bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronavirus Disease 2019 Temperature Trajectories Correlate With Hyperinflammatory and Hypercoagulable Subphenotypes
Authors: Bhavani Sivasubramanium V. , Verhoef Philip A. , Maier Cheryl L. , Robichaux Chad , Parker William F. , Holder Andre , Kamaleswaran Rishikesan , Wang May D. , Churpek Matthew M. , Coopersmith Craig M.
Published: January 2022

OBJECTIVES:

Body temperature trajectories of infected patients are associated with specific immune profiles and survival. We determined the association between temperature trajectories and distinct manifestations of coronavirus disease 2019.

DESIGN:

Retrospective observational study.

SETTING:

Four hospitals within an academic healthcare system from March 2020 to February 2021.

PATIENTS:

All adult patients hospitalized with coronavirus disease 2019.

INTERVENTIONS:

Using a validated group-based trajectory model, we classified patients into four previously defined temperature trajectory subphenotypes using oral temperature measurements from the first 72 hours of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes.

MEASUREMENTS AND MAIN RESULTS:

The 5,903 hospitalized coronavirus disease 2019 patients were classified into four subphenotypes: hyperthermic slow resolvers (n = 1,452, 25%), hyperthermic fast resolvers (1,469, 25%), normothermics (2,126, 36%), and hypothermics (856, 15%). Hypothermics had abnormal coagulation markers, with the highest d-dimer and fibrin monomers (p < 0.001) and the highest prevalence of cerebrovascular accidents (10%, p = 0.001). The prevalence of venous thromboembolism was significantly different between subphenotypes (p = 0.005), with the highest rate in hypothermics (8.5%) and lowest in hyperthermic slow resolvers (5.1%). Hyperthermic slow resolvers had abnormal inflammatory markers, with the highest C-reactive protein, ferritin, and interleukin-6 (p < 0.001). Hyperthermic slow resolvers had increased odds of mechanical ventilation, vasopressors, and 30-day inpatient mortality (odds ratio, 1.58; 95% CI, 1.13–2.19) compared with hyperthermic fast resolvers. Over the course of the pandemic, we observed a drastic decrease in the prevalence of hyperthermic slow resolvers, from representing 53% of admissions in March 2020 to less than 15% by 2021. We found that dexamethasone use was associated with significant reduction in probability of hyperthermic slow resolvers membership (27% reduction; 95% CI, 23–31%; p < 0.001).

CONCLUSIONS:

Hypothermics had abnormal coagulation markers, suggesting a hypercoagulable subphenotype. Hyperthermic slow resolvers had elevated inflammatory markers and the highest odds of mortality, suggesting a hyperinflammatory subphenotype. Future work should investigate whether temperature subphenotypes benefit from targeted antithrombotic and anti-inflammatory strategies.
The HAND-Q: Psychometrics of a New Patient-reported Outcome Measure for Clinical and Research Applications
Authors: Sierakowski Kyra L. , Dean Nicola R. , Evans Sanchez Kathleen , Griffin Philip A. , Wormald Justin C.R. , Rodrigues Jeremy N. , Mares Olivier , Repo Jussi P. , Hulkkonen Sina M. , Shah Neil V. , Koehler Steven , Bain Gregory I. , Cano Stefan J. , Pusic Andrea L. , Lalonde Don , Klassen Anne F.
Published: January 2022

Background:

The perspective of the patient in measuring the outcome of their hand treatment is of key importance. We developed a hand-specific patient-reported outcome measure to provide a means to measure outcomes and experiences of care from the patient perspective, that is, HAND-Q.

Methods:

Data were collected from people with a broad range of hand conditions in hand clinics in six countries between April 2018 and January 2021. Rasch measurement theory analysis was used to perform item reduction and to examine reliability and validity of each HAND-Q scale.

Results:

A sample of 1277 patients was recruited. Participants ranged in age from 16 to 89 years, 54% were women, and a broad range of congenital and acquired hand conditions were represented. Rasch measurement theory analysis led to the refinement of 14 independently functioning scales that measure hand appearance, health-related quality of life, experience of care, and treatment outcome. Each scale evidenced reliability and validity. Examination of differential item functioning by age, gender, language, and type of hand condition (ie, nontraumatic versus traumatic) confirmed that a common scoring algorithm for each scale could be implemented.

Conclusions:

The HAND-Q was developed following robust psychometric methods to provide a comprehensive modular independently functioning set of scales. HAND-Q scales can be used to assess and compare evidence-based outcomes in patients with any type of hand condition.
Interactions between the environmental and human microbiota in the preservation of health and genesis of disease: symposium report
Authors: Ramaboli Matsepo , Nesengani Lucky , Katsidzira Leolin , Haller Dirk , Kinross James , Ocvirk Soeren , O’Keefe Stephen J.D.
Published: January 2022

Purpose of review

The purpose of this symposium was to bring thought leaders in the microbiome from the west to Africa to share their unique experiences with African investigators in order to build the foundations for scientifically rigorous explorations into the African human and environmental microbiome that may explain why disease patterns are different in Africa where the chief killers are infectious diseases, whereas noncommunicable diseases (NCDs) are the major threat to healthcare resources in the developed world.

Recent findings

The application of new high throughput technologies to the investigation of the microbiome and its metabolome has revealed mechanisms whereby a traditional African high fiber diet can suppress NCDs which include colon cancer, inflammatory bowel diseases, obesity, type 2 diabetes and atherosclosis. There is concern that with migration and westernization, NCDs are becoming more common in Africa and that food security is becoming impaired by unbalanced obesogenic foods rather than inadequate food intake.

There is an urgent need for the formation of combined African-Western research programs to identify what is good and bad in the African diet-microbiome axis to develop strategies to prevent the incidence of NCDs rising to western levels in Africa, at the same time offering novel prevention strategies against the #1 healthcare threat in the developed world.
Corrigendum Compounds Errors and Again Fails to Support the Specificity of Acupoint Tapping
Authors: Spielmans Glen I. , Rosen Gerald M.
Published: January 2022

In a prior article (Spielmans, Rosen, Spence-Sing J Nerv Ment Dis 208:628–631, 2020), we demonstrated that Church, Stapleton, Yang, and Gallo's (J Nerv Ment Dis 206:783–793, 2018) meta-analytic finding that acupoint tapping had specific therapeutic benefit was highly flawed, both statistically and methodologically. Our analysis based on corrected effect sizes found no significant benefit for acupoint tapping at study endpoint. Church, Stapleton, Kip, and Gallo (J Nerv Ment Dis 208:632–635, 2020) issued a corrigendum in which they reported a new post hoc analysis using follow-up (rather than study endpoint) measures. Shifting to a post hoc outcome while pooling highly disparate follow-up endpoints is problematic; it ignored the nonsignificant result of the a priori analysis. Here, we clarify these issues and address Church, Stapleton, Kip, and Gallo's (J Nerv Ment Dis 208:632–635, 2020) often irrelevant or confusing responses to our methodological concerns. Considering this recent exchange of articles, and absent meaningful correction to the original incorrect findings, we remain concerned that emotional freedom technique proponents will continue to advance unfounded claims regarding the purported benefits of acupoint tapping.
Emergency Department Adolescent Suicidality
Authors: Sheridan David C. , Lin Amber
Published: January 2022

Objective

Adolescent mental health is a rapidly escalating presentation to emergency departments in the United States with depression and suicidal thoughts being the most prevalent condition. Much of the research and focus has been on preventing future attempts. However, one outcome that may be very important in addition to focus on is the impact of presentations for thoughts without self-injury. The aim was to evaluate outcomes of interest for a larger prospective observational adolescent suicidal trial including frequency of suicide attempts versus thoughts and factors associated with each outcome.

Methods

This is a prospective pilot study of adolescents at a single pediatric emergency department between December 2016 and September 2017 with acute suicidality. We used descriptive statistics to compare chief complaint, medical history, Patient Health Questionnaire-9 (PHQ-9), and outcomes including final disposition and total emergency department length of stay (LOS). We used t tests for continuous outcomes, χ2 test for categorical data, and Fisher exact tests for categorical and sparse data (20% of cell sizes of <5).

Results

Forty-one patients were enrolled, with 43.9% having an attempt; 72.2% of attempts were the result of an ingestion, and approximately 54% were over-the-counter medications. The average (SD) LOS was 30.8 (31.2) hours, and 63% were discharged home to outpatient services. There were no significant differences in age, chief complaint (except overdose), medical history, final disposition, total LOS in the ED, and the PHQ-9. Scores of the PHQ-9 were, on average (SD), 18.51 (4.7) across the entire cohort, 18.06 (5.75) in patients with an attempt, and 18.87 (3.77) in patients without an attempt (P = 0.59).

Conclusions

Adolescent mental health is a growing issue for pediatric emergency departments nationally. Prospective research to identify factors associated with worsening outcomes is important to identify and potentially modify if possible. This study did not find any specific factors associated with a suicide attempt, but found that less than half of patients presenting with suicidality actual made an attempt. Future research should focus on not only limiting suicide attempts but also using decreased emergency department visits for worsening thoughts as an outcome of interest.
A randomly stirred model for Bolgiano–Obukhov scaling in turbulence in a stably stratified fluid
Authors: Bhattacharjee Jayanta K.
Published: January 2022

A randomly stirred model, akin to the one used by DeDominicis and Martin for homogeneous isotropic turbulence, is introduced to study Bolgiano–Obukhov scaling in fully developed turbulence in a stably stratified fluid. The energy spectrum
E
(
k
), where
k
is a wavevector in the inertial range, is expected to show the Bolgiano–Obukhov scaling at a large Richardson number
Ri
(a measure of the stratification). We find that the energy spectrum is anisotropic. Averaging over the directions of the wavevector, we find

E
(
k
)
=

K
0

ε
θ

2

/

5

k

−
11

/

5

, where

ε
θ

is the constant energy transfer rate across wavenumbers with very little contribution coming from the kinetic energy flux. The constant
K
0
is estimated to be of O(0.1) as opposed to the Kolmogorov constant, which is O(1). Further for a pure Bolgiano–Obukhov scaling, the model requires that the large distance ‘stirring’ effects dominate in the heat diffusion and be small in the velocity dynamics. These could be reasons why the Bolgiano–Obukhov scaling is difficult to observe both numerically and experimentally.

This article is part of the theme issue ‘Scaling the turbulence edifice (part 2)’.
Theory of anisotropic superfluid4He counterflow turbulence
Authors: L'vov Victor S. , Lvov Yuri V. , Nazarenko Sergey , Pomyalov Anna
Published: January 2022

We develop a theory of strong anisotropy of the energy spectra in the thermally driven turbulent counterflow of superfluid4He. The key ingredients of the theory are the three-dimensional differential closure for the vector of the energy flux and the anisotropy of the mutual friction force. We suggest an approximate analytic solution of the resulting energy-rate equation, which is fully supported by our numerical solution. The two-dimensional energy spectrum is strongly confined in the direction of the counterflow velocity. In agreement with the experiments, the energy spectra in the direction orthogonal to the counterflow exhibit two scaling ranges: a near-classical non-universal cascade dominated range and a universal critical regime at large wavenumbers. The theory predicts the dependence of various details of the spectra and the transition to the universal critical regime on the flow parameters.

This article is part of the theme issue ‘Scaling the turbulence edifice (part 2)’.
Editorial: Scaling the Turbulence Edifice (part 2)
Authors: Bec Jérémie , Krstulovic Giorgio , Matsumoto Takeshi , Sankar Ray Samriddhi , Vincenzi Dario
Published: January 2022

This is the second part of a two-part special issue of the Philosophical Transactions of the Royal Society A, which recognizes, and hopefully encourages, the growing convergence of interests amongst mathematicians and physicists to scale the turbulence edifice. This convergence is explained in more detail in the editorial which accompanies the first part (Bec
et al
. 2022
Phil. Trans. R. Soc. A
380
, 20210101. (
doi:10.1098/rsta.2021.0101
)) and includes a tribute to our friend, collaborator and mentor Uriel Frisch, to whom these special issues are dedicated. Uriel, the principal architect of the Nice School of Turbulence, remains the finest example of this synthesis of mathematics and physics in tackling the outstanding problem of turbulence.

This article is part of the theme issue ‘Scaling the turbulence edifice (part 2)’.
λ-Navier–Stokes turbulence
Authors: Alexakis A. , Biferale L.
Published: January 2022

We investigate numerically the model proposed in Sahoo
et al.
(2017
Phys. Rev. Lett.
118
, 164501) where a parameter λ is introduced in the Navier–Stokes equations such that the weight of homochiral to heterochiral interactions is varied while preserving all original scaling symmetries and inviscid invariants. Decreasing the value of λ leads to a change in the direction of the energy cascade at a critical value

λ
c

∼
0.3

. In this work, we perform numerical simulations at varying λ in the forward energy cascade range and at changing the Reynolds number

R
e

. We show that for a fixed injection rate, as

λ
→

λ
c

, the kinetic energy diverges with a scaling law

E

∝

(
λ
−

λ
c

)

−
2

/

3

. The energy spectrum is shown to display a larger bottleneck as λ is decreased. The forward heterochiral flux and the inverse homochiral flux both increase in amplitude as

λ
c

is approached while keeping their difference fixed and equal to the injection rate. As a result, very close to

λ
c

a stationary state is reached where the two opposite fluxes are of much higher amplitude than the mean flux and large fluctuations are observed. Furthermore, we show that intermittency as

λ
c

is approached is reduced. The possibility of obtaining a statistical description of regular Navier–Stokes turbulence as an expansion around this newly found critical point is discussed.

This article is part of the theme issue ‘Scaling the turbulence edifice (part 2)’.
Cellulomonas fulva sp. nov., isolated from oil-contaminated soil
Authors: Dahal Ram Hari , Kim Jungmin , Kim Dong-Uk , Dong Ke , Hong Yongseok , Chaudhary Dhiraj Kumar
Published: January 2022

A yellow-coloured, Gram-stain-positive, motile, aerobic and rod-shaped bacteria, designated DKR-3T, was isolated from oil-contaminated experimental soil. Strain DKR-3T could grow at pH 5.0–10.5 (optimum, pH 7.0–8.5), at 10–40 °C (optimum, 25–32 °C) and tolerated 3.5 % of NaCl. Phylogenetic analyses based on its 16S rRNA gene sequence indicated that strain DKR-3T formed a lineage within the family

Cellulomonadaceae

and was clustered with members of the genus

Cellulomonas

. Strain DKR-3T had highest 16S rRNA gene sequence similarities to

Cellulomonas gelida

DSM 20111T (98.3 %),

Cellulomonas persica

JCM 18111T (98.2 %) and

Cellulomonas uda

DSM 20107T (97.8 %). The predominant respiratory quinone was tetrahydrogenated menaquinone with nine isoprene units [MK-9(H4)]. The principal cellular fatty acids were anteiso-C15 : 0, C16 : 0 and anteiso-C17 : 0. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The cell-wall diamino acid was l-ornithine whereas rhamnose and glucose were the cell-wall sugars. The DNA G+C content was 74.2mol %. The genome of strain DKR-3T was 3.74 Mb and contained three putative biosynthetic gene clusters. The average nucleotide identity and digital DNA–DNA hybridization relatedness values between strain DKR-3T and its phylogenetically related members were below the species threshold values. Based on a polyphasic study, strain DKR-3T represents a novel species belonging to the genus

Cellulomonas

, for which the name Cellulomonas fulva sp. nov. is proposed. The type strain is DKR-3T (=KACC 22071T=NBRC 114730T).
Breakthrough SARS-CoV-2 infections in MS patients on disease modifying therapies
Authors: Schiavetti Irene , Cordioli Cinzia , Stromillo Maria Laura , Ferrò Maria Teresa , Laroni Alice , Cocco Eleonora , Cola Gaia , Pasquali Livia , Rilla Maria Teresa , Signoriello Elisabetta , Iodice Rosa , Sapio Alessia Di , Lanzillo Roberta , Caleri Francesca , Annovazzi Pietro , Conte Antonella , Liberatore Giuseppe , Ruscica Francesca , Docimo Renato , Bonavita Simona , Ulivelli Monica , Cavalla Paola , Patti Francesco , Ferraro Diana , Clerico Marinella , Immovilli Paolo , Filippo Massimiliano Di , Salvetti Marco , Sormani Maria Pia ,   the “Breakthrough infections in MS” study group
Published: January 2022

Background

Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different Disease Modifying Therapy (DMT).

Methods

Data on number of vaccinated patients and of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT.

Findings

19641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. As compared to the other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, RR=3.55,95%CI=2.74-4.58, p<0.001) and fingolimod (0.58% vs 1.62%, RR=2.65,95%CI=1.75-4.00, p<0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% vs 19.4% in the pre-vaccination era (RR=0.86,p=0.74) and it was 3.9% in all the other DMT groups vs 11.9% in the pre-vaccination period (RR=0.33,p=0.02).

Interpretation

The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.
Low back pain and telecommuting in Japan: influence of work environment quality
Authors: Matsugaki Ryutaro , Ishimaru Tomohiro , Hino Ayako , Muramatsu Keiji , Nagata Tomohisa , Ikegami Kazunori , Tateishi Seiichiro , Tsuji Mayumi , Matsuda Shinya , Fujino Yoshihisa ,   the CORoNaWork Project
Published: January 2022

Objectives

This study examined the relationship between frequency of working from home and low back pain (LBP), considering the quality of work environment.

Methods

The study was based on a cross-sectional internet-based survey. Of 33,302 respondents, data from 12,774 desk workers were retained for analysis. We used a 0–10 numerical rating scale to assess LBP. Work environment was assessed using five subjective questions. Mixed-effects logistic regression nested by city level was used to analyze the relationship between frequency of working from home and LBP, stratified by work environment condition.

Results

The prevalence of LBP was 21.0%. Among those reporting a poor work environment, as opposed to almost never working from home, the multivariate odds ratio (OR) of LBP were as follows: working from home less than 1 day per week: OR=1.25, 95% CI: 0.89–1.76, p=0.190); 2-3 days per week: OR=1.58, 95% CI: 1.16–2.16, p=0.004; and 4 or more days per week: OR=1.82, 95% CI: 1.38–2.40, p<0.001. By contrast, among those reporting a good work environment the OR of LBP did not increase as the frequency of working from home increased.

Conclusions

The relationship between LBP and frequency of working from home was found to vary with the quality of the work environment; more specifically, LBP was associated with frequency of teleworking in a poor work environment. This study suggests that employers should give more support their employees in promoting a good work environment to prevent LBP. (Words: 240/250)
Measurement of subjective and objective indices after progressive resistance training compared with aerobic training in Patients with Haemophilia: a study protocol
Authors: Pereira Felicianus Anthony , Soomro Nabila Najam , Sulaiman Farheen
Published: January 2022

Background

Bleeding episodes in mild haemophilia may occur after major injuries or surgical procedures with some people not experiencing bleeding episodes. People suffering from moderate haemophilia bleed once a month, however they rarely experience spontaneous bleeding. Those suffering from severe haemophilia bleed quite often into muscles or joints, and episodes can occur once to twice a week. Bleeding usually occurs spontaneously.

Objective

To investigate the effects of progressive resistance training on quality of life, muscular strength and joint score in patients with haemophilia.

Methodology

Sixty patients will be enrolled in the study. Thirty patients will be allocated to control group, and thirty to intervention group. Controls will be administered active muscle stretching and aerobic exercises. Intervention group will be given active muscle stretching, and resistance training. Patients will be randomly allocated to each group. Anthropometric data will be measured pre-test to establish a baseline. Study variables include muscular strength, and quality of life. All tests will be measured pre-test and post-test to compare effects of treatment.

Results

Participant recruitment commenced in June 2021. The post intervention phase will be completed by August 2020. Data analysis will commence after this. A write-up for publication is expected to be completed after the follow-up phase is finalized in August 2021.

Conclusions

If resistance training is found to be effective in improving quality of life and muscular strength in participants, it could reduce the frequency of factor therapy given prophylactically, or even as acute treatment, thus directing it towards more severe cases. It will also provide financial relief to organizations supporting the treatment of the hemophilic population.
Longitudinal DNA Methylation Profiling of the Rectal Mucosa Identifies Cell-specific Signatures of Disease Status, Severity and Clinical Outcomes in Ulcerative Colitis
Authors: Venkateswaran Suresh , Somineni Hari K , Matthews Jason D. , Kilaru Varun , Hyams Jeffrey S , Denson Lee A , Kellamayer Richard , Gibson Greg , Cutler David J , Conneely Karen N , Smith Alicia K , Kugathasan Subra
Published: January 2022

In peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we studied DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, conducting a cell-type-specific EWAS in epithelial, immune and fibroblast cells to understand DNAm changes across disease states, course, and clinical outcomes. At diagnosis, rectal mucosa in UC exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, along with 3504, 910, and 2279 altered DNAm sites as detected in our cell-specific EWAS, respectively. While treatment had significant effects on DNAm of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Those requiring colectomy exhibited cell composition and DNAm patterns at follow-up more like disease onset than patients who did not require colectomy. Collectively DNAm and gene expression analysis suggest that targeting epithelial genes involved in barrier function may improve clinical outcomes.
Automatic Three-Dimensional Cephalometric Landmarking via Deep Learning
Authors: Dot Gauthier , Schouman Thomas , Chang Shaole , Rafflenbeul Frédéric , Kerbrat Adeline , Rouch Philippe , Gajny Laurent
Published: January 2022

The increasing use of three-dimensional (3D) imaging by orthodontists and maxillofacial surgeons to assess complex dentofacial deformities and plan orthognathic surgeries implies a critical need for 3D cephalometric analysis. Although promising methods were suggested to localize 3D landmarks automatically, concerns about robustness and generalizability restrain their clinical use. Consequently, highly trained operators remain needed to perform manual landmarking. In this retrospective diagnostic study, we aimed to train and evaluate a deep learning (DL) pipeline based on SpatialConfiguration-Net for automatic localization of 3D cephalometric landmarks on computed tomography (CT) scans. A retrospective sample of consecutive presurgical CT scans was randomly distributed between a training/validation set (n = 160) and a test set (n = 38). The reference data consisted in 33 landmarks, manually localized once by 1 operator (n = 178) or twice by 3 operators (n = 20, test set only). After inference on the test set, one CT scan showed “very low” confidence level predictions; we excluded it from the overall analysis but still assessed and discussed the corresponding results. The model performance was evaluated by comparing the predictions with the reference data; the outcome set included localization accuracy, cephalometric measurements and comparison to manual landmarking reproducibility. On the hold-out test set, the mean localization error was 1.0 ± 1.3mm, while success detection rates for 2.0, 2.5 and 3.0mm were 90.4%, 93.6% and 95.4%, respectively. Mean errors were −0.3 ± 1.3° and −0.1 ± 0.7mm for angular and linear measurements, respectively. When compared to manual reproducibility, the measurements were within the Bland-Altman 95% limits of agreement for 91.9% and 71.8% of skeletal and dentoalveolar variables, respectively. To conclude, while our DL method still requires improvement, it provided highly accurate 3D landmark localization on a challenging test set, with a reliability for skeletal evaluation on par with what clinicians obtain.
A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project
Authors: Blakes Alexander J.M. , Wai Htoo , Davies Ian , Moledian Hassan E. , Ruiz April , Thomas Tessy , Bunyan David , Thomas N Simon , Burren Christine P. , Greenhalgh Lynn , Lees Melissa , Pichini Amanda , Smithson Sarah F. , Tavares Ana Lisa Taylor , O’Donovan Peter , Douglas Andrew G.L. ,   Genomics England Research Consortium,   Splicing and Disease Working Group, Whiffin Nicola , Baralle Diana , Lord Jenny
Published: January 2022

Genomic variants which disrupt splicing are a major cause of rare genetic disease. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project, and assess the contribution of non-canonical splicing variants to rare genetic diseases. We show that splicing branchpoints are highly constrained by purifying selection, and harbour damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. We use phenotype matching and RNA studies to confirm a new diagnosis for six individuals to date. In summary, we demonstrate the clinical value of examining non-canonical splicing variants in participants with unsolved rare diseases.
User acceptability of saliva and gargle samples for identifying COVID-19 positive high-risk workers
Authors: McLennan Kirsty , Barton Ellen , Lang Christie , Adams Ian R. , McAllister Gina , Reijns Martin A. M. , Templeton Kate , Johannessen Ingólfur , Leckie Alastair , Gilbert Nick
Published: January 2022

Throughout the COVID-19 pandemic nasopharyngeal or nose/throat swabs (NTS) have been the primary approach for collecting patient samples for the subsequent detection of viral RNA. However, this procedure, if undertaken correctly, can be unpleasant and therefore deters individuals from providing high quality samples. To overcome these limitations other modes of sample collection have been explored. In a cohort of frontline healthcare workers we have compared saliva and gargle samples to gold-standard NTS. 93% of individuals preferred providing saliva or gargle samples, with little sex-dependent variation. Viral titres collected in samples were analysed using standard methods and showed that gargle and saliva were similarly comparable for identifying COVID-19 positive individuals compared to NTS (92% sensitivity; 98% specificity). We suggest that gargle and saliva collection are viable alternatives to NTS swabs and may encourage testing to provide better disease diagnosis and population surveillance.
Socio-demographic characteristics and their relation to medical service consumption among elderly in Israel during the COVID-19 lockdown in 2020 compared to the corresponding period in 2019
Authors: Shaked Ohad , Korn Liat , Shapira Yair , Zigdon Avi
Published: January 2022

Purpose

The COVID-19 pandemic has led to the isolation of the population in Israel, including the elderly, some of whom are chronically ill. The present study examines the consumption of medical services among adults over the age of 65 in Israel at the time of the first COVID-19 lockdown relative to the corresponding period the year before, according to various socio-demographic variables: gender, age, marital status, ethnicity, degree of religiosity and socioeconomic status.

Methods

A retrospective longitudinal observational quantitative research based on the “Natali Healthcare Solutions Israel” database of subscribers. Company subscribers over the age of 65 (N=103,955) were included in the sample (64.5% women) in two time periods, before the COVID-19 outbreak-P1, in 2019, and during the first COVID-19 lockdown-P2 in 2020. Medical needs included referrals to a medical or emergency services, ordering an ambulance, physician home visits and service refusal.

Results

The average number of referrals to services was lower during the COVID-19 lockdown period (M=0.3658, SD=0.781) compared to the corresponding period the previous year (M=0.5402, SD=0.935). At the time of the COVID-19 lockdown, the average number of referrals to medical services was lower, but the average number of ambulance orders, physician visits and service refusals was higher compared to the same period in the previous year. During both time periods, women (P1-M=0.5631, SD=0.951; P2-M=0.3846, SD=0.800) required significantly more (p<.000) services than men (P1-M=0.5114, SD=0.910; P2-M=0.3417, SD=0.753). In both time periods, subscribers who were older, widowed, living in non-Jewish/mixed localities or in average or below average socioeconomic status localities required more services relative to younger, married people living in Jewish localities, or in above-average socioeconomic localities (p<.000).

Summary and Conclusions

In a large sample of elderly in Israel, findings indicate a decrease in referrals to medical care during the first COVID-19 lockdown period, yet an increase in ambulance orders, physician visits and service refusals. There were no significant differences between the periods according to different socio-demographic characteristics. The period of the first COVID-19 lockdown was characterized by a higher incidence of medical service refusals compared to routine times. The incidence of requiring medical service at the time of the first COVID-19 lockdown was 2.5 times higher among those who required services during the previous year, 1.7 times higher among unmarried seniors, and 1.4 times higher among the older age group of 85 and over in comparison to the younger seniors.
Dynamics of antibody responses, cellular immunity, and breakthrough infections among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine
Authors: Uwamino Yoshifumi , Kurafuji Toshinobu , Takato Kumiko , Sakai Akiko , Tanabe Akiko , Noguchi Masayo , Yatabe Yoko , Arai Tomoko , Ohno Akemi , Tomita Yukari , Shibata Ayako , Yokota Hiromitsu , Yamasawa Wakako , Namkoong Ho , Sato Yasunori , Hasegawa Naoki , Wakui Masatoshi , Murata Mitsuru ,   the Keio Donner Project Team
Published: January 2022

Introduction

The waning of the antibody titre after the first two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine was reported. However, knowledge of the dynamics of cellular immunity is scarce. Here, we performed a prospective cohort study to disclose antibody and cellular immunity dynamics and discuss the relationship between immunity and breakthrough infection.

Methods

The study had a prospective cohort design. Antibody titres against SARS-CoV-2 in serially collected serum samples of 608 Japanese vaccinees after 6 months of vaccination were measured. Simultaneously, T-cell immunity dynamics were assessed using the QuantiFERON SARS-CoV-2 assay. Additionally, participants with suspected breakthrough infection were detected according to the positive conversion of the IgG assay for nucleocapsid proteins of SARS-CoV-2.

Results

Antibody titres were elevated 3 weeks after vaccination and waned over the remainder of the study period. The QuantiFERON SARS-CoV-2 assay performed on 536 participants demonstrated the similar dynamics. Six participants without predisposing medical conditions demonstrated positive conversion of the IgG assay for nucleocapsid proteins, while five were asymptomatic.

Conclusion

Waning of humoral and cellular immunity within 6 months of administration of two doses of BNT162b2 vaccine among Japanese healthcare professionals and the occurrence of asymptomatic breakthrough infection was suspected in approximately 1 of 100 vaccinees.

(UMIN000043340)
Evaluation of the systemic and mucosal immune response induced by COVID-19 and the BNT162b2 mRNA vaccine for SARS-CoV-2
Authors: Nickel Olaf , Rockstroh Alexandra , Wolf Johannes , Landgraf Susann , Kalbitz Sven , Kellner Nils , Borte Michael , Fertey Jasmin , Lübbert Christoph , Ulbert Sebastian , Borte Stephan
Published: January 2022

Background

Currently used vaccines to protect from COVID-19 mostly focus on the receptor-binding domain (RBD) of the viral spike protein, and induced neutralizing antibodies have shown to be protective. However, functional relevance of vaccine-generated antibodies are poorly understood on variants-of-concern (VOCs) and mucosal immunity.

Methods

We compared specific antibody production against the S1 subunit and the RBD of the spike protein, the whole virion of SARS-CoV-2, and monitored neutralizing antibodies in sera and saliva of 104 BNT162b2 vaccinees and 57 individuals with natural SARS-CoV-2 infection. Furthermore, we included a small cohort of 11 individuals which received a heterologous ChAdOx1-S/BNT162b2 prime-boost vaccination.

Results

Vaccinated individuals showed higher S1-IgG antibodies in comparison to COVID-19 patients, followed by a significant decrease 3 months later. Neutralizing antibodies (nAbs) were poorly correlated with initial S1-IgG levels, indicating that these might largely be non-neutralizing. In contrast, RBD IgGAM was strongly correlated to nAbs, suggesting that RBD-IgGAM is a surrogate marker to estimate nAb concentrations after vaccination. The protective effect of vaccine- and infection-induced nAbs was found reduced towards B.1.617.2 and B.1.351 VOCs. NAb titers are significantly higher after third vaccination compared to second vaccination. In contrast to COVID-19 patients, no relevant levels of RBD specific antibodies were detected in saliva samples from vaccinees.

Conclusions

Our data demonstrate that BNT162b2 vaccinated individuals generate relevant neutralizing antibodies, which begin to decrease within three months after immunization and show lower neutralizing potential to VOCs as compared to the original Wuhan virus strain. A third booster vaccination provides a stronger nAb antibody response than the second vaccination. The systemic vaccine does not seem to elicit readily detectable mucosal immunity.
Validation of Friedewald, Martin/Hopkins and Sampson Equations in the Low-Density Lipoprotein Cholesterol Estimation with Different Assays
Authors: Zararsız Gözde Ertürk , Bolat Serkan , Cephe Ahu , Kochan Necla , Yerlitaş Serra İlayda , Doğan Halef Okan , Zararsız Gökmen
Published: January 2022

Background

Low-density lipoprotein cholesterol (LDL-C) is an important biomarker for determining cardiovascular risk and regulating lipid lowering therapy. Therefore, the accurate estimation of LDL-C concentration is essential in cardiovascular disease diagnosis and prognosis. Sampson recently proposed a new formula for the estimation of LDL-C. However, little is known regarding the validation of this formula.

Objectives

This study aimed to validate this new formula with other well-known formulas in Turkish population, composed of adults.

Methods

A total of 88,943 participants above 18 years old at Sivas Cumhuriyet University Hospital (Sivas, Turkey) were included to this study. LDL-C was directly measured by homogeneous assays, i.e., Roche, Beckman and Siemens and estimated by Friedewald’s, Martin/Hopkins’, extended Martin/Hopkins’ and Sampson’s formulas. The accuracies between the estimations obtained by the formulas and the direct measurements were evaluated both in general and separately for the LDL-C, TG and non-HDL-C sublevels. Linear regression analysis was applied and residual error plots were generated between each estimation and direct measurement method. Coefficient of determination (R2) and mean absolute deviations were also calculated.

Results

The results showed that the extended Martin/Hopkins approach was the overall most accurate approach for LDL-C estimation. The results also showed that the highest concordances were obtained between the direct assays with the extended Martin/Hopkins formula calculated with the median statistics obtained from our own population. On the other hand, it was observed that the results of the methods may differ in different assays. Although the best performance was obtained by the Sampson formula in patients with “low LDL-C level and hypertriglyceridemia”, the extended Martin/Hopkins approach, calculated from the median statistics of our population, gave the most accurate results in patients with “low LDL-C level or hypertriglyceridemia”.

Conclusions

In conclusion, in patients with a low LDL-C level or hypertriglyceridemia, the extended Martin/Hopkins method; in patients with a low LDL-C level and hypertriglyceridemia, the Sampson method may be preferred. The validity of the Martin Hopkins’ and Sampson’s formulas has to be further investigated in different populations.
Medical student residency preferences and motivational factors: a longitudinal, single-institution perspective
Authors: Ladha Feria A. , Pettinato Anthony M. , Perrin Adam E.
Published: January 2022

Background

A high proportion of medical school graduates pursue specialties different from those declared at matriculation. While these choices influence the career paths, satisfaction, and potential regret students will experience, they also impact the supply and demand ratio of the shorthanded physician workforce across many specialties. In this study, we investigate how the choice of medical specialty and the factors motivating those choices change between the beginning and end of medical school training.

Methods

A questionnaire was administered annually from 2017 to 2020 to a cohort of medical students at the University of Connecticut to determine longitudinal preferences regarding residency choice, motivational factors influencing residency choice, future career path, and demographic information.

Results

The questionnaire respondent totals were as follows: n=76 (Year 1), n=54 (Year 2), n=31 (Year 3), and n=65 (Year 4). Amongst newly matriculated students, 25.0% were interested in primary care, which increased ∼1.4-fold to 35.4% in the final year of medical school. In contrast, 38.2% of matriculated students expressed interest in surgical specialties, which decreased ∼2.5-fold to 15.4% in the final year. Specialty choices in the final year that exhibited the largest absolute change from matriculation were orthopedic surgery (−9.9%), family medicine (+8.1%), radiology (+7.9%), general surgery (−7.2%), and anesthesiology (+6.2%). Newly matriculated students interested in primary care demonstrated no differences in their ranking of motivational factors compared to students interested in surgery, but many of these factors significantly deviated between the two career paths in the final year. Specifically, students interested in surgical specialties were more motivated by the rewards of salary and prestige compared to primary care students, who more highly ranked match confidence and family/location factors.

Conclusions

We identified how residency choices change from the beginning to the end of medical school, how certain motivational factors change with time, how these results diverge between primary care and surgery specialty choice, and propose a new theory based on risk-reward balance regarding residency choice. Our study promotes awareness of student preferences and may help guide school curricula in developing more student-tailored training approaches. This could foster positive long-term changes regarding career satisfaction and the physician workforce.
Doubtful Clinical Benefit of Casirivimab-Imdevimab Treatment for Disease Severity Outcome of High-Risk Patients with SARS-CoV-2 Delta Variant Infection
Authors: Shopen Noah , Dekel Michal , Mizrahi Michal , Zandberg Efrat , Bishouty Nancy , Talmud Daniel , Vaknin Ben , Haberman Shira , Shalhav Malka Katz , Zeltser David , Cohen Neta
Published: January 2022

Casirivimab/Imdevimab therapy reportedly retains neutralization potency against circulating SARS-CoV-2 variants, including Delta (B.1.617.2), but there are sparse data on its clinical benefit against the Delta variant among vaccinated and unvaccinated patients. We explored its therapeutic effect on COVID-19 severity outcome in terms of room air saturation <93% within 14 days of initial presentation and 45-day all-cause mortality among high-risk patients with SARS-CoV-2 Delta variant infection and compared its effect between vaccinated and unvaccinated patients. We conducted a retrospective cohort study at a tertiary care medical center between 6/2021 and 9/2021 and included patients who presented with a positive PCR for SARS-CoV-2 and fulfilled the criteria for Casirivimab/Imdevimab treatment. Of the 359 suitable patients (52% female, median age 63 years), 116 were treated with Casirivimab/Imdevimab and 243 were not. Two-hundred and one (56%) patients had received at least 2 SARS-CoV-2 vaccinations. Casirivimab/Imdevimab treatment was not an independent protective factor of COVID-19 severity outcome (multivariable analysis). Chronic kidney disease (aOR=3.51 [95%CI: 1.34-9.20],P=0.01), lower saturation levels (aOR=0.7 [95%CI: 0.58–0.85],P<0.01), abnormal chest x-ray findings (aOR=2.92, [95%CI: 1.24–6.87,P=0.01), and higher C-reactive protein levels (aOR=1.01 [95%CI: 1.00–1.01],P=0.008) were independent risk factors of COVID-19 severity. Positive immunization status was an independent protective factor (aOR=0.33 [95%CI: 0.14–0.77],P=0.01). A sub analysis of patients treated with Casirivimab/Imdevimab revealed no significant difference in COVID-19 severity between vaccinated and unvaccinated patients. These findings demonstrate no added benefit of Casrivimab/Imdevinab treatment for high-risk patients with the SARS-CoV-2 Delta variant infection, regardless of their vaccination status.
CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice
Authors: Sanchez-Roige Sandra , Jennings Mariela V , Thorpe Hayley H A , Mallari Jazlene E , van der Werf Lieke C , Bianchi Sevim B , Lee Calvin , Mallard Travis T , Barnes Samuel A , Wu Jin Yi , Barkley-Levenson Amanda M , Boussaty Ely C , Snethlage Cedric E , Schafer Danielle , Babic Zeljana , Winters Boyer D , Watters Katherine E , Biederer Thomas , Mackillop James , Stephens David N , Elson Sarah L , Fontanillas Pierre , Khokhar Jibran Y , Young Jared W , Palmer Abraham A
Published: January 2022

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N=123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N=130,684). Because these GWAS implicated the geneCADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants inCADM2in a multi-ancestral 23andMe cohort (N=3,229,317, European; N=579,623, Latin American; N=199,663, African American). Finally, we producedCadm2mutant mice and used them to perform a Mouse-PheWAS (“MouseWAS”) by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (∼6-11%), and moderate genetic correlations (rg=.20-.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such asTCF4andPTPRF, and also identified nominal associations proximal toDRD2andCRHR1. PheWAS forCADM2variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role ofCADM2in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.