bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optogenetic control of RelA reveals effect of transcription factor dynamics on downstream gene expression
Authors: Osimiri Lindsey C. , Bonny Alain R. , Takagishi Seesha R. , Luecke Stefanie , Riehs Nina , Hoffmann Alexander , El-Samad Hana 
Published: August 2022

AbstractMany transcription factors (TFs) translocate to the nucleus with varied dynamic patterns in response to different inputs. A notable example of such behavior is RelA, a subunit of NF-κB, which translocates to the nucleus with either pulsed or sustained dynamics, depending on the stimulus. Our understanding of how these dynamics are interpreted by downstream genes has remained incomplete, partly because ubiquitously used environmental inputs activate other transcriptional regulators in addition to RelA. Here, we use an optogenetic tool, CLASP (controllable light-activated shuttling and plasma membrane sequestration), to control RelA spatiotemporal dynamics in mouse fibroblasts and quantify their effect on downstream genes using RNA-seq. Using RelA-CLASP, we show for the first time that nuclear translocation of RelA, without post-translational modifications or activation of other transcriptional regulators, is sufficient to activate downstream genes. Furthermore, we find that TNFα, a common endogenous input, regulates many genes independently of RelA, and that this gene regulation is different from that induced by RelA-CLASP. Genes responsive to RelA-CLASP show a wide range of dynamics in response to a constant RelA input. We use a simple promoter model to recapitulate these diverse dynamic responses, as well as data collected in response to a pulsed RelA-CLASP input, and extract features of many RelA-responsive promoters. We also pinpoint many genes for which more complex models, involving feedback or multi-step promoters, may be needed to explain their response to constant and pulsed TF inputs. This study introduces a new robust tool for studying mammalian transcriptional regulation and demonstrates the power of optogenetic tools in dissecting the quantitative features of important cellular pathways.
Spatiotemporal variation in risk ofShigellainfection in childhood: a global risk mapping and prediction model using individual participant data
Authors: Badr Hamada S. , Colston Josh M. , Nguyen Nhat-Lan H. , Chen Yen Ting , Ali Syed Asad , Rayamajhi Ajit , Satter Syed M. , Van Trang Nguyen , Eibach Daniel , Krumkamp Ralf , May Jürgen , Adegnika Ayola Akim , Prince Manouana Gédéon , Kremsner Peter Gottfried , Chilengi Roma , Hatyoka Luiza , Debes Amanda K. , Ateudjieu Jerome , Faruque Abu S. G. , Hossain M. Jahangir , Kanungo Suman , Kotloff Karen L. , Mandomando Inácio , Nisar M. Imran , Omore Richard , Sow Samba O. , Zaidi Anita K. M. , Lambrecht Nathalie , Adu Bright , Page Nicola , Platts-Mills James A. , Freitas Cesar Mavacala , Pelkonen Tuula , Ashorn Per , Maleta Kenneth , Ahmed Tahmeed , Bessong Pascal , Bhutta Zulfiqar A. , Mason Carl , Mduma Estomih , Olortegui Maribel P. , Yori Pablo Peñataro , Lima Aldo A. M. , Kang Gagandeep , Humphrey Jean , Ntozini Robert , Prendergast Andrew J. , Okada Kazuhisa , Wongboot Warawan , Langeland Nina , Moyo Sabrina J. , Gaensbauer James , Melgar Mario , Freeman Matthew , Chard Anna N. , Thongpaseuth Vonethalom , Houpt Eric , Zaitchik Benjamin F. , Kosek Margaret N. 
Published: August 2022

AbstractBackgroundDiarrheal disease remains a leading cause of childhood illness and mortality andShigellais a major etiological contributor for which a vaccine may soon be available. This study aimed to model the spatiotemporal variation in pediatricShigellainfection and map its predicted prevalence across low- and middle-income countries (LMICs).MethodsIndependent participant data onShigellapositivity in stool samples collected from children aged ≤59 months were sourced from multiple LMIC-based studies. Covariates included household- and subject-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted, and prevalence predictions obtained by syndrome and age stratum.Findings20 studies from 23 countries contributed 66,563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture.Shigellaprobability exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhea cases at 33°C temperatures, above which it decreased. Improved sanitation and open defecation decreasedShigellaodds by 19% and 18% respectively compared to unimproved sanitation.InterpretationThe distribution ofShigellais more sensitive to climatological factors like temperature than previously recognized. Conditions in much of sub-Saharan Africa are particularly propitious forShigellatransmission, though hotspots also occur in South and Central America, the Ganges–Brahmaputra Delta, and New Guinea. These findings can inform prioritization of populations for future vaccine trials and campaigns.FundingNASA 16-GEO16-0047; NIH-NIAID 1R03AI151564-01; BMGF OPP1066146.
Forecasting COVID-19 activity in Australia to support pandemic response: May to October 2020
Authors: Moss Robert , Price David J. , Golding Nick , Dawson Peter , McVernon Jodie , Hyndman Rob J. , Shearer Freya M. , McCaw James M. 
Published: August 2022

AbstractAs of January 2021, Australia had effectively controlled local transmission of COVID-19 despite a steady influx of imported cases and several local, but contained, outbreaks in 2020. Throughout 2020, state and territory public health responses were informed by weekly situational reports that included an ensemble forecast for each jurisdiction. We present here an analysis of one forecasting model included in this ensemble across the variety of scenarios experienced by each jurisdiction from May to October 2020. We examine how successfully the forecasts characterised future case incidence, subject to variations in data timeliness and completeness, showcase how we adapted these forecasts to support decisions of public health priority in rapidly-evolving situations, evaluate the impact of key model features on forecast skill, and demonstrate how to assess forecast skill in real-time before the ground truth is known. Conditioning the model on the most recent, but incomplete, data improved the forecast skill, emphasising the importance of developing strong quantitative models of surveillance system characteristics, such as ascertainment delay distributions. Forecast skill was highest when there were at least 10 reported cases per day, the circumstances in which authorities were most in need of forecasts to aid in planning and response.
The Impact of Fasting the Holy Month of Ramadan on Colorectal Cancer Patients and Two Tumor Biomarkers: A Tertiary-Care Hospital Experience
Authors: Alshammari Kanaan , Alhaidal Haifa , Alharbi Reem , Alrubaiaan Alanood , Alyousif Ghadah , Alkaiyat Mohammad , Abdel-Razaq Wesam 
Published: August 2022

AbstractBackgroundFasting during the holy month of Ramadan is a religious ritual practiced by the majority of Muslims around the globe. This daytime fasting is short-term or intermittent fasting, which may be associated with valuable health benefits, particularly in cancer patients.MethodsA prospective cohort study of pre-and post-evaluation of 37 colorectal cancer (CRC) patients was conducted in the oncology outpatient clinics to assess the impact of fasting during Ramadan on the tolerability of chemotherapy side effects and to assess changes in the levels of carcinoembryonic antigen (CEA) and lactate dehydrogenase (LDH) tumor biomarkers.ResultThe vast majority of CRC patients (89.2%) had fasted at least part of the month of Ramadan. Most (73%) reported “Serenity” after fasting during Ramadan with improved tolerability of chemotherapy side effects. The results did not reveal any significant difference in the measured laboratory variables between pre-fasting values and by the end of the 30 days of Ramadan. Although statistically insignificant, the levels of CEA and LDH were reduced in 46.9% and 55.6% of CRC patients, respectively. The mean level of CEA in the fasting group was substantially reduced by more than 40%, attributed to the highly significant decline of CEA levels in three patients only (p=0.0283).ConclusionThe current study confirms the safety and tolerability of intermittent fasting in CRC patients actively receiving chemotherapy, which is consistent with several reports. Nonetheless, the results did not reveal a significant decrease in CEA and LDH tumor biomarkers.
Assessing Predictors of Mortality Among Children admitted with Sepsis at a Referral Tertiary Health Center, Northwestern Nigeria
Authors: Hassan-Hanga Fatimah , Ibrahim Baffa Sule , Kabir Halima , Hafsat Ibrahim U , Abdulsalam Kabiru , Ahmed Zainab Datti , Kabara Halima Salisu , Gaya Sule Abdullahi , Haliru Dalha Gwarzo , Sadiq Nasiru Magaji , Inuwa Salisu , Mohammad Mohammad Aminu 
Published: August 2022

AbstractBackgroundSepsis is a life-threatening infection that can lead to organ failure and death. We aim to assess predictors of mortality among children admitted with Septicemia at a referral health facility in Northwestern Nigeria.MethodsWe conducted a prospective cross-sectional study of children aged 0-14 years admitted to various units of the pediatrics department of the health facilities. Children were recruited between September 2018 and November 2019. All recruited children were followed up on clinical progress until either discharge, abscondment, or death. We assessed the children clinically daily and collected whole-blood samples for laboratory tests. We conducted a univariate and multivariable analysis using STATA-16 to assess identified predictive factors with our outcome variable.ResultsA total of 326 children were recruited, median age: 2-years. About 54.0% of the children were boys, and 53.1% were within 1-5 years age-group. Predominant organisms cultured from the blood of the children wereSalmonella typhi(5.7%),Klebsiella pneumoniae(2.3%), andStaphylococcus aureus(2.0%). A total of 35 deaths were recorded with a case fatality rate (CFR) of 10.7%. CFR is highest in children <1years (13.6%).Child’s vaccination status, mother’s education level as well as blood lactate levels, GCS, qSOFA score and positive blood culture were significantly associated with child’s mortality. Factors associated with increase mortality include; children with incomplete vaccination history [OR=1.72, 95%CI: 2.74–15.53] versus those with full vaccination; children whose mothers had no formal education [OR=14.39, 95%CI: 3.24–63.99] when compared to those children whose mothers have tertiary level of education. Furthermore, children with whole blood lactate level between 4-8mmol/l [OR=3.23, 95%CI: 1.15–9.07], or greater than 8mmol/l [OR=10.54, 95%CI: 3.68–30.14] versus children with whole blood lactate level less than 4mmol/l; children with qSOFA score of 3 [OR=15.62, 95%CI: 3.31–73.60] versus children with qSOFA score of 1; and children who had a positive blood culture [OR=6.90, 95%CI: 3.04–15.64].ConclusionWe found a high prevalence of severe sepsis at pediatrics department of AKTH. Serum lactate levels, GCS, and qSOFA scores were predictive of mortality. Routine measurement and monitoring of these parameters will improve case management and reduce sepsis related mortality in the hospital.
Determining population-level allocation strategies for COVID-19 treatments in the United States using a quantitative framework, a case study using nirmatrelvir/ritonavir
Authors: Savinkina Alexandra , Gonsalves Gregg , Ross Joseph S. , Paltiel A. David 
Published: August 2022

AbstractBackgroundNew COVID-19 medications force decision makers to weigh limited evidence of efficacy and cost in determining which patient populations to target for treatment. A case in point is nirmatrelvir/ritonavir, a drug that has been recommended for elderly, high-risk individuals, regardless of vaccination status, even though clinical trials have only evaluated it in unvaccinated patients. A simple optimization framework might inform a more reasoned approach to the tradeoffs implicit in the treatment allocation decision.MethodsWe used a mathematical model to analyze the cost-effectiveness of four nirmatrelvir/ritonavir allocation strategies, stratified by vaccination status and risk for severe disease. We considered treatment effectiveness at preventing hospitalization ranging from 21% to 89%. Sensitivity analyses were performed on major parameters of interest. A web-based tool was developed to permit decision-makers to tailor the analysis to their settings and priorities.ResultsProviding nirmatrelvir/ritonavir to unvaccinated patients at high-risk for severe disease was cost-saving when effectiveness against hospitalization exceeded 33% and cost-effective under all other data scenarios we considered. The cost-effectiveness of other allocation strategies, including those for vaccinated adults and those at lower-risk for severe disease, depended on willingness-to-pay thresholds, treatment cost and effectiveness, and the likelihood of severe disease.ConclusionsPriority for nirmatrelvir/ritonavir treatment should be given to unvaccinated persons at high-risk of severe disease from COVID-19. Further priority may be assigned by weighing treatment effectiveness, disease severity, drug cost, and willingness to pay for deaths averted.
Multi-ancestry genome-wide meta-analysis in Parkinson’s disease
Authors: Kim Jonggeol Jeffrey , Vitale Dan , Véliz Otani Diego , Lian Michelle , Heilbron Karl ,   the 23andMe Research Team, Iwaki Hirotaka , Lake Julie , Solsberg Caroline Warly , Leonard Hampton , Makarious Mary B. , Tan Eng-King , Singleton Andrew B. , Bandres-Ciga Sara , Noyce Alastair J , Blauwendraat Cornelis , Nalls Mike A. , Foo Jia Nee , Mata Ignacio 
Published: August 2022

AbstractAlthough over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, all studies have been performed in just one population at the time. Here we performed the first large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases, and 2,458,063 controls including individuals of European, East Asian, Latin American, and African ancestry. In a single joint meta-analysis, we identified 78 independent genome-wide significant loci including 12 potentially novel loci (MTF2, RP11-360P21.2, ADD1, SYBU, IRS2, USP8:RP11-562A8.5, PIGL, FASN, MYLK2, AJ006998.2, Y_RNA, PPP6R2) and finemapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 23 genes near these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.
Patterns and Drivers of Internal Migration and Its Association with Access to Reproductive and Maternity Care Among Women in Pakistan: Evidence from a Recent National Survey
Authors: Dadras Omid , Nakayama Takeo 
Published: August 2022

AbstractBackgroundDuring the last decades, migratory behavior has had a key role in population growth and redistribution in Pakistan. Migration has far-reaching socioeconomic implications for individuals and society at large that could influence the health integrity of Pakistani women. This study aimed to describe the migration patterns and drivers as well as its association with adequate access to reproductive and maternal care among married Pakistani women aged 15-49.MethodsThe data from the 2017-18 Pakistan Demographic Health Survey (PDHS) was used to extract the information on the explanatory (sociodemographic and migration backgrounds) and outcome variables (unmet needs for family planning, adequate antenatal care, and delivery at health facilities). Bivariate and multivariate logistic regression analyses were employed to examine the relationship between these explanatory and outcome variables before and after adjustment for sociodemographic inequalities.ResultsIn unadjusted models, the odds of having adequate ANC and delivery at health facilities were approximately 2 to 4 times higher in those living (urban non-migrant), moving to (urban to urban, rural to urban), or leaving the urban areas (rural to urban) as compared to rural non-migrants; likewise, the odds of the unmet needs for family planning was about 20-50% lower in the same migration streams compared to rural non-migrant. However, after adjustment for sociodemographic inequalities, most of these associations attenuated and only the association of urban to urban migration with unmet needs for family planning and the association of urban non-migrant with delivery at health facilities remained significant.ConclusionAlthough the findings suggest that Internal migration flows, particularly those to urban areas (urban to urban and rural to urban), could be associated with better access to reproductive and maternity care among married Pakistani women aged 15-49 years; adjustment for sociodemographic inequalities, particularly education and wealth, nullified this association to a great extent. This has important implications for current policies and interventions in Pakistan and calls for policy reform and women’s rights advocacy to enhance the literacy level of young Pakistani girls through well-tailored interventions, maintaining them at school.
Sensorimotor control of object manipulation following middle cerebral artery (MCA) stroke
Authors: Fercho Kelene A. , Scholl Jamie L. , Bikash KC , Bosch Taylor J. , Baugh Lee A. 
Published: August 2022

AbstractCurrent bedside diagnostics used for the assessment of the loss of hand function post-stroke examine limited aspects of motor performance. Further, they are not sensitive to subtle changes that can cause deficits in everyday object manipulation tasks. Efficiently lifting an object is a complex neurological event which entails a prediction of required forces based on intrinsic features of the object (sensorimotor integration), short-term updates in the forces required to lift objects that are poorly predicted (sensorimotor memory), as well as the ability to modulate distal fingertip forces. Unfortunately, this complexity is not represented by the existing assessment tools used in clinics for both diagnostic and rehabilitative purposes. The presented research examined these three critical components of skilled object manipulation—production of finely graded muscular forces, sensorimotor integration, and sensorimotor memory—in a heterogeneous population of 60 chronic, unilateral middle cerebral artery stroke participants. Performance was compared to age-matched control participants in each of the three tasks. To examine control of distal fingertip forces, a force-matching task was utilized. To examine sensorimotor integration, participants were presented with familiar objects –large wood or brass blocks—following lifting trials of small and medium sized blocks from the same size-weight families. To accurately predict the weight of the larger blocks, sensorimotor integration of object size and apparent material is required during the first lifts of the large blocks. To examine sensorimotor memory, participants were required to lift a series of size-weight blocks of different colors. One color signified an inverse size-weight relationship that required the modification of short-term sensorimotor memory to efficiently lift. Most post-stroke participants performed below control levels in at least one of the tasks. Importantly, post-stroke participants presented with several different combinations of deficits in each of the tasks performed. The presented research demonstrates MCA stroke patients may have deficits in one or more components required for the successful manipulation of hand-held objects. Further, this information may be used in future studies to aid efforts that target rehabilitation regimens to a stroke survivor’s specific pattern of deficits.
Differential Impacts of Perceived Social Support on Alcohol and Cannabis Use in Young Adults: Lessons from the COVID-19 Pandemic
Authors: Blumberg Michelle J. , Lo Lindsay A. , Harrison Geoffrey W. , Dodwell Alison , Irwin Samantha H. , Olmstead Mary C. 
Published: August 2022

AbstractCoronavirus (COVID-19) lockdowns provided a unique opportunity to examine how changes in the social environment impact mental health and wellbeing. We addressed this issue by assessing how perceived social support across COVID-19 restrictions alters alcohol and cannabis use in emerging adults, a population vulnerable to adverse outcomes of substance use. Four hundred sixty-three young adults in Canada and the United States completed online questionnaires for three retrospective time points: Pre-Covid, Lockdown and Eased Restrictions. Sociodemographic factors, perceived social support, and substance use were assessed. Overall, alcohol use decreased while cannabis use increased during Lockdown. Interestingly, social support negatively predicted alcohol use and positively predicted cannabis use during Lockdown. These findings suggest a difference in motives underlying alcohol and cannabis use in emerging adults. Importantly, these changes were not sustained when restrictions eased, suggesting that emerging adults exhibit resiliency to the impacts of COVID-19 restrictions on substance use.
COVID-19 rebound after Paxlovid treatment during Omicron BA.5 vs BA.2.12.1 subvariant predominance period
Authors: Wang Lindsey , Volkow Nora D. , Davis Pamela B. , Berger Nathan A. , Kaelber David C. , Xu Rong 
Published: August 2022

AbstractPaxlovid was authorized by FDA to treat mild-to-moderate COVID-19. In May 2022, the Centers for Disease Control and Prevention (CDC) issued a Health Alert Network Health Advisory on potential COVID-19 rebound after Paxlovid treatment. Since June 2022, Omicron BA.5 has become the dominant subvariant in the US, which is more resistant to neutralizing antibodies than the previous subvariant BA.2.12.1. Questions remain as to how COVID-19 rebound after Paxlovid treatment differs between the BA.5 and BA.2.12.1 subvariants. This is a retrospective cohort study of 15,913 patients who contracted COVID-19 between 5/8/2022-7/18/2022 and were prescribed Paxlovid within 5 days of their COVID-19 infection. The study population was divided into 2 cohorts: (1) BA.5 cohort (n=5,161) – contracted COVID-19 during 6/19/22-7/18/22 when BA.5 was the predominant subvariant2. (2) BA.2.12.1 cohort (n=10,752) – contracted COVID-19 during 5/8/22-6/18/22 when the BA.2.12.1 was the predominant subvariant. The risks of both COVID-19 rebound infections and symptoms 2-8 days after Paxlovid treatment were higher in the BA.5 cohort than in the propensity-score matched BA.2.12.1 cohort: rebound infections (Hazard Ratio or HR: 1.32, 95% CI: 1.06-1.66), rebound symptoms (HR: 1.32, 95% CI: 1.04-1.68). As SARS-CoV-2 evolves with successive subvariants more evasive to antibodies, continuous vigilant monitoring is necessary for COVID-19 rebounds after Paxlovid treatment and longer time duration of Paxlovid treatment warrants evaluation.