bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiological waves - types, drivers and modulators in the COVID-19 pandemic
Authors: Harvey John , Chan Bryan , Srivastava Tarun , Zarebski Alexander E. , Dłotko Paweł , Błaszczyk Piotr , Parkinson Rachel H. , White Lisa J. , Aguas Ricardo , Mahdi Adam 
Published: January 2022

AbstractIntroductionA discussion of ‘waves’ of the COVID-19 epidemic in different countries is a part of the national conversation for many, but there is no hard and fast means of delineating these waves in the available data and their connection to waves in the sense of mathematical epidemiology is only tenuous.MethodsWe present an algorithm which processes a general time series to identify substantial, significant and sustained periods of increase in the value of the time series, which could reasonably be described as ‘observed waves’. This provides an objective means of describing observed waves in time series.ResultsThe output of the algorithm as applied to epidemiological time series related to COVID-19 corresponds to visual intuition and expert opinion. Inspecting the results of individual countries shows how consecutive observed waves can differ greatly with respect to the case fatality ratio. Furthermore, in large countries, a more detailed analysis shows that consecutive observed waves have different geographical ranges. We also show how waves can be modulated by government interventions and find that early implementation of non-pharmaceutical interventions correlates with a reduced number of observed waves and reduced mortality burden in those waves.ConclusionIt is possible to identify observed waves of disease by algorithmic methods and the results can be fruitfully used to analyse the progression of the epidemic.
Infectious disease dynamics and restrictions on social gathering size
Authors: Boyer Christopher B , Rumpler Eva , Kissler Stephen M , Lipsitch Marc 
Published: January 2022

AbstractSocial gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating “allowed” from “prohibited” gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020.
Exploring the health impacts and inequalities of the new way of working: findings from a cross-sectional study
Authors: Griffiths Melda Lois , Gray Benjamin J , Kyle Richard G , Davies Alisha R 
Published: January 2022

AbstractAimTo explore the working Welsh adult population’s ability to work from home, their preferences for the future, and the self-reported health impacts of home-working.Subject and MethodsA nationally-representative household survey was undertaken across Wales (Public Health Wales’ COVID-19, Employment and Health in Wales study), with cross-sectional data on home-working being collected between November 2020 and January 2021 from 615 employed working-aged adults in Wales (63.7% female, 32.7% aged 50-59). Respondents were asked about their ability to work from home, their perceptions of its impact on their health and their preferences for time spent home-working in future.ResultsOver 50% were able to work from home, and showed a preference towards home-working to some capacity, with over a third wishing to work from home at least half the time. However, those living in the most deprived areas, in atypical employment, with high wage precarity or with limiting pre-existing conditions were less likely to report being able to work from home. Of those that could work from home, over 40% reported that it worsened their mental well-being and loneliness, and for people in poorer health, home-working negatively impacted their diet, physical activity, smoking and alcohol use. People aged 30 to 39 and those who lived alone were more likely to report wanting to spend some time working in an office/base instead of at home.ConclusionThe inequity in the ability to work from home reflects underlying inequalities in Wales, with those facing the greatest insecurity (e.g. those living in most deprived areas, those with more precarious work or financial circumstances) being less able to participate in home-working. Working from home offers greater flexibility, reduces the financial and time costs associated with commuting, and protects individuals from exposure to communicable diseases. However, working from home presents an enormous challenge to preserving the mental-wellbeing of the workforce, particularly for younger individuals and those with low mental well-being. Younger respondents and those in poorer health who could work from home were also more likely to engage in health-harming behaviours, and reduce their engagement in health-protective behaviours such as eating well and moving more. Reflecting on the future, providing pathways for accessing work from home arrangements, integrating hybrid models and preparing targeted health support for at risk groups may be best suited to the working population’s preferences and needs.
Estimation of excess all-cause mortality due to COVID-19 in Thailand
Authors: Wilasang Chaiwat , Modchang Charin , Lincharoen Thanchanok , Chadsuthi Sudarat 
Published: January 2022

AbstractThailand has experienced the most prominent COVID-19 outbreak, resulting in a new record for COVID-19 cases and deaths in 2021. To assess the influence of the COVID-19 outbreak on mortality, we estimated excess all-cause and pneumonia mortality in Thailand during the COVID-19 outbreak from April to October 2021. We used the previous five years’ mortality to estimate the baseline number of deaths using generalized linear mixed models (GLMMs). The models were adjusted for seasonality and demographics. We found that the estimated cumulative excess death was 14.3% (95% CI: 8.6%-18.8%) higher than the baseline. The results also showed that the excess deaths in males were higher than in females by approximately 26.3%. The excess deaths directly caused by the COVID-19 infections accounted for approximately 75.0% of the all-cause excess deaths. Furthermore, excess pneumonia deaths were also found to be 26.2% (95% CI: 4.8%-46.0%) above baseline. There was a significant rise in excess fatalities, especially in the older age groups. Therefore, the age and sex structure of the population are essential to assessing the mortality impact of COVID-19. Our modeling results could potentially provide insights into the COVID-19 outbreaks and provide a guide for outbreak control and intervention.
COVID-19 vaccine effectiveness among healthcare workers in Portugal: results from a hospital-based cohort study, December 2020 to November 2021
Authors: Gaio Vânia , Silva Adriana , Amaral Palmira , Viana João Faro , Leite Pedro Pinto , Dias Carlos Matias , Kislaya Irina , Nunes Baltazar , Machado Ausenda 
Published: January 2022

AbstractIntroductionHealthcare workers (HCW) were amongst the first prioritized for COVID-19 vaccination but data on COVID-19 vaccine effectiveness among HCW is still limited. This study aims to estimate the COVID-19 vaccine effectiveness (VE) against SARS-CoV-2 symptomatic infection among HCW from Portuguese hospitals.MethodsIn this prospective cohort study, we analysed data from HCW (all professional categories) from two central hospitals in the Lisbon and Tagus Valley and Centre regions of mainland Portugal between December 2020 and November 2021. VE against symptomatic SARS-CoV-2 infection was estimated as one minus the confounder adjusted hazard ratios by Cox models considering age group, sex, presence of chronic disease and occupational exposure to patients diagnosed with COVID-19 as adjustment variables.ResultsDuring the 11 months of follow up, the 2213 HCW contributed a total of 1950 person-years at risk and 171 SARS-CoV-2 events occurred. The COVID-19 incidence rate for unvaccinated HCW was 348.7 per 1000 person-years while for fully vaccinated HCW was 43.0 per 1000 person-years. We observed a VE against symptomatic SARS-CoV-2 infection of 73.9% (95% CI: 26.2–90.8%) for complete vaccination status.ConclusionThis cohort study found a high COVID-19 VE against symptomatic SARS-CoV-2 infection in Portuguese HCW, which is in concordance with previous studies from other countries. Monitoring of VE in this HCW cohort continues during the winter 2021/2022 to evaluate potential VE decay and booster vaccine effect.
Mendelian gene identification through mouse embryo viability screening
Authors: Cacheiro Pilar , Westerberg Carl Henrik , Mager Jesse , Dickinson Mary E. , Nutter Lauryl M.J. , Muñoz-Fuentes Violeta , Hsu Chih-Wei , Van den Veyver Ignatia B. , Flenniken Ann M. , McKerlie Colin , Murray Stephen A. , Teboul Lydia , Heaney Jason D. , Lloyd K. C. Kent , Lanoue Louise , Braun Robert E. , White Jacqueline K. , Creighton Amie K. , Laurin Valerie , Guo Ruolin , Qu Dawei , Wells Sara , Cleak James , Bunton-Stasyshyn Rosie , Stewart Michelle , Harrisson Jackie , Mason Jeremy , Mashhadi Hamed Haseli , Parkinson Helen , Mallon Ann-Marie ,   International Mouse Phenotyping Consortium,   Genomics England Research Consortium, Smedley Damian 
Published: January 2022

AbstractThe diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful.A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal.We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease.Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.
Inpatient COVID-19 Mortality Rates: What are the predictors?
Authors: Al-Amin Mona , Islam Md Nazmul , Li Kate , Sheils Natalie E. , Buresh John 
Published: January 2022

AbstractObjectiveThis study aims to investigate the relationship between registered nurses and hospital-based medical specialties staffing levels with inpatient COVID-19 mortality rates.MethodsWe rely on data from AHA Annual Survey Database, Area Health Resource File, and UnitedHealth Group Clinical Discovery Database. We use linear regression to analyze the association between hospital staffing levels and bed capacity with inpatient COVID-19 mortality rates from March 1, 2020, through December 31, 2020.ResultsHigher staffing levels of registered nurses, hospitalists, and emergency medicine physicians were associated with lower COVID-19 mortality rates. Moreover, a higher number of ICU and skilled nursing beds were associated with better patient outcomes. Hospitals located in urban counties with high infection rates had the worst patient mortality rates.ConclusionHigher staffing levels are associated with lower inpatient mortality rates for COVID-19 patients. A future assessment is needed to establish benchmarks on the minimum staffing levels for nursing and hospital-based medical specialties during pandemics.
Outcomes of COVID-19 infection in patients with chronic kidney disease on maintenance hemodialysis at a COVID hospital in India
Authors: Singh Ram , Krishnasamy Sudarsan , Meena Jitendra Kr , Sirohiya Prashant , Kumar Balbir , Ratre Brajesh kumar , Vig Saurabh , Pandit Anuja , Sagiraju Hari , Gupta Raghav , Bhatnagar Sushma 
Published: January 2022

AbstractBackgroundPatients with chronic kidney disease (CKD) on hemodialysis are highly vulnerable to COVID-19 infection with a mortality rate higher than the rest of the population. There are several clinical and laboratory parameters that can predict the course and the outcomes in this group of population.MethodsWe retrospectively collected the baseline demographic, clinical, in-hospital, and laboratory data of the patients with CKD on maintenance hemodialysis who were admitted to our COVID-19 hospital during the first and the second wave.ResultsWe obtained data for 35 patients from the first and 5 patients from the second wave. The analysis of the data for 35 patients from the first wave revealed shortness of breath (62.9%), and fever (54.3%) being the most common presenting symptoms, and the majority of the patients (57.2 %) presented with moderate to severe disease at admission with 57 % had bilateral lung infiltrates, and required oxygen support (65.7%) at admission. The comparison of clinical and laboratory markers between survivors (27 patients, 77.1%) and non-survivors (8 patients, 22.9%) revealed an older age, severe disease at presentation, invasive mechanical ventilation, baseline severe lymphocytopenia, high serum glutamic oxaloacetic transaminase, blood urea, and inflammatory markers like Interleukin-6 and procalcitonin, fibrinogen and low albumin in non survivors.ConclusionsThe older age, severe disease at presentation, the requirement of invasive mechanical ventilation, raised baseline Interleukin-6, procalcitonin, serum glutamic oxaloacetic transaminase, blood urea and a low albumin level could be valuable predictors of poor outcomes.
Generalized Michaelis–Menten rate law with time-varying molecular concentrations
Authors: Lim Roktaek , Martin Thomas L. P. , Chae Junghun , Kim WooJoong , Ghim Cheol-Min , Kim Pan-Jun 
Published: January 2022

AbstractThe Michaelis–Menten (MM) rate law has been the dominant paradigm of modeling biochemical rate processes for over a century with applications in biochemistry, biophysics, cell biology, systems biology, and chemical engineering. The MM rate law and its remedied form stand on the assumption that the concentration of the complex of interacting molecules, at each moment, approaches an equilibrium (quasi-steady state) much faster than the molecular concentrations change. Yet, this assumption is not always justified. Here, we relax this quasi-steady state requirement and propose the generalized MM rate law for the interactions of molecules with active concentration changes over time. Our approach for time-varying molecular concentrations, termed the effective time-delay scheme (ETS), is based on rigorously estimated time-delay effects in molecular complex formation. With particularly marked improvements in protein–protein and protein–DNA interaction modeling, the ETS provides an analytical framework to interpret and predict rich transient or rhythmic dynamics (such as autogenously-regulated cellular adaptation and circadian protein turnover), which goes beyond the quasi-steady state assumption.
Hexosamine pathway activation improves memory but does not extend lifespan in mice
Authors: Allmeroth Kira , Hartman Matías D. , Purrio Martin , Mesaros Andrea , Denzel Martin S. 
Published: January 2022

AbstractGlucosamine feeding and genetic activation of the hexosamine biosynthetic pathway (HBP) have been linked to improved protein quality control and lifespan extension in various species. Thus, there is considerable interest in the potential health benefits of dietary supplementation with glucosamine or other HBP metabolites in people. The HBP is a sensor for energy availability and its activation has been implicated in tumor progression and diabetes in higher organisms. As the activation of the HBP has been linked to longevity in lower animals, it is imperative to explore the long-term effects of chronic HBP activation in mammals, which has not been examined so far. To address this issue, we activated the HBP in mice both genetically and through metabolite supplementation, and evaluated metabolism, memory, and survival. GlcNAc supplementation in the drinking water had no adverse effect on weight gain in males but increased weight in young female mice. Glucose or insulin tolerance were not affected up to 20 months of age. Of note, we observed improved memory in the Morris water maze in young male mice supplemented with GlcNAc. Survival was not changed by GlcNAc supplementation. To assess the effects of genetic HBP activation we overexpressed the key enzyme GFAT1 as well as a constitutively activated point mutant form in all mouse tissues. We detected elevated UDP-GlcNAc levels in mouse brains, but did not find any effects on behavior, memory, or survival. Together, while dietary GlcNAc supplementation did not extend survival in mice, it positively affected memory and is generally well tolerated.
Homologous BHLH transcription factors induce distinct deformations of torsionally-stressed DNA: a potential transcription regulation mechanism
Authors: Hörberg Johanna , Moreau Kevin , Reymer Anna 
Published: January 2022

AbstractChanging torsional restraints on DNA is essential for the regulation of transcription. Torsional stress, introduced by RNA polymerase, can propagate along chromatin facilitating topological transitions and modulating the specific binding of transcription factors (TFs) to DNA. Despite the importance, the mechanistic details on how torsional stress impacts the TFs-DNA complexation remain scarce. Herein we address the impact of torsional stress on DNA complexation with homologous human basic-helix-loop-helix (BHLH) hetero- and homodimers: MycMax, MadMax, and MaxMax. The three TF dimers exhibit specificity towards the same DNA consensus sequences, the E-box response element, while regulating different transcriptional pathways. Using microseconds-long atomistic molecular dynamics simulations together with the torsional restraint that controls DNA total helical twist, we gradually over- and underwind naked and complexed DNA to a maximum of ±5°/b.p. step. We observe that the binding of the BHLH dimers results in a similar increase in DNA torsional rigidity. However, under torsional stress the BHLH dimers induce distinct DNA deformations, characterised by changes in DNA grooves geometry and a significant asymmetric DNA bending. Supported by bioinformatics analyses, our data suggest that torsional stress may contribute to the execution of differential transcriptional programs of the homologous TFs by modulating their collaborative interactions.
Resolving Protein Conformational Plasticity and Substrate Binding Through the Lens of Machine-Learning
Authors: Ahalawat Navjeet , Mondal Jagannath 
Published: January 2022

AbstractA long-standing target in elucidating the biomolecular recognition process is the identification of binding-competent conformations of the receptor protein. However, protein conformational plasticity and the stochastic nature of the recognition processes often preclude the assignment of a specific protein conformation to an individual ligand-bound pose. In particular, we consider multi-microsecond long Molecular dynamics simulation trajectories of ligand recognition process in solvent-inaccessible cavity of two archtypal systems: L99A mutant of T4 Lysozyme and Cytochrome P450. We first show that if the substrate-recognition occurs via long-lived intermediate, the protein conformations can be automatically classified into substrate-bound and unbound state through an unsupervised dimensionality reduction technique. On the contrary, if the recognition process is mediated by selection of transient protein conformation by the ligand, a clear correspondence between protein conformation and binding-competent macrostates can only be established via a combination of supervised machine learning (ML) and unsupervised dimension reduction approach. In such scenario, we demonstrate that an a priori random forest based supervised classification of the simulated trajectories recognition process would help characterize key amino-acid residue-pairs of the protein that are deemed sensitive for ligand binding. A subsequent unsupervised dimensional reduction via time-lagged independent component analysis of the selected residue-pairs would delineate a conformational landscape of protein which is able to demarcate ligand-bound pose from the unbound ones. As a key breakthrough, the ML-based protocol would identify distal protein locations which would be allosterically important for ligand binding and characterise their roles in recognition pathways.
A kinase translocation reporter reveals real-time dynamics of ERK activity in Drosophila
Authors: Yuen Alice C. , Prasad Anadika R. , Fernandes Vilaiwan M. , Amoyel Marc 
Published: January 2022

AbstractExtracellular Signal-Regulated Kinase (ERK) lies downstream of a core signalling cascade that controls all aspects of development and adult homeostasis. Recent developments have led to new tools to image and manipulate the pathway. However, visualising ERK activityin vivowith high temporal resolution remains a challenge in Drosophila. We adapted a kinase translocation reporter (KTR) for use in Drosophila, which shuttles out of the nucleus when phosphorylated by ERK. We show that ERK-KTR faithfully reports endogenous ERK signalling activity in developing and adult tissues, and that it responds to genetic perturbations upstream of ERK. Using ERK-KTR in time-lapse imaging, we made two novel observations: firstly, sustained hyperactivation of ERK by expression of dominant-active Epidermal Growth Factor Receptor raised the overall level but did not alter the kinetics of ERK activity; secondly, heterogeneity in ERK activity in retinal basal glia correlated with the direction of migration of individual cells. Our results show that KTR technology can be applied in Drosophila to monitor ERK activity in real-time and suggest that this modular tool can be further adapted to study other kinases.Summary StatementWe describe a reporter to study the dynamics of ERK signalling in Drosophila, use it to measure signalling in individual cells over time, and monitor development.