bluuebunny/crossref_metadata_2025 huggingface dataset:
Density-dependent selection and the maintenance of colour polymorphism in barn owls
Authors: Kvalnes Thomas , Sæther Bernt-Erik , Engen Steinar , Roulin Alexandre
Published: June 2022

The capacity of natural selection to generate adaptive changes is (according to the fundamental theorem of natural selection) proportional to the additive genetic variance in fitness. In spite of its importance for development of new adaptations to a changing environment, processes affecting the magnitude of the genetic variance in fitness-related traits are poorly understood. Here, we show that the red-white colour polymorphism in female barn owls is subject to density-dependent selection at the phenotypic and genotypic level. The diallelic melanocortin-1 receptor gene explained a large amount of the phenotypic variance in reddish coloration in the females (

R

2

=
59.8
%

). Red individuals (RR genotype) were selected for at low densities, while white individuals (WW genotype) were favoured at high densities and were less sensitive to changes in density. We show that this density-dependent selection favours white individuals and predicts fixation of the white allele in this population at longer time scales without immigration or other selective forces. Still, fluctuating population density will cause selection to fluctuate and periodically favour red individuals. These results suggest how balancing selection caused by fluctuations in population density can be a general mechanism affecting the level of additive genetic variance in natural populations.
Delayed early life effects in the threespine stickleback
Authors: Candolin Ulrika , Goncalves Sara , Pant Pankaj
Published: June 2022

Early life conditions can have a decisive influence on viability later in life. However, the influence of embryo density within a nest or body cavity on subsequent viability has received little attention within an ecological setting. This is surprising given that embryos often compete for limited resources, such as nutrients and oxygen, and this could influence their viability later in life through carry-over and compensatory effects. We show that the density of fertilized eggs within the nests of threespine stickleback males (Gasterosteus aculeatus) influences their viability after hatching. Embryos from larger broods hatch earlier and at a smaller size than those from smaller broods, which reduces their survival until the age of four weeks. This indicates a trade-off between the number and viability of offspring that males can raise to the hatching stage, which could explain the high incidence of partial egg cannibalism in nest-brooding fishes—as a strategy to improve the survival of remaining offspring. These results highlight the importance of considering conditions at the embryonic stage when evaluating the impact of early life conditions on viability and the adaptive value of reproductive decisions.
Fifty-one novel and replicated GWAS loci for polyunsaturated and monounsaturated fatty acids in 124,024 Europeans
Authors: Francis Michael , Sun Yitang , Xu Huifang , Brenna J. Thomas , Ye Kaixiong
Published: June 2022

Circulating polyunsaturated and monounsaturated fatty acid (PUFA and MUFA) levels, whose imbalances co-occur with human metabolic diseases, have strong heritable components. We performed the largest genome-wide association study (GWAS) to-date on fourteen PUFA and MUFA phenotypes, measured by nuclear magnetic resonance in plasma. We identified 612 significant locus-phenotype associations (115 unique loci; P < 1.678×10-8) in a European cohort from UK Biobank (UKB-EUR; n=101,729). Replication of five phenotypes (omega-3, omega-6, DHA, LA, MUFAs) was conducted in two external European studies: FinMetSeq (n=8,751) and a meta-analysis by Kettunnen et al. (n=3,644-13,544). Meta-analysis of these three studies yielded 254 significant locus-phenotype associations (109 unique loci; P < 2.439×10-8); we identified 87 novel loci, 51 of which were replicated. A transcriptome-wide association study of the UKB-EUR cohort revealed an additional twelve novel loci. This study improves our understanding of the genetic architecture of unsaturated fatty acids and can inform future genotype-based dietary interventions.
Impact of a blood-stage vaccine on Plasmodium vivax malaria
Authors: Hou Mimi M. , Barrett Jordan R. , Themistocleous Yrene , Rawlinson Thomas A. , Diouf Ababacar , Martinez Francisco J. , Nielsen Carolyn M. , Lias Amelia M. , King Lloyd D. W. , Edwards Nick J. , Greenwood Nicola M. , Kingham Lucy , Poulton Ian D. , Khozoee Baktash , Goh Cyndi , Mac Lochlainn Dylan J. , Salkeld Jo , Guilotte-Blisnick Micheline , Huon Christèle , Mohring Franziska , Reimer Jenny M. , Chauhan Virander S. , Mukherjee Paushali , Biswas Sumi , Taylor Iona J. , Lawrie Alison M. , Cho Jee-Sun , Nugent Fay L. , Long Carole A. , Moon Robert W. , Miura Kazutoyo , Silk Sarah E. , Chitnis Chetan E. , Minassian Angela M. , Draper Simon J.
Published: June 2022

Background

There are no licensed vaccines against Plasmodium vivax, the most common cause of malaria outside of Africa.

Methods

We conducted two Phase I/IIa clinical trials to assess the safety, immunogenicity and efficacy of two vaccines targeting region II of P. vivax Duffy-binding protein (PvDBPII). Recombinant viral vaccines (using ChAd63 and MVA vectors) were administered at 0, 2 months or in a delayed dosing regimen (0, 17, 19 months), whilst a protein/adjuvant formulation (PvDBPII/Matrix-M™) was administered monthly (0, 1, 2 months) or in a delayed dosing regimen (0, 1, 14 months). Delayed regimens were due to trial halts during the COVID-19 pandemic. Volunteers underwent heterologous controlled human malaria infection (CHMI) with blood-stage P. vivax parasites at 2-4 weeks following their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparison of parasite multiplication rate (PMR) in blood post-CHMI, modelled from parasitemia measured by quantitative polymerase-chain-reaction (qPCR).

Results

Thirty-two volunteers were enrolled and vaccinated (n=16 for each vaccine). No safety concerns were identified. PvDBPII/Matrix-M™, given in the delayed dosing regimen, elicited the highest antibody responses and reduced the mean PMR following CHMI by 51% (range 36-66%; n=6) compared to unvaccinated controls (n=13). No other vaccine or regimen impacted parasite growth. In vivo growth inhibition of blood-stage P. vivax correlated with functional antibody readouts of vaccine immunogenicity.

Conclusions

Vaccination of malaria-naïve adults with a delayed booster regimen of PvDBPII/ Matrix-M™ significantly reduces the growth of blood-stage P. vivax.

Funded by the European Commission and Wellcome Trust; VAC069, VAC071 and VAC079 ClinicalTrials.gov numbers NCT03797989, NCT04009096 and NCT04201431.
Is there a sex difference in mortality rates in Paediatric Intensive Care Units: A Systematic Review
Authors: Almossawi Ofran , Friend Amanda , Palla Luigi , Feltbower Richard G. , Sardo-Infiri Sofia , O’Brien Scott , Harron Katie , Nadel Simon , De Stavola Bianca
Published: June 2022

Introduction

Mortality rates in infancy and childhood are lower in females than males. However, for children admitted to Paediatric Intensive Care Units (PICU), mortality has been reported to be lower in males, although males have higher admission rates. This female mortality excess for the subgroup of children admitted in intensive care is not well understood. To address this, we carried out a systematic literature review to summarise the available evidence.

Our review studies the differences in mortality between males and females aged 0 to <18 years, while in a PICU, to examine whether there was a clear difference (in either direction) in PICU mortality between the two sexes, and, if present, to describe the magnitude and direction of this difference.

Methods and analysis

Any studies that directly or indirectly reported the rates of mortality in children admitted to intensive care by sex were eligible for inclusion. The search strings were based on terms related to the population (those admitted into a paediatric intensive care unit), the exposure (sex), and the outcome (mortality). We used the search databases MEDLINE, Embase, and Web of Science as these cover relevant clinical publications. We assessed the reliability of included studies using a modified version of the risk of bias in observational studies of exposures (ROBINS-E) tool. We considered estimating a pooled effect if there were at least three studies with similar populations, periods of follow-up while in PICU, and adjustment variables.

Results

We identified 124 studies of which 114 reported counts of deaths by males and females which gave a population of 278,274 children for analysis, involving 121,800 (44%) females and 156,474 males (56%). The number of deaths and mortality rate for females were 5,614 (4.61%), and for males 6,828 (4.36%). In the pooled analysis, the odds ratio of female to male mortality was 1.06 [1.01 to 1.11] for the fixed effect model, and 1.10 [1.00 to 1.21] for the random effects model.

Conclusion

Overall, males have a higher admission rate to PCU, and a lower overall mortality in PICU.

Systematic review registration

PROSPERO database reference number CRD42020203009.
Models and modelling practices for assessing the impact of outbreak response interventions to human vaccine-preventable diseases (1970-2019) - A systematic review
Authors: Azam James M. , Pang Xiaoxi , Are Elisha B. , Pulliam Juliet R.C. , Ferrari Matthew J.
Published: June 2022

Background

Mathematical modelling can aid outbreak response decision-making. However, this would require collaboration among model developers, decision-makers, and local experts to incorporate appropriate realism. We conducted a systematic review of modelling studies on human vaccine-preventable disease (VPD) outbreaks to identify patterns in modelling practices among collaborations. We complemented this with a mini review of eligible studies from the foot-and-mouth disease (FMD) literature.

Methods

Three databases were searched for studies published during 1970-2019 that applied models to assess the impact of an outbreak response. Per included study, we extracted data on author affiliation type (academic institution, governmental, and non-governmental organizations), whether at least one author was affiliated to the country studied, interventions, and model characteristics. Furthermore, the studies were grouped into two collaboration types: purely academic (papers with only academic affiliations), and mixed (all other combinations) to help investigate differences in modelling patterns between collaboration types in the human disease literature. Additionally, we compared modelling practices between the human VPD and FMD literature.

Results

Human VPDs formed 228 of 253 included studies. Purely academic collaborations dominated the human disease studies (56%). Notably, mixed collaborations increased in the last seven years (2013 - 2019). Most studies had an author in the country studied (75.2%) but this was more likely among the mixed collaborations. Contrasted to the human VPDs, mixed collaborations dominated the FMD literature (56%). Furthermore, FMD studies more often had an author affiliated to the country studied (92%) and used complex model design, including stochasticity, and model parametrization and validation.

Conclusion

The increase in mixed collaboration studies over the past seven years could suggest an increase in the uptake of modelling for outbreak response decision-making. We encourage more mixed collaborations between academic and non-academic institutions and the involvement of locally affiliated authors to help ensure that the studies suit local contexts.
Response of Wastewater-Based Epidemiology Predictor for the Second Wave of COVID-19 in Ahmedabad, India: A Long-term Data Perspective
Authors: Kumar Manish , Joshi Madhvi , Jiang Guangming , Yamada Rintaro , Honda Ryo , Srivastava Vaibhav , Mahlknecht Jürgen , Barcelo Damia , Chidambram Sabarathinam , Khursheed Anwar , Graham David , Joshi Chaitanya
Published: June 2022

Wastewater-based epidemiology (WBE) monitoring can play a key role in managing future pandemics because it covers both pre-symptomatic and asymptomatic cases, especially in densely populated areas with limited community health care. In the present work, wastewater monitoring was employed in Ahmedabad, India, after the successful containment of the first wave of COVID-19 to predict resurgence of the disease in the expected second wave of the pandemic. Here we show wastewater levels of COVID-19 virus particles (i.e., SARS-CoV-2) positively correlated with the number of confirmed clinical cases during the first wave, and provided early detection of COVID-19 presence before the second wave in Ahmedabad and an WBE-based city zonation plan was developed for health protection. A eight-month data of Surveillance of Wastewater for Early Epidemic Prediction (SWEEP) was gathered, including weekly SARS-CoV-2 RNA wastewater analysis (n=287) from nine locations between September 2020 and April 2021. Across this period, 258 out of 287 samples were positive for least two out of three SARS-CoV-2 genes (N, ORF 1ab, and S). Monitoring showed a substantial decline in all three gene markers between October and September 2020, followed by an abrupt increase in November 2020. Similar changes were seen in March 2021, which preceded the second COVID-19 wave. Measured wastewater ORF-1ab gene copies ranged from 6.1 × 102 (October, 2020) to 1.4 × 104 (November, 2020) copies/mL, and wastewater gene levels typically lead confirmed cases by one to two weeks. The study highlights the value of WBE as a monitoring tool to predict waves within a pandemic, identifying local disease hotspots within a city and guiding rapid management interventions.

Highlights

Eight-months of SARS-CoV-2 gene variations explicitly predicts 2nd COVID-19 wave.

258 out of 287 wastewater samples were positive for SARS-CoV-2 genes.

WBE offers a lead time of 1-2 weeks relative to clinical cases.

Model suggests that ORF 1ab gene is the most effective as a marker gene in WBE study.

WBE RT-PCR screening for pathogens should be mandatory for global health monitoring.
Safety and superior immunogenicity of heterologous boosting with an RBD-based SARS-CoV-2 mRNA vaccine in Chinese adults
Authors: Liu Xiaoqiang , Li Yuhua , Wang Zhongfang , Cao Shouchun , Huang Weijin , Yuan Lin , Huang Yi-Jiao , Zheng Yan , Chen Jingjing , Ying Bo , Xiang Zuoyun , Shi Jin , Zhao Jincun , Huang Zhen , Qin Cheng-Feng
Published: June 2022

Homologous and heterologous booster with COVID-19 mRNA vaccines represent the most effective strategy to prevent the ongoing Omicron pandemic. The additional protection from these prototype SARS-CoV-2 S-targeting vaccine was attributed to the increased RBD-specific memory B cells with expanded potency and breadth. Herein, we show the safety and immunogenicity of heterologous boosting with the RBD-targeting mRNA vaccine AWcorna (also term ARCoV) in Chinese adults who have received two doses inactivated vaccine. The superiority over inactivated vaccine in neutralization antibodies, as well as the safety profile, support the use of AWcorna as heterologous booster in China.
Young age, student status and reported non-binary gender associate strongly with decreased functioning during Covid-19 pandemic in a university community
Authors: Salokangas Raimo K. R. , From Tiina , Hietala Jarmo
Published: June 2022

Background

Covid-19 pandemic has had detrimental effects on physical and mental well-being whereas there are fewer studies on Covid-19 effects on everyday functioning.

Aims

We aimed to investigate effects of Covid-19 on functioning and related factors in a university community.

Method

In all, 2004 students and university personnel responded to a Webropol survey in May 2021, when the measures for preventing Covid-19 infections had sustained about a year and a half. Functioning included Visual Analog Scale (0 to 10) assessments on ability to function and ability to work.

Results

Young age, reported non-binary gender, being student, low resilience, loneliness, received mental care and minor physical exercise, as well as depressive symptoms associated with inferior functioning and negative effects of Covid-19 on functioning. Good school performance at adolescence associated with better, while childhood adversities associated with poorer functioning.

Conclusions

In the university community, young age and non-binary gender associated with decreased functioning during Covid-19 pandemic. Functioning of students was lower than in that of the university personnel. The need for therapeutic counselling and interventions is greatest among young students.
Attrition from HIV treatment after enrollment in a differentiated service delivery model: a cohort analysis of routine care in Zambia
Authors: Jo Youngji , Jamieson Lise , Phiri Bevis , Grimsrud Anna , Mwansa Muya , Shakwelele Hilda , Haimbe Prudence , Mukumbwa-Mwenechanya Mpande , Mulenga Priscilla Lumano , Nichols Brooke E , Rosen Sydney
Published: June 2022

Background

Many sub-Saharan Africa countries are scaling up differentiated service delivery (DSD) models for HIV treatment to increase access and remove barriers to care. We assessed factors associated with attrition after DSD model enrollment in Zambia, focusing on patient-level characteristics.

Methods

We conducted a retrospective record review using electronic medical records (EMR) of adults (≥15 years) initiated on antiretroviral (ART) between 01 January 2018 and 30 November 2021. Attrition was defined as lost to follow-up (LTFU) or died by November 30, 2021. We categorized DSD models into eight groups: fast-track, adherence groups, community pick-up points, home ART delivery, extended facility hours, facility multi-month dispensing (MMD, 4–6-month ART dispensing), frequent refill care (facility 1-2 month dispensing), and conventional care (facility 3 month dispensing, reference group). We used Fine and Gray competing risk regression to assess patient-level factors associated with attrition, stratified by sex and rural/urban setting.

Results

Of 547,281 eligible patients, 68% (n=372,409) enrolled in DSD models, most commonly facility MMD (n=306,430, 82%), frequent refill care (n=47,142, 13%), and fast track (n=14,433, 4%), with <2% enrolled in the other DSD groups. Retention was higher in nearly all DSD models for all dispensing intervals, compared to the reference group, except fast track for the ≤2 month dispensing group. Retention benefits were greatest for patients in the extended clinic hours group and least for fast track dispensing.

Conclusion

Although retention in HIV treatment differed by DSD type, dispensing interval, and patient characteristics, nearly all DSD models out-performed conventional care. Understanding the factors that influence the retention of patients in DSD models could provide an important step towards improving DSD implementation.
Impact of Subthalamic Nucleus Stimulation on Urinary Dysfunction and Constipation in Parkinson’s Disease
Authors: Askari Asra , Zhu Brandon , Lam Jordan , Wyant Kara , Chou Kelvin , Patil Parag
Published: June 2022

Introduction

The effect of subthalamic nucleus deep brain stimulation (STN DBS) on urinary dysfunction and constipation in Parkinson’s disease (PD) is variable. This study aims to identify potential surgical and non-surgical variables predicting their outcome.

Methods

We used the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Part I to assess urinary dysfunction (item 10) and constipation (item 11) preoperatively and 6-12 months postoperatively. A multiple linear regression model was used to investigate the impact of Global Cerebral Atrophy (GCA) and active electrode contact location on the urinary dysfunction and constipation follow-up score, controlling for age, disease duration, baseline score, motor improvement, and levodopa-equivalent dose changes. An electric field model was applied to localize the maximal effect-site for constipation and urinary dysfunction compared to motor improvement.

Result

Among 74 patients, 23 improved, 28 deteriorated, and 23 remained unchanged for urinary dysfunction; 25 improved, 15 deteriorated, and 34 remained unchanged for constipation. GCA score and age significantly predicted urinary dysfunction follow-up score (R2 = 0.36, P<0.001). Increasing GCA and age independently were associated with worsening urinary symptoms. Disease duration, baseline constipation score, and anterior active electrode contacts in both hemispheres were significant predictors for constipation follow-up score (R2 =0.31, P<0.001). Higher baseline constipation score and disease duration were associated with worsening constipation; anterior active contact location was associated with improvement in constipation.

Conclusion

Anterior active contact locations are associated with improvement in constipation in PD patients after STN DBS. PD patients with greater GCA scores before surgery were more likely to experience urinary deterioration after DBS.
Dorsal Subthalamic Deep Brain Stimulation Improves Pain in Parkinson’s Disease
Authors: Askari Asra , Lam Jordan , Zhu Brandon J. , Lu Charles , Chou Kelvin L. , Wyant Kara J. , Patil Parag G.
Published: June 2022

Introduction

Inconsistent effects of subthalamic deep brain stimulation (STN DBS) on pain, a common non-motor symptom of Parkinson’s disease (PD), may be due to variations in active contact location relative to a pain-reducing locus of stimulation.

Objective

To distinguish the loci of maximal effect for pain and motor improvement in the STN region.

Methods

We measured Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part I pain score (item-9), and MDS-UPDRS Part III motor score, preoperatively and 6-12 months after STN DBS. An ordinary least-squares regression model was used to examine active contact location as a predictor of follow-up pain score while controlling for baseline pain, age, dopaminergic medication, and motor improvement. An atlas-independent electric field model was applied to distinguish sites of maximally effective stimulation for pain and motor improvement.

Results

In 74 PD patients, mean pain score significantly improved after STN DBS (p = 0.01). In a regression model, more dorsal active contact location was the only significant predictor of pain improvement (R2 = 0.17, p = 0.03). The stimulation locus for maximal pain improvement was lateral, anterior, and dorsal to that for maximal motor improvement.

Conclusions

More dorsal STN DBS improves pain. Stimulation of the zona incerta, a region known to modulate pain in humans, may explain this observation.
Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure
Authors: Vicente Anna Luiza Silva Almeida , Novoloaca Alexei , Cahais Vincent , Awada Zainab , Cuenin Cyrille , Spitz Natália , Carvalho André Lopes , Evangelista Adriane Feijó , Crovador Camila Souza , Reis Rui Manuel , Herceg Zdenko , de Lima Vazquez Vinicius , Ghantous Akram
Published: June 2022

Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have never been characterized in clinical biospecimen. Here, we integrate clinical and epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival.TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.
DRUG-RESISTANT TUBERCULOSIS CASE-FINDING STRATEGIES: A SCOPING REVIEW PROTOCOL
Authors: van Wyk Susanna S , Nliwasa Marriott , Seddon James A , Hoddinott Graeme , Viljoen Lario , Nepolo Emmanuel , Günther Gunar , Ruswa Nunurai , Lin Hsien-Ho , Niemann Stefan , Gandhi Neel , Shah Sarita , Claassens Mareli
Published: June 2022

Background

Transmission of drug-resistant tuberculosis (TB) is ongoing, and many households face catastrophic costs when a member is diagnosed and treated for drug-resistant TB. Finding individuals with drug-resistant TB and initiating treatment as early as possible is important to improve patient clinical outcomes and to break the chain of transmission to help control the pandemic.

To our knowledge systematic reviews assessing effectiveness, cost-effectiveness, acceptability and feasibility of different drug-resistant TB case-finding strategies to inform research, policy and practice, have not been conducted and it is unknown whether enough research exists to conduct such reviews. It is also unknown whether case-finding strategies are similar for drug-resistant TB and drug-susceptible TB and whether we can draw on findings from drug-susceptible reviews to inform decisions on drug-resistant TB case-finding strategies.

Methods

The question for our review is: what literature is available on drug-resistant TB case finding and which case-finding strategies are described? We will look at studies that have sought to improve drug-resistant TB case detection. We will search the academic databases of CENTRAL, MEDLINE and EMBASE using no language or date restrictions. We will apply broad criteria for screening titles, abstracts and full text articles. A data extraction form will be developed in excel and applied to all primary research reports to collect standard information on each study. We will provide a narrative report with supporting figures and/or tables to summarize the data. A systems-based logic model, developed from a synthesis of drug-susceptible TB case-finding strategies, will be used as a framework to describe different strategies, resulting pathways and enhancements of pathways.

Discussion

This scoping review will chart existing literature on drug-resistant TB case finding and identify priority question(s) for a systematic review. It will also describe drug-resistant TB case-finding strategies and how they fit into a model of drug-susceptible TB case-finding pathways. The review will guide further research to inform decisions on drug-resistant TB case finding policy and practice.
SARS-COV-2 Delta and Omicron community transmission networks
Authors: Murray John M. , Murray Daniel D. , Schvoerer Evelyne , Akand Elma H.
Published: June 2022

To date, calculations of SARS-CoV-2 transmission networks at a population level have not been performed. Networks that estimate infections between individuals and whether this results in a mutation, can evaluate fitness of a mutational clone by how much it expands in number as well as determining the likelihood a transmission results in a new variant.

Transmission networks of SARS-CoV-2 infection between individuals in Australia were estimated for Delta and Omicron variants using a novel method. Many of the sequences were identical, with clone sizes following power law distributions driven by negative binomial probability distributions for both the number of infections per individual and the number of mutations per transmission (mean 1.0 nucleotide change for Delta and 0.79 for Omicron). Using these distributions, an agent based model was able to replicate the observed clonal network structure, providing a basis for more detailed COVID-19 modelling. Recombination events, tracked by insertion/deletion (indel) patterns, occurred for each variant in these outbreaks. The residue at position 142 in the S open reading frame (ORF), frequently changed between G and D for Delta sequences, but this was independent of other mutations. On the other hand, several Omicron mutations were significantly connected across different ORF. This model reveals key transmission characteristics of SARS-CoV-2 and may complement traditional contact tracing and other public health strategies. This methodology can also be applied to other diseases as genetic sequencing of viruses becomes more commonplace.

Author summary

As SARS-COV-2 spreads through a community, it can mutate and generate new variants. How likely this is to occur and how much a particular viral clone expands, can indicate mutational probabilities and whether some mutations are fitter than others. By better understanding these aspects, future predictions can more accurately encapsulate possible changes in the epidemic within a community. We have developed a new method for piecing together the individual SARS-COV-2 cases that have been sequenced, to generate the structure of transmissions and mutational clones for an outbreak. While this method can be applied to other virus epidemics given sufficient sequenced data, we apply it to Delta and Omicron outbreaks in Australia. Interestingly, transmissions between individuals frequently do not result in mutations, with some clones growing very large. We characterise the probability that a mutation will occur, and track how these changes lead to sequential mutations in these outbreaks.
Auditory grouping ability predicts speech-in-noise performance in cochlear implants
Authors: Choi Inyong , Gander Phillip E. , Berger Joel I. , Hong Jean , Colby Sarah , McMurray Bob , Griffiths Timothy D.
Published: June 2022

Objectives

Cochlear implant (CI) users exhibit a large variance in understanding speech in noise (SiN). Past works in CI users found that spectral and temporal resolutions correlate with the SiN ability, but a large portion of variance has been remaining unexplained. Our group’s recent work on normal-hearing listeners showed that the ability of grouping temporally coherent tones in a complex auditory scene predicts SiN ability, highlighting a central mechanism of auditory scene analysis that contributes to SiN. The current study examined whether the auditory grouping ability contributes to SiN understanding in CI users as well.

Design

47 post-lingually deafened CI users performed multiple tasks including sentence-in-noise understanding, spectral ripple discrimination, temporal modulation detection, and stochastic figure-ground task in which listeners detect temporally coherent tone pips in the cloud of many tone pips that rise at random times at random frequencies. Accuracies from the latter three tasks were used as predictor variables while the sentence-in-noise performance was used as the dependent variable in a multiple linear regression analysis.

Results

No co-linearity was found between any predictor variables. All the three predictors exhibited significant contribution in the multiple linear regression model, indicating that the ability to detect temporal coherence in a complex auditory scene explains a further amount of variance in CI users’ SiN performance that was not explained by spectral and temporal resolution.

Conclusions

This result indicates that the across-frequency comparison builds an important auditory cognitive mechanism in CI users’ SiN understanding. Clinically, this result proposes a novel paradigm to reveal a source of SiN difficulty in CI users and a potential rehabilitative strategy.
Retrospective behavioral sampling (RBS): a method to effectively track the cognitive fluctuations driven by naturalistic stimulation
Authors: Brandman Talia , Malach Rafael , Simony Erez
Published: June 2022

Everyday experiences are dynamic, driving fluctuations across simultaneous cognitive processes. A key challenge in the study of naturalistic cognition is to disentangle the complexity of these dynamic processes, without altering the natural experience itself. Retrospective behavioral sampling (RBS) is a novel approach to track the cognitive fluctuations throughout the time-course of naturalistic stimulation, across a variety of cognitive dimensions. We tested the effectiveness and reliability of RBS in a web-based experiment, in which 53 participants viewed short movies and listened to a story, followed by retrospective reporting. Participants recalled their experience of 55 discrete events from the stimuli, rating their quality of memory, magnitude of surprise, intensity of negative and positive emotions, perceived importance, reflectivity state, and mental time travel. In addition, a subset of the original cohort re-rated their memory of events in a follow-up questionnaire. Results show highly replicable fluctuation patterns across distinct cognitive dimensions, thereby revealing a stimulus-driven experience that is substantially shared among individuals. Remarkably, memory ratings more than a week after stimulation resulted in an almost identical time-course of memorability as measured immediately following stimulation. In addition, idiosyncratic response patterns were preserved across different stimuli, indicating that RBS characterizes individual differences that are stimulus invariant. The current findings highlight the potential of RBS as a powerful tool for measuring dynamic processes of naturalistic cognition. We discuss the promising approach of matching RBS fluctuations with dynamic processes measured via other testing modalities, such as neuroimaging, to study the neural manifestations of naturalistic cognitive processing.
Assessing germline mutational profile and its clinicopathological associations in Triple Negative Breast Cancer
Authors: John Jisha , Bapat Ashwini , Gahlaut Siddharth , Luke Naveen , Kumar Rahul , Thakur Yashaswi , Konnur Aishwarya , Namewar Namrata , Reddy Ruhi , Shaikh Shaheen , Banale Rituja , Nagarkar Sanket , Nare Smeeta , Thomas George , Busheri Laleh , Reddy Asha , Kelkar Devaki , Dixit Santosh , Mannan Ashraf ul , Sabarinathan Radhakrishnan , Radhakrishna Selvi , Mishra Rupa , Koppiker Chaitanyanand B
Published: June 2022

Purpose

Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25%) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are however predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in India

Methods

Using a multi-gene NGS (next-generation sequencing) panel of 26 ACMG recommended genes associated with inherited cancers.

Results

In our study cohort of 193 TNBC patients, we identified 57 pathogenic mutations of whichBRCA1(71.93%) andBRCA2(14.03%) were most commonly mutated. Additionally, 8 pathogenic mutations were identified in non-BRCA genes associated with the HR pathway. 10 novel mutations were identified in 3 genes namelyBRCA1,BRCA2andPALB2. Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100K indicated that the novel mutations were unique. Furthermore, we identified 48 variants of uncertain significance (VUS) (24.9%).

Conclusions

Our study confirms the major proportion of mutations inBRCA1/2genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Additionally, large scale studies are also warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.
Data Quality in health research: a systematic literature review
Authors: Bernardi Filipe Andrade , Alves Domingos , Crepaldi Nathalia Yukie , Yamada Diego Bettiol , Lima Vinícius Costa , Lopes Rijo Rui Pedro Charters
Published: June 2022

Decision-making and strategies to improve service delivery need to be supported by reliable health data to generate consistent evidence on health status, so the data quality management process must ensure the reliability of the data collected. Thus, through an integrative literature review, the main objective of this work is to identify and evaluate digital health technology interventions designed to support the conduct of health research based on data quality. After analyzing and extracting the results of interest, 33 articles were included in the review. This transdisciplinarity may be reaching the threshold of significant growth and thus forcing the need for a metamorphosis of the area from focusing on the measurement and evaluation of data quality, today focused on content, to a direction focused on use and context

In general, the main barriers reported in relation to the theme of research in the area of health data quality cite circumstances regarding a) use, b) systems and c) health services.. The resources presented can help guide medical decisions that do not only involve medical professionals, and indirectly contribute to avoiding decisions based on low-quality information that can put patients’ lives at risk
Assessing the effectiveness of newborn resuscitation training and skill retention program on neonatal outcomes in Madhesh Province, Nepal
Authors: Chalise Mala , Dhungana Ranjan , Visick Michael K , Clark Robert B
Published: June 2022

Background

Intrapartum events leading to asphyxia at birth is one of the leading causes of neonatal morbidity and mortality in Nepal. In response to this, the Nepal Ministry of Health and Population adopted Helping Babies Breathe (HBB) as a tool to improve neonatal resuscitation. The effectiveness of HBB trainings in developing newborn resuscitation knowledge and skills of service providers have been well established. However, challenges remain in maintaining skills over time. Safa Sunaulo Nepal (SSN), with support from LDS Charities designed an initiative for scaling up newborn resuscitation training and maintaining skills over time. This paper reports on the implementation of SSN’s model of newborn resuscitation trainings and skill retention, and changes in perinatal outcomes that occurred during the program.

Methods

The program capacitated facility-based trainers for scale up and maintaining resuscitation skills in 20 facilities in Madhesh Province, Nepal. A single external mentor coached and assisted the facility-based trainers, provided general support, and monitored progress. Prospective outcome monitoring tracked changes in health metrics for a period of 14 months. To analyze changes over the time, the neonatal mortality, morbidity, and stillbirths at the baseline (first two months) of the program was compared with the endline (last two months) measures.

Results

Data was gathered on neonatal health outcomes of 68,435 vaginal deliveries and 9,253 cesarean sections. Results indicate decreases in <24 hours neonatal deaths (p<0.001), intrapartum stillbirths (p<0.001), and number of sick newborns transferred from the maternity unit (p<0.001). During the program, facility-based trainers taught resuscitation skills to 231 medical personnel and supported skill retention.

Conclusions

SSN’s model is a low-cost, evidence-based program focusing on facility-based trainers, who are mentored and supported to scale-up and sustain resuscitation skills over time. Findings from the report are suggestive that the model had a substantial influence on critical neonatal outcomes. Future programs focused on improving neonatal outcomes may benefit by incorporating program elements of SSN model.
Heterogeneous evolution of SARS-CoV-2 seroprevalence in school-age children: Results from the school-based cohort study Ciao Corona in November-December 2021 in the canton of Zurich
Authors: Haile Sarah R , Raineri Alessia , Rueegg Sonja , Radtke Thomas , Ulyte Agne , Puhan Milo A , Kriemler Susi
Published: June 2022

Background

Much remains unknown regarding the evolution of SARS-CoV-2 seroprevalence and variability in seropositive children in districts, schools, and classes as only a few school-based co-hort studies exist. Vaccination of children, initiated at different times for different age groups, adds additional complexity to understand how seroprevalence developed in the school aged population.

Aim

We investigated the evolution of SARS-CoV-2 seroprevalence in children and its variability in districts, schools, and classes in Switzerland from June/July 2020 to November/December 2021.

Methods

In this school-based cohort study, SARS-CoV-2 antibodies were measured in primary and secondary school children from randomly selected schools in the canton of Zurich in October/November 2020, March/April 2021, and November/December 2021. Seroprevalence was estimated using Bayesian logistic regression to adjust for test sensitivity and specificity. Variability of seroprevalence between school classes was expressed as maximum minus minimum sero-prevalence in a class and summarized as median (interquartile range).

Results

1875 children from 287 classes in 43 schools were tested, with median age 12 (range 6-17), 51% 12+ vaccinated. Seroprevalence increased from 5.6% (95% CrI: 3.5-7.6%) to 31.1% (27.0-36.1%) in unvaccinated children, and 46.4% (42.6-50.9%) in all children (including vaccinated). Earlier in the pandemic, seropositivity rates in primary schools were similar to or slightly higher (<5%) than those in secondary schools, but by late 2021, primary schools had 12.3% (44.3%) lower seroprevalence for unvaccinated (all) subjects. Variability in seroprevalence among districts and schools increased more than twofold over time, and in classes from 11% (7-17%) to 40% (22-49%).

Conclusion

Seroprevalence in children increased greatly, especially in 2021 following introduction of vaccines. Variability in seroprevalence was high and increased substantially over time, suggesting complex transmission chains.

Trial Registration:ClinicalTrials.govNCT04448717
Descriptive Epidemiology of SARS-CoV-2 Gamma (P.1/501Y.V3) variant cases in England, August 2021
Authors: Aziz Nurin Abdul , Twohig Katherine A , Sinnathamby Mary , Zaidi Asad , Aliabadi Shirin , Groves Natalie , Nash Sophie , Thelwall Simon , Dabrera Gavin
Published: June 2022

Purpose

The Gamma variant of SARS-CoV-2, first detected in travellers from Brazil, was found to have high transmissibility and virulence; following this finding, this paper aims to describe the epidemiology of Gamma cases in England from its first detection on 12 February 2021 to 31 August 2021.

Methods

The demographic analysis of Gamma cases was stratified by travel exposure. Travel-associated cases were further analysed by countries travelled from, stratified by categories set in place by the Red (highest risk countries), Amber, Green (lowest risk countries) travel policy, which was implemented from May to October 2021.

Results

There were 251 confirmed Gamma cases detected in England in the study period. 35.1% were imported, 5.6% were secondary, and 29.5% were not travel associated. Early cases were predominantly travel-associated, with later cases likely obtained through community transmission. 51.0% of travel-related cases were travellers from Amber countries, and 40.2% had at least one Red country in their journey.

Conclusion

The Gamma variant has not seen the same expansion as other variants such as Delta, most likely due to Delta out-competing community transmission of Gamma. Findings indicate the travel policy requiring quarantine for Red and Amber list travellers may have also contributed to preventing onward transmission of Gamma.
GDNF-RET signaling and EGR1 form a positive feedback loop that promotes tamoxifen resistance via cyclin D1
Authors: Marks Brooke A. , Pipia Ilissa M. , Mukai Chinatsu , Horibata Sachi , Rice Edward J. , Danko Charles G. , Coonrod Scott A.
Published: June 2022

Background

Rearranged during transfection (RET) tyrosine kinase signaling has been previously implicated in endocrine resistant breast cancer, however the mechanism by which this signaling cascade promotes resistance is currently not well described. We recently reported that glial-cell derived neurotrophic factor (GDNF)-RET signaling appears to promote a positive feedback loop with the transcription factor early growth response 1 (EGR1). Here we investigate the mechanism behind this feedback loop and test the hypothesis that GDNF-RET signaling forms a regulatory loop with EGR1 to upregulate cyclin D1 (CCND1) transcription, leading to cell cycle progression and tamoxifen resistance.

Methods

To gain a better understanding of the GDNF-RET-EGR1 resistance mechanism, we studied the GDNF-EGR1 positive feedback loop and the role of GDNF and EGR1 in endocrine resistance by modulating their transcription levels using CRISPR-dCAS9 in tamoxifen sensitive (TamS) and tamoxifen resistant (TamR) MCF-7 cells. Additionally, we performed kinetic studies using recombinant GDNF (rGDNF) treatment of TamS cells. Statistical significance for qPCR and chromatin immunoprecipitation (ChIP)-qPCR was determined using a student’s t-test.

Results

GDNF-RET signaling formed a positive feedback loop with EGR1 and also downregulated estrogen receptor 1 (ESR1) transcription. Upregulation of GDNF and EGR1 promoted tamoxifen resistance in TamS cells and downregulation of GDNF promoted tamoxifen sensitivity in TamR cells. Additionally, we show that rGDNF treatment activated GDNF-RET signaling in TamS cells, leading to recruitment of p-ELK-1 to the EGR1 promoter, upregulation of EGR1 mRNA and protein, binding of EGR1 to the GDNF and CCND1 promoters, increased GDNF protein expression, and subsequent upregulation of CCND1 mRNA levels.

Conclusion

Outcomes from these studies support the hypotheses that GDNF-RET signaling forms a positive feedback loop with the transcription factor EGR1, and that GDNF-RET-EGR1 signaling promotes endocrine resistance via signaling to cyclin D1. Inhibition of components of this signaling pathway could lead to therapeutic insights into the treatment of endocrine resistant breast cancer.
Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins
Authors: Oatman Stephanie R. , Reddy Joseph S. , Quicksall Zachary , Carrasquillo Minerva M. , Wang Xue , Liu Chia-Chen , Yamazaki Yu , Nguyen Thuy T. , Malphrus Kimberly , Heckman Michael , Biswas Kristi , Baker Matthew , Martens Yuka A. , Zhao Na , Rademakers Rosa , DeTure Michael , Murray Melissa E. , Kanekiyo Takahisa , Dickson Dennis W. , Bu Guojun , Allen Mariet , Ertekin-Taner Nilüfer
Published: June 2022

Alzheimer’s disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Main protein components of these hallmarks include Aβ40, Aβ42, tau, phospho-tau and APOE. With the exception of the APOE-ε4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for quantitative levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD- related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.