bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing Lifestyle Medicine Education in a New Public Health and General Preventive Medicine Residency Program
Authors: Bidwell Josie H. , Dent Elena , Lewis Fiona , Mann Joshua R.
Published: March 2021

Mississippi ranks as the nation's least-healthy state. There is a shortage of trained preventive medicine (PM) physicians in the state. The Department of Preventive Medicine at The University of Mississippi Medical Center was reinstated in 2015 to address this need. Initial PM residency accreditation was awarded in November of 2017 with subsequent notification of 10-year accreditation status in April of 2020 allowing up to 4 PGY-2 and 4 PGY-3 resident positions per year. The residency experiences provided by the program are varied and unique due to the program being housed in both the School of Medicine and the School of Population Health. Preventive medicine residents have the opportunity to complete the American College of Lifestyle Medicine's Lifestyle Medicine Residency Curriculum. Through our diverse didactic and clinical experiences, we are optimistic that our program will continue to attract, train, and retain PM physicians for our state.
Interpregnancy Care: An Opportunity to Improve Women's Health and Reduce the Risk of Maternal Morbidity and Mortality
Authors: Erondu Chioma , Dunlop Anne
Published: March 2021

Interpregnancy care is the health care provided to a woman during the postpartum and preconception periods between pregnancies. Half of maternal deaths occur postpartum and cardiometabolic complications of pregnancy increase the risk for maternal morbidity and mortality and development of chronic conditions. By improving women's health between and beyond pregnancies, interpregnancy care has the potential to improve pregnancy outcomes and women's long-term health. This practice brief report summarizes evidence regarding the impact of interpregnancy care on pregnancy and long-term health outcomes for women with hypertension, diabetes, substance use, and mental health disorders. Existing evidence is limited but demonstrates that the utilization of interventions during this period may result in improved health outcomes. Additional research efforts are needed to better understand the impact of interpregnancy care on women's health throughout the life course.
Population Health Rounds: A Novel Vehicle for Training in Population Medicine and Clinical Preventive Medicine
Authors: Jadotte Yuri T. , Lane Dorothy S.
Published: March 2021

Context:

Preventive medicine residents must train in population medicine (including analytics and population health) and clinical preventive medicine (including screening, behavioral counseling, and chemoprophylaxis). Yet, opportunities to perform both functions concurrently for the same population are scarce. Residents must also master the art of preventive medicine, but they often lack an established community of practice that provides a continuous forum to do so. This project explored Population Health Rounds as a novel vehicle to optimize preventive medicine residency training.

Program Description:

Modeled after traditional medical rounds, Population Health Rounds consist of a 1-hour weekly meeting engaging preventive medicine residents and supervising attendings at Stony Brook Medicine in both population medicine and clinical preventive medicine concurrently, including patient case discussions and targeted population health analytics.

Evaluation and Results:

Because of the pandemic, the rounds have predominantly focused on COVID-19 and its effects on the hospital employee population. In addition to providing direct patient care to COVID-19–positive and exposed employees, residents have analyzed data on this population and made recommendations to hospital leadership based on COVID-19's institutional epidemiology, including incidence, prevalence, and predictive factors. A formative qualitative survey of resident perceptions offers insights on the value and learning outcomes of this new model.

Discussion and Conclusion:

Factors that may impact the implementation, sustainability, and feasibility of this model are discussed. The preventive medicine residency program is commissioned to address gaps in clinical preventive services for the patient-centered medical home tied to the sponsoring institution's family medicine practice. Additional plans are underway to expand the rounds to other clinical contexts, such as lifestyle medicine in the occupational setting, and for targeted populations, such as the underserved. Replication of the Population Health Rounds model is recommended to determine its effectiveness.
Multicenter Randomized Controlled Trial of Pelvic Floor Muscle Training with a Motion-based Digital Therapeutic Device versus Pelvic Floor Muscle Training Alone for Treatment of Stress-predominant Urinary Incontinence
Authors: Weinstein Milena M. , Collins Sarah , Quiroz Lieschen , Anger Jennifer T. , Paraiso Marie Fidela R. , DeLong Jessica , Richter Holly E.
Published: March 2021

Objective

To determine whether use of an intravaginal motion-based digital therapeutic device for pelvic floor muscle training (PFMT) was superior to PFMT alone in women with stress-predominant urinary incontinence (SUI).

Methods

A multicenter, randomized-controlled trial was conducted where women with SUI or SUI-predominant mixed urinary incontinence were treated with either PFMT using the device (intervention group) or PFMT alone (control group). Primary outcomes, measured at 8 weeks, included change in Urinary Distress Inventory, short-version and improvement in the Patient Global Impression of Improvement, defined as “much better” or “very much better.” Participants also completed Pelvic Organ Prolapse and Colorectal-anal Distress Inventories, Pelvic-Floor-Impact Questionnaire and a 3-day bladder diary. Primary analysis used a modified intention-to-treat approach. Statistical analysis used Student t test and χ2 test. The trial was prematurely halted due to device technical considerations.

Results

Seventy-seven women were randomized, and final analysis included 61 participants: 29 in intervention and 32 in control group. There was no statistical difference in Urinary Distress Inventory, short-version scores between the intervention (−13.7 ± 18.7) and the control group (−8.7 ± 21.8; P = 0.85), or in Patient Global Impression of Improvement (intervention 51.7% and control group 40.6%; P = 0.47). Pelvic Organ Prolapse and Colorectal-anal Distress Inventories and Pelvic-Floor-Impact Questionnaire scores improved significantly more in the intervention group than the control group (all P < 0.05). Median number of SUI episodes decreased from baseline to 8 weeks by −1.7 per-day [(−3)-0] in the intervention group and −0.7[(−1)-0] in the control group, (P = 0.047).

Conclusions

In this prematurely terminated trial, there were no statistically significant differences in primary outcomes; however, PFMT with this digital therapeutic device resulted in significantly fewer SUI episodes and greater improvement in symptom-specific quality of life outcomes. A larger powered trial is underway.
Achyranthes bidentata polypeptide k enhances the survival, growth and axonal regeneration of spinal cord motor neurons in vitro
Authors: Cai Ergai , Cheng Qiong , Yu Shu , Ding Fei
Published: March 2021

Achyranthes bidentata polypeptide k (ABPPk), a powerful active component from a traditional Chinese medicinal herb-Achyranthes bidentata Bl., has exhibited promising neuroprotective activity due to its multiple-targeting capability. However, the effect of ABPPk on the survival, growth and axonal regeneration of spinal cord motor neurons remains unclear. Here, a modified method, which is more optimized for embryonic cells in ambient carbon dioxide levels, was used for acquisition of rat embryonic spinal cord motor neurons with high survival and purity. ABPPk concentration-dependently enhanced the neuronal viability and promoted the neurite outgrowth. Co-culture of motor neurons and skeletal myocytes model indicated that ABPPk enhanced the neuromuscular junction development and maturation. A microfluidic axotomy model was further established for the axonal disconnection, and ABPPk significantly accelerated the axonal regeneration of motor neurons. Furthermore, we demonstrated that the upregulation of three neurofilament protein subunits in motor neurons might be relevant to the mechanisms of the growth-promoting effect of ABPPk. Our findings provide an experimental and theoretical basis for the development of ABPPk as a potential application in the development of treatment strategy for nerve injury diseases.
Detecting flying insects using car nets and DNA metabarcoding
Authors: Svenningsen Cecilie S. , Frøslev Tobias Guldberg , Bladt Jesper , Pedersen Lene Bruhn , Larsen Jonas Colling , Ejrnæs Rasmus , Fløjgaard Camilla , Hansen Anders Johannes , Heilmann-Clausen Jacob , Dunn Robert R. , Tøttrup Anders P.
Published: March 2021

Monitoring insects across space and time is challenging, due to their vast taxonomic and functional diversity. This study demonstrates how nets mounted on rooftops of cars (car nets) and DNA metabarcoding can be applied to sample flying insect richness and diversity across large spatial scales within a limited time period. During June 2018, 365 car net samples were collected by 151 volunteers during two daily time intervals on 218 routes in Denmark. Insect bulk samples were processed with a DNA metabarcoding protocol to estimate taxonomic composition, and the results were compared to known flying insect richness and occurrence data. Insect and hoverfly richness and diversity were assessed across biogeographic regions and dominant land cover types. We detected 15 out of 19 flying insect orders present in Denmark, with high proportions of especially Diptera compared to Danish estimates, and lower insect richness and diversity in urbanized areas. We detected 319 species not known for Denmark and 174 species assessed in the Danish Red List. Our results indicate that the methodology can assess the flying insect fauna at large spatial scales to a wide extent, but may be, like other methods, biased towards certain insect orders.
Hypothetical control of postural sway
Authors: Mangalam Madhur , Kelty-Stephen Damian G.
Published: March 2021

Quiet standing exhibits strongly intermittent variability that has inspired at least two interpretations. First, variability can be intermittent through the alternating engagement and disengagement of complementary control processes at distinct scales. A second and perhaps deeper way to interpret this intermittency is through the possibility that postural control depends on cascade-like interactions across many timescales at once, suggesting specific non-Gaussian distributional properties at different timescales. Multiscale probability density function (PDF) analysis shows that quiet standing on a stable surface exhibits a crossover from low, increasing non-Gaussianity (consistent with exponential distributions) at shorter timescales, reflecting inertial control, towards higher non-Gaussianity. Feedback-based control at medium to longer timescales yields a linear decrease that is characteristic of cascade dynamics. Destabilizing quiet standing with an unstable surface or closed eyes serves to attenuate inertial control and to elicit more of the feedback-based control over progressively shorter timescales. The result was to strengthen the appearance of the linear decay indicating cascade dynamics. Finally, both linear and nonlinear indices of postural sway also govern the relative strength of crossover or of linear decay, suggesting that tempering of non-Gaussianity across log-timescale is a function of both extrinsic constraints and endogenous postural control. These results provide new evidence that cascading interactions across longer timescales supporting postural corrections can even recruit shorter timescale processes with novel task constraints that can destabilize posture.
Analytical approximation for invasion and endemic thresholds, and the optimal control of epidemics in spatially explicit individual-based models
Authors: Suprunenko Yevhen F. , Cornell Stephen J. , Gilligan Christopher A.
Published: March 2021

Computer simulations of individual-based models are frequently used to compare strategies for the control of epidemics spreading through spatially distributed populations. However, computer simulations can be slow to implement for newly emerging epidemics, delaying rapid exploration of different intervention scenarios, and do not immediately give general insights, for example, to identify the control strategy with a minimal socio-economic cost. Here, we resolve this problem by applying an analytical approximation to a general epidemiological, stochastic, spatially explicit SIR(S) model where the infection is dispersed according to a finite-ranged dispersal kernel. We derive analytical conditions for a pathogen to invade a spatially explicit host population and to become endemic. To derive general insights about the likely impact of optimal control strategies on invasion and persistence: first, we distinguish between ‘spatial' and ‘non-spatial' control measures, based on their impact on the dispersal kernel; second, we quantify the relative impact of control interventions on the epidemic; third, we consider the relative socio-economic cost of control interventions. Overall, our study shows a trade-off between the two types of control interventions and a vaccination strategy. We identify the optimal strategy to control invading and endemic diseases with minimal socio-economic cost across all possible parameter combinations. We also demonstrate the necessary characteristics of exit strategies from control interventions. The modelling framework presented here can be applied to a wide class of diseases in populations of humans, animals and plants.
Limited recovery from post-acute sequelae of SARS-CoV-2 (PASC) at eight months in a prospective cohort
Authors: Darley DR , Dore GJ , Byrne A , Plit M , Brew BJ , Kelleher A , Matthews GV
Published: March 2021

There is increasing recognition of the prolonged illness following acute coronavirus disease 2019 (COVID-1). In a longitudinal cohort of 99 patients, 32% reported persistent symptoms and 19% had Long COVID (Defined as fatigue or dyspnoea or chest tightness) at median 240 days after initial infection. There was no significant improvement in symptoms or measures of health-related quality of life between 4 and 8-month assessments. In multivariable analysis, female gender (OR 3.2, 95%CI 1.3-7.8, p=0.01) and acute COVID-19 hospitalisation (OR 3.8, 95% 1.1-13.6, p=0.04) were independently associated with Long COVID at 8-months. Only 80% patients reported full recovery at 8 months. Further research is required to understand the immunologic correlates of abnormal recovery and the long-term significance.
Upregulated miR-200c may increase the risk of obese individuals to severe COVID-19
Authors: Papannarao Jayanthi Bellae , Schwenke Daryl O , Manning Patrick , Katare Rajesh
Published: March 2021

Obesity is a risk factor for coronavirus disease 2019 (COVID-19) infection, the prevalence of obese individuals admitted with COVID-19 ranging between 30 and 60%. Herein we determined whether early changes in microRNAs (miRNAs) could be the underlying molecular mechanism increasing the risk of obese individuals to COVID-19 infection. Quantitative real-time PCR analysis of plasma samples for circulating miRNAs showed a significant upregulation of miR-200c and a small increase in miR-let-7b obese individuals. This was associated with significant downregulation of angiotensin-converting enzyme 2 (ACE2). Both the miRNAs are the direct targets of ACE2, the specific functional receptor for severe acute respiratory syndrome coronavirus 2. Correlation analysis confirmed a significant negative correlation between ACE2 and both the miRNAs. Recent studies showed that despite being the functional receptor, inhibition/downregulation of ACE2 did not reduce the severity of COVID-19 infection. In contrast, increased angiotensin II following inhibition of ACE2 may increase the severity of the disease. Taken together, our novel results identify that upregulation of miR-200c may increase the susceptibility of obese individuals to COVID-19. Considering miRNA are the earliest molecular regulators, circulating miR-200c could be a potential biomarker in the early identification of those at the risk of severe COVID-19.
Half Year Longitudinal Seroprevalence of SARS-CoV-2-antibodies and Rule Compliance in German Hospital Employees
Authors: Herzberg Jonas , Vollmer Tanja , Fischer Bastian , Becher Heiko , Becker Ann-Kristin , Sahly Hany , Honarpisheh Human , Guraya Salman Yousuf , Strate Tim , Knabbe Cornelius
Published: March 2021

Introduction

COVID-19, caused by SARS-CoV-2, is an occupational health risk especially for healthcare employees. This study was designed to determine the longitudinal seroprevalence of specific immunglobolin-G (IgG)-antibodies in employees in a hospital setting.

Methods

All employees including healthcare and non-healthcare workers in a secondary care hospital were invited to participate in this single-center study. After an initial screening, a 6 months follow-up was done which included serological examination for SARS-CoV-2-IgG-antibodies and a questionnaire for self-reported symptoms, self-perception and thoughts about the local and national hygiene and pandemic plans.

Results

The seroprevalence of SARS-CoV-2-IgG-antibodies was 0.74% among 406 hospital employees (95% confidence interval) (0.75% in healthcare workers, 0.72% in non-healthcare workers), initially recruited in April 2020, in their follow-up blood specimen in October 2020.

In this study, 30.54% of the participants reported using the official German corona mobile application and the majority were content with the local and national rules in relation to Coronavirus restrictions.

Discussion

At the 6 months follow-up, the 0.74% seroprevalence was below the reported seroprevalence of 1.35% in the general German population. The prevalence in healthcare workers in direct patient care compared with those without direct patient contact did not differ significantly.
The implementation of a virtual ward using digital solutions informing community clinicians in early supported discharge of patients with SARS-Cov2 respiratory symptoms from an acute hospital setting
Authors: Swift J , Harris Z , Woodward A , O’Kelly NI , Barker C , Ghosh S
Published: March 2021

Objectives

To assess the short run successes and challenges of the implementation of a digitally supported accelerated acute hospital discharge scheme for patients admitted with Covid-19.

Design

Analysis of the safety, resource use and health outcomes within the virtual service for the first 65 patients that have been discharged from a virtual respiratory ward.

Setting

Community based intervention using digital technology and a multi-disciplinary team of specialist clinicians to monitor patients at home.

Participants

65 patients discharged from hospital followed until discharge from the virtual ward.

Results

24.6% of 65 patients had symptoms that were coded red (urgent response required) in CliniTouch Vie in the first day after hospital discharge falling to 7.7% on their final day on the virtual ward; p=0.049. Reductions in red days decreased significantly over time, from 33.8% of patients in their first three days to 10.8% in their final three days; all patients p=0.002. Four patients were re-admitted to hospital, all for clotting disorders. There was one death within this group, which following senior clinical review was deemed to be unrelated to infection with Covid-19.

The most important gain for Glenfield hospital was in expediting the rapid discharge of patients admitted with Covid-19 into a supported environment and the freeing up of beds. On 15th January, 48% of beds were taken up with patients admitted with Covid-19 symptoms.

In November 2020, immediately prior to the launch of the virtual ward, the mean length of stay for patients who did not access high dependency care or oxygen was 5.5 (+/-1.3) days. The mean length of stay in patients discharged into the virtual ward thereafter was 3.3 (+/-0.4) days; relative reduction, 40.3% (p<0.001).

The cost of care provision in the virtual ward was 8,662 UK Pounds in total and 133.26 UK pounds per patient. The estimated overall savings were 68,052 UK Pounds and the mean saving per patient was estimated at £1,047 UK Pounds.

Conclusions

The virtual ward appeared to assist with earlier discharges, had a low rate of clinically necessary re-admissions, the safety of patients was not compromised and whilst cost savings were not the primary objective, it seemed to also reduce overall resource use and costs.
Rapid genotyping of tilapia lake virus (TiLV) using Nanopore sequencing
Authors: Delamare-Deboutteville Jerome , Taengphu Suwimon , Gan Han Ming , Kayansamruaj Pattanapon , Debnath Partho Pratim , Barnes Andrew , Wilkinson Shaun , Kawasaki Minami , Mohan Chadag Vishnumurthy , Senapin Saengchan , Dong Ha Thanh
Published: March 2021

Infectious diseases represent one of the major challenges to sustainable aquaculture production. Rapid, accurate diagnosis and genotyping of emerging pathogens during early-suspected disease cases is critical to facilitate timely response to deploy adequate control measures and prevent or reduce spread. Currently, most laboratories use PCR to amplify partial pathogen genomic regions, occasionally combined with sequencing of PCR amplicon(s) using conventional Sanger sequencing services for confirmatory diagnosis. The main limitation of this approach is the lengthy turnaround time. Here, we report an innovative approach using a previously developed specific PCR assay for pathogen diagnosis combined with a new Oxford Nanopore Technologies (ONT)-based amplicon sequencing method for pathogen genotyping. Using fish clinical samples, we applied this approach for the rapid confirmation of PCR amplicon sequences identity and genotyping of tilapia lake virus (TiLV), a disease-causing virus affecting tilapia aquaculture globally. The consensus sequences obtained after polishing exhibit strikingly high identity to references derived by Illumina and Sanger methods (99.83-100%). This study suggests that ONT-based amplicon sequencing is a promising platform to deploy in regional aquatic animal health diagnostic laboratories in low and medium income countries, for fast identification and genotyping of emerging infectious pathogens from field samples within a single day.
Mitigating the identity and health threat of COVID-19: Perspectives of Middle-Class South Asians living in the UK
Authors: Hanson Kristin , O’Dwyer Emma , Chauduri Sharmistha , Silva Souza Luiz Gustavo , Vandrevala Tushna
Published: March 2021

The recognition and representation of BAME community as “high risk” of Covid-19 in the UK presents both a health and an identity threat to this ethnic group. This study employed thematic analysis to explore response to these threats as related by a sample of thirteen middle class members of the South Asian community. This work advances both health and identity psychological theory by recognising the affinity between expressions of health efficacy and identity. Our findings identify South Asian intragroup stigmatisation and commonalities that have implications for the promotion of health behaviour and health communications for minority groups.
An individual participant data meta-analysis of prognostic blood biomarkers in IPF
Authors: Khan Fasihul A , Stewart Iain , Saini Gauri , Robinson Karen A. , Jenkins R Gisli
Published: March 2021

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with variable disease trajectory. Blood biomarkers reflecting disease severity that can accurately predict outcomes are urgently needed. Through systematic review and meta-analysis, we evaluate the prognostic potential of matrix-metalloproteinase-7 (MMP-7) and other frequently studied blood biomarkers in patients with IPF.

Methods

Electronic databases were searched on 12th November 2020 to identify prospective studies reporting outcomes in patients with untreated IPF, stratified according to at least one pre-specified biomarker, measured at either baseline or change over three months. Individual participant data (IPD) was sought for studies investigating MMP-7 as a prognostic factor. The primary outcome was overall mortality, with secondary outcomes including disease progression, defined as >10% relative FVC decline or death.

Results

29 studies reporting outcomes from 3950 IPF participants were included, investigating a total of 16 biomarkers. IPD from MMP-7 studies was available for eleven cohorts. Baseline MMP-7 levels were associated with increased mortality (adjusted HR1.23 per SD increase, 95%CI 1.03;1.48, I2=64.3%) and disease progression (adjusted OR1.27 per SD increase, 95%CI 1.11;1.46, I2=5.9%), but change in MMP-7 over three-months was not associated with any of the measured outcomes. There was insufficient data for quantitative analysis in non-MMP7 studies, and whilst many biomarkers showed an association with clinical outcomes, replication of effects across studies was weak.

Conclusion

Baseline MMP-7 levels were associated with an increased risk of overall mortality and disease progression in patients with untreated IPF. The evidence for other biomarkers is currently insufficient with further studies needed.
A time series forecasting of the proportion of SARS-CoV-2 N501Y lineage in North America
Authors: Quinonez Elena , Vahed Majid , Shahraki Abdolrazagh Hashemi , Mirsaeidi Mehdi
Published: March 2021

Introduction

The outbreak of pneumonia known as SARS-COV-2 and newly-emerging South African (B.1.351), the United Kingdom (B.1.1.7) and Brazil (P.1) variants have led to a more infectious virus and potentially more substantial loss of neutralizing activity by natural infection or vaccine-elicited antibodies.

Methods

We identified prevalent mutations using the spike receptor-binding domain (S-RBD) of SARS-CoV-2 deposited in the Nextstrain global database and comparing them to the Wuhan-Hu-1/2019 genomic sequence as a reference. Then we calculated the percentages of mutant genomes from the total regional subsample isolates from December 2019 to the end of January 2021. We developed two separate time series forecasting models for the SARS-CoV-2 B.1.1.7 variant. The computational model used the structure of the S-RBD to examine its interactions with the neutralizing antibody, named CV30 (isolated from a patient), and human angiotensin-converting enzyme 2 (hACE-2), based on a hybrid algorithm of template-based modeling to predict the affinity of S protein to the neutralizing antibodies and hACE-2 receptor.

Results

The proportion of the B.1.1.7 strain in North America is growing fast. From these computations, it seems that the S-RBD and hACE-2 proteins are less favorable for the South African strain (K417N, E484K, and N501Y) as compared to the wild type structure and more favorable for B.1.1.7 and P.1 variants. In the present of crystallized CV30 neutralizing antibodies, docking scores suggest antibodies can be partially neutralize the B.1.1.7 variant, and, less efficiently, the B.1.351 and P.1 variants.

Conclusion

The rapid evolution of SARS-CoV-2 has the potential to allow the newly-emerged B.1.351, and P.1 variants to escape from natural or vaccine-induced neutralizing immunity and viral spreading.
Has the age distribution of hospitalized Covid-19 patients changed in Brazil?
Authors: de Andrade Carla Lourenço Tavares , Lima Sheyla Maria Lemos , Martins Monica , Pereira Claudia Cristina de Aguiar , Portela Margareth Crisóstomo
Published: March 2021

The aim of this study was to compare the age profile of hospitalized Covid-19 patients during the first year of the pandemic, as well as hospital mortality and use of ICUs, by age group, in large geographic regions of Brazil. We used data from the Influenza Epidemiological Surveillance Information System for patients who presented the first symptoms of the disease between the epidemiological weeks 8 of 2020 and 7 of 2021, which were divided into three periods.

779,257 records of patients hospitalized by Covid-19 were obtained. Of this total, 720,363 (92.4%) referred to discharged hospitalizations, considered in the analysis of ICU use and death. Among 244,611 hospitalizations (34.0%) with indication for use of ICU, 190,833 allowed the calculation of the time in ICU. There was variation in the age profile of hospitalized patients between the three periods, but there was no evidence in favor of the hypothesis of an increase, in the last period, in the participation of adults between 18 and 50 years old in hospitalizations by Covid-19. A differentiated increase in the mortality of young adults in the North suggests the possibility of greater severity of the P1 variant in this population. The results also show that the participation of young adults in hospitalizations and hospital deaths was never negligible and is related to hospital mortality rates close to or above 10%.

The Covid-19 “youthening” phenomenon in Brazil is based on the country’s own sociodemographic and economic characteristics and may have been strengthened by the increasing circulation of viral variants. It is important to continue monitoring its progression and effects.
Why did the children stop coming? Reasons for paediatric emergency department attendance decrease during the first wave of the COVID-19 pandemic in the United Kingdom: A qualitative study
Authors: Breckons Matthew , Thorne Sophie , Walsh Rebecca , Bhopal Sunil , Owens Stephen , Rankin Judith
Published: March 2021

UK ‘Lockdown’ measures introduced in March 2020 aimed to mitigate the spread of Covid-19. Although seeking healthcare was still permitted within restrictions, paediatric emergency department attendances reduced dramatically and led to concern over risks caused by delayed presentation. Our aim was to gain insight into healthcare decisions faced by parents during the first wave of the Covid-19 pandemic and to understand if use of urgent healthcare, self-care, and information needs differed during lockdown as well as how parents perceived risks of Covid-19.

We undertook qualitative telephone interviews with a purposive sample of parents living in the North East of England recruited through online advertising. We used a semi-structured topic guide to explore past and current healthcare use, perceptions of risk and the impact of the pandemic on healthcare decisions. Interviews were transcribed and analysed using Thematic Analysis.

Three major themes were identified which concerned (i) how parents made sense of risks posed to, and by their children, (ii) understanding information regarding health services and (iii) attempting to make the right decision. These themes contribute to the understanding of the initial impact of Covid-19 and associated restrictions on parental decisions about urgent healthcare for children. These findings are important to consider when planning for potential future public health emergencies but also in the wider context of encouraging appropriate use of urgent healthcare.
Erasing motion: Scrambling direction selectivity in visual cortex during saccades
Authors: Miura Satoru K. , Scanziani Massimo
Published: March 2021

Distinguishing sensory stimuli caused by changes in the environment from those caused by an animal’s own actions is a hallmark of sensory processing. Saccades are rapid eye movements that shift the image on the retina. How visual systems differentiate motion of the image induced by saccades from actual motion in the environment is not fully understood. Here, we discovered that in mouse primary visual cortex (V1), the two types of motion evoke distinct activity patterns. This is because during saccades, V1 combines the visual input with a strong non-visual input arriving from the thalamic pulvinar nucleus. Thus, the pulvinar input ensures differential V1 responses to external and self-generated motion and may allow the animal to interpret sensory stimuli within the context of its actions.
Multiple timescales in bacterial growth homeostasis
Authors: Stawsky Alejandro , Vashistha Harsh , Salman Hanna , Brenner Naama
Published: March 2021

In balanced exponential growth, bacterial cells maintain the stability of multiple properties simultaneously: cell size, growth rate, cycle time and more. These are not independent but strongly coupled variables; it is nota-prioriclear which are under direct regulation and which are stabilized as a by-product of interactions. Here, we address this problem by separating different timescales in bacterial single-cell dynamics. Disentangling homeostatic set-points from fluctuations around them, we find that some properties have flexible set-points that highly sensitive to environment - defining “sloppy” variables, while other set-points are buffered and held tightly controlled - “stiff” variables. These control variables are combinations of sloppy ones that compensate one another over long times, creating a hierarchical buffering that protects them from environmental perturbations. This is manifested geometrically as a control manifold in the space of growth and division variables, whose in-plane directions span sloppy variables, while out-of-plane deviations are highly constrained. Cell size is found to be a sloppy variable, which is coupled to growth and division only on the short, single-cycle timescale. Our results show that cellular homeostasis involves multi-level regulation operating on multiple timescales. More generally, our work offers a data-driven approach for identifying control variables in a multi-dimensional system that can be applicable also in other contexts.
The ascending arousal system shapes low-dimensional neural dynamics to mediate awareness of intrinsic cognitive states
Authors: Munn Brandon , Müller Eli J. , Wainstein Gabriel , Shine James M.
Published: March 2021

Models of cognitive function typically focus on the cerebral cortex and hence overlook functional links to subcortical structures. This view neglects the highly-conserved ascending arousal system’s role and the computational capacities it provides the brain. In this study, we test the hypothesis that the ascending arousal system modulates cortical neural gain to alter the low-dimensional energy landscape of cortical dynamics. Our analyses of spontaneous functional magnetic resonance imaging data and phasic bursts in both locus coeruleus and basal forebrain demonstrate precise time-locked relationships between brainstem activity, low-dimensional energy landscapes, network topology, and spatiotemporal travelling waves. We extend our analysis to a cohort of experienced meditators and demonstrate locus coeruleus-mediated network dynamics were associated with internal shifts in conscious awareness. Together, these results present a novel view of brain organization that highlights the ascending arousal system’s role in shaping both the dynamics of the cerebral cortex and conscious awareness.
TGIF1is required for chicken ovarian cortical development and generation of the juxtacortical medulla
Authors: Estermann Martin Andres , Hirst Claire Elizabeth , Major Andrew Thomas , Smith Craig Allen
Published: March 2021

During early embryogenesis in amniotic vertebrates, the gonads differentiate into either ovaries or testes. The first cell lineage to differentiate gives rise to the supporting cells; Sertoli cells in males and pre-granulosa cells in females. These key cell types direct the differentiation of the other cell types in the gonad, including steroidogenic cells. The gonadal surface epithelium and the interstitial cell populations are less well studied, and little is known about their sexual differentiation programs. Here, we show the requirement of the transcription factor geneTGIF1for ovarian development in the chicken embryo.TGIF1is expressed in the two principal ovarian somatic cell populations, the cortex and the pre-granulosa cells of the medulla.TGIF1expression is associated with an ovarian phenotype in sex reversal experiments. In addition, targeted over-expression and gene knockdown experiments indicate that TGIF1 is required for proper ovarian cortical formation.TGIF1is identified as the first known regulator of juxtacortical medulla formation. These findings provide new insights into chicken ovarian differentiation and development, specifically in the process of cortical and juxtacortical medulla formation, a poorly understood area.

SUMMARY STATEMENT

The transcription factor TGIF1 is required for proper ovarian sex differentiation in chicken embryos, regulating development of the cortical and juxtacortical medulla, independently of the supporting cell sex lineage.
A morpho-transcriptomic map of brassinosteroid action in the Arabidopsis root
Authors: Graeff Moritz , Rana Surbhi , Wendrich Jos R. , Dorier Julien , Eekhout Thomas , Fandino Ana Cecilia Aliaga , Guex Nicolas , Bassel George W. , De Rybel Bert , Hardtke Christian S.
Published: March 2021

The effects of brassinosteroid signaling on shoot and root development have been characterized in great detail but did not identify a simple consistent positive or negative impact on a basic cellular parameter that would comprehensively explain the phenotype of brassinosteroid-related mutants. Here we combined digital 3D single-cell shape analysis and single-cell mRNA sequencing to characterize root meristems and mature root segments of brassinosteroid-blind mutants and wildtype. These data demonstrate that brassinosteroid signaling neither affects cell volume nor cell proliferation capacity. Instead, brassinosteroid signaling is essential for the precise orientation of cell division planes and the extent and timing of anisotropic cell expansion. Moreover, we found that the cell-aligning effects of brassinosteroid signaling can propagate to normalize the anatomy of both adjacent and distant brassinosteroid-blind cells through non-cell-autonomous functions, which are sufficient to restore overall root growth vigor. Finally, single-cell transcriptome data discern directly brassinosteroid-responsive genes from genes that can react to non-cell-autonomous brassinosteroid-dependent signals and highlight arabinogalactans as sentinels of brassinosteroid-dependent anisotropic cell expansion.
Probing the killing potency of tumor-infiltrating lymphocytes on microarrayed autologous tumoroids
Authors: Dutta Devanjali , Rivest François , Lorenzo-Martín L. Francisco , Broguiere Nicolas , Tillard Lucie , Ragusa Simone , Brandenberg Nathalie , Höhnel Sylke , Saugy Damien , Rusakiewicz Sylvie , Homicsko Krisztian , Coukos George , Lutolf Matthias P.
Published: March 2021

Immunotherapy has shown promise as an approach to fight cancer by harnessing the immune system. However, due to the lack of biomarkers to guide treatment regimens and predict response rates, there is an unmet need for more robustex vivoandin vitrosystems that recapitulate patient-specific tumor biology and enable response prediction for immune therapies in an autologous setting. To address this issue, we developed a high-content screening-compatible assay based on microcavity arrays to study tumor-infiltrating lymphocyte (TIL) functionality on 3D tumoroid models. We validated our system using the pmel-1 activated T cell mouse model to assess both cancer immunogenicity and T cell functionality. To demonstrate the translational potential of the platform, we used it to evaluate the response of patient-derived TILs to autologous human colorectal cancer (CRC) tumoroids. Using a combination of imaging and flow cytometry, we determined several features of the antitumor activity of TILs, including the extent of tumoroid killing and secretion of cytokines. We then used the approach to identify responders to immunotherapy, such as the immune checkpoint blockade (ICB) agent Nivolumab (PD-1 inhibitor) and Ipilimumab (CTLA-4 inhibitor). Our system allows not only the identification of immunogenic tumors, but also the testing of patients for response to immunomodulators, enabling personalized immuno-oncology.
Ultra-deep whole genome bisulfite sequencing reveals a single methylation hotspot in human brain mitochondrial DNA
Authors: Guitton Romain , Dölle Christian , Alves Guido , Tysnes Ole-Bjørn , Nido Gonzalo S. , Tzoulis Charalampos
Published: March 2021

While DNA methylation is established as a major regulator of gene expression in the nucleus, the existence of mitochondrial DNA (mtDNA) methylation remains controversial. Here, we characterised the mtDNA methylation landscape in the prefrontal cortex of neurological healthy individuals (n=26) and patients with Parkinson’s disease (n=27), using a combination of whole genome bisulfite sequencing (WGBS) and bisulfite-independent methods. Accurate mtDNA mapping from WGBS data required alignment to an mtDNA reference only, to avoid misalignment to nuclear mitochondrial pseudogenes. Once correctly aligned, WGBS data provided ultra-deep mtDNA coverage (16,723±7,711), and revealed overall very low levels of cytosine methylation. The highest methylation levels (5.49±0.97%) were found on CpG position m.545, located in the heavy-strand promoter 1 region. The m.545 methylation was validated using a combination of methylation-sensitive DNA digestion and quantitative PCR analysis. We detected no association between mtDNA methylation profile and Parkinson’s disease. Interestingly, m.545 methylation correlated with the levels of mtDNA transcripts, suggesting a putative role in regulating mtDNA gene expression. In addition, we propose a robust framework for methylation analysis of mtDNA from WGBS data, which is less prone to false-positive findings due to misalignment of nuclear mitochondrial pseudogene sequences.

Graphical abstract of the analyses and main findings

Fresh-frozen brain tissue was obtained from the prefrontal cortex (Brodmann area 9) of 53 individuals, comprising 27 patients with idiopathic PD and 26 healthy controls. Tissue from the same samples was used in three different downstream analyses. WGBS was conducted on all 53 samples and the data were analysed using three different alignment strategies. Alignment against an mtDNA reference only was clearly superior as it gave the highest and most even depth of coverage. WGBS analysis revealed that mtDNA harbours very low levels of cytosine methylation, with the exception of the CpG position m.545 within the HSP1 region (lower right inset). The m.545 methylation was confirmed by bisulfite- and sequencing-independent methods, employing methylation-specific MspJI DNA digestion, followed by quantification with qPCR or fluorescent PCR and capillary electrophoresis. Finally, mtDNA transcript levels were determined by RT-qPCR and correlated to m.545 methylation levels, showing a positive association.
Depleting Hypothalamic Somatostatinergic Neurons Recapitulates Diabetic Phenotypes in Brain, Bone Marrow, Adipose, and Retina
Authors: Huang Chao , Rosencrans Robert Follett , Bugescu Raluca , Vieira Cristiano P. , Hu Ping , Adu-Agyeiwaah Yvonne , Gamble Karen L , Longhini Ana Leda F. , Fuller Patrick M , Leinninger Gina M. , Grant Maria B.
Published: March 2021

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunologic pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor deficient (db/db) mice exhibit reduced hypothalamic somatostatinergic cells, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus (AAV) delivery of diphtheria toxin (DTA) driven by an SST-cre system to deplete these cells in SSTcre/gfpmice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed hematopoiesis, generating excess granulocyte-monocyte precursors and increased pro-inflammatory (CCR2hi) monocytes. Visceral adipose tissue from DTA-treated animals was resistant to catecholamine induced lipolysis. Finally, SST-DTA mice exhibited a “diabetic retinopathy like” phenotype: reduced visual function by optokinetic response and electroretinogram, as well as increased percentages of retinal monocytes. Importantly, hyperglycemia was not observed in SST-DTA mice. Thus, the isolated reduction in hypothalamic somatostatinergic neurons was able to recapitulate several hallmark features of type 2 diabetes in disease relevant tissues.
Deficiency of SYCP3-related XLR3 disrupts the initiation of meiotic sex chromosome inactivation in mouse spermatogenesis
Authors: Naveh Natali Sobel , Foley Robert J. , DeNegre Katelyn R. , Evans Tristan C. , Czechanski Anne , Reinholdt Laura G. , O’Neill Michael J.
Published: March 2021

In mammals, the X and Y chromosomes share only small regions of homology called pseudo-autosomal regions (PAR) where pairing and recombination in spermatocytes can occur. Consequently, the sex chromosomes remain largely unsynapsed during meiosis I and are sequestered in a nuclear compartment known as the XY body where they are transcriptionally silenced in a process called meiotic sex chromosome inactivation (MSCI). MSCI mirrors meiotic silencing of unpaired chromatin (MSUC), the sequestration and transcriptional repression of unpaired DNA observed widely in eukaryotes. MSCI is initiated by the assembly of the axial elements of the synaptonemal complex (SC) comprising the structural proteins SYCP2 and SYCP3 followed by the ordered recruitment of DNA Damage Response (DDR) factors to effect gene silencing. However, the precise mechanism of how unsynapsed chromatin is detected in meiocytes is poorly understood. The sex chromosomes in eutherian mammals harbor multiple clusters ofSYCP3-like amplicons comprising theXlrgene family, only a handful of which have been functionally studied. We used a shRNA-transgenic mouse model to create a deficiency in the testis-expressed multicopyXlr3genes to investigate their role in spermatogenesis. Here we show that knockdown ofXlr3in mice leads to spermatogenic defects and a skewed sex ratio that can be traced to MSCI breakdown. Spermatocytes deficient in XLR3 form the XY body and the SC axial elements therein, but are compromised in their ability to recruit DDR components to the XY body.

Author Summary

A key event in the production of sperm is the pairing and synapsis of homologous chromosome pairs to facilitate genetic recombination during the first meiotic division. Chromosomal abnormalities that undermine pairing and synapsis in spermatocytes trigger a checkpoint that leads to removal of the abnormal cells via programmed cell death. In mammals, the sex chromosomes, X and Y, lack homology through most of their length and remain largely unpaired. To avoid triggering the checkpoint the X and Y are sequestered in a specialized nuclear compartment called the XY body. DNA damage response (DDR) proteins are recruited to the XY body in a highly ordered progression leading to repression of all gene transcription from the sex chromosomes. We show that knocking down expression of the X-linkedSYCR3-like gene,Xlr3,disrupts sex chromosome gene silencing by interfering with recruitment of DDR factors, leading to compromised sperm production.