bluuebunny/crossref_metadata_2025_split huggingface dataset:
TwoStepCisMR: A novel method and R package for attenuating bias in cis-MR
Authors: Woolf Benjamin , Gill Dipender 
Published: June 2022

AbstractMendelian randomisation (MR) is an increasingly popular method for strengthening causal inference in epidemiological studies. cis-MR in particular uses genetic variants in the gene region for a genetic proxy of a drug target to provide quasi-experimental evidence for drug efficacy. A major problem for this framework is when the causal variant is correlated to another variant which effects the outcome of interest (confounding through linkage disequilibrium). Methods for correcting bias such as multivariable MR struggle in a cis setting because of the high correlation among genetic variants. Here, we therefore present an alternative method for attenuating bias which does not suffer from this problem. We have additionally developed a simple R package to facilitate the implementation of the method.
Sensitivity of rapid antigen tests for COVID-19 during the Omicron variant outbreak
Authors: Murakami Michio , Sato Hitoshi , Irie Tomoko , Kamo Masashi , Naito Wataru , Yasutaka Tetsuo , Imoto Seiya 
Published: June 2022

AbstractBackgroundRapid antigen tests have been used to prevent the spread of the coronavirus disease 2019 (COVID-19); however, there have been concerns about their decreased sensitivity to the Omicron variant.AimsIn this study, we compared the sensitivity and specificity of the rapid antigen and the polymerase chain reaction (PCR) tests among the players and staff members of the Japan Professional Football League and clubs. Furthermore, we evaluated the relationship between the sensitivity and the duration from the onset of the symptoms to testing, the manufacturer of the rapid antigen test kits, and the PCR test analyte.Design and methodsThis was a retrospective observational study. We used 656 results from both the rapid antigen and PCR tests for COVID-19 using the analytes collected on the same day from January 12 to March 2, 2022, during the Omicron variant outbreak in Japan.ResultsThe sensitivity of the rapid antigen test compared with the PCR test was 0.63 (95% confidence interval: 0.54–0.72) and the specificity was 0.998 (95% confidence interval: 0.995–1.000). There were no significant associations between the sensitivity and the duration from the onset of the symptoms to testing (including asymptomatic cases in the category), vaccination status, manufacturer of the rapid antigen test kit or PCR analyte (P > 0.05) with small effect sizes (Cramer’s V or φ: ≤ 0.22).ConclusionsEven during the Omicron outbreak, the sensitivity of the rapid antigen tests did not depend on the duration from the onset of the symptoms to testing.
An exploratory assessment of the impact of a novel risk assessment test on breast cancer clinic waiting times and workflow: a discrete event simulation model
Authors: Smith Alison F. , Frempong Samuel N. , Sharma Nisha , Neal Richard D. , Hick Louise , Shinkins Bethany 
Published: June 2022

AbstractBackgroundBreast cancer clinics across the UK have long been struggling to cope with high demand. Novel risk prediction tools – such as the PinPoint test – could help to reduce unnecessary clinic referrals. Using early data on the expected accuracy of the test, we explore the potential impact of PinPoint on: (a) the percentage of patients meeting the two-week referral target, and (b) the number of clinic ‘overspill’ appointments generated.MethodsA simulation model was built to reflect the annual flow of patients through a single UK clinic. Due to current uncertainty around the exact impact of PinPoint testing on standard care, two primary scenarios were assessed. Scenario 1 assumed complete GP adherence to testing, with only non-referred cancerous cases returning for delayed referral. Scenario 2 assumed GPs would overrule 20% of low-risk results, and that 10% of non-referred non-cancerous cases would also return for delayed referral. A range of sensitivity analyses were conducted to explore the impact of key uncertainties on the model results. Service reconfiguration scenarios, removing individual weekly clinics from the clinic schedule, were also explored.ResultsUnder standard care, 66.3% (95% CI: 66.0 to 66.5) of patients met the referral target, with 1,685 (1,648 to 1,722) overspill appointments. Under both PinPoint scenarios, >98% of patients met the referral target, with overspill appointments reduced to between 727 (707 to 746) [Scenario 1] and 886 (861 to 911) [Scenario 2]. The reduced clinic demand was sufficient to allow removal of one weekly low-capacity clinic [N=10], and the results were robust to sensitivity analyses.ConclusionsThe findings from this early analysis indicate that risk prediction tools could have the potential to alleviate pressure on cancer clinics, and are expected to have increased utility in the wake of heightened pressures resulting from the COVID-19 pandemic. Further research is required to validate these findings with real world evidence; evaluate the broader clinical and economic impact of the test; and to determine outcomes and risks for patients deemed to be low-risk on the PinPoint test and therefore not initially referred.
Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction
Authors: Kageyama Tatsuto , Shimizu Akihiro , Anakama Riki , Nakajima Rikuma , Suzuki Kohei , Okubo Yusuke , Fukuda Junji 
Published: June 2022

AbstractDuring embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that microenvironmental reprogramming via control over these interactions enabled hair follicle induction in vitro. A key approach is to modulate spatial distributions of epithelial and mesenchymal cells in their spontaneous organization. The de novo hair follicles with typical morphological features emerged in aggregates of the two cell types, termed hair follicloids, and hair shafts sprouted with near 100% efficiency in vitro. The hair shaft length reached ∼3 mm in culture. Typical trichogenic signaling pathways were upregulated in hair follicloids. Owing to replication of hair follicle morphogenesis in vitro, production and transportation of melanosomes were also monitored in the hair bulb region. This in vitro hair follicle model might be valuable for better understanding hair follicle induction, for evaluating hair growth as well as the inhibition of hair growth by drugs, and modeling gray hairs in a well-defined environment.TeaserIn tissue morphogenesis, different types of cells harmonize in a pre-programmed manner using messenger systems such as epithelial-mesenchymal interactions. Organoids are a promising tool to elucidate such mechanisms on a molecular level. This work describes a strategy for reprograming three-dimensional microenvironments to trigger the initiation of in vitro regeneration of hair follicle organoids. Hair follicle organoids generated fully matured hair follicles, enabling the monitoring of hair follicle morphogenesis in vitro and determination of signaling pathways involved in early hair follicle morphogenesis. The principles uncovered herein may be relevant to other organ systems and will contribute to our understanding of developmental phenomena in physiological and pathological processes, eventually opening up new research avenues for the development of new treatment strategies.
Modeled grid cells aligned by a flexible attractor
Authors: Benas Sabrina , Fernandez Ximena , Kropff Emilio 
Published: June 2022

ABSTRACTEntorhinal grid cells implement a spatial code with hexagonal periodicity, signaling the position of the animal within an environment. Grid maps of cells belonging to the same module share spacing and orientation, only differing in relative two-dimensional spatial phase, which could result from being part of a two-dimensional attractor guided by path integration. However, this architecture has the drawbacks of being complex to construct and rigid, path integration allowing for no deviations from the hexagonal pattern such as the ones observed under a variety of experimental manipulations. Here we show that a simpler one-dimensional attractor is enough to align grid cells equally well. Using topological data analysis, we show that the resulting population activity is a sample of a torus, while the ensemble of maps preserves features of the network architecture. The flexibility of this low dimensional attractor allows it to negotiate the geometry of the representation manifold with the feedforward inputs, rather than imposing it. More generally, our results represent a proof of principle against the intuition that the architecture and the representation manifold of an attractor are topological objects of the same dimensionality, with implications to the study of attractor networks across the brain.
A simple, cost-effective and extraction-free molecular diagnostic test for sickle cell disease in noninvasive buccal swab specimen for a limited-resource setting
Authors: Thakur Priya , Gupta Pragya , Bhargava Nupur , Soni Rajat , Verma Narendra , Goswami Sangam Giri , Kharya Gaurav , Saravanakumar Vinodh , G Padma , Jain Suman , Dass Jasmita , Aggarwal Mukul , Ramalingam Sivaprakash 
Published: June 2022

AbstractSickle cell disease (SCD) is the most prevalent life threatening blood monogenic disorder. Currently, there is no cure available, apart from bone marrow transplantation. Early and efficient diagnosis of SCD is key to disease management which would make considerable strides in alleviating morbidity and reducing mortality. However, the cost and complexity of diagnostic procedures like Sanger sequencing impede the early detection of SCD in a resource-limited setting. To address this, the current study demonstrates a simple and efficient proof-of-concept assay for detection of patients and carriers from extraction free non-invasive buccal swab samples by isothermal DNA Amplification coupled Restrictase-mediated cleavage (iDAR). This study is a first of its kind reporting the use of buccal swab specimens for iDA in molecular diagnosis of a genetic disease all the while being cost effective and time saving with the total assay time of around 150 minutes at a cost of USD 5. Further, iDAR demonstrates 91.5% sensitivity and 100% specificity for detecting all three alleles; SS, AS and AA having 100% concordance with Sanger sequencing. The applicability of iDAR assay is further demonstrated with its adaptation to a one-pot reaction format, which simplifies the assay system. Overall, iDAR is a simple, cost-effective, precise and non-invasive assay for SCD screening with the potential for use in a limited resource setting.
Characteristics and costs of electric scooter injuries in Helsinki: a retrospective cohort study
Authors: Vasara Henri , Toppari Linda , Harjola Veli-Pekka , Virtanen Kaisa , Castrén Maaret , Kobylin Arja 
Published: June 2022

AbstractBackground and purposeThe incidence of electric scooter (e-scooter) injuries has increased drastically in numerous countries after widespread availability of shared e-scooters. Most publications on e-scooter injuries focus on a specific category of injuries. The economic impact on society from a broader perspective has not been studied.Patients and methodsWe performed a retrospective cohort study including all e-scooter-related injuries presented in the three adult emergency departments in Helsinki in 2021. We collected the patient data from the university hospital information system. Injury severity was evaluated based on the abbreviated injury score. Cost of the hospital treatment was analyzed based on our hospital district’s service price listing. In addition, we recorded the total amount of sick leave days and estimated their economic impact.ResultsIn total, 446 e-scooter injuries were identified and taken into the analysis (434 affecting riders and 12 non-riders). The median age of the patients was 26 (IQR 22-33) and 59 % were male. 257 (58 %) of the of the injuries were minor, whereas 155 (35 %) were moderate, 30 (7 %) serious, 3 (0.7 %) severe, and one (0.2 %) critical. Furthermore, 220 (49 %) of the patients sustained head injuries. A major spike in accident incidence was seen during weekend (Friday to Sunday) nights, which was accompanied by a proportional increase in patients with alcohol intoxication. Including both the costs of the hospital care and absence from work, the approximated total cost of e-scooter injuries was 1.7 million euros, with a median cost of a single accident being 1148 euros (IQR 399 – 4263 €).InterpretationComprehensive preventive measures must be conducted to decrease the incidence of e-scooter injuries. The usage of helmets should be strongly encouraged in order to prevent severe head injuries. The night-time bans during weekends and speed-limits on e-scooters appear to be justifiable.
Population knowledge, attitudes and practice towards Yellow Fever among nomadic populations: A cross-sectional study in Yellow Fever outbreak Communities in Ghana
Authors: Inusah Abdul-Wahab , Collins Gbeti , Dzomeku Peter , Head Michael , Ziblim Shamsu-Deen 
Published: June 2022

AbstractDespite the government and Global health initiatives toward yellow fever epidemic control in Ghana, the country continues to witness sporadic outbreaks of yellow fever mostly among the unvaccinated population and suspected migrates(nomadic) who enter the country through the porous borders. Little is known about nomadic knowledge, attitudes and practice regarding this communicable disease in Ghana.We conducted a community-based cross-sectional survey in 22 yellow fever outbreak communities to assess nomadic household heads’ knowledge, attitudes and practices regarding yellow fever after the November, 2021 outbreak. Our study results were analyzed using descriptive statistics, and univariate and multivariate logistics regression with dichotomous outcomes.About 90% of the nomadic had poor knowledge of the signs and symptoms of yellow with only 16% knowing the vector that transmits yellow fever. The most common source of information on yellow fever was the health campaign.Over 80% of household heads surveyed had positive attitudes regarding yellow fever with about 84% worried about the disease outbreak in their community. In a multivariate analysis, Age group, gender ideology, occupation, source of health information, duration of in the community and Nationality were associated with positive attitudes towards yellow fever.Close to 74% have a positive practice, with 97.3% adopting a strategy to control mosquitoes in their household. Nationality, duration of stay in the community, and age group were associated with Positive practices.Our findings show that yellow fever epidemic control can be improved in hard-to-reach communities through locally-tailored education and health promotion campaigns to improve knowledge and preventive practices against this infectious disease.
XLID Syndrome Gene Med12 Promotes Ig Isotype Switching through Chromatin Modification and Enhancer RNA regulation
Authors: Haque Farazul , Honjo Tasuku , Begum Nasim A. 
Published: June 2022

ABSTRACTThe transcriptional co-activator Med12 regulates gene expression through the function of its kinase module and by interacting with the larger Mediator complex and associated RNA Polymerase II (RNAPII). Here, we show a kinase module-independent function of Med12 in antibody class switching recombination (CSR). Med12 is essential for IgH 3’ regulatory region (3’RR) or super-enhancer activation and functions with p300 and Jmjd6/Carm1 coactivator complexes. Med12 deficiency leads to a dramatic decrease in H3K27 acetylation and enhancer RNA (eRNA) transcription at 3’RR, with concomitant impairment of AID-induced DNA double strand breaks, long-range S-S synapse formation, and 3’RR-Eμ interaction. CRISPR/dCas9-mediated enhancer activation re-establishes the epigenomic and transcriptional hallmarks of the 3’RR super-enhancer, fully restoring Med12 depletion defects. Notably, we find that 3’RR derived eRNAs are critical for promoting proper S region epigenetic regulation, S-S synapse formation and recruitment of Med12 and AID to the IgH locus. We find specific X-Linked intellectual disability syndrome associated Med12 mutations are defective in both 3’RR eRNA transcription and CSR, suggesting B and neuronal cells may have cell-specific super-enhancer dysfunctions. We conclude Med12 is essential for IgH3’RR activation and eRNA transcription and plays a central role in AID-induced antibody gene diversification and genomic instability in B cells.
Neither kin selection nor familiarity explain affiliative biases towards maternal siblings in wild mountain gorillas
Authors: Grebe Nicholas M. , Hirwa Jean Paul , Stoinski Tara S. , Vigilant Linda , Rosenbaum Stacy 
Published: June 2022

AbstractEvolutionary theories predict that sibling relationships will reflect a complex balance of cooperative and competitive dynamics. In most mammals, dispersal and death patterns mean that sibling relationships occur in a relatively narrow window during development, and/or only with same-sex individuals. Besides humans, one notable exception are mountain gorillas, in which non-sex biased dispersal, relatively stable group composition, and the long reproductive tenures of alpha males mean that animals routinely reside with both same and opposite-sex, and full and half siblings, throughout their lives. Using nearly 40,000 hours of observation data collected over 14 years on 699 sibling and 1258 non-sibling pairs of wild mountain gorillas, we demonstrate that individuals have strong affiliative preferences for full and maternal siblings over paternal siblings or unrelated animals, consistent with an inability to discriminate paternal kin. Intriguingly, however, aggression data imply the opposite. Aggression rates were statistically indistinguishable among all types of dyads except one: in mixed-sex dyads, non-siblings engaged in substantially more aggression than siblings of any type. This pattern suggests mountain gorillas may be capable of distinguishing paternal kin, but nonetheless choose not to affiliate with them over non-kin. A preference for maternal kin occurs despite gorillas not possessing low male reproductive skew, the key characteristic believed to underlie such biases. These results call into question reasons for strong maternal kin biases when paternal kin are identifiable, familiar, and similarly likely to be long-term social partners, and suggest behavioral mismatches at play during a transitional period in mountain gorilla society.
Exploring the lifetime effect of children on wellbeing using two-sample Mendelian randomisation
Authors: Woolf Benjamin , Sallis Hannah , Munafò Marcus R. 
Published: June 2022

AbstractObjectivesTo provide Mendelian randomisation evidence of the effect of having children on parental wellbeing.DesignTwo sample Mendelian randomisation.SettingNon-clinical European ancestry participants.ParticipantsWe used the UK Biobank (460,654 male and female European ancestry participants) as a source of genotype-exposure associations, and the Social Science Genetics Consortia (SSGAC) (298,420 male and female European ancestry participants) and Within-Family Consortia (effective sample of 22,656 male and female European ancestry participants) as sources of genotype-outcome associations.InterventionsThe lifetime effect of an increase in the genetic liability to having children.Primary and secondary outcome measuresThe primary analysis was an inverse variance weighed analyses of subjective wellbeing measured in the 2016 SSGAC GWAS. Secondary outcomes included pleiotropy robust estimators applied in the SSGAC and an analysis using the Within-Family consortia GWAS.ResultsThe primary IVW estimate found evidence of a 0.153 standard deviation increase for every child a parent has (95% CI: -0.210 to 0.516). Secondary outcomes were generally slightly deflated (e.g. -0.049 [95% CI: -0.533 to 0.435] for the WFC and 0.090 [95% CI: -0.167 to 0.347] for weighted median) implying the presence of some residual confounding and pleiotropy.ConclusionsContrary to the existing literature, our results are not compatible with a measurable negative effect of number of children on the average wellbeing of a parent over their life course. However, we were unable to explore non-linearities, interactions, or time varying effects.Strengths and limitations of this study-Mendelian randomisation (MR) is a natural experiment which is theoretically robust to confounding and reverse causation.-We were able to use two negative control analyses to explore the robustness of our study to two potential sources of residual confounding (populations structure and passive gene-environment correlation).-We additionally use pleiotropy robust estimates (like MR-PRESSO, MR-Egger, weighted median, and weighed mode) to explore if our result was affected by direct effects of the genetic variants on the outcome, not mediated by the exposure.-Because we use summary data, we were unable to explore interactions, non-linear and time-varying, or time sensitive, effects.-Our study is a proof of concept for using MR to explore the causal effect of the heritable environment.
The effect of altruism on COVID-19 vaccination rates*
Authors: Hierro Luis Á. , Patiño David , Atienza Pedro , Garzón Antonio J. , Cantarero David 
Published: June 2022

AbstractContextAfter the emergence of the first vaccines against the COVID-19, public health authorities have promoted mass vaccination in order to achieve herd immunity and reduce the effects of the disease. Vaccination rates have differed between countries, depending on supply (availability of resources) and demand (altruism and resistance to vaccination) factors.MethodsThis work considers the hypothesis that individuals’ health altruism has been an important factor to explain the different levels of vaccination between countries, using the number of transplants as a proxy for altruism. Taking European Union’s countries to remove, as far as possible, supply factors that might affect vaccination, we carry out cross-sectional regressions for the most favorable date of the vaccination process (maximum vaccination speed) and for each month during the vaccination campaign.ResultsOur findings confirm that altruism has affected vaccination rates against the COVID-19. We find a direct relationship between transplants rates (proxy variable) and vaccination rates during periods in which the decision to be vaccinated depended on the individual’s choice, without supply restrictions. The results show that other demand factors have worked against vaccination: political polarization and belonging to the group of countries of the former Eastern bloc.ConclusionsAltruism is a useful tool to define future vaccination strategies, since it favors the individuals’ awareness for vaccination.