bluuebunny/crossref_metadata_2025 huggingface dataset:
Using dual EEG to analyse event-locked changes in child-adult neural connectivity
Authors: Marriott Haresign I. , Phillips E. , Whitehorn M. , Goupil L. , Wass S.V.
Published: June 2021

Current approaches typically measure the connectivity between interacting physiological systems as a time-invariant property. This approach obscures crucial information about how connectivity between interacting systems is established and maintained. Here, we describe methods, and present computational algorithms, that will allow researchers to address this deficit. We focus on how two different approaches to measuring connectivity, namely concurrent (e.g., power correlations, phase locking) and sequential (e.g., Granger causality), can be applied to three aspects of the brain signal, namely amplitude, power, and phase. We guide the reader through worked examples using mainly simulated data on how to leverage these methods to measure changes in interbrain connectivity between adults and children/infants relative to events identified within continuous EEG data during a free-flowing naturalistic interaction. For each, we aim to provide a detailed explanation of the interpretation of the analysis and how they can be usefully used when studying early social interactions.
Thyroid function and the risk of Alzheimer’s disease: A Mendelian Randomisation study
Authors: Marouli Eirini , Yusuf Lina , Kjaergaard Alisa D. , Omar Rafat , Kuś Aleksander , Babajide Oladapo , Sterenborg Rosalie , Åsvold Bjørn O. , Burgess Stephen , Ellervik Christina , Teumer Alexander , Medici Marco , Deloukas Panos
Published: June 2021

Background

Observational epidemiological studies propose that variations in thyroid function are associated with the risk of dementia; however, there have been inconsistent findings regarding the direction of the association. It is still unclear whether these associations are causal or not. We aim to test whether genetically determined variation within the normal range of thyroid function and hypothyroidism are causally associated with the risk of Alzheimer’s disease (AD).

Methods

Mendelian Randomisation (MR) analyses_using genetic instruments associated with normal range TSH and FT4 levels. Secondary analyses included investigation of the role of hypothyroidism. Bidirectional MR was conducted to address the presence of a potential reverse causal association. Summary statistics were obtained from the ThyroidOmics Consortium and the latest available GWAS meta-analyses.

Results

MR analyses show a causal association between normal range TSH levels and decreased risk of AD (OR = 0.98, 95% CI=0.97-0.99, p = 0.01). There was no evidence for a causal association between FT4 or hypothyroidism and Alzheimer’s disease. Bidirectional MR did not show any effect of Alzheimer’s disease on TSH or FT4.

Conclusions

This Mendelian Randomisation study shows for the first time a causal association between normal-range thyroid function and AD. Future studies should clarify the underlying pathophysiological mechanisms.
Potential environmental transmission routes of SARS-CoV-2 inside a large meat processing plant experiencing COVID-19 clusters
Authors: de Rooij Myrna M.T. , Sikkema Reina S. , Bouwknegt Martijn , de Geus Yvette , Stanoeva Kamelia R. , Nieuwenweg Sigrid , van Dam A.S.G. (Sandra) , Raben Ceder , Dohmen Wietske , Heederik Dick , Reusken Chantal , Meijer Adam , Koopmans Marion P.G. , Franz Eelco , Smit Lidwien A.M.
Published: June 2021

Worldwide exceptionally many COVID-19 clusters were observed in meat processing plants. Many contributing factors, promoting transmission, were suggested, including climate conditions in cooled production rooms favorable for environmental transmission but actual sampling studies are lacking. We aimed to assess SARS-CoV-2 contamination of air and surfaces to gain insight in potential environmental transmission in a large Dutch meat processing plant experiencing COVID-19 clusters.

We performed SARS-CoV-2 screening of workers operating in cooled production rooms and intensive environmental sampling during a two-week study period in June 2020. Sampling of air (both stationary and personal), settling dust, ventilation systems, and sewage was performed. Swabs were collected from high-touch surfaces and workers’ hands. Screening of workers was done using oronasopharyngeal swabs. Samples were tested for presence of SARS-CoV-2 RNA by RT-qPCR.

Of the 76 (predominantly asymptomatic) workers tested, 27 (35.5%) were SARS-CoV-2 RNA positive with modest to low viral loads (Ct≥29.7). In total, 6 out of 203 surface swabs were positive (Ct ≥38), being swabs taken from communal touchscreens/handles. One of the 12 personal air samples and one of the 4 sewage samples were positive, RNA levels were low (Ct≥38). All other environmental samples tested negative.

Although one-third of workers tested SARS-CoV-2 RT-PCR positive, environmental contamination was limited. Hence widespread transmission of SARS-CoV-2 via air and surfaces was considered unlikely within this plant at the time of investigation in the context of strict COVID-19 control measures in place.
Clinical Manifestations and Pregnancy Outcomes of Covid-19 in Indonesian Referral Hospital in Central Pandemic Area
Authors: Aldika Akbar Muhammad Ilham , Gumilar Khanisyah Erza , Andriya Rino , Wardhana Manggala Pasca , Mulawardhana Pungky , Anas Jimmy Yanuar , Ernawati  , Cahya Laksana Muhammad Ardian , Dekker Gustaaf
Published: June 2021

Objectives

The data on clinical manifestations and pregnancy outcomes of pregnant women with COVID-19 are limited, particularly in developing countries. The aim of this study is to analyze the clinical manifestations and pregnancy outcomes in COVID-19 maternal cases in a large referral hospital in Indonesia

Methods

The study used a prospective cohort design of all pregnant women with suspected COVID-19. Subjects were divided into COVID-19 and non COVID-19 group based on real-time polymerase chain reaction (RT-PCR) of SARS-CoV-2. The clinical characteristics, laboratory results, and pregnancy outcomes were then compared between both groups.

Results

From 141 suspected maternal cases, 62 COVID-19 cases were confirmed (43.9%), while 79 suspected cases were found to be negative (56.1%). The clinical manifestations and laboratory findings between the two groups were not significantly different (p>0.05). However, the maternal mortality directly caused by COVID-19 was significantly higher compared to the non-COVID-19 group (8.3 vs 1.3%; p=0.044; OR 6.91, 95% CI: 0.79-60.81).

Conclusions

The clinical manifestation and laboratory of suspected pregnant women with positive and negative RT-PCR COVID-19 result are similiar. However, within the Indonesian setting, COVID-19 strongly increases the risk of maternal death through both direct and indirect factors.
P. acnes qPCR-based antibiotics resistance assay (ACQUIRE) reveals widespread macrolide resistance in acne patients and can eliminate macrolide misuse in acne treatment
Authors: Zhang Jingheng , Yu Fang , Fu Keyun , Ma Xinyu , Han Yi , Ali Chi Ching , Zhou Haonan , Xu Yantao , Zhang Tingyue , Kang Shuntong , Xu Yiming , Li Zhuolin , Shi Jiaqi , Gao Shuai , Chen Yongyi , Zhang Jianglin , Chen Liyu , Zhu Feizhou
Published: June 2021

Background

Macrolides have been widely used to treat moderate-to-severe acne for more than 50 years. However, prevalent antibiotic resistance of Propionibacterium acnes, along with the absence of clinically available resistance tests, has made macrolide misuse a frequent occurrence, with serious consequences.

Objective

We developed P. acnes qPCR-based antibiotics resistance assay (ACQUIRE) to enable fast and accurate detection of P. acnes macrolide resistance in clinical settings, representing an opportunity to administer antibiotics more wisely and improve the quality of care.

Methods

A cross-sectional observational study was conducted to probe into the macrolide resistance of P. acnes in acne patients.

Results

The high sensitivity of ACQUIRE enabled us to reveal a much higher P. acnes 23S rDNA point mutation rate (52%) and thus a higher macrolide resistance (75.5%) compared to previous reports. Carriage of ermX gene was discovered on 472 (53%) subjects, which concurs with previous studies.

Conclusion

Macrolide resistance of P. acnes is much higher than previously reported.
TEleRehabilitation Nepal (TERN) to improve quality of life of people with spinal cord injury and acquired brain injury. A proof-of-concept study
Authors: Dhakal Raju , Baniya Mandira , Solomon Rosie M , Rana Chanda , Ghimire Prajwal , Hariharan Ram , Makower Sophie G , Meng Wei , Halpin Stephen , Xie Shane , O’Connor Rory J , Allsop Matthew J , Sivan Manoj
Published: June 2021

Background

Spinal Cord Injury (SCI) and Acquired Brain Injury (ABI) lead to unemployment, poverty, increased mortality, and decreased quality of life in low-and middle-income countries (LMICs). Telemedicine is increasingly facilitating access to healthcare, in LMICs. This prospective cohort intervention study aims to investigate feasibility and acceptability of telerehabilitation to provide long-term follow-up of individuals with SCI and ABI, in Nepal, post-discharge from hospital.

Methods

TERN was delivered by Spinal Injury Rehabilitation Centre, Nepal, in collaboration with University of Leeds, UK. A home visit connected participants to the Multidisciplinary Team (MDT), through a specialised video conference system. The MDT performed a comprehensive assessment before recommending personalised interventions. Outcome measures assessed functional independence in performing activities of daily living, health-related quality of life and emotional disturbances using Modified Barthel Index, EuroQoL-5D, and Depression, Anxiety, Stress Scale, respectively. A subset of participants was interviewed, exploring acceptability of telerehabilitation.

Findings

Between January and December 2020, 97 participants with SCI (n = 82) and ABI (n = 15) were enrolled. After receiving telerehabilitation, significant improvement to self-reported functional independence (p<.001) and quality of life were found, (p<.001). Self-reported severity of depression, anxiety and stress significantly decreased (p<.001). Qualitative interviews (n = 18) revealed participants accepted telerehabilitation, they valued regular contact with professionals without costly, difficult travel.

Interpretation

This is the first study to test telerehabilitation in Nepal. This approach can be safely delivered for long-term follow-up for individuals with SCI or ABI, overcoming geographical barriers to healthcare access. A larger-scale controlled study is required to further explore clinical and cost-effectiveness.
Stepwise evolution of carbapenem-resistance, captured in patient samples and evident in global genomics of Klebsiella pneumoniae
Authors: Perlaza-Jiménez Laura , Wilksch Jonathan J. , Stubenrauch Christopher J. , Chen Tao , Zhao Yajie , Zhou Tieli , Lithgow Trevor , Dhanasekaran Vijaykrishna
Published: June 2021

The World Health Organization ranks Klebsiella pneumoniae as a priority antimicrobial-resistant (AMR) pathogen requiring urgent study. New strategies for diagnosis and treatment, particularly for those Klebsiella that are classified as carbapenem-resistant Enterobacteriaceae (CRE) need to recognize the increased prevalence of non-carbapenemase producing CRE (non-CP CRE). By integrating diverse Klebsiella genomes with known CRE phenotypes, we successfully identified a synchronized presence of CRE phenotype-related genes in plasmids and chromosomes in comparison to strains with carbapenem susceptible phenotypes. The data revealed a major contribution to CRE comes from the combined effect of chromosome and plasmid genes potentiated by modifications of outer membrane porins. Our computational workflow identified key gene contributors to the non-CP CRE phenotype, including those that lead to an increase of antibiotic expulsion by enhanced efflux pump activity and mobile elements that reduce antibiotic intake, such as IS1 and Tn3-like elements. These findings are consistent with a new model wherein a change to the balance in drug influx and efflux potentiates the ability of some beta-lactamases to enable survival in the presence of carbapenems. Analysis of the large numbers of documented CRE infections, as well as forensic analysis of a case study, showed that this potentiation can occur in short timeframes to deliver a non-CP CRE infection. Our results suggest that the multiple genes that function to build an AMR phenotype can be diagnosed, so that strains that will resist treatment with carbapenem treatment will be evident if a comprehensive genome-based diagnostic for CRE considers all of these sequence-accessible features.

SIGNIFICANCE

Carbapenem-resistant Enterobacteriaceae (CRE) has emerged as an important challenge in health-care settings, with Klebsiella pneumoniae playing a major role in the global burden of CRE infections. Through systematic characterisation of the chromosome and plasmid genes of K. pneumoniae strains and their antimicrobial traits we identified new CRE mechanisms that are important for accurate diagnosis of carbapenem-resistant AMR. The development of comprehensive genomics-based diagnostics for CRE will need to consider the multiple gene signatures that impact together to deliver non-carbapenemase, carbapenem-resistant infections.
Integrating epidemiological and clinical predictors of SARS-CoV-2 infection in students and school staff in the state of São Paulo
Authors: Quijano Fredi A. Diaz , da Silva José Mário Nunes , D’Agostini Tatiana Lang , de Camargo Jéssica Pires , de Moraes Nathalia Cristina Soares Franceschi , Haddad Ricardo , Pereira Maria Cecília Gomes , Covas Dimas Tadeu , de Paula Regiane A. Cardoso
Published: June 2021

Background

There is a great deal of uncertainty concerning which contexts would be safe for returning to school and about individual criteria that would reduce contact between the infected and susceptible people in the school setting. Therefore, the purpose of this study was to estimate the prevalence of infection by SARS-CoV-2 in students and school staff; and to identify predictors of infection, including both municipal epidemiological indicators and individual variables reported by the participants.

Methods

This was a virological survey carried out among students (over 14 years old) and school staff in São Paulo state, between epidemiological weeks 43 to 49 of the year 2020. A self-administrated questionnaire including sociodemographic and clinical information was applied. Moreover, a nasopharynx swab was performed for virological testing (RT-PCR). We evaluate the relationship of COVID-19 epidemiological indicators of the residence municipality with the odds of SARS-CoV-2 infection. For this, a composite index relating recent mortality and previous incidence (RM/PI) was proposed based on the ratio of deaths recorded in the second and third week counted back to the sum of cases during the previous seven weeks (weeks 4 to 10 counted back). We obtained a multiple model using random-effects logit regression integrating epidemiological indicators and individual variables.

Results

In total, 3436 participants were included, residents of 72 municipalities. The overall prevalence of infection was 1.7% (95%CI: 1.3%-2.2%). SARS-CoV-2 infection was independently associated with loss of smell, a history of pulmonary disease, and a recent trip outside the municipality. Moreover, the RM/PI index consistently predicted the SARS-CoV-2 infection (adjusted OR: 1.45; 95%CI 1.02-2.04). Based on these associations, we proposed a classification in four groups with different SARS-Cov-2 infection prevalence (0.54%, 1.27%, 3.8%, and 4.13%).

Conclusion

Epidemiological and individual variables allowed classifying groups according to the infection probability in a school population of the state of São Paulo. This classification could help guide the return to classes in situations in which epidemiological control is evident, maintaining basic protection measures and increasing vaccination coverage.
Evaluation of the Panbio™ rapid antigen test for COVID-19 diagnosis in symptomatic health care workers
Authors: Bruins Marjan J. , dos Santos Claudy Oliveira , Spoelman-Lunsche Marjan , van den Bos-Kromhout Marieke I. , Debast Sylvia B.
Published: June 2021

If a health care workers (HCW) experiences COVID-19 associated symptoms, SARS-CoV-2 testing must be performed as soon as possible, to prevent transmission of the virus and to guarantee continuity of care. The gold standard for the detection of SARS-CoV-2, RT-PCR, has a high sensitivity but usually takes 6-8 hours. Lateral flow antigen assays take only 15-30 minutes and do not need any high tech equipment.

In a prospective study of our hospital’s HCWs, we evaluated the sensitivity of the Panbio™ COVID-19 Ag Rapid Test (Abbott) against the molecular test Aptima™ SARS-CoV-2 Assay (Hologic) which uses Transcription Mediated Amplification (TMA). TMA positive samples were further subjected to a quantitative real-time SARS-CoV-2 PCR to obtain Ct values as an indication of the viral load.

Of 1101 HCWs included in the study between November 2020 and February 2021, 84 (7.6%) were TMA positive, of which 48 (57.1%) were antigen test positive. Most false negative antigen test results occurred if the duration of symptoms had been ≤1 day or ≥7 days. Sensitivities for symptom onset of ≤1, 2 or 3 days were 47.1%, 63.0% and 66.7% respectively.

The Panbio™ rapid test is fast and easy to perform, but is not a suitable SARS-CoV-2 test to confirm or exclude COVID-19 in HCWs with a very recent onset of symptoms.
Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families
Authors: Ahangari Mohammad , Gentry Amanda E. ,   Irish Schizophrenia Genomics Consortium, Nguyen Tan-Hoang , Kirkpatrick Robert , Verrelli Brian C. , Bacanu Silviu-Alin , Kendler Kenneth S. , Webb Bradley T. , Riley Brien P.
Published: June 2021

Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia genome-wide association study data (N=156,509) to construct polygenic risk scores (PRS) in 1,005 individuals from 257 multiplex schizophrenia families, 2,114 ancestry-matched sporadic cases, and 2,205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.92, FH+ cases p = 0.88, FH-cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.
Unbiased sequencing of Mycobacterium tuberculosis urinary cell-free DNA reveals extremely short fragment lengths
Authors: Oreskovic Amy , Waalkes Adam , Holmes Elizabeth A. , Rosenthal Christopher A. , Wilson Douglas P.K. , Shapiro Adrienne E. , Drain Paul K. , Lutz Barry R. , Salipante Stephen J.
Published: June 2021

Urine cell-free DNA (cfDNA) presents an attractive target for diagnosing pulmonary Mycobacterium tuberculosis (TB) infection but has not been thoroughly characterized. Here, we aimed to investigate the size and composition of TB-derived urine cfDNA with minimal bias using next-generation DNA sequencing (NGS). To enable analysis of highly fragmented urine cfDNA, we used a combination of DNA extraction (Q sepharose) and single-stranded sequence library preparation methods demonstrated to recover short, highly degraded cfDNA fragments. We examined urine cfDNA from ten HIV-positive patients with confirmed pulmonary TB (nine of which had TB cfDNA detectable by qPCR) and two TB-negative controls. TB-derived cfDNA was identifiable by NGS from all TB-positive patients. TB urine cfDNA was significantly shorter than human urine cfDNA, with median fragment lengths of ≤19–52 bp and 42–92 bp, respectively. TB cfDNA abundance increased exponentially with decreased fragment length, with a peak fragment length of ≤19 bp in most samples. Our methodology also revealed a larger fraction of short human genomic cfDNA than previously reported, with peak fragment lengths of 29–53 bp. Urine cfDNA fragments spanned the TB genome with relative uniformity, but nucleic acids derived from multicopy elements were proportionately overrepresented, providing regions of inherent signal amplification beneficial for molecular diagnosis. This study demonstrates the potential of urine cfDNA as a diagnostic biomarker for TB and will inform improved design of TB urine cfDNA assays. Methods capable of targeting the shortest cfDNA fragments possible will be critical to maximize TB urine cfDNA detection sensitivity.
Prefrontal Cortex Definitions and Their Use in Distinguishing Pornography Addicted Juveniles
Authors: Prawiroharjo Pukovisa , Edison Rizki Edmi , Ellydar Hainah , Pratama Peter , Imelda Suaidy Sitti Evangeline , Amani Nya’ Zata , Carissima Diavitri , Hatta Ghina Faradisa
Published: June 2021

Background and aims

Increasing popularity of Internet has exposed our children pornography addiction. As in other types of addiction, it affects a brain region known as prefrontal cortex (PFC), which is important in executive functions and inhibitory control. However, this region was loosely defined, and there was no consensus for that definition. We aimed to use volumetric MRI in finding the defining region of PFC which would be suitable in distinguishing pornography addicted juveniles.

Methods

We enrolled 30 juveniles (12-16 y.o.) consisting of 15 pornography addiction and 15 non-addiction subjects. We proposed several models of PFC definition from mix-and-matched subregions, consisting of orbitofrontal (OFC), inferior frontal gyrus (IFG; pars orbitalis, opercularis, and triangularis), dorsolateral PFC (DLPFC), and anterior cingulate (ACC). Suitable PFC definition was defined as models which volume statistically different between both groups. Brain volumetric was measured using 3D-T1 3T MRI images and analyzed using FreeSurfer® for automatic cortical reconstruction and brain segmentation (recon-all command).

Results

We found significant differences between groups in 6 models, which mainly included OFC, ACC, and DLPFC, with models devoid of DLPFC had lowest mean differences.

Conclusion

The most suitable definition of PFC for pornography addiction study should consist of OFC, ACC, and especially DLPFC. Inferior frontal gyrus pars orbitalis was not necessary for this purpose, but may increase effect size if it is included.
Into the thirteenth Month: A Case Study on the Outbreak Analytics and Modeling the spread of SARS-CoV-2 Infection in Pune City, India
Authors: Monteiro Joy , Pujari Bhalchandra , Bhattacharrya Sarika Maitra , Raghunathan Anu , Keskar Ashwini , Shaikh Arsh , Bogam Prasad , Kadu Shweta , Raut Nikita , Vavale Devendra , Mishra Rupa , Kembhavi Ajit , Shashidhara L.S. , Mave Vidya
Published: June 2021

With more than 140 million people infected globally and 3 million deaths, the COVID 19 pandemic has left a lasting impact. A modern response to a pandemic of such proportions needs to focus on exploiting all available data to inform the response in real-time and allow evidence-based decision-making. The intermittent lockdowns in the last 13 months have created economic adversity to prevent anticipated large-scale mortality and relax the lockdowns have been an attempt at recovering and balancing economic needs and public health realities. This article is a comprehensive case study of the outbreak in the city limits of Pune, Maharashtra, India, to understand the evolution of the disease and transmission dynamics starting from the first case on March 9, 2020. A unique collaborative effort between the Pune Municipal Corporation (PMC), a government entity, and the Pune knowledge Cluster (PKC) allowed us to layout a context for outbreak response and intervention. We report here how access to granular data for a metropolitan city with pockets of very high-density populations will help analyze, in real-time, the dynamics of the pandemic and forecasts for better management and control of SARS-CoV-2. Outbreak data analytics resulted in a real-time data visualization dashboard for accurate information dissemination for public access on the epidemic’s progress. As government agencies craft testing and vaccination policies and implement intervention strategies to mitigate a second wave, our case study underscores the criticality of data quality and analytics to decode community transmission of COVID-19.
Association between SARS-Cov-2 infection during pregnancy and adverse pregnancy outcomes: a re-analysis of data from Wei et al. (2021)
Authors: Ludwig Serge Aho Glele , Simon Emmanuel , Bouit Camille , Serrand Maeva , Filipuzzi Laurence , Astruc Karine , Kadhel Philippe , Sagot Paul
Published: June 2021

Background

Wei et al. have published a meta-analysis (MA) which aimed to “evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes”.

Using classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth.

Performing MA with low event rates or with few studies may be challenging as MA relies on several within and between study distributional assumptions.

Methods

to assess the robustness of the results provided by Wei et al., we performed a sensitivity analysis using several frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes.

Results

For eclampsia (patients with Covid-19 vs without), the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method ranges from 0.75 to 2.38. The fragility index is 2 for the DL method.

For preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10.

For stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1.The prediction interval ranges from 0.52 to 8.49. The fragility index is 3.

Interpretation

Given the available data and the results of our broad sensitivity analysis, we can only suggest that SARS-CoV-2 infection during pregnancy is associated to preterm, and may be associated to preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.
GRADING prognostic factors for severe and recurrentClostridioides difficileinfection: expected and unexpected findings. A systematic review
Authors: van Rossen Tessel M. , Ooijevaar Rogier E. , Vandenbroucke-Grauls Christina M.J.E. , Dekkers Olaf M. , Kuijper Ed. J. , Keller Josbert J. , van Prehn Joffrey
Published: June 2021

Background

Clostridioides difficileinfection (CDI), its subsequent recurrences (rCDI), and severe CDI (sCDI) provide a significant burden for both patients and the healthcare system. Treatment consists of oral antibiotics. Fidaxomicin, bezlotoxumab and fecal microbiota transplantion (FMT) reduce the number of recurrences compared to vancomycin, but are more costly. Identifying patients diagnosed with initial CDI who are at increased risk of developing sCDI/rCDI could lead to more cost-effective therapeutic choices.

Objectives

In this systematic review we aimed to identify clinical prognostic factors associated with an increased risk of developing sCDI or rCDI.

Methods

PubMed, Embase, Emcare, Web of Science and COCHRANE Library databases were searched from database inception through March, 2021. Study selection was performed by two independent reviewers on the basis of predefined selection criteria; conflicts were resolved by consensus. Cohort and case-control studies providing an analysis of clinical or laboratory data to predict sCDI/rCDI in patients ≥18 years diagnosed with CDI, were included. Risk of bias was assessed with the Quality in Prognostic Research (QUIPS) tool and the quality of evidence by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool, modified for prognostic studies. Overview tables of prognostic factors were constructed to assess the number of studies and the respective direction of an association (positive, negative, or no association).

Results and conclusions

136 studies were included for final analysis. Higher age and the presence of multiple comorbidities were prognostic factors for sCDI. Identified risk factors for rCDI were higher age, healthcare-associated CDI, prior hospitalization, PPIs started during/after CDI diagnosis and previous rCDI. Some variables that were found as risk factors for sCDI/rCDI in previous reviews were not confirmed in the current review, which can be attributed to differences in methodology. Risk stratification for sCDI/rCDI may contribute to a more personalized and optimal treatment for patients with CDI.
Can Auxiliary Indicators Improve COVID-19 Forecasting and Hotspot Prediction?
Authors: McDonald Daniel J. , Bien Jacob , Green Alden , Hu Addison J. , DeFries Nat , Hyun Sangwon , Oliveira Natalia L. , Sharpnack James , Tang Jingjing , Tibshirani Robert , Ventura Valérie , Wasserman Larry , Tibshirani Ryan J.
Published: June 2021

Short-term forecasts of traditional streams from public health reporting (such as cases, hospitalizations, and deaths) are a key input to public health decision-making during a pandemic. Since early 2020, our research group has worked with data partners to collect, curate, and make publicly available numerous real-time COVID-19 indicators, providing multiple views of pandemic activity in the U.S. This paper studies the utility of five such indicators—derived from de-identified medical insurance claims, self-reported symptoms from online surveys, and COVID-related Google search activity—from a forecasting perspective. For each indicator, we ask whether its inclusion in an autoregressive (AR) model leads to improved predictive accuracy relative to the same model excluding it. Such an AR model, without external features, is already competitive with many top COVID-19 forecasting models in use today. Our analysis reveals that (a) inclusion of each of these five indicators improves on the overall predictive accuracy of the AR model; (b) predictive gains are in general most pronounced during times in which COVID cases are trending in “flat” or “down” directions; (c) one indicator, based on Google searches, seems to be particularly helpful during “up” trends.
Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia
Authors: Goswami Meghali , Gui Gege , Dillon Laura W. , Lindblad Katherine E. , Thompson Julie , Valdez Janet , Kim Dong-Yun , Ghannam Jack Y. , Oetjen Karolyn A. , Destefano Christin B. , Smith Dana M. , Tekleab Hanna , Li Yuesheng , Dagur Pradeep K. , Hughes Thomas , Marte Jennifer L. , del Rivero Jaydira , Klubo-Gwiezdzinksa Joanna , Gulley James L. , Calvo Katherine R. , Lai Catherine , Hourigan Christopher S.
Published: June 2021

The powerful “graft versus leukemia” effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable pre-clinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. We report here the results of 17-H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label ten-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using TCRβ sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable anti-leukemic response during treatment. Addition of pembrolizumab to ten-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

One Sentence Summary

AML patients receiving a novel combination of a PD-1 immune checkpoint inhibitor with a hypomethylating agent demonstrated clear evidence of induced immunological responses in those developing autoimmune toxicity during treatment but not in those demonstrating an anti-leukemic response.
Averting an outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a university residence hall through wastewater surveillance
Authors: Corchis-Scott Ryland , Geng Qiudi , Seth Rajesh , Ray Rajan , Beg Mohsan , Biswas Nihar , Charron Lynn , Drouillard Kenneth D. , D’Souza Ramsey , Heath Daniel D. , Houser Chris , Lawal Felicia , McGinlay James , Menard Sherri Lynne , Porter Lisa A. , Rawlings Diane , Tong Yufeng , Scholl Matthew L. , Siu K.W. Michael , Weisener Christopher G. , Wilhelm Steven. W. , McKay R. Michael L.
Published: June 2021

A wastewater surveillance program targeting a university residence hall was implemented during the spring semester 2021 as a proactive measure to avoid an outbreak of COVID-19 on campus. Over a period of 7 weeks from early February through late March 2021, wastewater originating from the residence hall was collected as grab samples 3 times per week. During this time, there was no detection of SARS-CoV-2 by RT-qPCR in the residence hall wastewater stream. Aiming to obtain a sample more representative of the residence hall community, a decision was made to use passive samplers beginning in late March onwards. Adopting a Moore Swab approach, SARS-CoV-2 was detected in wastewater samples on just two days after passive samplers were activated. These samples were also positive for the B.1.1.7 (Alpha) Variant of Concern (VOC) by RT-qPCR. The positive result triggered a public health case finding response including a mobile testing unit deployed to the residence hall the following day with testing of nearly 200 students and staff, which identified two laboratory-confirmed cases of B.1.1.7 variant COVID-19. These individuals were re-located to a separate quarantine facility averting an outbreak on campus. Aggregating wastewater and clinical data, the campus wastewater surveillance program has yielded the first estimates of fecal shedding rates of the B.1.1.7 VOC of SARS-CoV-2 in individuals from a non-clinical setting.
Risk factors for long COVID: analyses of 10 longitudinal studies and electronic health records in the UK
Authors: Thompson Ellen J. , Williams Dylan M. , Walker Alex J. , Mitchell Ruth E. , Niedzwiedz Claire L. , Yang Tiffany C. , Huggins Charlotte F. , Kwong Alex S. F. , Silverwood Richard J. , Gessa Giorgio Di , Bowyer Ruth C.E. , Northstone Kate , Hou Bo , Green Michael J. , Dodgeon Brian , Doores Katie J. , Duncan Emma L. , Williams Frances M. K. ,   OpenSAFELY Collaborative, Steptoe Andrew , Porteous David J. , McEachan Rosemary R. C. , Tomlinson Laurie , Goldacre Ben , Patalay Praveetha , Ploubidis George B. , Katikireddi Srinivasa Vittal , Tilling Kate , Rentsch Christopher T. , Timpson Nicholas J , Chaturvedi Nishi , Steves Claire J.
Published: June 2021

Background

The impact of long COVID is considerable, but risk factors are poorly characterised. We analysed symptom duration and risk factor from 10 longitudinal study (LS) samples and electronic healthcare records (EHR).

Methods

Samples: 6907 adults self-reporting COVID-19 infection from 48,901 participants in the UK LS, and 3,327 adults with COVID-19, were assigned a long COVID code from 1,199,812 individuals in primary care EHR. Outcomes for LS included symptom duration lasting 4+ weeks (long COVID) and 12+ weeks. Association with of age, sex, ethnicity, socioeconomic factors, smoking, general and mental health, overweight/obesity, diabetes, hypertension, hypercholesterolaemia, and asthma was assessed.

Results

In LS, symptoms impacted normal functioning for 12+ weeks in 1.2% (mean age 20 years) to 4.8% (mean age 63 y) of COVID-19 cases. Between 7.8% (mean age 28 y) and 17% (mean age 58 y) reported any symptoms for 12+ weeks, and greater proportions for 4+ weeks. Age was associated with a linear increased risk in long COVID between 20 and 70 years. Being female (LS: OR=1.49; 95%CI:1.24-1.79; EHR: OR=1.51 [1.41-1.61]), having poor pre-pandemic mental health (LS: OR=1.46 [1.17-1.83]; EHR: OR=1.57 [1.47-1.68]) and poor general health (LS: OR=1.62 [1.25-2.09]; EHR: OR=1.26; [1.18-1.35]) were associated with higher risk of long COVID. Individuals with asthma (LS: OR=1.32 [1.07-1.62]; EHR: OR=1.56 [1.46-1.67]), and overweight or obesity (LS: OR=1.25 [1.01-1.55]; EHR: OR=1.31 [1.21-1.42]) also had higher risk. Non-white ethnic minority groups had lower risk (LS: OR=0.32 [0.22-0.47]), a finding consistent in EHR. . Few participants had been hospitalised (0.8-5.2%).

Conclusion

Long COVID is associated with sociodemographic and pre-existing health factors. Further investigations into causality should inform strategies to address long COVID in the population.
Analysis of host immunological response of adenovirus-based COVID-19 vaccines
Authors: Farhang-Sardroodi Suzan , Korosec Chapin , Gholami Samaneh , Craig Morgan , Moyles Iain R , Ghaemi Mohammad Sajjad , Ooi Hsu Kiang , Heffernan Jane M
Published: June 2021

During the SARS-CoV-2 global pandemic, several vaccines, including mRNA and ade-novirus vector approaches, have received emergency or full approval. However, supply chain logistics have hampered global vaccine delivery, which is impacting mass vaccination strategies. Recent studies have identified different strategies for vaccine dose administration so that supply constraints issues are diminished. These include increasing the time between consecutive doses in a two-dose vaccine regimen and reducing the dosage of the second dose. We consider both of these strategies in a mathematical modeling study of a non-replicating viral vector adenovirus vaccine in this work. We investigate the impact of different prime-boost strategies by quantifying their effects on immunological outcomes based on simple ordinary differential equations. The boost dose is administered either at a standard dose (SD) of 1000 or at a low dose (LD) of 500 or 250 vaccine particles. Simulated Second dose fractionation highlights previously shown dose-dependent features of the immune mechanism. In agreement with clinical characteristics of 175 COVID-19 recovered patients, the model predictions for either SD/SD or SD/LD regimens mainly show that by stretching the prime-boost interval until 18 or 20 weeks, the minimum promoted antibody (Nab) response is comparable with the neutralizing antibody level of COVID-19 recovered patients. The minimum stimulated antibody in SD/SD regimen is identical with the high level of clinical trial data. It is at the same range of the medium-high level of Nab in SD/LD, where the second dose is half or quarter of the standard dose.
Predicting elimination of evolving virus variants
Authors: Hughes Elliott , Binny Rachelle , Hendy Shaun , James Alex
Published: June 2021

As the SARS-CoV-2 virus spreads around the world new variants are appearing regularly. Although some countries have achieved very swift and successful vaccination campaigns, on a global scale the vast majority of the population is unvaccinated and new variants are proving more resistant to the current set of vaccines. We present a simple model of disease spread which includes the evolution of new variants and varying vaccine effectiveness to these new strains. We show that rapid vaccine updates to target new strains are more effective than slow updates and containing spread through non-pharmaceutical interventions is vital whilst these vaccines are delivered. Finally when measuring the key model inputs, e.g. the rate at which new mutations and variants of concern emerge, is difficult we show how an observable model output, the number of new variants which have been seen, is strongly correlated with the probability the virus is eliminated.
Probing Neuro-Endocrine Interactions Through Wireless Magnetothermal Stimulation of Peripheral Organs
Authors: Maeng Lisa Y. , Rosenfeld Dekel , Simandl Gregory J. , Koehler Florian , Senko Alexander W. , Moon Junsang , Varnavides Georgios , Murillo Maria F. , Reimer Adriano E. , Wald Aaron , Anikeeva Polina , Widge Alik S.
Published: June 2021

Exposure to stress alters hypothalamic-pituitary-adrenal (HPA) axis reactivity; however, it is unclear exactly how or where within the HPA pathway these changes occur. Dissecting these mechanisms requires tools to reliably probe HPA function, particularly the adrenal component, with temporal precision. We previously demonstrated magnetic nanoparticle (MNP) technology to remotely trigger adrenal hormone release by activating thermally sensitive ion channels. Here, we applied adrenal magnetothermal stimulation to probe stress-induced HPA axis changes. MNP and control nanoparticles were injected into the adrenal glands of outbred rats subjected to a tone-shock conditioning/extinction/recall paradigm. We measured MNP-triggered adrenal release before and after conditioning through physiologic (heart rate) and serum (epinephrine, corticosterone) markers. Aversive conditioning altered adrenal function, reducing corticosterone and blunting heart rate increases post-conditioning. MNP-based organ stimulation provides a novel approach to probing the function of HPA and other neuro-endocrine axes and could help elucidate changes across stress and disease models.
PpRPK2 modulates auxin homeostasis and transport to specify stem cell identity and plant shape in the moss Physcomitrella
Authors: Venza Zoe Nemec , Madden Connor , Stewart Amy , Liu Wei , Novák Ondřej , Pěnčík Aleš , Cuming Andrew C. , Kamisugi Yasuko , Harrison C. Jill
Published: June 2021

Plant shape is determined by the activity of stem cells in the growing tips, and evolutionary changes in shape are linked to changes in stem cell function. The CLAVATA pathway is a key regulator of stem cell function in the multicellular shoot tips of Arabidopsis, acting via the WUSCHEL transcription factor to modulate hormone homeostasis. Broad scale evolutionary comparisons have shown that CLAVATA is a conserved regulator of land plant stem cell function, but CLAVATA acts independently of WUSCHEL-like (WOX) proteins in bryophytes, raising questions about the evolution of stem cell function and the role of the CLAVATA pathway.

Here we show that the moss (Physcomitrella) CLAVATA pathway affects stem cell activity and overall plant shape by modulating hormone homeostasis. CLAVATA pathway components are expressed in the tip cells of filamentous tissues, regulating cell identity, filament branching patterns and plant spread. The PpRPK2 receptor-like kinase plays the major role and is expressed more strongly than other receptor-encoding genes. Pprpk2 mutants have abnormal responses to cytokinin, and auxin transport inhibition and show reduced PIN auxin transporter expression.

We propose a model whereby PpRPK2 modulates PIN activity to determine stem cell identity and overall plant form in Physcomitrella. Our data indicate that CLAVATA-mediated auxin homeostasis is a fundamental property of plant stem cell function likely exhibited by the last shared common ancestor of land plants.
Synthesis and Structure Elucidation of the Human tRNA Nucleoside Mannosyl-Queuosine
Authors: Hillmeier Markus , Wagner Mirko , Ensfelder Timm , Korytiakova Eva , Thumbs Peter , Müller Markus , Carell Thomas
Published: June 2021

Queuosine (Q) is a structurally complex, non-canonical RNA nucleoside. It is present in many eukaryotic and bacterial species, where it is part of the anticodon loop of certain tRNAs. In higher vertebrates, including humans, two further modified queuosine-derivatives exist - galactosyl-(galQ) and mannosyl-queuosine (manQ). The function of these low abundant hypermodified RNA nucleosides remains unknown. While the structure of galQ was elucidated and confirmed by total synthesis, the reported structure of manQ still awaits confirmation. By combining total synthesis and LC-MS-co-injection, together with a metabolic feeding study of labelled hexoses, we show here that the natural compound manQ isolated from mouse liver deviates from the literature-reported structure. The chemical structure of the natural product manQ features a novel α-allyl connectivity. The data reported here shows that the yet unidentified glycosylases that attach galactose and mannose to the Q-base have different constitutional connectivity preferences. Knowing the correct structure of manQ will now pave the way towards further elucidation of its biological function.
Unidirectional migration of populations with Allee effect
Authors: Röst Gergely , Sadeghimanesh AmirHosein
Published: June 2021

In this note we consider two populations living on identical patches, connected by unidirectional migration, and subject to strong Allee effect. We show that by increasing the migration rate, there are more bifurcation sequences than previous works showed. In particular, the number of steady states can change from 9 (small migration) to 3 (large migration) at a single bifurcation point, or via a sequences of bifurcations with the system having 9,7,5,3 or 9,7,9,3 steady states, depending on the Allee threshold. This is in contrast with the case of bidirectional migration, where the number of steady states always goes through the same bifurcation sequence of 9,5,3 steady states as we increase the migration rate, regardless of the value of the Allee threshold.
Superior colliculus saccade motor bursts do not dictate movement kinematics
Authors: Zhang Tong , Malevich Tatiana , Baumann Matthias , Hafed Ziad M.
Published: June 2021

The primate superior colliculus (SC) contains a topographic map of space, such that the anatomical location of active neurons defines a desired eye movement vector. Complementing such a spatial code, SC neurons also exhibit saccade-related bursts that are tightly synchronized with movement onset. Current models suggest that such bursts constitute a rate code dictating movement kinematics. Here, using two complementary approaches, we demonstrate a dissociation between the SC rate code and saccade kinematics. First, we show that SC burst strength systematically varies depending on whether saccades of the same amplitude are directed towards the upper or lower visual fields, but the movements themselves have similar kinematics. Second, we show that for the same saccade vector, when saccades are significantly slowed down by the absence of a visible saccade target, SC saccade-related burst strengths can be elevated rather than diminished. Thus, SC saccade-related motor bursts do not necessarily dictate movement kinematics.