bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends and variation in prescribing of suboptimal statin treatment regimes: a cohort study in English primary care
Authors: Curtis Helen J , Walker Alex J , MacKenna Brian , Croker Richard , Goldacre Ben
Published: October 2019

Objectives

We set out to describe trends and variation in statin prescribing in England that breaches 2014 national guidance on “high-intensity” statins. We identify factors associated with breaching; and assess the feasibility of rapid prescribing behaviour change.

Design, Setting and Participants

Retrospective cohort study in NHS primary care in England, including all 8,142 standard general practices from August 2010 to March 2019.

Main Outcome Measures

We categorised statins as high or low/medium-intensity based on two different thresholds, and calculated the proportion prescribed below these thresholds across all practices. We plotted trends and geographical variation, carried out mixed effects logistic regression to identify practice characteristics associated with breaching guidance, and used indicator saturation to identify practices exhibiting sudden changes in prescribing.

Results

We included all 8,142 practices across the study period. The proportion of statin prescriptions below the recommended 40% LDL-lowering threshold decreased gradually since 2012 from 80% to 45%; the proportion below a pragmatic 37% threshold decreased from 30% to 18%. The 2014 guidance had minimal impact on these trends. We found wide variation between practices (interdecile ranges 20% to 85% and 10% to 30% respectively in 2018). Mixed effects logistic regression did not identify practice characteristics strongly associated with breaching guidance. Indicator saturation identified several practices exhibiting sudden changes in prescribing towards greater guideline compliance.

Conclusions

Breaches of English guidance on choice of statin remain common, with substantial variation between GP practices. Some practices and regions have implemented rapid change, indicating the feasibility of rapid prescribing behaviour change. We discuss the potential for a national strategic approach, using data and evidence to optimise care, including targeted education alongside audit and feedback to outliers through services such as OpenPrescribing.

What is already known on this topic

English national guidance recommends the use of a high-intensity statin, capable of reducing LDL (low-density lipoprotein) cholesterol by 40% or more. Adherence at the time of guideline release was low, but has not been documented since.

What this study adds

Adherence is improving, but breaches of national guidance remain common, with 45% of prescriptions below the recommended strength, and there is very substantial variation between practices. Some practices have exhibited rapid positive change in prescribing, which indicates that better adherence could readily be achieved. We have produced a live data tool allowing anyone to explore any practice’s current statin prescribing behaviour.
Investigation of an estimate of daily resting heart rate using a consumer wearable device
Authors: Russell Allison , Heneghan Conor , Venkatraman Subbu
Published: October 2019

Resting heart rate is accepted as a valid overall indicator of cardiovascular risk and is a low-cost easy-to-measure metric that can be collected in both home and clinical settings. Wearable devices such as smartwatches and trackers can measure heart rate continuously using optical technology. This study reports initially on the agreement between the resting heart rate reported by a wearable device (Fitbit Charge HR and Fitbit Blaze) and a chest-based consumer electrocardiogram (Polar H7). In 45 subjects, the reported resting heart rates agreed within 0.89 bpm over a resting period of 5 mins. The same device and algorithm was then used in a population of 168 subjects (45.9± 15.6 yrs) who were asked to collect their resting heart rate for four days under seven different conditions and times (at wake sitting/lying down, pre-breakfast, pre-lunch, pre-dinner, and before bed sitting/lying down). The reported values were compared with the Daily Resting Heart Rate (DRHR) reported by the wearable device. The measurement lying down before wake were closest to the DRHR (mean error of 0.0 bpm with a 25-75th percentile spread of ±3.5bpm. There was a significant circadian variation in the reported resting heart rate across subjects, with the highest values reported in the middle of the day. Within individual subjects, the median standard deviation of heart rate at rest was 3-5bpm even measured under nominally similar conditions over four days.
Improving parents’ knowledge of early signs of pediatric eye disease: A double-blind RCT
Authors: Staffieri Sandra E. , Rees Gwyneth , Sanfilippo Paul G. , Cole Stephen , Mackey David A. , Hewitt Alex W.
Published: October 2019

Background and Objectives

Early diagnosis and intervention is essential to achieve optimal outcomes for most pediatric eye diseases. Educating parents/caregivers to recognize early signs of disease and consult a healthcare professional is critical to achieving this aim. We evaluate the effectiveness of an eye-health information pamphlet on parents’ level of concern and their help-seeking intention if they observed leukocoria or strabismus.

Methods

Pregnant women attending a metropolitan antenatal clinic were recruited to the study. Participants were randomly assigned to receive a pamphlet on either pediatric eye health (intervention) or strategies for play (control). The primary outcome measure was a change in the parents’ level of concern if they observed leukocoria or strabismus. The secondary outcome measure was a change in their help-seeking intention if either sign was observed.

Results

Of the 518 women enrolled, 382 (73.7%) completed the post-test survey. At follow-up, women who received the intervention were more likely to report a higher level of concern if they observed leukocoria (OR 1.711 [CI: 1.176-2.497] p=0.005]) and were less likely to have a delayed help-seeking intention. (OR 0.560 [CI 0.382-0.817] p =0.003) No change in the level of concern for strabismus was identified between the groups; however, at follow-up, women who received the intervention were less likely to delay help-seeking (OR 0.318 [CI 0.125-0.806] p=0.016).

Conclusion

Providing parents with relevant, evidence-based information can significantly improve their knowledge and positively influence help-seeking intentions if leukocoria or strabismus are observed.

Trial registration

ANZCTR.org.auidentifier: ACTRN12617001431314p;

World Health Organization Universal Trial Number: U1111-1203-0485

Table of Contents Summary

This study reports the results of a randomised controlled trial evaluating a novel, evidence-based, theory-informed pediatric eye-health information pamphlet for parents.

What is known on this subject

Lack of parental awareness of signs of pediatric eye disease (leukocoria and strabismus) delays consultation with healthcare professionals (help-seeking), contributing to late diagnosis and poor outcomes. Providing parents with relevant health information can improve their child’s health outcomes.

What this study adds

Using an RCT to evaluate a novel health intervention, this study demonstrates that providing parents with evidence-based, theory informed pediatric eye-health information can improve their knowledge and help-seeking intentions if leukocoria or strabismus are observed in their child.
Female genital schistosomiasis and reproductive tract infections. A cross-sectional study in rural adolescents in South Africa
Authors: Shukla Jilna Dilip , Kleppa Elisabeth , Holmen Sigve , Ndhlovu Patricia D. , Mtshali Andile , Sebitloane Motshedisi , Vennervald Birgitte Jyding , Gundersen Svein Gunnar , Taylor Myra , Kjetland Eyrun Floerecke
Published: October 2019

Background and objectives

The aim of the current study was to establish the relative prevalences of Female Genital Schistosomiasis (FGS) and sexually transmitted infections (STIs). We hypothesised that due to the use of syndromic management for STIs it is possible that FGS is being misdiagnosed and mismanaged as an STI. We therefore wanted to examine the relationship between FGS and the individual STIs in schistosomiasis endemic areas.

Methods

Between 2011 and 2013, a cross-sectional study was performed in 32 randomly selected secondary schools in rural KwaZulu-Natal, South Africa, where each school had at least 300 pupils. In a research clinic, FGS diagnosis, STI testing, and face-to-face interviews were performed in sexually active, young women aged 16 – 22 years.

Results

FGS was the second most prevalent current genital infection (23%). There were significantly more women who had presented FGS among those who had detectable urinary schistosomiasis (35%), compared to those without (19%, p< 0.001). In the FGS positive group 35% were positive for HPV infection, compared to 24 % in the FGS negative group (p=0.010). In the FGS positive group 37% were sero-positive for HSV infection, compared to 30% in the FGS negative group (p=0.079). There were significantly fewer chlamydia infections amongst women with FGS (20%, p=0.018) compared with those who did not have FGS (28%).

Conclusions

FGS was the second most common genital infection after HSV but the two were not significantly associated. HPV infection was significantly associated with FGS. Surprisingly Chlamydia infection were negatively associated with FGS. The results show the importance of the inclusion of FGS in the management protocols for genital infections in areas endemic for urinary schistosomiasis, and highlight the importance for more research on suitable differential diagnostic tools and disease management.

Key messages box

FGS was the second most common genital infection in this rural population after HSV.

FGS was positively associated with HPV.

FGS was negatively associated with genital chlamydia infections.

FGS should be included in the syndromic management of genital infections.
A Network Analysis Framework to Improve the Delivery of Mosquito Abatement Services in Machala, Ecuador
Authors: Lippi Catherine A. , Mao Liang , Stewart-Ibarra Anna M. , Heydari Naveed , Ayala Efraín Beltrán , Burkett-Cadena Nathan D. , Blackburn Jason K. , Ryan Sadie J.
Published: October 2019

Background

Vector-borne disease places a high health and economic burden in the American tropics. Comprehensive vector control programs remain the primary method of containing local outbreaks. With limited resources, many vector control operations struggle to serve all affected communities within their districts. In the coastal city of Machala, Ecuador, vector control services, such as application of larvicides and truck-mounted fogging, are delivered through two deployment facilities managed by the Ecuadorian Ministry of Health. Public health professionals in Machala face several logistical issues when delivering mosquito abatement services, namely applying limited resources in ways that will most effectively suppress vectors of malaria, dengue, and encephalitis viruses.

Methods

Using a transportation network analysis framework, we built models of service areas and optimized delivery routes based on distance costs associated with accessing neighborhoods throughout the city. Optimized routes were used to estimate the relative cost of accessing neighborhoods for mosquito control services in Machala, creating a visual tool to guide decision makers and maximize mosquito control program efficiency. Location-allocation analyses were performed to evaluate efficiency gains of moving service deployment to other available locations with respect to distance to service hub, neighborhood population, dengue incidence, and housing condition.

Results

Using this framework, we identified different locations for targeting mosquito control efforts, dependent upon management goals and specified risk factors of interest, including human population, housing condition, and reported dengue incidence. Our models indicate that neighborhoods on the periphery of Machala with the poorest housing conditions are the most costly to access. Optimal locations of facilities for deployment of control services change depending on pre-determined management priorities, increasing the population served via inexpensive routes up to 34.9%, and reducing overall cost of accessing neighborhoods up to 12.7%.

Conclusions

Our transportation network models indicate that current locations of mosquito control facilities in Machala are not ideal for minimizing driving distances or maximizing populations served. Services may be optimized by moving vector control operations to other existing public health facilities in Machala. This work represents a first step in creating a spatial tool for planning and critically evaluating the systematic delivery of mosquito control services in Machala and elsewhere.
Hepatitis B virus resistance to tenofovir: fact or fiction? A synthesis of the evidence to date
Authors: Mokaya Jolynne , McNaughton Anna L , Bester Phillip A , Goedhals Dominique , Barnes Eleanor , Marsden Brian D , Matthews Philippa C
Published: October 2019

Background

Tenofovir (TFV) is a widely used antiviral treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood, and the topic remains contentious. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into the mechanisms of resistance and potential clinical significance.

Methods

We carried out a systematic literature search in PubMed to identify clinical,in vitroandin silicoevidence of TFV resistance. The structure of HBV reverse transcriptase (RT) has not been solved; we therefore compared HBV RT to the crystal structure for HIV RT to map the likely sites of RAMs.

Results

We identified a ‘long-list’ of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. Based on quality and quantity of supporting data, we generated a ‘short-list’ of nine sites that are supported by the most robust evidence. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.

Conclusion

There is emerging evidence for polymorphisms that may reduce susceptibility to TVF. A better understanding of HBV drug resistance is imperative to optimise approaches to public health elimination targets.
Dengue importation into Europe: a network connectivity-based approach
Authors: Salami Donald , Capinha César , Martins Maria do Rosário Oliveira , Sousa Carla Alexandra
Published: October 2019

The spread of dengue through global human mobility is a major public health concern. A key challenge is understanding the transmission pathways and mediating factors that characterized the patterns of dengue importation into non-endemic areas. Utilizing a network connectivity-based approach, we analyze the importation patterns of dengue fever into European countries.

Seven connectivity indices were developed to characterize the role of the air passenger traffic, seasonality, incidence rate, geographical proximity, epidemic vulnerability, and wealth of a source country, in facilitating the transport and importation of dengue fever. We used generalized linear mixed models (GLMMs) to examine the relationship between dengue importation and the connectivity indices while accounting for the air transport network structure. We also incorporated network autocorrelation within a GLMM framework to investigate the propensity of a European country to receive an imported case, by virtue of its position within the air transport network.

The connectivity indices and dynamical processes of the air transport network were strong predictors of dengue importation in Europe. With more than 70% of the variation in dengue importation patterns explained. We found that transportation potential was higher for source countries with seasonal dengue activity, high passenger traffic, high incidence rates, lower economic status, and geographical proximity to a destination country in Europe. We also found that position of a European country within the air transport network was a strong predictor of the country’s propensity to receive an imported case.

Our findings provide evidence that the importation patterns of dengue into Europe can be largely explained by appropriately characterizing the heterogeneities of the source, and topology of the air transport network. This contributes to the foundational framework for building integrated predictive models for bio-surveillance of dengue importation.
Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization
Authors: Yang Qian , Sanderson Eleanor , Tilling Kate , Borges M Carolina , Lawlor Deborah A
Published: October 2019

Background

Our aim is to produce guidance on exploring and mitigating possible bias when genetic instrumental variables (IVs) associate with traits other than the exposure of interest in Mendelian randomization (MR) studies.

Methods

We use causal diagrams to illustrate scenarios that could result in IVs being related to (non-exposure) traits. We recommend that MR studies explore possible IV-non-exposure associations across a much wider range of traits than is usually the case. Where associations are found, confounding by population stratification should be assessed through adjusting for relevant population structure variables. To distinguish vertical from horizontal pleiotropy we suggest using bidirectional MR between the exposure and non-exposure traits and MR of the effect of the non-exposure traits on the outcome of interest. If vertical pleiotropy is plausible, standard MR methods should be unbiased. If horizontal pleiotropy is plausible, we recommend using multivariable MR to control for observed pleiotropic traits and conducting sensitivity analyses which do not require prior knowledge of specific invalid IVs or pleiotropic paths.

Results

We applied our recommendations to an illustrative example of the effect of maternal insomnia on offspring birthweight in the UK Biobank. We found little evidence that unexpected IV-non-exposure associations were driven by population stratification. Three out of six observed non-exposure traits plausibly reflected horizontal pleiotropy. Multivariable MR and sensitivity analyses suggested an inverse association of insomnia with birthweight, but effects were imprecisely estimated in some of these analyses.

Conclusions

We provide guidance for MR studies where genetic IVs associate with non-exposure traits.

Key messages

Genetic variants are increasingly found to associate with more than one social, behavioural or biological trait at genome-wide significance, which is a challenge in Mendelian randomization (MR) studies.

Four broad scenarios (i.e. population stratification, vertical pleiotropy, horizontal pleiotropy and reverse causality) could result in an IV-non-exposure trait association.

Population stratification can be assessed through adjusting for population structure with individual data, while two-sample MR studies should check whether the original genome-wide association studies have used robust methods to properly account for it.

We apply currently available MR methods for discriminating between vertical and horizontal pleiotropy and mitigating against horizontal pleiotropy to an example exploring the effect of maternal insomnia on offspring birthweight.

Our study highlights the pros and cons of relying more on sensitivity analyses without considering particular pleiotropic paths versus systematically exploring and controlling for potential pleiotropic paths via known characteristics.
Unmasking selective path integration deficits in Alzheimer’s disease risk carriers
Authors: Bierbrauer Anne , Kunz Lukas , Gomes Carlos A. , Luhmann Maike , Deuker Lorena , Getzmann Stephan , Wascher Edmund , Gajewski Patrick D. , Hengstler Jan G. , Fernandez-Alvarez Marina , Atienza Mercedes , Cammisuli Davide M. , Bonatti Francesco , Pruneti Carlo , Percesepe Antonio , Bellaali Youssef , Hanseeuw Bernard , Strange Bryan A. , Cantero Jose L. , Axmacher Nikolai
Published: October 2019

Alzheimer’s disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOEε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance inAPOEε4-carriers during a virtual navigation task. We report a selective impairment inAPOEε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits inAPOEε4-carriers. Furthermore, retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.
Multi-level analysis of reproduction in the Antarctic midge,Belgica antarctica, identifies female and male accessory gland products that are altered by larval stress and impact progeny viability
Authors: Finch Geoffrey , Nandyal Sonya , Perrieta Carlie , Davies Benjamin , Rosendale Andrew J. , Holmes Christopher J. , Gantz Josiah D. , Spacht Drew , Bailey Samuel T. , Chen Xiaoting , Oyen Kennan , Didion Elise M. , Chakraborty Souvik , Lee Richard E. , Denlinger David L. , Matter Stephen F. , Attardo Geoffrey M. , Weirauch Matthew T. , Benoit Joshua B.
Published: October 2019

The Antarctic midge,Belgica antarctica, is a wingless, non-biting midge endemic to Antarctica. Larval development requires at least two years, but adult life lasts only two weeks. The nonfeeding adults mate in swarms and females die shortly after oviposition. Eggs are suspended in a gel of unknown composition that is expressed from the female accessory gland. This project characterizes molecular mechanisms underlying reproduction in this midge by examining differential gene expression in whole males, females, and larvae, as well as in male and female accessory glands. Functional studies were used to assess the role of the gel encasing the eggs, as well as the impact of stress on reproductive biology. RNA-seq analyses revealed sex- and development-specific gene sets along with those associated with the accessory glands. Proteomic analyses were used to define the composition of the egg-containing gel, which is generated during multiple developmental stages and derived from both the accessory gland and other female organs. Functional studies indicate the gel provides a larval food source and thermal and dehydration buffer, all of which are critical for viability. Larval dehydration stress directly reduces production of storage proteins and key accessory gland components, a feature that impacts adult reproductive success. Modeling reveals that bouts of dehydration may significantly impact population growth. This work lays a foundation for further examination of reproduction in midges and provides new information related to general reproduction in dipterans. A key aspect is that reproduction and stress dynamics, currently understudied in polar organisms, are likely to prove critical for determining how climate change will alter survivability.
Reader Engagement with Wikipedia’s Medical Content
Authors: Maggio Lauren A. , Steinberg Ryan M. , Piccardi Tiziano , Willinsky John M.
Published: October 2019

Wikipedia’s extensive health and medical entries, maintained by WikiProject Medicine (WPM), are well supported by external links that provide readers with both a means of verifying the sources drawn upon and visiting those sources to learn more about a topic. In analysing how readers approach these links, data was collected on reader engagement with these links on WPM pages and on the rest of Wikipedia over a 32-day period. Readers of WPM pages were found to engage with external links more frequently than readers of the rest of Wikipedia, with WPM readers favoring hovering over a link and footnote clicking, compared to W readers who tended to click more external links per page viewed. Compared to readers of the rest of Wikipedia, WPM readers appear more attentive to the external link’s function in verifying and authorizing Wikipedia content, than to the educational potential of examining the sources themselves.
Evaluating the granularity and statistical structure of lesions and behaviour in post-stroke aphasia
Authors: Zhao Ying , Halai Ajay D. , Ralph Matthew A. Lambon
Published: October 2019

The pursuit of relating the location of neural damage to the pattern of acquired language and general cognitive deficits post-stroke stems back to 19th century behavioural neurology. Whilst spatial specificity has improved dramatically over time, from the large areas of damage specified by post-mortem investigation to the millimetre precision of modern MRI, there is an underlying issue that is rarely addressed, which relates to the fact that damage to a given area of the brain is not random but constrained by the brain’s vasculature. Accordingly, the aim of this study was to uncover the statistical structure underlying the lesion profile in chronic aphasia post-stroke. By applying varimax-rotated principal component analysis to the lesions of 70 patients with chronic post-stroke aphasia, we identified 17 interpretable clusters, largely reflecting the vascular supply of middle cerebral artery sub-branches and other sources of individual variation in vascular supply as shown in classical angiography studies. This vascular parcellation produced smaller displacement error in simulated lesion-symptom analysis compared with individual voxels and Brodmann regions. A second principal component analysis of the patients’ detailed neuropsychological data revealed a four factor solution reflecting phonological, semantic, executive-demand and speech fluency abilities. As a preliminary exploration, stepwise regression was used to relate behavioural factor scores to the lesion principal components. Phonological ability was related to two components, which covered the posterior temporal region including the posterior segment of the arcuate fasciculus, and the inferior frontal gyrus. Three components were linked to semantic ability and were located in the white matter underlying the anterior temporal lobe, the supramarginal gyrus and angular gyrus. Executive-demand related to two components covering the dorsal edge of the middle cerebral artery territory, while speech fluency was linked to two components that were located in the middle frontal gyrus, precentral gyrus, and subcortical regions (putamen and thalamus). Future studies can explore in formal terms the utility of these PCA-derived lesion components for relating post-stroke lesions and symptoms.
Passenger mutations confound phenotypes of SARM1-deficient mice
Authors: Uccellini Melissa B. , Bardina Susana V. , Sánchez-Aparicio Maria Teresa , White Kris M. , Hou Ying-Ju , Lim Jean K. , García-Sastre Adolfo
Published: October 2019

The Toll/IL-1R domain-containing adaptor protein SARM1 is expressed primarily in the brain, where it mediates axonal degeneration. Additional roles for SARM1 in a number of other processes including TLR-signaling, viral infection, chemokine expression, and expression of the proapoptotic protein XAF1 have also been described. Much of the supporting evidence for SARM1 function has been generated by comparing WT C57BL/6 (B6) mice to SARM1-deficient mice backcrossed to the B6 background. Here we show that the Sarm1 gene lies in a gene-rich region encompassing XAF1, and the MIP and MCP chemokine family loci among other genes. Because gene-targeting of SARM1-deficient strains was done with 129 ES cells and these genes are too close to segregate, they remain 129 in sequence. As this could account for phenotypes attributed to SARM1, we generated new knockout mouse strains on a pure B6 background using CRISPR. Experiments in these new strains confirmed the role of SARM1 in axonal degeneration and susceptibility to WNV infection, but not in susceptibility to VSV or LACV infection, or chemokine or Xaf1 expression. Notably, the Xaf1 gene shows sequence variation between B6 and 129, resulting in coding changes and novel splice variants. Given its known role in apoptosis, XAF1 variants may account for some phenotypes described in previously made SARM1-deficient strains. RNAseq in the new strains reveal changes in the mitochondrial electron transport chain and ribosomal proteins, suggesting possible downstream targets of SARM1. Re-evaluation of described phenotypes in these new strains will be critical for defining the function of SARM1.
Optimized data representation and convolutional neural network model for predicting tumor purity
Authors: Sun Gerald J. , Jenkins David F. , Cingolani Pablo E. , Dry Jonathan R. , Lai Zhongwu
Published: October 2019

Here we present a machine learning model, Deep Purity (DePuty) that leverages convolutional neural networks to accurately predict tumor purity from next-generation sequencing data from clinical samples without matched normals. As input, our model utilizes SNP-based copy number and minor allele frequency data formulated as a scatterplot image. With a representation matching that used by expert human annotators, we best an existing algorithm using only ~100 manually curated samples. Our simple, data-efficient approach can serve as a straightforward alternative to traditional, more complex statistical methods, for building performant purity prediction models that enable downstream bioinformatic analysis of tumor variants and absolute copy number alterations relevant to cancer genomics.
Structural basis for adhesion G protein-coupled receptor Gpr126 function
Authors: Leon Katherine , Cunningham Rebecca L. , Riback Joshua A. , Feldman Ezra , Li Jingxian , Sosnick Tobin R. , Zhao Minglei , Monk Kelly R. , Araç Demet
Published: October 2019

Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR Gpr126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human. Here, we determine the structure of the complete zebrafish Gpr126 ECR and reveal five domains including a previously-unknown domain. Strikingly, the Gpr126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the newly-characterized calcium-binding site abolishes Gpr126 function in vivo. These results demonstrate that Gpr126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide novel insights into ECR-targeted drug design.
Time distributed data analysis by Cosinor.Online application
Authors: Molcan Lubos
Published: October 2019

Disturbed biological oscillations often represent pathology and thus have a prognostic character. The most studied are 24-h (circadian) and shorter (ultradian) oscillations from them. A cosinor analysis often evaluates the presence and significance of circadian and ultradian rhythms. Skilled researchers can use MATLAB, R, Python, or other programming languages, while those less experienced often use outdated applications that require a specific operating system version or outdated add-ons. Therefore, we developed CosinorOnline, a simple web-based application coded in PHP and JavaScript to evaluate the presence and significance of different oscillations. Users can set the period length on the application’s page and insert their data. The results consist of a numerical evaluation and an adjustable plot. There is also a unique identifier to reload or immediately delete data analysis within one month. After this period, all data are automatically deleted from the app. We compared the functionality of CosinorOnline with Cosinor2 (R package) and Chronos-Fit (Windows app). The 24-h variability analysis was identical for all three applications. The evaluation of ultradian variability was the same for CosinorOnline and Cosinor2 and slightly different for Chronos-Fit. CosinorOnline and Chronos-Fit result in acrophase in units of time (decimal form), while Cosinor2 is in radians. In conclusion, CosinorOnline is a simple, easy-to-use web application to inspect time data that provides reliable results without additional installation and runs in modern web browsers. The application does not track users and aims to help users quickly decide whether their data is suitable for more profound analysis using cosinor analysis.
Can genome-based analysis be the new gold-standard for routine Salmonella serotyping?
Authors: Banerji Sangeeta , Simon Sandra , Tille Andreas , Flieger Antje
Published: October 2019

Salmonella enterica is the second most reported bacterial cause of food-borne infections in Europe. Therefore molecular surveillance activities based on pathogen subtyping are an important measure of controlling Salmonellosis by public health agencies. In Germany, at the federal level, this work is carried out by the National Reference Center for Salmonella and other Bacterial Enteric Pathogens (NRC). With rise of next generation sequencing techniques, the NRC has introduced whole-genome-based typing methods for S. enterica in 2016. In this study we report on the feasibility of genome-based in silico serotyping in the German setting using raw sequence reads. We found that SeqSero and seven gene MLST showed 98% and 95% concordance, respectively, with classical serotyping for the here evaluated serotypes, including the most common German serotypes S. Enteritidis and S. Typhimurium as well as less frequently found serotypes. The level of concordance increased to >99% when the results of both in silico methods were combined. However, both tools exhibited misidentification of monophasic variants, in particular monophasic S. Typhimurium and therefore need to be fine-tuned for reliable detection of this epidemiologically important variant. We conclude that with adjustments Salmonella genome-based serotyping might become the new gold standard.
Factorial design as a tool to evaluate image analysis workflows systematically: its application to the filament tracing problem
Authors: Scholz Leandro Aluisio , Caznok Silveira Ana Clara , Sugai-Guérios Maura Harumi , Mitchell David Alexander
Published: October 2019

The effect of image enhancement methods on the final result of image analysis workflows is often left out of discussions in scientific papers. In fact, before reaching a definitive enhancement workflow and its settings, there often is a great amount of pre-testing and parameter tweaking. In this work, we take the biofilament tracing problem and propose a systematic approach to testing and evaluating major image enhancement methods that are applied prior to execution of six filament tracing methods (APP, APP2, FarSIGHT Snake, NeuronStudio, Neutube and Rivulet2). We used a full factorial design of experiments to analyse five enhancement methods (deconvolution, background subtraction, pixel intensity normalization, Frangi vessel enhancement and smoothing) and the order in which they are applied, evaluating their effect on the signal-to-noise ratio, structural similarity index and geometric tracing scores of 3D images of a fungal mycelium and a synthetic neuronal tree. Our approach proved valuable as a tool to support the choice of enhancement and filament tracing workflow. For example, the use of deconvolution followed by median filtering gives the best geometric tracing scores if Neutube is used in the image of the fungal mycelium. Also, we show that FarSIGHT Snake and Neutube are the most robust filament tracing methods to changes in image quality. In addition, we reinforce the importance of extensive testing of new filament tracing methods against a broad range of image qualities and filament characteristics.
Precise regulation of the relative rates of surface area and volume synthesis in dynamic environments
Authors: Shi Handuo , Hu Yan , Huang Kerwyn Casey
Published: October 2019

Bacterial cells constantly face complex environmental changes in their natural habitats. While steady-state cell size correlates with nutrient-determined growth rate, it remains unclear how cells regulate their morphology during rapid environmental changes. Here, we systematically quantified cellular dimensions throughout passage cycles of stationary-phase cells diluted into fresh medium and grown back to saturation, and found that cells exhibit characteristic dynamics in surface area to volume ratio (SA/V). SA/V dynamics were conserved across many genetic/chemical perturbations, as well as across species and growth temperatures. We developed a model with a single fitting parameter, the time delay between surface and volume synthesis, that quantitatively explained our SA/V observations, and showed that the time delay was indeed due to differential expression of volume and surface-related genes. The first division after dilution occurred at a tightly controlled SA/V, a previously unrecognized size-control mechanism highlighting the relevance of SA/V. Finally, our time-delay model successfully predicted the quantitative changes in SA/V dynamics due to altered surface area synthesis rates or time delays from translation inhibition. Our minimal model thus provides insight into how cells regulate their morphologies through differential regulation of surface area and volume synthesis and potentiates deep understanding of the connections between growth rate and cell shape in complex environments.
Synergistic effect: a common theme in mixed-species litter decomposition
Authors: Liu Jun , Liu Xiaoyu , Song Qingni , Luan Fenggang , Wang Hui , Hu Yalin , Yang Qingpei
Published: October 2019

Litter decomposition plays a key role in ecosystem nutrients cycling, yet, to date science is lacking a comprehensive understanding of the non-additive effect in mixing litter decomposition.

In order to fill that gap, we compiled 69 individual studies for the purpose of performing two sub-meta-analyses on the non-additive effect.

Our results show that a significantly synergistic effect occurs at global scale with the average increase by 2-4% in litter mixture decomposition; In particular, low-quality litter in mixture shows a significantly synergistic effect, while no significant change is observed with high-quality species. Additionally, the synergistic effect turns into the antagonistic effect when soil fauna is absent or litter decomposition enters into humus-near stage. In contrast to temperate and tropical areas, studies in frigid area also show a significantly antagonistic effect.

Our meta-analysis provides a systematic evaluation of the non-additive effect in decomposition mixed litters, which is critical for understanding and improving the carbon forecasts and nutrient dynamics.
Understanding patterns of HIV multi-drug resistance through models of temporal and spatial drug heterogeneity
Authors: Feder Alison F. , Harper Kristin , Brumme Chanson J. , Pennings Pleuni S.
Published: October 2019

1

Triple-drug therapies have transformed HIV from a fatal condition to a chronic one. These therapies should prevent HIV drug resistance evolution, because one or more drugs suppress any partially-resistant viruses. In practice, such therapies drastically reduced, but did not eliminate, resistance evolution. In this article, we reanalyze published data from an evolutionary perspective and demonstrate several intriguing patterns about HIV resistance evolution - resistance evolves (1) even after years on successful therapy, (2) sequentially, often via one mutation at a time and (3) in a partially predictable order. We describe how these observations might emerge under two models of HIV drugs varying in space or time. Despite decades of work in this area, much opportunity remains to create models with realistic parameters for three drugs, and to match model outcomes to resistance rates and genetic patterns from patients on triple-drug therapy. Further, lessons from HIV may inform other systems.
AUTOPILOT: Automating experiments with lots of Raspberry Pis
Authors: Saunders Jonny L. , Ott Lucas A. , Wehr Michael
Published: October 2019

Neuroscience needs behavior, and behavioral experiments require the coordination of large numbers of heterogeneous hardware components and data streams. Currently available tools strongly limit the complexity and reproducibility of experiments. Here we introduce Autopilot, a complete, open-source Python framework for experimental automation that distributes experiments over networked swarms of Raspberry Pis. Autopilot enables qualitatively greater experimental flexibility by allowing arbitrary numbers of hardware components to be combined in arbitrary experimental designs. Research is made reproducible by documenting all data and task design parameters in a human-readable and publishable format at the time of collection. Autopilot provides a high-level set of programming tools while maintaining submillisecond performance at a fraction of the cost of traditional tools. Taking seriously the social nature of code, we scaffold shared knowledge and practice with a publicly editable semantic wiki and a permissive plugin system. Autopilot’s flexible, scalable architecture allows neuroscientists to work together to design the next generation of experiments to investigate the behaving brain.
Pegasus, a small extracellular peptide regulating the short-range diffusion of Wingless
Authors: Magny Emile G , Pueyo Jose I , Bishop Sarah A , Aguilar-Hidalgo Daniel , Couso Juan Pablo
Published: October 2019

Small Open Reading Frames (smORFs) coding for peptides of less than 100 amino-acids are emerging as a fundamental and pervasive gene class, found in the hundreds of thousands in metazoan genomes. Even though some of these genes are annotated, their function, if any, remains unknown. Here we characterize the function of a smORF encoding a short 80 aa peptide,pegasus(peg), which facilitates Wg diffusion during the development of theDrosophilawing imaginal disc. During wing development, Wg has sequential functions, and in the later stages, whenpegis strongly expressed, it patterns the presumptive wing margin. A reduction in Wg protein secretion at this stage produces effects ranging from total abolition of the wing margin to partial loss of bristles and reduction of proneural gene expression. Here we show that the Peg peptide enhances the short-range of Wg diffusion in this context, in order to produce a proper wing margin. We show that CRISPR/Cas9-mediated mutations ofpegasusgenerate wing margin phenotypes, and changes in target gene expression, consistent with a role in Wg signalling. We find that Peg is secreted, and that it co-localizes and co-immunoprecipitates with Wg, suggesting that Peg directly binds Wg in order to enhance its signalling, and our data from fixed andin-vivoWg gradient measurements supports a model in which this enhancement occurs by increasing diffusion of extracellular Wg. Our results unveil a new element in the regulation of the Wg signalling pathway, and shed light on the functional consequences of the miss-regulation of Wg diffusion in this developmental context, while also reminding us of the functional diversity, and relevance of small open reading frame genes.
Feature selection for the classification of fall-risk in older subjects: a combinational approach using static force-plate measures
Authors: Reilly D’Ó’
Published: October 2019

Introduction

Feature selection prevents over-fitting in predictive models. This study aimed to present an effective feature selection method that leads to a reliable classification of fall-risk in older subjects using static force-platform data across four conditions only.

Method

528 features were generated from a publicly available dataset of force-plate signals from 45 low-risk and 28 high-risk subjects. Subjects were classified as high- or low-risk if they recorded ≥1 falls in the prior 12 months and/or were rated as high-risk on the FES. The feature selection protocol included SVM-RFE, GA and ReliefF and finally SAFE. Several machine-learning models were then used to evaluate classification performance.

Results

67 features were identified after the three-fold process which was further reduced to 18 features after SAFE. The MLP achieved the highest average classification accuracy of 80%. All classification models evaluating this final subset displayed high variance across all performance metrics, especially in terms of sensitivity to high-risk subjects.

Interpretation

An optimal feature set of static force-plate measures was insufficient in creating a reliable classifier of fall-risk. This was due potentially to the limited information about fall-risk that could be provided by such measures leading to under-fitting/over-fitting being unavoidable and appeared to be centered around an insensitivity to high-risk subjects.

Conclusion

Static stability measures have shown some usability in fall-risk classification however feature sets limited to such measures are inadequately sensitive to high-risk subjects. The utilized feature selection methods demonstrated their ability to identify relevant stability measures and could be used successfully on dynamic measures.
A history-derived reward prediction error signal in ventral pallidum
Authors: Ottenheimer David J. , Bari Bilal A. , Sutlief Elissa , Fraser Kurt M. , Kim Tabitha H. , Richard Jocelyn M. , Cohen Jeremiah Y. , Janak Patricia H.
Published: October 2019

Learning from past interactions with the environment is critical for adaptive behavior. Within the framework of reinforcement learning, the nervous system builds expectations about future reward by computing reward prediction errors (RPEs), the difference between actual and predicted rewards. Correlates of RPEs have been observed in the midbrain dopamine system, which is thought to locally compute this important variable in service of learning. However, the extent to which RPE signals may be computed upstream of the dopamine system is largely unknown. Here, we quantify history-based RPE signals in the ventral pallidum (VP), an input region to the midbrain dopamine system implicated in reward-seeking behavior. We trained rats to associate cues with future delivery of reward and fit computational models to predict individual neuron firing rates at the time of reward delivery. We found that a subset of VP neurons encoded RPEs and did so more robustly than nucleus accumbens, an input to VP. VP RPEs predicted trial-by-trial task engagement, and optogenetic inhibition of VP reduced subsequent task-related reward seeking. Consistent with reinforcement learning, activity of VP RPE cells adapted when rewards were delivered in blocks. We further found that history- and cue-based RPEs were largely separate across the VP neural population. The presence of behaviorally-instructive RPE signals in the VP suggests a pivotal role for this region in value-based computations.