett Jennifer A. , Pesci Anna , Zannoni Gian F. , Ip Philip P.C. , Nielsen G. Petur , Oliva Esther
Published: November 2021

We report 27 solitary fibrous tumors of the female genital tract emphasizing nonvulvar locations, variant histology, and prognostic factors. The patients ranged from 25 to 78 years (most were over 40), and tumors occurred in the vulva (7), vagina (2), cervix (2), corpus (6), fallopian tube/paratubal soft tissue (5), and ovary (5). They ranged from 1.5 to 39 (mean=10.5) cm and were typically solid, but 4 were predominantly cystic. All had a haphazard arrangement of spindled to ovoid cells, with most demonstrating alternating cellular and hypocellular areas and prominent vessels, but 13 lacked hypocellular areas, and 7 had focal diffuse growth with inconspicuous vasculature. Other patterns included corded (8), fascicular (5), trabecular (1), and nested (1). Microcysts (6), myxoid background (8), hyalinization (8), lipomatous differentiation (2), and multinucleated cells (6) were also present, and 10 tumors had necrosis. Vasculature included thin-walled branching “staghorn” (27), thick-walled (7), and hyalinized vessels (5) or dilated anastomosing vascular channels (3). Nuclear atypia ranged from mild (19), moderate (7), to severe (1), and mitoses from 0 to 24/10 HPF (mean=4). STAT6 was positive in all 25 tumors tested. One tumor showed dedifferentiation; the remainder were classified as benign (19) or malignant (7) based on mitotic rate (univariate stratification model) and as low risk (14), intermediate risk (8), or high risk (4) based on the Demicco multivariate risk stratification score. Follow-up (median=23 mo) was available for 16 patients. Six tumors recurred (2 intermediate risk, 3 high risk, and the dedifferentiated tumor), 5 in the abdomen; the dedifferentiated tumor metastasized to the lung. Multivariate risk stratification was superior to univariate classification, as 5 “benign” tumors were reclassified as intermediate risk using the multivariate model; of these, 2 recurred, and 1 patient died of disease. Upper female genital tract tumors occurred in older patients, were larger, and more frequently classified as high risk compared with those of the lower tract. A trend toward increased cellularity was also seen in the upper tract tumors. Only size (P=0.04), necrosis (P=0.04), and Demicco score (P=0.01) independently correlated with recurrence. Female genital tract solitary fibrous tumors demonstrate a wide range of variant morphologies and occur in diverse sites in addition to the vulva. Tumors were often misdiagnosed as other neoplasms; thus, awareness of solitary fibrous tumors occurring at these sites is crucial in prompting staining for STAT6 to establish this diagnosis. The Demicco risk stratification system effectively predicts behavior.
Global Positioning System Activity Profile in Male Para Footballers With Cerebral Palsy
Authors: Goh Alvin M. , Ma’ayah Fadi , Harms Craig A. , Newton Robert U. , Drinkwater Eric J.
Published: November 2021

Objective

The aim of the study was to compare training and match loads for cerebral palsy football athletes in a state-level development program to assess the specificity of training for competition in the para sport.

Design

Time-motion analysis and heart-rate monitoring were applied during 20 training sessions of the Western Australia CP Football 2017 training season and seven competition matches of the 2017 Australian National Championships. The study used an observational study design with between-subjects and within-subjects comparisons of training and match loads.

Results

There were no significant differences between training and match loads in players’ measurements of speed components and heart rates, with two exceptions: higher match distance covered in very high speed (g = 0.33) and time in heart rate zone 1 (<75% heart rate max, g = 0.45) and less time in heart rate zone 2 (g = 0.42).

Conclusions

Our results indicate that the athletes were conditioned to perform at similar intensities implemented during training, as demonstrated by the consistency between competition and training data in total distance, relative speed zones, and relative heart rate zones. Coaches should apply this knowledge in the programming of training volume and intensities to obtain peak match fitness and specifically prepare athletes for competition in cerebral palsy football.
Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia
Authors: Lillywhite Amanda , Woodhams Stephen G. , Gonçalves Sara V. , Watson David J.G. , Li Li , Burston James J. , Gowler Peter R.W. , Canals Meritxell , Walsh David A. , Hathway Gareth J. , Chapman Victoria
Published: November 2021

Introduction:

Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises.

Objectives:

We tested the hypothesis that the interaction between anxiety, chronic pain, and opioid use results from altered endogenous opioid function.

Methods:

A genetic model of negative affect, the Wistar–Kyoto (WKY) rat, was combined with intra-articular injection of monosodium iodoacetate (MIA; 1 mg) to mimic clinical presentation. Effects of systemic morphine (0.5–3.5 mg·kg−1) on pain behaviour and spinal nociceptive neuronal activity were compared in WKY and normo-anxiety Wistar rats 3 weeks after MIA injection. Endogenous opioid function was probed by the blockade of opioid receptors (0.1–1 mg·kg−1 systemic naloxone), quantification of plasma β-endorphin, and expression and phosphorylation of spinal mu-opioid receptor (MOR).

Results:

Monosodium iodoacetate–treated WKY rats had enhanced OA-like pain, blunted morphine-induced analgesia, and greater mechanical hypersensitivity following systemic naloxone, compared with Wistar rats, and elevated plasma β-endorphin levels compared with saline-treated WKY controls. Increased MOR phosphorylation at the master site (serine residue 375) in the spinal cord dorsal horn of WKY rats with OA-like pain (P = 0.0312) indicated greater MOR desensitization.

Conclusions:

Reduced clinical analgesic efficacy of morphine was recapitulated in a model of high anxiety and OA-like pain, in which endogenous opioid tone was altered, and MOR function attenuated, in the absence of previous exogenous opioid ligand exposure. These findings shed new light on the mechanisms underlying the increased opioid analgesic use in high anxiety patients with chronic pain.
Scarring Caused by the Percutaneous Approach to Fractures of the Orbit and Orbital Rim
Authors: Kashiyama Kazuya , Yano Hiroki , Imamura Yoshinobu , Iwao Atsuhiko , Higashi Akihito , Moriuti Yuki , Ashizuka Shoko , Adachi Yurie , Koga Kazufumi , Hirano Akiyoshi , Tanaka Katsumi
Published: November 2021

Percutaneous and transconjunctival approaches are commonly used for fractures of the orbit and orbital rim. However, it leaves visible scarring on the face. Although previous studies reported scarring from the percutaneous approach, few reported the degree of such scarring. The authors examined the degree of scarring associated with percutaneous approaches to fractures of the orbit and orbital rim in the Japanese population. The authors reviewed photographs of patients who were treated surgically for fractures of the orbital floor, medial orbital wall, or zygomatic bone via percutaneous approaches to examine the presence of scarring and deformation. In 36% of all patients, the observers were unable to determine the side on which the surgery was performed. Furthermore, the site of scarring was identified accurately in only 20.6% of the cases in which observers were able to identify the surgical side. The authors’ study demonstrated that the subciliary approach left minimal scarring under the eyelashes. On the other hand, the medial canthal approach left depressed and wide scarring, whereas pigmentation was apparent in patients who underwent surgery via the lateral eyebrow approach. Similarly, pigmentation under the eyelashes and at the site of secondary incision was common after the subciliary approach.
A Comparison of Dexmedetomidine and Propofol on Emergence Delirium in Children Undergoing Cleft Palate Surgery With Sevoflurane-Based Anesthesia
Authors: Huang Lili , Wang Li , Peng Wei , Qin Chuanqi
Published: November 2021

Emergence delirium is a common complication after sevoflurane-anesthesia and have a serious impact on children undergoing cleft palate surgery. The aim of this study was to compare the effect of propofol and dexmedetomidine on emergence delirium in children. Ninety children aged 8 to 24 months, underwent cleft palate repair, were enrolled in the study. Children were randomly assigned to 3 groups after the induction: Group C (intravenous infusion 0.9% saline), Group P (intravenous infusion 2 mg/kg/hour propofol), and Group D (intravenous infusion 0.5 μg/kg/hour dexmedetomidine). Emergence delirium was diagnosed using the pediatric anesthesia emergence delirium scale and pain using the face, legs, activity, cry, consolability scale. Heart rate, mean arterial pressure, respiratory recovery time, extubation time, post anesthesia care unit observation time, and adverse events were also evaluated. A total of 86 patients were analyzed. The incidence of emergence delirium was 20.1% in group D, 58.6% in group P and 85.7% in group C (P < 0.05). A lower face, legs, activity, cry, consolability score was seen in group D than in group P and group C (3.9 + 1.1 versus 6.1 ± 0.9 and 7.1 ± 1.0, P < 0.05). The value of heart rate and mean arterial pressure during emergence in group P and group C were significantly higher than that in group D (All P < 0.05). These findings suggest that dexmedetomidine as a sedative, analgesic, and sympatholytic agent was superior to propofol in reducing the incidence of emergence delirium in children undergoing cleft palates surgery with sevoflurane-based anesthesia.
Antiepileptics in Electroconvulsive Therapy
Authors: Cinderella Margaret A. , Nichols Nona A. , Munjal Sahil , Yan Jason , Kimball James N. , Gligorovic Predrag
Published: November 2021

Although prior conventional wisdom strongly recommended complete discontinuation of medications increasing the seizure threshold before electroconvulsive therapy (ECT), more recent literature suggests that anticonvulsants should be considered a relative rather than an absolute contraindication to proceeding with therapy. Most literature regarding the use of use antiepileptic drugs in ECT focuses on antiepileptic mood stabilizers with which most psychiatrists are familiar. However, there is considerably less information available about the use of newer antiepileptics in conjunction with ECT, which may be prescribed to a patient with epilepsy or off-label for psychiatric reasons.

In this article, we provide a mechanism-based review of recent available literature concerning the use of antiepileptics during ECT and discuss which medications have the most robust evidence supporting their continued use in select patients. Finally, we highlight important considerations for psychiatrists when deciding how to proceed with patients on antiepileptics who require ECT.
Pseudoalteromonas ostreae sp. nov., a new bacterial species harboured by the flat oyster Ostrea edulis
Authors: Cuny Héléna , Offret Clément , Boukerb Amine M. , Parizadeh Leila , Lesouhaitier Olivier , Le Chevalier Patrick , Jégou Camille , Bazire Alexis , Brillet Benjamin , Fleury Yannick
Published: November 2021

Three bacterial strains, named hOe-66T, hOe-124 and hOe-125, were isolated from the haemolymph of different specimens of the flat oysterOstrea eduliscollected in Concarneau bay (Finistère, France). These strains were characterized by a polyphasic approach, including (i) whole genome analyses with 16S rRNA gene sequence alignment and pangenome analysis, determination of the G+C content, average nucleotide identity (ANI), andin silicoDNA–DNA hybridization (isDDH), and (ii) fatty acid methyl ester and other phenotypic analyses. Strains hOe-66T, hOe-124 and hOe-125 were closely related to both type strainsPseudoalteromonas rhizosphaeraeRA15TandPseudoalteromonas neustonicaPAMC 28425Twith less than 93.3% ANI and 52.3%isDDH values. Regarding their phenotypic traits, the three strains were Gram-negative, 1–2 µm rod-shaped, aerobic, motile and non-spore-forming bacteria. Cells grew optimally at 25 °C in 2.5% NaCl and at 7–8 pH. The most abundant fatty acids were summed feature 3 (C16:1ω7c/C16:1ω6c), C16:0and C17:1ω8c. The strains carried a genome average size of 4.64 Mb and a G+C content of 40.28 mol%. The genetic and phenotypic results suggested that strains hOe-66T, hOe-124 and hOe-125 belong to a new species of the genusPseudoalteromonas. In this context, we propose the namePseudoalteromonas ostreaesp. nov. The type strain is hOe-66T(=CECT 30303T=CIP 111911T).
ICTV Virus Taxonomy Profile: Nyamiviridae 2021
Authors: Dietzgen Ralf G. , Firth Andrew E. , Jiāng Dàohóng , Junglen Sandra , Kondo Hideki , Kuhn Jens H. , Paraskevopoulou Sofia , Vasilakis Nikos ,   ICTV Report Consortium
Published: November 2021

Nyamiviridae is a family of viruses in the order Mononegavirales, with unsegmented (except for members of the genus Tapwovirus), negative-sense RNA genomes of 10–13 kb. Nyamviruses have a genome organisation and content similar to that of other mononegaviruses. Nyamiviridae includes several genera that form monophyletic clades on phylogenetic analysis of the RNA polymerase. Nyamiviruses have been found associated with diverse invertebrates as well as land- and seabirds. Members of the genera Nyavirus and Socyvirus produce enveloped, spherical virions. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Nyamiviridae, which is available at ictv.global/report/nyamiviridae.
Cell-free supernatants produced by lactic acid bacteria reduce Salmonella population in vitro
Authors: Evangelista Alberto Gonçalves , Corrêa Jessica Audrey Feijó , dos Santos João Vitor Garcia , Matté Eduardo Henrique Custódio , Milek Mônica Moura , Biauki Gabrieli Camila , Costa Leandro Batista , Luciano Fernando Bittencourt
Published: November 2021

The genus

Salmonella

is closely associated with foodborne outbreaks and animal diseases, and reports of antimicrobial resistance in

Salmonella

species are frequent. Several alternatives have been developed to control this pathogen, such as cell-free supernatants (CFS). Our objective here was to evaluate the use of lactic acid bacteria (LAB) CFS against Salmonella in vitro. Seventeen strains of LAB were used to produce CFS, and their antimicrobial activity was screened towards six strains of

Salmonella

. In addition, CFS were also pH-neutralized and/or boiled. Those with the best results were lyophilized. MICs of lyophilized CFS were 11.25–22.5 g l–1. Freeze-dried CFS were also used to supplement swine and poultry feed (11.25 g kg–1) and in vitro simulated digestion of both species was performed, with

Salmonella

contamination of 5×106 and 2×105 c.f.u. g−1 of swine and poultry feed, respectively. In the antimicrobial screening, all acidic CFS were able to inhibit the growth of

Salmonella

. After pH neutralization,

Lactobacillus acidophilus

Llorente,

Limosilactobacillus fermentum

CCT 1629,

Lactiplantibacillus plantarum

PUCPR44,

Limosilactobacillus reuteri

BioGaia,

Lacticaseibacillus rhamnosus

ATCC 7469 and

Pediococcus pentosaceus

UM116 CFS were the only strains that partially maintained their antimicrobial activity and, therefore, were chosen for lyophilization. In the simulated swine digestion,

Salmonella

counts were reduced ≥1.78 log c.f.u. g–1 in the digesta containing either of the CFS. In the chicken simulation, a significant reduction was obtained with all CFS used (average reduction of 0.59±0.01 log c.f.u. ml–1). In general, the lyophilized CFS of

L. fermentum

CCT 1629,

L. rhamnosus

ATCC 7469 and

L. acidophilus

Llorente presented better antimicrobial activity. In conclusion, CFS show potential as feed additives to control

Salmonella

in animal production and may be an alternative to the use of antibiotics, minimizing problems related to antimicrobial resistance.
Neural reinstatement tracks attentional selection of object features in working memory
Authors: Printzlau Frida A. B. , Myers Nicholas E. , Manohar Sanjay G. , Stokes Mark G.
Published: November 2021

Attention can be allocated in working memory (WM) to select and privilege relevant content. It is unclear whether attention selects individual features or whole objects in WM. Here, we used behavioural measures, eye-tracking and electroencephalography (EEG) to test the hypothesis that attention spreads between an object’s features in WM. Twenty-six participants completed a WM task that asked them to recall the angle of one of two oriented, coloured bars after a delay while EEG and eye-tracking data was collected. During the delay, an orthogonal ‘incidental task’ cued the colour of one item for a match/mismatch judgement. On congruent trials (50%), the cued item was probed for subsequent orientation recall; on incongruent trials (50%), the other memory item was probed. As predicted, selecting the colour of an object in WM brought other features of the cued object into an attended state as revealed by EEG decoding, oscillatory α-power, gaze bias and improved orientation recall performance. Together, the results show that attentional selection spreads between an object’s features in WM, consistent with object-based attentional selection. Analyses of neural processing at recall revealed that the selected object was automatically compared with the probe, whether it was the target for recall or not. This provides a potential mechanism for the observed benefits of non-predictive cueing in WM, where a selected item is prioritised for subsequent decision-making.
Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin
Authors: Burbelo Peter D. , Castagnoli Riccardo , Shimizu Chisato , Delmonte Ottavia M. , Dobbs Kerry , Discepolo Valentina , Vecchio Andrea Lo , Guarino Alfredo , Licciardi Francesco , Ramenghi Ugo , Rey Emma , Vial Maria Cecilia , Marseglia Gian Luigi , Licari Amelia , Montagna Daniela , Rossi Camillo , Montealegre Sanchez Gina A. , Barron Karyl , Warner Blake M. , Chiorini John A. , Espinosa Yazmin , Noguera Loreani , Dropulic Lesia , Truong Meng , Gerstbacher Dana , Mató Sayonara , Kanegaye John , Tremoulet Adriana H. ,   Pediatric Emergency Medicine Kawasaki Group, Eisenstein Eli M. , Su Helen C. , Imberti Luisa , Poli Maria Cecilia , Burns Jane C. , Notarangelo Luigi D. , Cohen Jeffrey I.
Published: November 2021

The autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin(IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoringin vivodecay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.
Likelihood based Mendelian randomization analysis with automated instrument selection and horizontal pleiotropic modeling
Authors: Yuan Zhongshang , Liu Lu , Guo Ping , Yan Ran , Xue Fuzhong , Zhou Xiang
Published: November 2021

Mendelian randomization (MR) is a common tool for identifying causal risk factors underlying diseases. Here, we present a method, MRAID, for effective MR analysis. MRAID borrows ideas from fine mapping analysis to model an initial set of candidate SNPs that are in potentially high linkage disequilibrium with each other and automatically selects among them the suitable instruments for causal inference. MRAID also explicitly models both uncorrelated and correlated horizontal pleiotropic effects that are widespread for complex trait analysis. MRAID achieves both tasks through a joint likelihood framework and relies on a scalable sampling-based algorithm to compute calibratedp-values. Comprehensive and realistic simulations show MRAID can provide calibrated type I error control, reduce false positives, while being more powerful than existing approaches. We illustrate the benefits of MRAID for an MR screening analysis across 645 trait pairs in UK Biobank, identifying multiple lifestyle causal risk factors of cardiovascular disease-related traits.
Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis
Authors: Junker Alex , Wang Jennifer , Gouspillou Gilles , Ehinger Johannes K. , Elmér Eskil , Sjövall Fredrik , Fisher-Wellman Kelsey , Darrell Neufer P. , Molina Anthony J.A. , Ferrucci Luigi , Picard Martin
Published: November 2021

Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in biomedical knowledge. This meta-analysis systematically examined 4 domains and 6 subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge’s g) of sex differences were computed for each measure using data in 2,258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women (g = 0.20, χ2p = 0.01), and higher ROS production in skeletal muscle in men (g = 0.49, χ2p < 0.0001). differences showed weak to Sex no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -0.17, p < 0.001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.
Turnover of MCMV-expanded CD8+ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response
Authors: Baliu-Piqué Mariona , Drylewicz Julia , Zheng Xiaoyan , Borkner Lisa , Swain Arpit C. , Otto Sigrid , de Boer Rob J. , Tesselaar Kiki , Cicin-Sain Luka , Borghans José A.M.
Published: November 2021

The potential of memory T-cells to provide protection against re-infection is beyond question. Yet, it remains debated whether long-term T-cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8+ T-cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T-cells, depending on factors such as exposure to cognate antigen. Cytomegalovirus (CMV) infection induces not only conventional, contracting T-cell responses, but also inflationary CD8+ T-cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T-cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8+ T-cells. Using in vivo deuterium labelling and mathematical modelling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8+ T-cells are very similar to those of bulk memory-phenotype CD8+ T-cells. Even CMV-specific inflationary CD8+ T-cell responses that differ three-fold in size, were found to turn over at similar rates.
Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerases (PARPs), blocks in vitro replication of SARS-CoV-2 variants
Authors: Zarn Katherine E , Jaramillo Sierra A , Zapata Anthony R , Stone Nathan E , Jones Ashley N , Nunnally Haley E , Settles Erik W , Ng Ken , Keim Paul S , Knudsen Steen , Nuijten Patricia M , Tijsma Aloys SL , French Christopher T
Published: November 2021

We recently published a preliminary assessment of the activity of a poly (ADP-ribose) polymerase (PARP) inhibitor, stenoparib, also known as 2X-121, which inhibits viral replication by affecting pathways of the host. Here we show that stenoparib effectively inhibits a SARS-CoV-2 wt (BavPat1/2020) strain and four additional variant strains; alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 μM, 8.5 μM, 24.1 μM, 8.2 μM and 13.6 μM, respectively. A separate experiment focusing on a combination of 10 μM stenoparib and 0.5 μM remdesivir, an antiviral drug, resulted in over 80% inhibition of the alpha (B.1.1.7) variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.
Immediate and mid-term effect of a natural topical product in patients with musculoskeletal pain: randomized, double-blinded, and placebo-controlled clinical trial
Authors: Ramon Silvia , de Unzurrunzaga Rocio , Nishishinya Betina , Lucenteforte Giacomo , García Miguel , Barastegui David , Unzueta Itziar , Arcalis Antonio , Cugat Ramon
Published: November 2021

Introduction

Musculoskeletal pain is a common affection due to ageing, sedentarism and injuries. The objective of this trial is to prove efficacy of a natural topical composition containing Arnica montana, Hypericum perforatum, Calendula officinalis, Melaleuca sp. and menthol in pain management in adults with acute or chronic pain.

Methods

This randomized, double-blinded and placebo-controlled trial included 200 patients with musculoskeletal pain, 100 in the intervention group receiving the topical formula and 100 in the placebo group, receiving a similar formula without active ingredients. The products were applied topically twice daily for 14 days in affected areas. Immediate pain alleviation and stiffness perception were monitored for two hours at days 0, 7 at 14. Pain reduction and recovery perception upon sustained application were assessed after 7 and 14 days.

Results

Intervention immediately reduced pain and stiffness at rest and in motion 30 minutes after application and kept being superior to placebo in all short-term timepoints (p < 0.05). Immediate pain reduction was maintained even at late stages of recovery. A two-week sustained intervention resulted in significant pain reduction and improvement in recovery perception. Even if both groups reached statistical significance with respect to baseline due to spontaneous lesion recovery, a significantly improved recovery was reported in the intervention group with respect to placebo.

Conclusions

Intervention was found to reduce pain and stiffness upon minutes of its application and to improve pain and mobility over the 14 days of treatment, showing benefits both for immediate alleviation and for longer term recovery.

Level of Evidence

Therapeutic Level I
Creation and evaluation of full-text literature-derived, feature-weighted disease models of genetically determined developmental disorders
Authors: Yates T.M , Lain A. , Campbell J. , Simpson T.I. , FitzPatrick D.R.
Published: November 2021

There are >2500 different genetically-determined developmental disorders (DD), which, as a group, show very high levels of both locus and allelic heterogeneity. This has led to the wide-spread use of evidence-based filtering of genome-wide sequence data as a diagnostic tool in DD. Determining whether the association of a filtered variant at a specific locus is a plausible explanation of the phenotype in the proband is crucial and commonly requires extensive manual literature review by both clinical scientists and clinicians. Access to a database of weighted clinical features extracted from rigorously curated literature would increase the efficiency of this process and facilitate the development of robust phenotypic similarity metrics. However, given the large and rapidly increasing volume of published information, conventional biocuration approaches are becoming impractical.

Here, we present a scalable, automated method for extraction of categorical phenotypic descriptors from full-text literature. Papers identified through literature review were downloaded and parsed using the Cadmus custom retrieval package. Human Phenotype Ontology terms were extracted using MetaMap, with 76-83% precision and 72-81% recall. Mean terms per paper increased from 9 in title + abstract, to 69 using full text. We demonstrate that these literature-derived disease models plausibly reflect true disease expressivity more accurately than gold standard manually-curated models, through comparison with prospectively gathered data from the Deciphering Developmental Disorders study. AUC for ROC curves increased by 5-10% through use of literature-derived models. This work shows that scalable automated literature curation increases performance and adds weight to the need for this strategy to be integrated into informatic variant analysis pipelines.
Of masks and methylene blue - the use of methylene blue photochemical treatment to decontaminate surgical masks contaminated with a tenacious small non-enveloped norovirus
Authors: Wielick Constance , Fries Allyson , Dams Lorène , Razafimahefa Ravo M. , Heyne Belinda , Harcourt Brian H. , Lendvay Thomas S. , Willaert Jean François , de Jaeger Simon , Haubruge Eric , Thiry Etienne , Ludwig-Begall Louisa F.
Published: November 2021

Background

In the context of the SARS-CoV-2 pandemic, reuse of personal protective equipment, specifically that of medical face coverings, has been recommended. The reuse of these typically single-use only items necessitates procedures to inactivate contaminating human respiratory and gastrointestinal pathogens. We previously demonstrated decontamination of surgical masks and respirators contaminated with infectious SARS-CoV-2 and various animal coronaviruses via low concentration- and short exposure methylene blue photochemical treatment (10 µM methylene blue, 30 minutes of 12,500-lux red light or 50,000 lux white light exposure).

Methods

Here, we describe the adaptation of this protocol to the decontamination of a more resistant, non-enveloped gastrointestinal virus and demonstrate efficient photodynamic inactivation of murine norovirus, a human norovirus surrogate.

Results

Methylene blue photochemical treatment (100 µM methylene blue, 30 minutes of 12,500-lux red light exposure) of murine norovirus-contaminated masks reduced infectious viral titres by over four orders of magnitude on surgical mask surfaces.

Discussion and Conclusions

Inactivation of a norovirus, the most difficult to inactivate of the respiratory and gastrointestinal human viruses, can predict the inactivation of any less resistant viral mask contaminant. The protocol developed here thus solidifies the position of methylene blue photochemical decontamination as an important tool in the package of practical pandemic preparedness.
Exposure contrasts of pregnant women during the Household Air Pollution Intervention Network randomized controlled trial
Authors: Johnson Michael , Pillarisetti Ajay , Piedrahita Ricardo , Balakrishnan Kalpana , Peel Jennifer L. , Steenland Kyle , Underhill Lindsay J. , Rosa Ghislaine , Kirby Miles A. , Díaz-Artiga Anaité , McCracken John , Clark Maggie L. , Waller Lance , Chang Howard , Wang Jiantong , Dusabimana Ephrem , Ndagijimana Florien , Sambandam Sankar , Mukhopadhyay Krishnendu , Kearns Katherine , Campbell Devan , Kremer Jacob , Rosenthal Joshua , Checkley William , Clasen Thomas , Naeher Luke
Published: November 2021

Background

Exposure to PM2.5 arising from solid fuel combustion is estimated to result in approximately 2.3 million premature deaths and 90 million lost disability-adjusted life years annually. ‘Clean’ cooking interventions attempting to mitigate this burden have had limited success in reducing exposures to levels that may yield improved health outcomes.

Objectives

This paper reports exposure reductions achieved by a liquified petroleum gas (LPG) stove and fuel intervention for pregnant mothers in the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial.

Methods

The HAPIN trial included 3,195 households primarily using biomass for cooking in Guatemala, India, Peru, and Rwanda. 24-hour exposures to PM2.5, carbon monoxide (CO), and black carbon (BC) were measured for pregnant women once before randomization into control (n=1605) and LPG arms (n=1590) and twice thereafter (aligned with trimester). Changes in exposure were estimated by directly comparing exposures between intervention and control arms and by using linear mixed-effect models to estimate the impact of the intervention on exposure levels.

Results

Median exposures of PM2.5, BC, and CO post-randomization in the intervention arm were lower by 66% (70.7 versus 24.0 μg/m3), 71% (9.6 versus 2.8 μg/m3), and 83% (1.2 versus ppm), respectively, compared to the control arm. Exposure reductions were similar across research locations. Post-intervention PM2.5 exposures in the intervention arm were at the lower end of what has been reported for LPG and other clean fuel interventions, with 69% of PM2.5 samples falling below the WHO Annual Interim Target 1 of 35 μg/m3.

Discussion

This study indicates that an LPG intervention with high displacement of traditional cooking can reduce exposures to levels thought to be associated with health benefits. Success in reducing exposures was likely due to strong performance of, and high adherence to the intervention.
Engineering of extracellular vesicles for small molecule-regulated cargo loading and cytoplasmic delivery of bioactive proteins
Authors: Somiya Masaharu , Kuroda Shun’ichi
Published: November 2021

Cytoplasmic delivery of functional proteins into target cells remains challenging for many biological agents to exert their therapeutic effects. Extracellular vesicles (EVs) are expected to be a promising platform for protein delivery; however, efficient loading of proteins of interest (POIs) into EVs remains elusive. In this study, we utilized small compound-induced heterodimerization between FK506 binding protein (FKBP) and FKBP12-rapamycin-binding (FRB) domain, to sort bioactive proteins into EVs using the FRB-FKBP system. When CD81, a typical EV marker protein, and POI were fused with FKBP and FRB, respectively, rapamycin induced the binding of these proteins through FKBP-FRB interaction and recruited the POIs into EVs. The released EVs, displaying virus-derived membrane fusion protein, delivered the POI cargo into recipient cells and their functionality in the recipient cells was confirmed. Furthermore, we demonstrated that CD81 could be replaced with other EV-enriched proteins, such as CD63 or HIV Gag. Thus, the FRB-FKBP system enables the delivery of functional proteins and paves the way for EV-based protein delivery platforms.
3D reconstruction of cell nuclei in a full Drosophila brain
Authors: Mu Shang , Yu Szi-chieh , Turner Nicholas L. , McKellar Claire E. , Dorkenwald Sven , Collman Forrest , Koolman Selden , Moore Merlin , Morejohn Sarah , Silverman Ben , Willie Kyle , Willie Ryan , Bland Doug , Burke Austin , Ashwood Zoe , Luther Kyle , Castro Manuel , Ogedengbe Oluwaseun , Silversmith William , Wu Jingpeng , Halageri Akhilesh , Macrina Thomas , Kemnitz Nico , Murthy Mala , Seung H. Sebastian
Published: November 2021

We reconstructed all cell nuclei in a 3D image of a Drosophila brain acquired by serial section electron microscopy (EM). The total number of nuclei is approximately 133,000, at least 87% of which belong to neurons. Neuronal nuclei vary from several hundred down to roughly 5 cubic micrometers. Glial nuclei can be even smaller. The optic lobes contain more than two times the number of cells than the central brain. Our nuclear reconstruction serves as a spatial map and index to the cells in a Drosophila brain.
Mouse oocytes develop in cysts with the help of nurse cells
Authors: Niu Wanbao , Spradling Allan C.
Published: November 2021

Mammalian oocytes develop initially in cysts containing many more germ cells than the primordial oocytes they generate. We identified abundant nurse cells with reduced unique molecular identifiers (UMI)/cell from ovaries aged E14.5 to P1. Low UMI nurse cells are found in cysts and express the same major meiotic genes as pro-oocytes of the same stage, suggesting they are oocyte sisters that are signaled to transfer cytoplasm at different times and only subsequently diverge. Oocyte vs nurse cell selection occurs in cysts with a robust microtubule cytoskeleton, that closely interact with somatic cells and that develop a dense actin cytoskeleton around nurse cell nuclei that are held back from cytoplasmic transfer. Mouse and Drosophila nurse cells undergo programmed cell death by acidification from adjacent somatic pre-granulosa cells that express V-ATPases and cathepsin proteins. Disrupting acidification in cultured mouse ovaries blocked nurse cell turnover. About 200 genes are induced in mouse dictyate oocytes as previously reported, including Tuba1c and Tubb2b, genes that we find contribute to Balbiani body formation. Thus, mouse oocytes are specified within germline cysts and develop with the assistance of nurse cells using highly conserved mechanisms.
A New Bioink for Improved 3D Bioprinting of Bone-Like Constructs
Authors: Marsh Adam C. , Apu Ehsanul Hoque , Bunn Marcus , Contag Christopher H. , Ashammakhi Nureddin , Chatzistavrou Xanthippi
Published: November 2021

Bone tissue loss can occur due to disease, trauma or following surgery, in each case treatment involving the use of bone grafts or biomaterials is usually required. Recent development of three-dimensional (3D) bioprinting (3DBP) has enabled the printing of customized bone substitutes. Bioinks used for bone 3DBP employ various particulate phases such as ceramic and bioactive glass particles embedded in the bioink creating a composite. When composite bioinks are used for 3DBP based on extrusion, particles are heterogeneously distributed causing damage to cells due to stresses created during flow in the matrix of the composite. Therefore, the objective of this study was to develop cell-friendly osteopromotive bioink mitigating the risk of cell damage due to the flow of particles. Towards this end, we have linked organic and inorganic components, gelatin methacryloyl (GelMA) and Ag-doped bioactive glass (Ag-BaG), to produce a hybrid material, GelMA-Ag-BaG (GAB). The distribution of the elements present in the Ag-BaG in the resulting hybrid GAB structure was examined. Rheological properties of the resulting hydrogel and its printability, as well as the degree of swelling and degradation over time, were also evaluated. GAB was compared to GelMA alone and GelMA-Ag-BaG nanocomposites. Results showed the superiority of the hybrid GAB bioink in terms of homogenous distribution of the elements in the structure, rheological properties, printability, and degradation profiles. Accordingly, this new bioink represents a major advance for bone 3DBP.