bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of Pain Catastrophizing With Urinary Biomarkers in Women With Bladder Pain Syndrome
Authors: Soriano Alex , Allen Antoinette , Malykhina Anna P. , Andy Uduak , Harvie Heidi , Arya Lily
Published: March 2021

Objectives

Brain-derived neurotrophic factor (BDNF) has been implicated in central neurological processes. We hypothesize that greater pain catastrophizing is associated with higher urinary BDNF levels in women with bladder pain syndrome.

Methods

A secondary analysis of a database of women with urinary urgency was conducted. We identified women who met AUA criteria of bladder pain syndrome. Urinary symptoms, pain catastrophizing, and neuropathic pain were measured using the Female Genitourinary Pain Index, Pain Catastrophizing Scale and painDETECT questionnaires respectively. The relationship of the catastrophizing score with urinary BDNF (primary outcome) and other urinary biomarkers, including nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and osteopontin, was evaluated using univariable and multivariable analyses.

Results

In 62 women with bladder pain syndrome, 15 (24%) reported pain catastrophizing symptoms (Pain Catastrophizing Scale score >30). Higher catastrophizing scores were associated with worse urinary symptoms, greater pelvic pain, greater neuropathic pain, and worse quality of life scores (all P < 0.01). On multivariable analysis, after controlling for age, body mass index and urinary symptoms, a higher pain catastrophizing score was associated with lower BDNF (P = 0.04) and lower VEGF levels (P = 0.03). Urinary urgency was associated with a higher NGF level (P = 0.04) while bladder pain was associated with higher levels of NGF (P = 0.03) and VEGF (P = 0.01).

Conclusions

Neuroinflammatory mechanisms contribute to the central processing of pain in women with bladder pain syndrome. Worse urinary symptoms are associated with higher NGF and VEGF levels, but worse pain catastrophizing is associated with lower BDNF and VEGF levels. Urinary BDNF levels may be useful in phenotyping women who have central augmentation of pain processing.
Finger motion and contact by a second finger influence the tactile perception of electrovibration
Authors: Vardar Yasemin , Kuchenbecker Katherine J.
Published: March 2021

Electrovibration holds great potential for creating vivid and realistic haptic sensations on touchscreens. Ideally, a designer should be able to control what users feel independent of the number of fingers they use, the movements they make, and how hard they press. We sought to understand the perception and physics of such interactions by determining the smallest 125 Hz electrovibration voltage that 15 participants could reliably feel when performing four different touch interactions at two normal forces. The results proved for the first time that both finger motion and contact by a second finger significantly affect what the user feels. At a given voltage, a single moving finger experiences much larger fluctuating electrovibration forces than a single stationary finger, making electrovibration much easier to feel during interactions involving finger movement. Indeed, only about 30% of participants could detect the stimulus without motion. Part of this difference comes from the fact that relative motion greatly increases the electrical impedance between a finger and the screen, as shown via detailed measurements from one individual. By contrast, threshold-level electrovibration did not significantly affect the coefficient of kinetic friction in any conditions. These findings help lay the groundwork for delivering consistent haptic feedback via electrovibration.
Regulatory effects of protein S-acylation on insulin secretion and insulin action
Authors: Chamberlain Luke H. , Shipston Michael J. , Gould Gwyn W.
Published: March 2021

Post-translational modifications (PTMs) such as phosphorylation and ubiquitination are well-studied events with a recognized importance in all aspects of cellular function. By contrast, protein S-acylation, although a widespread PTM with important functions in most physiological systems, has received far less attention. Perturbations in S-acylation are linked to various disorders, including intellectual disability, cancer and diabetes, suggesting that this less-studied modification is likely to be of considerable biological importance. As an exemplar, in this review, we focus on the newly emerging links between S-acylation and the hormone insulin. Specifically, we examine how S-acylation regulates key components of the insulin secretion and insulin response pathways. The proteins discussed highlight the diverse array of proteins that are modified by S-acylation, including channels, transporters, receptors and trafficking proteins and also illustrate the diverse effects that S-acylation has on these proteins, from membrane binding and micro-localization to regulation of protein sorting and protein interactions.
Use of deep learning for structural analysis of computer tomography images of soil samples
Authors: Wieland Ralf , Ukawa Chinatsu , Joschko Monika , Krolczyk Adrian , Fritsch Guido , Hildebrandt Thomas B. , Schmidt Olaf , Filser Juliane , Jimenez Juan J.
Published: March 2021

Soil samples from several European countries were scanned using medical computer tomography (CT) device and are now available as CT images. The analysis of these samples was carried out using deep learning methods. For this purpose, a VGG16 network was trained with the CT images (X). For the annotation (y) a new method for automated annotation, ‘surrogate’ learning, was introduced. The generated neural networks (NNs) were subjected to a detailed analysis. Among other things, transfer learning was used to check whether the NN can also be trained to other y-values. Visually, the NN was verified using a gradient-based class activation mapping (grad-CAM) algorithm. These analyses showed that the NN was able to generalize, i.e. to capture the spatial structure of the soil sample. Possible applications of the models are discussed.
The binding behaviours between cyclopentanocucurbit[6]uril and three amino acids
Authors: Cheng Siyuan , Zhao Weiwei , Yang Xinan , Meng Ye , Wei Liantong , Tao Zhu , Ma Peihua
Published: March 2021

Binding behaviours between cyclopentanocucurbit[6]uril (CyP
6
Q[6]) and three amino acids have been investigated by means of X-ray crystallography, proton nuclear magnetic resonance spectroscopy and isothermal titration calorimetry. The results showed that CyP
6
Q[6] forms a 1 : 2 inclusion complex with glycine, but 1 : 1 complexes with both leucine and lysine. Whereas the carboxyl group of glycine can enter the interior of the cavity of CyP
6
Q[6], only the alkyl chains of leucine and lysine can enter this cavity. Interestingly, leucine can adopt two different self-assembly modes upon its interaction with cucurbituril, depending on the external conditions, whereas glycine and lysine do not exhibit such behaviour.
Projecting a second wave of COVID-19 in Japan with variable interventions in high-risk settings
Authors: Jung Sung-mok , Endo Akira , Kinoshita Ryo , Nishiura Hiroshi
Published: March 2021

An initial set of interventions, including the closure of host and hostess clubs and voluntary limitation of non-household contact, probably greatly contributed to reducing the disease incidence of coronavirus disease (COVID-19) in Japan, but this approach must eventually be replaced by a more sustainable strategy. To characterize such a possible exit strategy from the restrictive guidelines, we quantified the next-generation matrix, accounting for high- and low-risk transmission settings. This matrix was used to project the future incidence in Tokyo and Osaka after the state of emergency is lifted, presenting multiple ‘post-emergency’ scenarios with different levels of restriction. The effective reproduction numbers (
R
) for the increasing phase, the transition phase and the state-of-emergency phase in the first wave of the disease were estimated as 1.78 (95% credible interval (CrI): 1.73–1.82), 0.74 (95% CrI: 0.71–0.78) and 0.63 (95% CrI: 0.61–0.65), respectively, in Tokyo and as 1.58 (95% CrI: 1.51–1.64), 1.20 (95% CrI: 1.15–1.25) and 0.48 (95% CrI: 0.44–0.51), respectively, in Osaka. Projections showed that a 50% decrease in the high-risk transmission is required to keep
R
less than 1 in both locations—a level necessary to maintain control of the epidemic and minimize the risk of resurgence.
Causes of death in people with cardiovascular disease: a prospective UK Biobank cohort study
Authors: Drozd Michael , Pujades-Rodriguez Mar , Sun Fei , Franks Kevin N , Lillie Patrick J , Witte Klaus K , Kearney Mark T , Cubbon Richard M
Published: March 2021

Cardiovascular disease (CVD) mortality has substantially improved over recent decades. Some evidence indicates this has been paralleled by an increasing proportion of non-cardiovascular mortality in people with CVD. However, the contemporary causes of death across a broad spectrum of CVDs, either alone or in combination, remains unclear.

We analysed cardiovascular, infection, cancer and other causes of death prior to the COVID-19 pandemic in 493,280 participants in the prospective UK Biobank study. Studied CVDs included baseline: abdominal aortic aneurysm, atrial fibrillation, coronary artery disease, heart failure, hypertension, peripheral vascular disease, stroke, valvular heart disease and venous thromboembolic disease; we separately considered cardiovascular multimorbidity defined as the total number of these baseline CVDs. Crude mortality rates and Poisson regression analysis were used to quantify the absolute and relative risk of cause-specific death. Associations are reported as incidence rate ratios (IRR) with 95% CIs.

During a median follow-up of 10.9 [IQR 10.1-11.6] years per participant, there were 27,729 deaths (20.4% primarily attributed to CVD, 53.6% to cancer, 5.0% to infection and 21.0% to other causes). As the number of co-morbid CVDs increased, the proportion of cardiovascular and infection-related deaths increased, whereas cancer and other deaths decreased. Accrual of multiple CVDs was associated with marked increases in relative risk of infection and cardiovascular death; versus those without CVD, people with three or more CVDs, the relative risk of cardiovascular death increased most (IRR 3.89; 95%CI 3.59-4.21), followed by infection (4.41; 3.44-5.64), with other (2.01; 1.72-2.35) and cancer (1.52; 1.35-1.72) being substantially less increased. All studied CVDs except atrial fibrillation were independently associated with increased risk of infection death, with heart failure (2.73; 1.60-4.66) and valvular heart disease (3.09; 2.38-4.00) posing the greatest risk.

In conclusion, causes of death vary substantially between differing baseline CVDs, and according to the number of baseline CVDs, with non-cardiovascular deaths due to cancer and infection making an important contribution. Holistic and personalized care are likely to be important tools for continuing to improve outcomes in people with CVD.
Effect of antibiotic consumption on self-reported recovery from uncomplicated urinary tract infection
Authors: Gadalla Amal , Wise Hannah , Hughes Kathryn , Llor Carl , Moore Michael , Verheij Theo J M , Little Paul , Butler Chris C , Francis Nick
Published: March 2021

Background

Randomised trials provide high-quality data on the effects of antibiotics for urinary tract infections (UTI) but are prone to selection bias and may not accurately reflect effects in those who actually consume antibiotics.

Aim

To estimate the effect of antibiotic consumption, rather than prescription, on self-reported time to recovery in women with uncomplicated UTI.

Design and setting

Secondary analysis of data from a randomised control trial on point of care diagnostic to guide antibiotic prescribing in primary care. Antibiotic prescribing decisions were not mandated by the trial protocol.

Methods

413 adult women presenting with UTI symptoms and who either consumed (n=333) or did not consume (n=80) one or more doses of antibiotics during a 14-day follow-up were included. Antibiotic consumption was standardised using defined daily dose (DDD) and described as “days-worth of antibiotics”. Cox-proportional hazard model was used to estimate the effect of antibiotic consumption upon time to self-reported recovery, controlling for potential confounders and propensity of consuming antibiotics based on baseline symptom severity and history of UTI treatment.

Results

The crude median time to recovery was 3 days longer among patients who did not consume antibiotics (10 days; 95% CI= 8.5-11.5) compared to those who consumed antibiotics (7 days; 95% CI= 6.5-7.5). Patients who consumed >0 to <3, ≥3 to ≤5, and >5 days-worth of antibiotics recovered at approximately 2 – 3 times faster than the rate of those who consumed no antibiotics, adjusted HR 3.2 (95% CI 2.0, 5.1), 2.8 (1.8, 4.3), 2.3 (1.5, 3.7), respectively.

Conclusion

Consuming antibiotics was associated with a reduction in self-reported time to recovery in this study which is consistent with results from previous trials.
SARS-CoV-2 infections in children and adolescents with rheumatic musculoskeletal diseases – data from the National Pediatric Rheumatology Database in Germany
Authors: Sengler Claudia , Eulert Sascha , Niewerth Martina , Minden Kirsten , Horneff Gerd , Kuemmerle-Deschner Jasmin B. , Siemer Caroline , Berendes Rainer , Girschick Hermann , Hühn Regina , Borte Michael , Hospach Anton , Emminger Wolfgang , Armann Jakob , Klein Ariane , Kallinich Tilmann
Published: March 2021

Objectives

Due to their underlying disease as well as therapeutic immunosuppression, children and adolescents with rheumatic and musculoskeletal diseases (RMD) may be at higher risk for a severe course or worse outcome of COVID-19, and SARS-CoV2 infection may trigger a flare of the RMD. To address these issues, a specific SARS-CoV-2 questionnaire was implemented in the National Pediatric Rheumatology Database (NPRD) in Germany.

Methods

Demographic, clinical and treatment data from juvenile patients with RMD as well as data about SARS-CoV-2 infection like test date and method, clinical characteristics, disease course, outcome and impact on the disease activity of the RMD documented on this questionnaire were analyzed.

Results

From April 17th, 2020, to February 14th, 2021, data were collected from 79 patients (53% female) with RMD with median age of 14 years, diagnosed with juvenile idiopathic arthritis (57%), autoinflammatory (23%) and connective tissue disease (8%). Sixty-one patients (77%) received disease-modifying antirheumatic drugs (DMARDs), 43% biologic DMARDs, and 9% systemic glucocorticoids. Sixty patients (76%) developed symptoms of COVID-19. Disease severity was mild and outcome was good in the majority of patients. Two patients were hospitalized, one of whom required intensive care and died of cardiorespiratory failure. In 84% of SARS-CoV-2-positive patients, no relevant increase in disease activity of the RMD was observed.

Conclusions

In our cohort, COVID-19 in juvenile patients with RMD under various medications was mild with good outcome in the majority of cases. SARS-CoV-2 infection does not appear to have a relevant impact on disease activity of the underlying condition.
Returning to the workplace during the COVID-19 pandemic: The concerns of Australian workers
Authors: Griffiths Daniel , Sheehan Luke , van Vreden Caryn , Whiteford Peter , Collie Alex
Published: March 2021

Purpose

To determine the nature and prevalence of workers’ concerns regarding workplaces reopening during the pandemic. To identify characteristics of workers and industries where particular concerns are more common.

Methods

Prospective cohort study of 1063 employed Australian adults, enrolled at the start of the pandemic. Data on attitudes to workplaces reopening were collected 1 July – 30 September 2020. The frequency of concerns describes infection risk and changes to work and impact on home life. Regression models examined associations between demographic and industry factors with reopening concerns.

Results

More than four in five (82.4%) of workers reported concerns about workplace infection risk. Just over half (53.4%) reported concerns about impacts to work and home life. Concerns were more prevalent for workers reporting psychological distress, financial stress, and among those exclusively working from home. Concerns regarding infection risk were common for workers in health care (IRR=1.16, 95% CI=[1.01, 1.33]), retail (IRR=1.31, 95% CI=[1.06, 1.61]), and accommodation/food service industries (IRR=1.25, 95% CI=[1.01, 1.55]). Concerns regarding changes to work and home life were more common for female workers (IRR=1.24, 95% CI=[1.07, 1.43]), and partners/spouses with dependent children (IRR=1.44, 95% CI=[1.16, 1.79]).

Conclusion

Concerns of COVID-19 infection in the workplace are common. Many workers are also concerned about changes to their work and home life. The prevalence of concerns is related to the nature of work and responsibilities at home. Actions that reduce risk of workplace transmission, coupled with effective communication of infection controls, may alleviate worker concerns whilst recognising workers’ family and social circumstances.
Estimating the asymptomatic proportion of SARS-CoV-2 infection in the general population: Analysis of a nationwide serosurvey in the Netherlands
Authors: McDonald SA , Miura F , Vos ERA , Boven M van , de Melker H , van der Klis F , van Binnendijk R , Hartog G den , Wallinga J
Published: March 2021

Background

The proportion of SARS-CoV-2 positive persons who are asymptomatic – and whether this proportion is age-dependent – are still open research questions. Because an unknown proportion of reported symptoms among SARS-CoV-2 positives will be attributable to another infection or affliction, the observed, or ‘crude’ proportion without symptoms may underestimate the proportion of persons without symptoms that are caused by SARS-CoV-2 infection.

Methods

Based on a large population-based serological study comprising test results on seropositivity and self-reported symptom history conducted in April/May 2020 in the Netherlands (n=3147), we estimated the proportion of reported symptoms among those persons infected with SARS-CoV-2 that is attributable to this infection, where the set of relevant symptoms fulfills the ECDC case definition of COVID-19, using inferential methods for the attributable risk (AR). Generalised additive regression modelling was used to estimate the age-dependent relative risk (RR) of reported symptoms, and the AR and asymptomatic proportion (AP) were calculated from the fitted RR.

Results

Using age-aggregated data, the estimated AP was 70% (95% CI: 65-77%). The estimated AP decreased with age, from 80% (95% CI: 67-100%) for the <20 years age-group, to 55% (95% CI: 48-68%) for the 70+ years age-group.

Conclusion

Whereas the ‘crude’ AP represents a lower bound for the proportion of persons infected with SARS-CoV-2 without COVID-19 symptoms, the AP as estimated via an attributable risk approach represents an upper bound. Age-specific AP estimates can inform the implementation of public health actions such as targetted virological testing and therefore enhance containment strategies.
Characterization of antibody response in asymptomatic and symptomatic SARS-CoV-2 infection
Authors: Marchi S , Viviani S , Remarque EJ , Ruello A , Bombardieri E , Bollati V , Milani GP , Manenti A , Lapini G , Rebuffat A , Montomoli E , Trombetta CM
Published: March 2021

SARS-CoV-2 pandemic is causing high morbidity and mortality burden worldwide with unprecedented strain on health care systems.

To elucidate the mechanism of infection, protection, or rapid evolution until fatal outcome of the disease we performed a study in hospitalized COVID-19 patients to investigate the time course of the antibody response in relation to the outcome. In comparison we investigated the time course of the antibody response in SARS-CoV-2 asymptomatic subjects.

Study results show that patients produce a strong antibody response to SARS-CoV-2 with high correlation between different viral antigens (spike protein and nucleoprotein) and among antibody classes (IgA, IgG, and IgM and neutralizing antibodies). The peak is reached by 3 weeks from hospital admission followed by a sharp decrease. No difference was observed in any parameter of the antibody classes, including neutralizing antibodies, between subjects who recovered or with fatal outcome. Only few asymptomatic subjects developed antibodies at detectable levels.
Circadian immunity, sunrise time and the seasonality of respiratory infections
Authors: Mo Ziyi , Scheben Armin , Steinberg Joshua , Siepel Adam , Martienssen Robert
Published: March 2021

The innate and adaptive immune response are regulated by biological clocks, and circulating lymphocytes are lowest at sunrise. Accordingly, severity of disease in mouse models is highly dependent on the time of day of viral infection. Here, we explore whether circadian immunity contributes significantly to seasonality of respiratory viruses, including influenza and SARS-CoV-2. Susceptibility-Infection-Recovery-Susceptibility (SIRS) models of influenza and SIRS-derived models of COVID-19 suggest that local sunrise time is a better predictor of the basic reproductive number (R0) than climate, even when day length is taken into account. Moreover, these models predict a window of susceptibility when local sunrise time corresponds to the morning commute and contact rate is expected to be high. Counterfactual modeling suggests that retaining daylight savings time in the fall would reduce the length of this window, and substantially reduce seasonal waves of respiratory infections.
Innate immune deficiencies in patients with COVID-19
Authors: Peyneau Marine , Granger Vanessa , Wicky Paul-Henri , Khelifi-Touhami Dounia , Timsit Jean-François , Lescure François-Xavier , Yazdanpanah Yazdan , Tran-Dihn Alexy , Montravers Philippe , Monteiro Renato C. , Chollet-Martin Sylvie , Hurtado-Nedelec Margarita , de Chaisemartin Luc
Published: March 2021

COVID-19 can cause acute respiratory distress syndrome (ARDS), leading to death in a significant number of individuals. Evidence of a strong role of the innate immune system is accumulating, but the precise cells and mechanism involved remain unclear. In this study, we investigated the links between circulating innate phagocyte phenotype and functions and severity in COVID-19 patients. Eighty-four consecutive patients were included, 44 of which were in intensive care units (ICU). We performed an in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, myeloid cell functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Resulting parameters were linked to disease severity and prognosis. Both ICU and non-ICU patients had circulating neutrophils and monocytes with an activated phenotype, as well as elevated concentrations of soluble activation markers (calprotectin, myeloperoxidase, neutrophil extracellular traps, MMP9, sCD14) in their plasma. ICU patients were characterized by increased CD10low CD13low immature neutrophils, LOX-1+ and CCR5+ immunosuppressive neutrophils, and HLA-DRlow CD14low downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity and poor outcome. Moreover, neutrophils and monocytes of ICU patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Our study reveals a marked dysregulation of innate immunity in COVID-19 patients, which was correlated with severity and prognosis. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options.

One Sentence Summary

Our study reveals a marked dysregulation of innate immunity in COVID-19 patients, which correlates with severity and prognosis.
Development of clinical virtual care pathways to engage and support families requiring neonatal intensive care in response to the COVID-19 pandemic (COVES Study)
Authors: Campbell-Yeo Marsha , Dol Justine , Richardson Brianna , McCulloch Holly , Hundert Amos , Foye Sarah , Dorling Jon , Afifi Jehier , Bishop Tanya , Earle Rebecca , Rose Annette Elliott , Inglis Darlene , Kim Theresa , Leighton Carye , Loring Sally , MacRae Gail , Melanson Andrea , Simpson David C , Smit Michael , Whitehead Leah
Published: March 2021

Background

In response to the COVID-19 pandemic, family presence restrictions in neonatal intensive care units (NICU) were enacted to limit disease transmission and protect infants, families, and healthcare providers. The effects of pandemic parental restrictions on providing optimal family integrated neonatal care is unknown.

Aim

To ensure optimal neonatal care using virtual care pathways to engage and support families in response to parental presence restrictions imposed during the COVID-19 pandemic. The research had two objectives: (1) conduct a needs assessment with families and healthcare providers (HCPs) of infants in the NICU to understand the impact of COVID-19 restrictions; and (2) develop virtual clinical care pathways to meet identified needs.

Methods

This study used focus groups and individual semi-structured interviews with families and HCPs for the needs assessment and identification of barriers and facilitators, and co-design for the development of the clinical virtual care pathways. For objective 1, content analysis was conducted by two independent reviewers to categorize findings and identify important barriers and facilitators of family-integrated care. For objective 2, an agile, co-design process utilizing expert consensus of a large interdisciplinary team was used to develop the care pathways.

Results

A total of 23 participants were included in the needs assessment (objective 1): 12 families and 11 HCPs. Themes identified were: (1) the need to maintain and build relationships and support systems; (2) challenges in accessing education and resources to integrate families in care; and (3) lack of standardized, accessible messaging related to COVID-19. For objective 2, we used the themes identified in the needs assessment to co-design three clinical virtual care pathways: (1) building and maintaining relationships between family and healthcare providers; (2) awareness of resources; and (3) standardized COVID-19 messaging.

Conclusion

Families reported that restrictive parental presence policies affected their mental health, well-being and social support. Families and HCPs reported the restrictions impacted delivery of family integrated care, education, transition to home, and standardized messaging. Clinical care virtual pathways were designed to meet these needs to ensure more equitable family centred care.
A new Reproduction Index Ri and its Usefulness for Germany’s Covid19-Data
Authors: Conradt Robert N.J.
Published: March 2021

In the course of a large-scale infectious disease a time-dependent Reproduction rate is an important parameter for political, economic and social decisions. In this paper we focus on that parameter and introduce a mathematical implementation in addition to the mostly used definition of Robert-Koch-Institute (RKI) in Germany.

Such value is of particular interest in order to serve as a criterion for possible Lock-Downs and “LockUps” in society and can provide deep insights into a pandemic event.

Both the definition of the new Reproduction index and the RKI’s Reproduction number are compared analytically, applied to simple model calculations and finally on real Covid19 data. Clear advantages of the new Reproduction index become apparent and some weaknesses of the RKI’s Reproduction number become clearly visible.

In addition we propose two additional ways of displaying pandemic data to have the pandemic behaviour at a glance. We find that some signatures of the pandemic appear now very well expressed - especially in conjunction with the new Reproduction index Ri.

This all could be very helpful for future political, social and economic decisions.
Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT
Authors: Bell Melanie L , Catalfamo Collin J , Farland Leslie V. , Ernst Kacey C , Jacobs Elizabeth T , Klimentidis Yann C , Jehn Megan , Pogreba-Brown Kristen
Published: March 2021

Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as post-acute sequelae of SAR-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of various symptoms of PASC, defined as experiencing at least one symptom 30 days or longer. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30-250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95%CI 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress (30.8%). The median number of symptoms was 3 (range 1-20). Amongst 157 participants with longer follow-up (≥60 days), PASC prevalence was 77.1%.
Impact of COVID-19 pandemic on rare diseases- A case study on thalassaemia patients in Bangladesh
Authors: Hossain Mohammad Sorowar , Runa Farhana , Mosabbir Abdullah Al
Published: March 2021

Objectives

Thalassaemia is a life-threatening rare disease, which requires regular blood transfusion and medical care. The information on how thalassaemia patients are affected during the unprecedented COVID-19 crisis is scarce. This study aimed to assess the impact of the COVID-19 pandemic on the blood transfusion and healthcare access of thalassaemia patients at the community level in Bangladesh.

Methods

A cross-sectional study was conducted among thalassaemia patients registered in a community-based ‘ thalassaemia registry’ in Jamapur, Bangladesh.

Results

As compared to pre-COVID-19 time, the number of blood transfusions among patients under the thalassaemia registry was significantly reduced during COVID-19 pandemic (190 units versus 81 units). In addition, the median number of red cell transfusions per patient was dropped significantly from 4 units to one unit. Over 80% of patient had no access to healthcare services at all during the early phase of the pandemic.

Conclusions

Emergency response with appropriate mitigative measures must be a priority for addressing an acute shortage of blood supply in situations like COVID-19 pandemic.
Biallelic mutations in cancer genomes reveal local mutational determinants
Authors: Demeulemeester Jonas , Dentro Stefan C. , Gerstung Moritz , Van Loo Peter
Published: March 2021

The infinite sites model of molecular evolution requires that every position in the genome is mutated at most once1. It is a cornerstone of tumour phylogenetic analysis2, and is often implied when calling, phasing and interpreting variants3,4or studying the mutational landscape as a whole5. Here we identify 20,555 biallelic mutations, where the same base is mutated independently on both parental copies, in 722 (26.0%) bulk sequencing samples from the Pan-Cancer Analysis of Whole Genomes study (PCAWG). Biallelic mutations reveal UV damage hotspots at ETS and NFAT binding sites, and hypermutable motifs inPOLE-mutant and other cancers. We formulate recommendations for variant calling and provide frameworks to model and detect biallelic mutations. These results highlight the need for accurate models of mutation rates and tumour evolution, as well as their inference from sequencing data.
Relationship between constitutive and acute gene regulation, and physiological and behavioral responses, mediated by the neuropeptide PACAP
Authors: Bakalar Dana , Sweat Sean , Drossel Gunner , Jiang Sunny Z. , Samal Babru S. , Stroth Nikolas , Xu Wenqin , Zhang Limei , Zhang Haiying , Eiden Lee E.
Published: March 2021

Since the advent of gene knockout technology in 1987, insight into the role(s) of neuropeptides in centrally- and peripherally-mediated physiological regulation has been gleaned by examining altered physiological functioning in mammals, predominantly mice, after genetic editing to produce animals deficient in neuropeptides or their cognate G-protein coupled receptors (GPCRs). These results have complemented experiments involving infusion of neuropeptide agonists or antagonists systemically or into specific brain regions. Effects of gene loss are often interpreted as indicating that the peptide and its receptor(s) are required for the physiological or behavioral responses elicited in wild-type mice at the time of experimental examination. These interpretations presume that peptide/peptide receptor gene deletion affects only the expression of the peptide/receptor itself, and therefore impacts physiological events only at the time at which the experiment is conducted. A way to support ‘real-time’ interpretations of neuropeptide gene knock-out is to demonstrate that the wild-type transcriptome, except for the deliberately deleted gene(s), in tissues of interest, is preserved in the knock-out mouse. Here, we show that there is a cohort of genes (constitutively PACAP-Regulated Genes, or cPRGs) whose basal expression is affected by constitutive knock-out of the Adcyap1 gene in C57Bl6/N mice, and additional genes whose expression in response to physiological challenge, in adults, is altered or impaired in the absence of PACAP expression (acutely PACAP-Regulated Genes, or aPRGs). Distinguishing constitutive and acute transcriptomic effects of neuropeptide deficiency on physiological function and behavior in mice reveals alternative mechanisms of action, and changing functions of neuropeptides, throughout the lifespan.
Evidence for glutamine synthetase function in mouse spinal cord oligodendrocytes
Authors: Haim Lucile Ben , Schirmer Lucas , Zulji Amel , Sabeur Khalida , Tiret Brice , Chang Sandra , Lamers Wouter H. , Chaumeil Myriam M. , Rowitch David H.
Published: March 2021

Glutamine synthetase (GS) is a key enzyme that metabolizes glutamate into glutamine. While GS is expressed by astrocytes of the central nervous system (CNS), expression in other glial lineages has been noted. Using a combination of reporter mice and cell typespecific markers, we show that GS is expressed in myelinating oligodendrocytes (OL) but not oligodendrocyte progenitor cells (OPC) of the mouse spinal cord abutting ventral horn motor neurons. To investigate the role of GS in mature OL, we used a conditional knockout (cKO) approach to selectively delete GS-encoding gene (Glul) in OL, which caused a significant decrease in glutamine levels on spinal cord extracts. We evaluated the effect on ventral spinal cord sensorimotor circuits and observed thatGS cKOmice (CNP-cre+:Glulfl/fl) showed no differences in motor neuron numbers, size or axon density; OL differentiation and myelination in the ventral spinal cord at 1- and 6-months of age was normal. Interestingly,GS cKOmice showed an early and specific decrease in peak force while motor function remained otherwise unaffected. These findings provide evidence OL-encoded GS functions in spinal cord sensorimotor circuit.

Main points

Glutamine synthetase (GS) is highly expressed in oligodendrocytes (OL) of the mouse spinal cord.

OL-specific GS loss of function causes transient decrease in peak force, but other substantial neurological dysfunction was not detected.
Occipital and parietal cortex participate in a cortical network for transsaccadic discrimination of object shape and orientation
Authors: Baltaretu B. R. , Stevens W. Dale , Freud E. , Crawford J. D.
Published: March 2021

Saccades change eye position and interrupt vision several times per second, necessitating neural mechanisms for continuous perception of object identity, orientation, and location. Neuroimaging studies suggest that occipital and parietal cortex play complementary roles for transsaccadic perception of intrinsic versus extrinsic spatial properties, e.g., dorsomedial occipital cortex (cuneus) is sensitive to changes in spatial frequency, whereas the supramarginal gyrus (SMG) is modulated by changes in object orientation. Based on this, we hypothesized that both structures would be recruited to simultaneously monitor identityandorientation across saccades. To test this, we merged two previous neuroimaging protocols: 21 participants viewed a 2D object and then, after sustained fixation or a saccade, judged whether the shapeororientation of the represented object changed. We, then, performed a bilateral region-of-interest analysis on identified cuneus and SMG sites. As hypothesized, cuneus showed both saccade and feature (i.e., orientation vs. shape change) modulations, and right SMG showed saccade-feature interactions. Further, the cuneus activity time course correlated with several other cortical saccade / visual areas, suggesting a ‘functional network’ for feature discrimination. These results confirm the involvement of occipital / parietal cortex in transsaccadic vision and support complementary roles in spatial versus identity updating.
H3K9 methyltransferase EHMT2/G9a controls ERVK-driven non-canonical imprinted genes
Authors: Zeng Tie-Bo , Pierce Nicholas , Szabó Piroska E.
Published: March 2021

Unlike regular imprinted genes, non-canonical imprinted genes are known to not depend on gamete-specific DNA methylation difference. Instead, the paternal allele-specific expression of these genes in the extra-embryonic lineages depends on an H3K27me3-based imprint in the oocyte, but this marking is not maintained beyond pre-implantation development. The maintenance of non-canonical imprinting corresponds to maternal allele-specific DNA methylation and paternal allele-specific H3K4me3 at their somatic DMRs, which occur at ERVK repeats. We hypothesized that EHMT2, the main euchromatic H3K9 methyltransferase, also has a role in this process. Using reciprocal mouse crosses and allele-specific RNA-seq analysis, we found that the maternal allele of each known non-canonical imprinted gene was derepressed from its ERVK promoter in theEhmt2−/−ectoplacental cone of somite-matched 8.5 dpc embryos. In theEhmt2−/−embryos, loss of DNA methylation accompanied the derepression of both parental alleles of those ERVK promoters. Our study identifies EHMT2 as an essential player that maintains the repressed chromosomal state in non-canonical imprinting.
Multisystem inflammatory syndrome in European White children – study of 274 cases
Authors: Ludwikowska Kamila Maria , Okarska-Napierała Magdalena , Dudek Natalia , Tracewski Paweł , Kusa Jacek , Piwoński Krzysztof , Afelt Aneta , Cysewski Dominik , Biela Mateusz , Werner Bożena , Jackowska Teresa , Suski Catherine , Kursa Miron Bartosz , Kuchar Ernest , Szenborn Leszek
Published: March 2021

Background

Despite the growing literature on multisystem inflammatory syndrome in children (MIS-C), the data in European White population is limited. Our aim was to capture MIS-C emergence in Poland (central Europe) and to describe its characteristics with a focus on severity determinants.

Methods

Patients who met the MIS-C definition (fever, multiorgan failure, inflammation, and proven SARS-CoV-2 infection or contact) were reported retrospectively and prospectively in an online survey. Study definitions fulfilment was automatically evaluated by a dedicated software. For the assessment of univariate relationships, either directed or divided by sex, age, or disease severity, we used the test for two categorical variables and the Kruskal-Wallis test for categorical-continuous variable pairs.

Findings

The analysis involved 274 children, 62.8% boys, median age 8.8 years. Besides one Asian, all were European White. Merely 23 (8.4%) required paediatric intensive care treatment (PICU). They were older (11.2 vs. 8.4 years), and at hospital admission had higher respiratory rate (30 v. 20/minute), lower systolic blood pressure (89 vs. 100 mmHg), prolonged capillary refill time (40% vs. 11%), and decreased consciousness (22% vs. 5%).

Teenage boys had more common cardiac involvement (fraction 25.9% vs. 14.7%) and macrophage activation syndrome (31.0% vs. 15.2%) than others. Boys were also more often hospitalised in PICU with age (from median 11.2 years to 9.1).

Interpretation

The severity of MIS-C is not as uniform as it seemed, ethnicity and sex may affect MIS-C phenotype. Management might not be universally applicable and should rather be adjusted to the specific population.

Funding

PSP: 501-D402-20-0006100
Genomic analysis of patient-derived xenograft models reveals intra-tumor heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib
Authors: Bonazzi Vanessa F. , Kondrashova Olga , Smith Deborah , Nones Katia , Sengal Asmerom T. , Ju Robert , Packer Leisl M. , Koufariotis Lambros T. , Kazakoff Stephen H. , Davidson Aimee L. , Ramarao-Milne Priya , Lakis Vanessa , Newell Felicity , Rogers Rebecca , Davies Claire , Nicklin James , Garrett Andrea , Chetty Naven , Perrin Lewis , Pearson John V. , Patch Ann-Marie , Waddell Nicola , Pollock Pamela
Published: March 2021

Background

Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.

Methods

Here, we report whole exome or whole genome sequencing of 11 PDX models and the matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these within vivoresponses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the different molecular subtypes of EC.

Results

PDX models were successfully generated from all four molecular subtypes of EC and uterine carcinosarcomas, and they recapitulated morphology and the molecular landscape of primary tumors without major genomic drift. We also observed a wide range of inter-tumor and intra-tumor heterogeneity, well captured by different PDX lineages, which could lead to different treatment responses. Anin vivoresponse to talazoparib was detected in two p53mut models consistent with stable disease, however both lacked the HR deficiency genomic signature.

Conclusions

EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the p53mut molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.
DataJoint Elements: Data Workflows for Neurophysiology
Authors: Yatsenko Dimitri , Nguyen Thinh , Shen Shan , Gunalan Kabilar , Turner Christopher A. , Guzman Raphael , Sasaki Maho , Sitonic Daniel , Reimer Jacob , Walker Edgar Y. , Tolias Andreas S.
Published: March 2021

A new resource—DataJoint Elements—provides modular designs for assembling complete workflow solutions to organize data and computations for common neurophysiology experiments. The designs are derived from working solutions developed in leading research groups using the open-source DataJoint framework to integrate data collection and analysis in collaborative workflows.
Robust phylogenetic position of the enigmatic hydrozoanMargelopsis haeckeliirevealed within the family Corymorphidae
Authors: Kupaeva Daria , Lebedeva Tatiana , Kobrinsky Zachariah , Vanwalleghem Daniel , Prudkovsky Andrey , Kremnyov Stanislav
Published: March 2021

The life-cycle and polyp morphology of representatives of Margelopsidae are very different from all other species in the hydrozoan clade Aplanulata. Their evolutionary origin and phylogenetic position has been the subject of significant speculation. A recent molecular study based only on COI data placed Margelopsidae as a sister group to all Aplanulata, an unexpected result because margelopsid morphology suggests affiliation with Tubulariidae or Corymorphidae. Here we used multigene analyses, including nuclear (18S rRNA and 28S rRNA) and mitochondrial (16S rRNA and COI) markers of the hydroid stage of the margelopsid speciesMargelopsis haeckeliiHartlaub, 1897 and the medusa stage ofMargelopsis hartlaubiiBrowne, 1903 to resolve their phylogenetic position with respect to other hydrozoans. Our data provide strong evidence thatM. haeckelii, the type species ofMargelopsis, is a member of the family Corymorphydae. In contrast,M. hartlaubiiBrowne, 1903 is sister toPlotocnide borealisWagner, 1885, a member of Boreohydridae. These results invalidate the family Margelopsidae. The phylogenetic signal of polyp and medusa stages is discussed in light of concept of inconsistent evolution and molecular phylogenetic analysis.
Micrococcal nuclease sequencing of porcine sperm suggests a nucleosomal involvement on semen quality and early embryo development
Authors: Gòdia Marta , Hammoud Saher Sue , Naval-Sanchez Marina , Ponte Inma , Rodríguez-Gil Joan Enric , Sánchez Armand , Clop Alex
Published: March 2021

Background

The mammalian mature spermatozoon has a unique chromatin structure in which the vast majority of histones are replaced by protamines during spermatogenesis and a small fraction of nucleosomes are retained at specific locations of the genome. The chromatin structure of sperm remains unresolved in most livestock species, including the pig. However, its resolution could provide further light into the identification of the genomic regions related to sperm biology and embryo development and it could also help identifying molecular markers for sperm quality and fertility traits. Here, for the first time in swine, we performed Micrococcal Nuclease coupled with high throughput sequencing on pig sperm and characterized the mono-nucleosomal (MN) and sub-nucleosomal (SN) chromatin fractions.

Results

We identified 25,293 and 4,239 peaks in the mono-nucleosomal and sub-nucleosomal fractions, covering 0.3% and 0.02% of the porcine genome, respectively. A cross-species comparison of nucleosome-associated DNAs in sperm revealed positional conservation of the nucleosome retention between human and pig. Gene ontology analysis of the genes mapping nearby the mono-nucleosomal peaks and identification of putative transcription factor binding motifs within the mono-nucleosomal peaks showed enrichment for sperm function and embryo development related processes. We found motif enrichment for the transcription factor Znf263, which in humans was suggested to be a key regulator of the genes with paternal preferential expression during early embryo development. Moreover, we found enriched co-occupancy between the RNAs present in pig sperm and the RNA related to sperm quality, and the mono-nucleosomal peaks. We also found preferential co-location between GWAS hits for semen quality in swine and the mono-nucleosomal sites identified in this study.

Conclusions

These results suggest a clear relationship between nucleosome positioning in sperm and sperm and embryo development.