bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Pandemic Prevalence on the Reported Efficacy of SARS-CoV-2 Vaccine Candidates: A Systematic Review and Meta-analysis
Authors: Sharma Rajeev , Anand Abhijith 
Published: June 2021

AbstractImportanceThe efficacy of SARS-CoV-2 vaccine candidates reported in Phase 3 trials varies from ∼45% to ∼95%. It is important to explain the reasons for this heterogeneity.ObjectiveTo test the hypothesis that the efficacy of SARS-CoV-2 vaccine candidates falls with increasing prevalence of the COVID-19 pandemic.Data SourcesClinicalTrials.gov, WHO, McGill and LSHTM trackers of COVID-19 candidate vaccines, peer reviewed publications, and press releases were searched until March 31st, 2021.Study SelectionAll RCTs reporting efficacy outcomes from Phase 3 trials till March 31st, 2021 were included. Of the 11 vaccine candidates that had started their Phase 3 trials by November 1, 2020. Phase 3 efficacy outcomes were available for 8 vaccine candidates. (PROSPERO CRD42021243121).Data Extraction and SynthesisBoth authors independently extracted the data required from identified sources, using PRISMA guidelines. The analysis included all RCTs reported in peer reviewed publications and publicly available sources. A random effects model with restricted maximum likelihood estimator was used to summarize the treatment effects. Cochrane Risk of Bias Assessment Tool was used to assess risk of bias. Certainty of evidence was assessed using the GRADE tool.Main Outcomes and MeasuresSARS-CoV-2 infections per protocol in vaccine and placebo groups, risk ratio, prevalence of the COVID-19 infection rate in the populations where the Phase 3 trials were conducted.Results8 vaccine candidates had reported efficacy data from a total of 20 independent Phase 3 trials, representing a total of 221,968 subjects, 453 infections across the vaccinated groups and 1,554 infections across the placebo groups. The overall estimate of the risk-ratio is 0.24 (95% CI, 0.17-0.34, p < 0.01), with an I2 statistic of 88.73%. The meta-regression analysis with pandemic prevalence as the moderator explains almost half the variance in risk ratios across trials (R2=49.06%, p<0.01).Conclusion and RelevancePandemic prevalence explains almost half of the between-trial variance in reported efficacies. Efficacy of SARS-CoV-2 vaccine candidates declines as the pandemic prevalence increases.Key PointsQuestionDoes the prevalence of the COVID-19 pandemic explain the heterogeneity in efficacies reported across Phase 3 trials of SARS-CoV-2 vaccine candidates?FindingsAlmost 50% of the variance in efficacies reported across Phase 3 trials can be explained by differences in COVID-19 infection rate prevailing across trials. Efficacy of evaluated SARS-CoV-2 vaccine candidates falls significantly with increasing prevalence of the COVID-19 pandemic across trial sites.MeaningEfficacy of SARS-CoV-2 vaccine candidates needs to be interpreted in conjunction with the prevalence of the COVID-19 pandemic. Adjustment for location-level prevalence analysis would provide better insights into the efficacy results of Phase 3 trials.
“Time does not heal all wounds”: Sexual victimisation is associated with depression, anxiety and PTSD in old age
Authors: Nobels Anne , Lemmens Gilbert M.D. , Thibau Lisa , Beaulieu Marie , Vandeviver Christophe , Keygnaert Ines 
Published: June 2021

AbstractBackgroundSexual violence (SV) has an important impact on mental health. Childhood sexual abuse is linked to internalising disorders in later life. In older adults, SV occurs more often than previously believed. Moreover, health care workers lack the skills to address SV in later life. Studies researching the mental health impact of lifetime SV, i.e. SV during childhood, adulthood and old age, are lacking.MethodsBetween July 2019 and March 2020, 513 older adults living in Belgium participated in structured face-to-face-interviews. Selection occurred via a cluster random probability sampling with a random walk finding approach. Depression, anxiety and posttraumatic stress syndrome (PTSD) were measured using validated scales. Participants were asked about suicide attempts and self-harm during their lifetime and in the past 12-months. SV was measured using behaviourally specific questions based on a broad SV definition.ResultsRates for depression, anxiety and PTSD were 27%, 26% and 6% respectively, 2% had attempted suicide, 1% reported self-harm in the past 12-months. Over 44% experienced lifetime SV, 8% in the past 12-months. Lifetime SV was linked to depression (p =.001), anxiety (p =.001), and PTSD in participants with a chronic illness/disability (p = .002) or no/lower education (p <.001). We found no link between lifetime SV and suicide attempts or self-harm in the past 12-months.ConclusionsLifetime SV is linked to mental health problems in late life. Tailored mental health care for older SV victims is necessary. Therefore, capacity building of professionals, and development of clinical guidelines and care procedures are important.
Identifying Charismatic Bird Species and Traits with Community Science Observations
Authors: Stoudt Sara , Goldstein Benjamin R. , De Valpine Perry 
Published: June 2021

AbstractIdentifying which species are perceived as charismatic can improve the impact and efficiency of conservation outreach, as charismatic species receive more conservation funding and have their conservation needs prioritized (9; 17; 13). Sociological experiments studying animal charisma have relied on stated preferences to find correlations between hypothetical “willingness to pay” or “empathy” for a species’ conservation and species’ size, color, and aesthetic appeal (51; 13; 16). Recognizing the increasing availability of digital records of public engagement with animals that reveal preferences, an emerging field of “culturomics” uses Google search results, Wikipedia article activities, and other digital modes of engagement to identify charismatic species and traits (46; 31; 10; 41). In this study, we take advantage of community science efforts as another form of digital data that can reveal observer preferences. We apply a multi-stage analysis to ask whether opportunistic birders contributing to iNaturalist engage more with larger, more colorful, and rarer birds relative to a baseline, from eBird contributors, approximating unbiased detection. We find that body mass, color contrast, and range size all predict over-representation in the opportunistic dataset. We also find evidence that, across 473 modeled species, 52 species are significantly overreported and 158 are significantly underreported, indicating a wide variety of species-specific effects. Understanding which birds are charismatic can aid conservationists in creating impactful outreach materials and engaging new naturalists. The quantified differences between two prominent community science efforts may also be of use for researchers leveraging the data from one or both of them to answer scientific questions of interest.
DeepCME: A deep learning framework for solving the Chemical Master Equation
Authors: Gupta Ankit , Schwab Christoph , Khammash Mustafa 
Published: June 2021

AbstractStochastic models of biomolecular reaction networks are commonly employed in systems and synthetic biology to study the effects of stochastic fluctuations emanating from reactions involving species with low copy-numbers. For such models, the Kolmogorov’s forward equation is called the chemical master equation (CME), and it is a fundamental system of linear ordinary differential equations (ODEs) that describes the evolution of the probability distribution of the random state-vector representing the copy-numbers of all the reacting species. The size of this system is given by the number of states that are accessible by the chemical system, and for most examples of interest this number is either very large or infinite. Moreover, approximations that reduce the size of the system by retaining only a finite number of important chemical states (e.g. those with non-negligible probability) result in high-dimensional ODE systems, even when the number of reacting species is small. Consequently, accurate numerical solution of the CME is very challenging, despite the linear nature of the underlying ODEs. One often resorts to estimating the solutions via computationally intensive stochastic simulations.The goal of the present paper is to develop a novel deep-learning approach for solving high-dimensional CMEs by reformulating the stochastic dynamics using Kolmogorov’s backward equation. The proposed method leverages superior approximation properties of Deep Neural Networks (DNNs) and is algorithmically based on reinforcement learning. It only requires a moderate number of stochastic simulations (in comparison to typical simulation-based approaches) to train the “policy function”. This allows not just the numerical approximation of the CME solution but also of its sensitivities to all the reaction network parameters (e.g. rate constants). We provide four examples to illustrate our methodology and provide several directions for future research.
SC-MEB: spatial clustering with hidden Markov random field using empirical Bayes
Authors: Yang Yi , Shi Xingjie , Liu Wei , Zhou Qiuzhong , Lau Mai Chan , Lim Jeffrey Chun Tatt , Sun Lei , Yeong Joe , Liu Jin 
Published: June 2021

AbstractSpatial transcriptomics has been emerging as a powerful technique for resolving gene expression profiles while retaining tissue spatial information. These spatially resolved transcriptomics make it feasible to examine the complex multicellular systems of different microenvironments. To answer scientific questions with spatial transcriptomics and expand our understanding of how cell types and states are regulated by microenvironment, the first step is to identify cell clusters by integrating the available spatial information. Here, we introduce SC-MEB, an empirical Bayes approach for spatial clustering analysis using a hidden Markov random field. We have also derived an efficient expectation-maximization algorithm based on an iterative conditional mode for SC-MEB. In contrast to BayesSpace, a recently developed method, SC-MEB is not only computationally efficient and scalable to large sample sizes but is also capable of choosing the smoothness parameter and the number of clusters. We performed comprehensive simulation studies to demonstrate the superiority of SC-MEB over some existing methods. We applied SC-MEB to analyze the spatial transcriptome of human dorsolateral prefrontal cortex tissues and mouse hypothalamic preoptic region. Our analysis results showed that SC-MEB can achieve a similar or better clustering performance to BayesSpace, which uses the true number of clusters and a fixed smoothness parameter. Moreover, SC-MEB is scalable to large ‘sample sizes’. We then employed SC-MEB to analyze a colon dataset from a patient with colorectal cancer (CRC) and COVID-19, and further performed differential expression analysis to identify signature genes related to the clustering results. The heatmap of identified signature genes showed that the clusters identified using SC-MEB were more separable than those obtained with BayesSpace. Using pathway analysis, we identified three immune-related clusters, and in a further comparison, found the mean expression of COVID-19 signature genes was greater in immune than non-immune regions of colon tissue. SC-MEB provides a valuable computational tool for investigating the structural organizations of tissues from spatial transcriptomic data.
The influence of stimulus and behavioral histories on predictive control of smooth pursuit eye movements
Authors: Miyamoto Takeshi , Hirata Yutaka , Katoh Akira , Miura Kenichiro , Ono Seiji 
Published: June 2021

AbstractThe pursuit system has the ability to perform predictive control of eye movements. Even when the target motion is unpredictable due to velocity or direction changes, preceding changes in eye velocity are generated based on weighted averaging of past stimulus timing. However, it is still uncertain whether behavioral history influences the control of predictive pursuit. Thus, we attempted to clarify the influences of stimulus and behavioral histories on predictive pursuit to randomized target velocity. We used alternating-ramp stimuli, where the rightward velocity was fixed while the leftward velocity was either fixed (predictable) or randomized (unpredictable). Predictive eye deceleration was observed regardless of whether the target velocity was predictable or not. In particular, the predictable condition showed that the predictive pursuit responses corresponded to future target velocity. The linear mixed-effects model showed that both stimulus and behavioral histories of the previous two or three trials had influences on the predictive pursuit responses to the unpredictable target velocity. Our results suggest that the predictive pursuit system allows to track randomized target motion using the information from previous several trials, and the information of sensory input (stimulus) and motor output (behavior) in the past time sequences have partially different influences on predictive pursuit.
Cardiac sympathovagal activity initiates a functional brain-body response to emotional processing
Authors: Candia-Rivera Diego , Catrambone Vincenzo , Thayer Julian F. , Gentili Claudio , Valenza Gaetano 
Published: June 2021

AbstractA century-long debate on bodily states and emotions persists. While the involvement of bodily activity in emotion physiology is widely recognized, the specificity and causal role of such activity related to brain dynamics has not yet been demonstrated. We hypothesize that the peripheral neural monitoring and control of cardiovascular activity prompts and sustains brain dynamics during an emotional experience, so these afferent inputs are processed by the brain by triggering a concurrent efferent information transfer to the body. To this end, we investigated the functional brain-heart interplay under emotion elicitation in publicly available data from 62 healthy participants using a computational model based on synthetic data generation of EEG and ECG signals. Our findings show that sympathovagal activity plays a leading and causal role in initiating the emotional response, in which ascending modulations from vagal activity precede neural dynamics and correlate to the reported level of arousal. The subsequent dynamic interplay observed between the central and autonomic nervous systems sustains emotional processing. These findings should be particularly revealing for the psychophysiology and neuroscience of emotions.SignificanceWe investigate the temporal dynamics of brain and cardiac activities in healthy subjects who underwent an emotional elicitation through videos. We demonstrate that, within the first few seconds, emotional stimuli modulate the heart activity, which in turn stimulate an emotion-specific cortical response in the brain. Then, the conscious emotional experience is sustained by a bidirectional brain-heart interplay and information exchange. Moreover, the perceived intensity of an emotional stimulus is predicted by the intensity of neural control regulating the heart activity. These findings may constitute the fundamental knowledge linking neurophysiology and psychiatric disorders, including the link between depressive symptoms and cardiovascular disorders.
Effects of immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19
Authors: Alfano Gaetano , Damiano Francesca , Fontana Francesco , Ferri Camilla , Giaroni Francesco , Melluso Andrea , Montani Martina , Morisi Niccolò , Tei Lorenzo , Plessi Jessica , Giovanella Silvia , Ligabue Giulia , Mori Giacomo , Guaraldi Giovanni , Magistroni Riccardo , Cappelli Gianni 
Published: June 2021

AbstractBackgroundKidney transplant recipients with COVID-19 are at high risk of poor outcome because of comorbidities and immunosuppression. The effects of immunosuppressive therapy reduction are unclear in patients with COVID-19.MethodsWe conducted a retrospective study on 45 consecutive kidney transplant recipients followed at the University Hospital of Modena who tested positive for COVID-19 by RT-PCR analysis.ResultsThe median age of patients was 56.1 (interquartile range, [IQR] 47.3-61.1) years with a predominance of male (64.4%). Kidney transplantation vintage was 10.1 (2.7-16) years, and more than half of patients (55.6%) was on triple immunosuppressive therapy. Early reduction of immunosuppression occurred in 62.8% of patients and included antimetabolite (88.8%) and calcineurin inhibitor withdrawal (22.2%).Of the 45 patients, 88.9% became symptomatic and 40% required hospitalization. Overall mortality was 17.8%. There were no differences in outcomes between full- and reduced-dose immunosuppressive therapy at the end of follow-up. One hospitalized patient experienced irreversible graft failure. There were no differences in serum creatinine level and proteinuria in non-hospitalized patients with COVID-19. Admitted patients had better kidney function after dismission (P=0.019). Risk factors for death were age (odds ratio [OR]: 1.19; 95%CI: 1.01-1.39), and duration of kidney transplant (OR: 1.17; 95%CI: 1.01-1.35). One kidney transplant recipient experienced symptomatic COVID-19 reinfection after primary infection and anti-SARS-CoV-2 mRNA vaccine.ConclusionsDespite the reduction of immunosuppression, COVID-19 affected survival of kidney transplant recipients with COVID-19. Age and duration of kidney transplant were independent predictors of death in COVID-19. Early kidney function was favorable in most survivors after COVID-19.
Structural insights into the modes of relaxin-binding and tethered-agonist activation of RXFP1 and RXFP2
Authors: Sethi Ashish , Bruell Shoni , Ryan Tim , Yan Fei , Tanipour Mohammad , Mok Yee-Foong , Draper-Joyce Chris , Khandokar Yogesh , Metcalfe Riley D. , Griffin Michael D. W. , Scott Daniel J. , Hossain Mohammad Akhter , Petrie Emma J. , Bathgate Ross A. D. , Gooley Paul R. 
Published: June 2021

AbstractOur poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signalling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors.
Resource-efficient pooled sequencing expands translational impact in solid tumors
Authors: DiNatale Renzo G. , Mano Roy , Makarov Vladimir , Rusk Nicole , Drill Esther , Winer Andrew , Sankin Alexander , Yoo Angela , Freeman Benjamin A. , Hsieh James J. , Chen Ying-Bei , Coleman Jonathan A. , Berger Michael , Ostrovnaya Irina , Chan Timothy A. , Russo Paul , Reznik Ed , Hakimi A. Ari 
Published: June 2021

ABSTRACTIntratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.
The role of the cannabinoid system in fear memory and extinction in male and female mice
Authors: Mizuno Ikumi , Matsuda Shingo , Tohyama Suguru , Mizutani Akihiro 
Published: June 2021

AbstractThe prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in processes of fear extinction are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms for fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It has been unclear whether there are sex differences in the role of the CB system in fear memory and extinction. To explore the possibility of such differences, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 [an inhibitor of the 2-AG hydrolase monoacylglycerol lipase (MAGL)], augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval or extinction of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in the 2-AG level on the retrieval of contextual fear memory differ between the sexes.