bluuebunny/crossref_metadata_2025_split huggingface dataset:
An assessment of the vaccination of school-aged children in England
Authors: Keeling Matt J. , Moore Sam E. 
Published: February 2022

BackgroundChildren and young persons are known to have a high number of close interactions, often within the school environment, which can facilitate rapid spread of infection; yet for SARS-CoV-2 it is the elderly and vulnerable that suffer the greatest health burden. Vaccination, initially targeting the elderly and vulnerable but later expanded to the entire adult population, has been transformative in the control of SARS-CoV-2 in England. However, early concerns over adverse events and the lower risk associated with infection in younger individuals means that the expansion of the vaccine programme to those under 18 year of age needs to be rigorously and quantitatively assessed.MethodsHere, using a bespoke mathematical model matched to case and hospital data for England, we consider the potential impact of vaccinating 12-17 and 5-11 year olds. This analysis is reported from an early model (generated in June 2021) that formed part of the evidence base for the decisions in England, and a later model (from November 2021) that benefits from a richer understanding of vaccine efficacy, greater knowledge of the Delta variant wave and uses data on the rate of vaccine administration. For both models we consider the population wide impact of childhood vaccination as well as the specific impact on the age-group targeted for vaccination.ResultsProjections from June suggested that an expansion of the vaccine programme to those 12-17 years old could generate substantial reductions in infection, hospital admission and deaths in the entire population, depending on population behaviour following the relaxation of control measures. The benefits within the 12-17 year old cohort were less marked, saving between 656 and 1077 (95% prediction interval 281-2260) hospital admissions and between 22 and 38 (95% PI 9-91) deaths depending on assumed population behaviour. For the more recent model, the benefits within this age group are reduced, saving on average 631 (95% PI 304-1286) hospital admissions and 11 (95% PI 5-28) deaths for 80% vaccine uptake, while the benefits to the wider population represent a reduction of 8-10% in hospital admissions and deaths. The vaccination of 5-11 year olds is projected to have a far smaller impact, in part due to the later roll-out of vaccines to this age-group.ConclusionsVaccination of 12-17 year olds and 5-11 year olds is projected to generate a reduction in infection, hospital admission and deaths for both the age-groups involved and the population in general. For any decision involving childhood vaccination, these benefits needs to be balanced against potential adverse events from the vaccine, the operational constraints on delivery and the potential for diverting resources from other public health campaigns.
Causal relationship between Environmental Enteric Dysfunction (EED), WaSH practices and growth failure in children from Rukwa-Tanzania
Authors: Modern Grantina , Mpolya Emmanuel , Sauli Elingarami 
Published: February 2022

AbstractThis was a hospital based prospective cohort study aimed at assessing causal relationship between environmental enteric dysfunction (EED), WaSH practices and growth failure in children aged between 1-2 years from Rukwa, Tanzania, using univariate and multivariate logistic regression models. We found very significant causal relationship between growth failure and combined water availability (p=0.0055), toilet sharing by parents/caregivers (OR= 2.632, CI: 1.156 - 6.233, p=0.023 from univariate analysis, and OR=4.067, CI: 1.484 - 12.206, p=0.008 from multivariate analysis), and handwashing by parents/caregivers before food (OR=3.363, CI: 0.928 -11.454, p=0.05 from univariate analysis and OR=15.038, CI:2.422 - 115.8, p=0.005 from multivariate analysis). This significant causal relationship may be linked to increased diarrheal incidence and intestinal worm infections among the studied children, which may then lead to inadequate absorption of nutrients and subsequent growth failure. The findings herein should therefore improve policy and programs designed to deliver targeted intervention strategies in Tanzania, to also identify and include other entry points for managing child growth failure and improving WaSH practices.
Anterior Connectivity Critical for Recovery of Connected Speech after Stroke
Authors: Ding Junhua , Schnur Tatiana T. 
Published: February 2022

AbstractConnected speech recovers to different degrees across people after left hemisphere stroke, but white matter predictors of differential recovery from the acute stage of stroke are unknown. We assessed changes in lexical-syntactic aspects of connected speech in a longitudinal analysis of 40 individuals (18 females) from the acute stage of left hemisphere stroke (within an average 4 days post-stroke) to subacute (within 2 months) and chronic stages (early: 6 months, late: 1 year) while measuring the extent of acute lesions on white matter tracts to identify tracts predictive of recovery. We found that acute damage to the frontal aslant tract led to decreased recovery of the fluency and structural complexity of connected speech during the year following left hemisphere stroke. Results were independent of baseline performance, overall lesion volume, and the proportion damage to tract-adjacent gray matter. This longitudinal analysis from acute to chronic stroke provides the first evidence that recovery of fluent and structurally complex spontaneous connected speech requires intact left frontal connectivity via the frontal aslant tract. That the frontal aslant tract was critical for recovery at early as well as later stages of stroke demonstrates that anterior connectivity plays a lasting and important role for the reorganization of function related to the successful production of connected speech.
Sibling Experiences of Adverse Childhood Experiences: A Scoping Review
Authors: Donagh Ben , Taylor Julie , Mushaikni Muna al , Bradbury-Jones Caroline 
Published: February 2022

AbstractAdverse childhood experiences (ACEs) are traumatic events during childhood known to affect health and wellbeing across the life-span. The purpose of this scoping review was to understand what we currently know about the experiences of siblings living with ACEs. Sibling relationships are unique, and for some the most enduring we experience. These relationships can be categorised by love and warmth, however, can also be a point of escalating conflict and problems. This scoping review was conducted following Arksey and O’Malley’s (2005) methodological framework, complemented by the PAGER framework (Bradbury-Joneset al, 2021), offering a structured approach to the review’s analysis and reporting through presenting thePatterns,Advances,Gaps, andEvidence for practice andResearch. In June 2020 we searched 12 databases, with 11,469 results. Articles were screened for eligibility by the review team leaving a total of 148 articles meeting the inclusion criteria. Findings highlighted five main patterns: (1) the influence of birth order (older siblings shielding younger); (2) the influence of sibling relationships (lack of research exploring sibling types outside of biological siblings); (3) identifying siblings experiencing ACEs (when one sibling experiences adversity, it is likely that their other siblings also do, or experience vicariously); (4) siblings who cause harm (siblings harming other siblings is often normalised and minimised, especially by parents); (5) focus on individual ACEs (the majority of studies explore ACEs in isolation). Our findings suggest future research would benefit from an increase in theoretical understanding and exploration of different types of sibling relationships (full, step, half).
Unpicking the Gordian knot: Mendelian randomization to elucidate the risk factors for infectious diseases, using EBV as a model pathogen
Authors: Muckian Marisa D. , Wilson James. F , Taylor Graham S. , Stagg Helen R. , Pirastu Nicola 
Published: February 2022

AbstractBackgroundWhy particular individuals are more at risk of a given infectious disease than others has been a topic of interest for scientists, clinicians, and polymaths for millennia. Complex webs of factors-sociodemographic, clinical, genetic, environmental-intersect, rendering causality difficult to decipher. We aimed to demonstrate the ability of Mendelian Randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of infectious diseases, using Epstein Barr Virus (EBV) as a model pathogen.MethodsWe mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8,422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal.ResultsOur GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed educational attainment, number of sexual partners, and smoking as causal risk factors for EBV serostatus.ConclusionsOur study demonstrates the power of MR to decipher complex webs of putative risk factors and determine which are causal for the acquisition of an infectious disease. The factors identified for EBV will be important for vaccine deployment.Key messagesThe risk of infectious disease acquisition is dependent on many interacting sociodemographic, lifestyle, clinical, genetic, environmental, and national and international health governance factors.Traditional epidemiological studies of these risk factors are often hindered by issues of confounding and therefore whether a given putative risk factor is causally associated with infection acquisition is difficult to decipher.Using Epstein Barr Virus (EBV) as a model pathogen, we demonstrate the power of Mendelian randomization to understand if putative risk factors are causal, while controlling for confounding.Better understanding of infectious disease risk factors using Mendelian randomization can inform vaccine strategies and deployment e.g. by identifying priority populations for vaccination.
Interactions among 17 respiratory pathogens: a cross-sectional study using clinical and community surveillance data
Authors: Burstein Roy , Althouse Benjamin M. , Adler Amanda , Akullian Adam , Brandstetter Elizabeth , Cho Shari , Emanuels Anne , Fay Kairsten , Gamboa Luis , Han Peter , Huden Kristen , Ilcisin Misja , Izzo Mandy , Jackson Michael L. , Kim Ashley E. , Kimball Louise , Lacombe Kirsten , Lee Jover , Logue Jennifer K. , Rogers Julia , Chung Erin , Sibley Thomas R. , Van Raay Katrina , Wenger Edward , Wolf Caitlin R. , Boeckh Michael , Chu Helen , Duchin Jeff , Rieder Mark , Shendure Jay , Starita Lea M. , Viboud Cecile , Bedford Trevor , Englund Janet A. , Famulare Michael 
Published: February 2022

AbstractBackgroundCo-circulating respiratory pathogens can interfere with or promote each other, leading to important effects on disease epidemiology. Estimating the magnitude of pathogen-pathogen interactions from clinical specimens is challenging because sampling from symptomatic individuals can create biased estimates.MethodsWe conducted an observational, cross-sectional study using samples collected by the Seattle Flu Study between 11 November 2018 and 20 August 2021. Samples that tested positive via RT-qPCR for at least one of 17 potential respiratory pathogens were included in this study. Semi-quantitative cycle threshold (Ct) values were used to measure pathogen load. Differences in pathogen load between monoinfected and coinfected samples were assessed using linear regression adjusting for age, season, and recruitment channel.Results21,686 samples were positive for at least one potential pathogen. Most prevalent were rhinovirus (33·5%), Streptococcus pneumoniae (SPn, 29·0%), SARS-CoV-2 (13.8%) and influenza A/H1N1 (9·6%). 140 potential pathogen pairs were included for analysis, and 56 (40%) pairs yielded significant Ct differences (p < 0.01) between monoinfected and co-infected samples. We observed no virus-virus pairs showing evidence of significant facilitating interactions, and found significant viral load decrease among 37 of 108 (34%) assessed pairs. Samples positive with SPn and a virus were consistently associated with increased SPn load.ConclusionsViral load data can be used to overcome sampling bias in studies of pathogen-pathogen interactions. When applied to respiratory pathogens, we found evidence of viral-SPn facilitation and several examples of viral-viral interference. Multipathogen surveillance is a cost-efficient data collection approach, with added clinical and epidemiological informational value over single-pathogen testing, but requires careful analysis to mitigate selection bias.
Bi-steric mTORC1-selective Inhibitors activate 4EBP1 reversing MYC-induced tumorigenesis and synergize with immunotherapy
Authors: Mahauad-Fernandez Wadie D. , Yang Yu Chi , Lai Ian , Park Jangho , Yao Lilian , Evans James W. , Burnett G. Leslie , Gill Adrian , Smith Jacqueline A. M. , Singh Mallika , Felsher Dean W. 
Published: February 2022

AbstractThe MYC oncogene is causally involved in the pathogenesis of most types of human cancer but it remains therapeutically untargeted. The mTORC1 protein complex regulates cap-dependent translation through 4EBP1 and S6K and thereby, downstream MYC protein expression. However, to date, agents such as rapalogs that selectively target mTORC1 (as compared to mTORC2) fail to reactivate 4EBP1 and thus, to block MYCin vivo.In contrast, agents that nonselectively inhibit both protein complexes of the mTOR pathway, mTORC1 and mTORC2, can activate 4EBP1, but often suffer from a lack of tolerability includingin vivohepatotoxicity and immunosuppression. Here, we report the anti-tumor activity of bi-steric mTORC1-selective inhibitors, including Revolution Medicines’ clinical candidate RMC-5552, that potently and selectively target mTORC1 over mTORC2. In an autochthonous transgenic mouse model of MYC-amplified and MYC-driven hepatocellular carcinoma (HCC), representative bi-steric mTORC1-selective inhibitors suppress translation initiation via activation of 4EBP1, thereby suppressing MYC protein expression and blocking tumor growth. Furthermore, in human HCC samples, the low levels of 4EBP1 and MYC is correlated with immune reactivation. Immunohistochemistry, CIBERSORT, and CODEX reveal that selective mTORC1 inhibition results in activation of both CD4+ T cell- and NKp46+ NK cell-mediated immune surveillance. Moreover, bi-steric mTORC1-selective inhibitors synergize with α-PD-1 to induce sustained tumor regression, with immune cell degranulation and release of perforins and granzyme B. These agents also exhibit anti-tumor activity in human patient-derived xenografts of HCC, colorectal cancer, head and neck cancer, and ovarian cancer harboring genomic amplifications inMYC. We infer that selective mTORC1 inhibition is a potential therapeutic strategy to drive effective MYC inactivation in cancer, and the consequent restoration of immune surveillance against neoplasia.
Chronic Alcohol Consumption Alters Home-Cage Behaviors and Responses to Ethologically Relevant Predator Tasks in Mice
Authors: Neira Sofia , Hassanein Leslie A. , Stanhope Christina M. , Buccini Michelle C. , D’Ambrosio Shannon L. , Flanigan Meghan E. , Haun Harold L. , Boyt Kristen M. , Bains Jaideep S. , Kash Thomas L. 
Published: February 2022

AbstractAlcohol use disorders (AUD) are the most prevalent substance use disorders worldwide. Considering recent reports indicating an increase in alcohol use particularly in females, it is vital to understand how alcohol history impacts behavior. Animal model research on withdrawal-associated affective states tends to focus on males, forced alcohol paradigms, and a few traditional anxiety/stress tests. While this has been essential, heavy alcohol use triggers adverse withdrawal-related affective states that can influence how people respond to a large variety of life events and stressors. To this end, we show that behaviors in the home-cage, open field, looming disc, and robogator predator threat task, which vary in task demand and intensity, are altered in mice with a history of voluntary alcohol consumption. In alcohol-exposed males, behaviors in the home cage, a low anxiety baseline environment, suggest increased vigilance/exploration. However, in the open field and robogator task, which induce heightened arousal and task demands, a more hesitant/avoidant phenotype is seen. Female alcohol mice show no behavioral alterations in the home cage and open field test, however, in the looming disc task, which mimics an overhead advancing predator and forces a behavioral choice, we see greater escape responses compared to water controls, indicative of active stress coping behaviors. This suggests females may begin to show alcohol-induced alterations as task demands increase. To date, few drugs have advanced past clinical trials for the treatment of AUD, and those that have are predominately used in life-threatening situations only. No treatments exist for ameliorating negative withdrawal related states, which could aid in harm reduction related to heavy alcohol use. Understanding how withdrawal alters a variety of behavioral responses that are linked to stress coping can widen our understanding of alcohol abuse and lead us closer to better therapeutics to help individuals with AUD.
Distinct mechanisms of germ cell factor regulation for an inductive germ cell fate
Authors: Foster Stephany , Oulhen Nathalie , Fresques Tara , Zaki Hossam , Wessel Gary 
Published: February 2022

AbstractSpecification of primordial germ cells (PGCs), the lineage which gives rise to eggs and sperm, is essential for sexually reproducing organisms. The mechanism by which animals specify their PGCs generally falls into two categories: inherited or inductive. The inductive mechanism, used by mammals, relies on cell signaling interactions to direct a subset of embryonic cells to a germ cell fate. Previous work suggested that sea star embryos, which develop in simple culture and are markedly transparent, also use inductive mechanisms to specify their germline. The germ cell factors Nanos and Vasa become restricted during early development into a localized region of cells within the posterior enterocoel (PE), the presumptive germline. Nodal signaling was observed to negatively regulate Vasa and Nanos mRNAs outside of the PE and restrict the germline to the PE. Here we employed single cell RNA sequencing to identify the transcriptional program of germ cells and their changes during development. We never see Nodal pathway members within Nanos/Vasa positive cells in the region known to give rise to the PE, and instead see members of the Wnt-signaling pathway and the FoxY family of transcription factors. We learned that Wnt and Delta/Notch signaling enhances expression of both Nanos and Vasa, whereas a test of cell interactions reveals that Nanos and Vasa are regulated distinctly. This work provides insights into the sequence of events that leads to PGC specification and enables deeper mechanistic studies in a tractable in vivo model.HighlightsSingle-cell RNA-sequencing of sea star embryos demonstrates temporal differences in cell fate commitment among echinoderms.Sea urchin and sea star embryos appear to ascribe their germ line by two extreme different mechanisms but share similar pathways in regulation of the germline genes.Expression of the germline factors, Vasa and Nanos, is regulated by distinct mechanisms in the sea star.Germline induction in the sea star uses similar signaling mechanisms as mammals.
IL-34 deficiency impairs FOXP3+ Treg function and increases susceptibility to autoimmunity
Authors: Freuchet Antoine , Salama Apolline , Bézie Séverine , Tesson Laurent , Rémy Séverine , Humeau Romain , Règue Hadrien , Flippe Léa , Peterson Pärt , Vimond Nadège , Usal Claire , Ménoret Séverine , Heslan Jean-Marie , Duteille Franck , Blanchard Frédéric , Giral Magali , Colonna Marco , Anegon Ignacio , Guillonneau Carole 
Published: February 2022

AbstractImmune homeostasis requires fully functional Tregs with a stable phenotype to control autoimmunity. Although IL-34 is a cytokine first described as mainly involved in monocyte cell survival and differentiation, we recently described its expression by CD8+ Tregs in a rat model of transplantation tolerance and by activated FOXP3+ CD4+ and CD8+ Tregs in human healthy individuals. However, its role in autoimmunity and potential in human diseases remain to be determined. Here we report that the absence of expression of IL-34 in Il34-/- rodents leads to an unstable phenotype, with production of multiple auto-antibodies, exacerbated under inflammatory conditions with increased susceptibility to DSS- and TNBS-colitis in deficient animals. Moreover, we strikingly revealed the inability of Il34-/- CD4+ Tregs to protect Il2rg-/- rats from a wasting disease induced by transfer of pathogenic cells, in contrast to Il34+/+ CD4+ Tregs. We also showed that IL-34 treatment delayed EAE in mice as well as GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, we show that presence of IL-34 in the serum is associated with a longer rejection-free period in kidney transplanted patients. Altogether, our data emphasize on the crucial necessity of IL-34 for immune homeostasis and for CD4+ Tregs suppressive function. Our data also shows the therapeutic potential of IL-34 in human transplantation and auto-immunity.
Reward contingency gates selective cholinergic suppression of amygdala neurons
Authors: Kimchi Eyal Y. , Burgos-Robles Anthony , Matthews Gillian A. , Chakoma Tatenda , Patarino Makenzie , Weddington Javier , Siciliano Cody A. , Yang Wannan , Foutch Shaun , Simons Renee , Fong Ming-fai , Jing Miao , Li Yulong , Polley Daniel B. , Tye Kay M. 
Published: February 2022

AbstractBasal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward – even in prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs.In vivoelectrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex (PFC). Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic-receptor-signaling, while also facilitating firing in GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.