bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Bisphosphonate use and COVID-19 related outcomes: a retrospective cohort study
Authors: Thompson Jeffrey , Wang Yidi , Dreischulte Tobias , Barreiro Olga , Gonzalez Rodrigo J. , Hanč Pavel , Matysiak Colette , Neely Harold R. , Rottenkolber Marietta , Haskell Tom , Endres Stefan , von Andrian Ulrich H.
Published: June 2022

Background

Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

Methods

A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance from 1-1-2019 to 6-30-2020 was performed. The primary exposure of interest was use of any bisphosphonate from 1-1-2019 to 2-29-2020. Outcomes of interest included: (a) testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with COVID-19 diagnosis between 3-1-2020 and 6-30-2020.

Results

7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR=0.22; 95%CI:0.21-0.23; p<0.001), COVID-19 diagnosis (OR=0.23; 95%CI:0.22-0.24; p<0.001), and COVID-19-related hospitalization (OR=0.26; 95%CI:0.24-0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR=0.23; 95%CI:0.22-0.23; p<0.001) or pneumonia (OR=0.32; 95%CI:0.31-0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

Conclusions

Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.
Ventilation Requirements and Recommendations for Controlling SARS-CoV-2 and Variants Outbreaks in Indoor Gathering Places with Close Contact
Authors: Chow W.K.
Published: June 2022

Unexpected rapid infection involving SARS-CoV-2 variant Omicron known as the fifth wave of outbreak occurred since early January 2022 in Hong Kong. Almost 1.2 million citizens were infected in three months. Ventilation provisions in some gathering places with close contact such as restaurants were found to be lower than requirements, believed to be one of the main causes of transmission in these indoor spaces. At the end of the fifth outbreak in mid-May 2022, group infections were still found in several such gathering places including restaurants and pubs due to inadequate ventilation provisions. There are worries about triggering the sixth wave of outbreak.

Key points related to ventilation requirements in such gathering places are discussed in this paper. Adequate ventilation of 6 air changes per hour minimum must be provided to avoid direct air transmission of virus. Indoor aerodynamics induced by ventilation system must be considered too. However, it is difficult to measure ventilation rate quickly and accurately. A control scheme on virus outbreaks is proposed on installing mechanical ventilation energy use meters and carbon dioxide sensors for checking ventilation provisions adequacy quickly.
Breathlessness in a virtual world: An experimental paradigm testing how discrepancy between VR visual gradients and pedal resistance during stationary cycling affects breathlessness perception
Authors: Finnegan Sarah L. , Dearlove David J. , Morris Peter , Freeman Daniel , Sergeant Martin , Taylor Stephen , Pattinson Kyle T.S.
Published: June 2022

Introduction

The sensation of breathlessness is often attributed to perturbations in cardio-pulmonary physiology, leading to changes in afferent signals. New evidence suggests that these signals are interpreted in the light of prior “expectations”. A misalignment between afferent signals and expectations may underly unexplained breathlessness. Using a novel immersive virtual reality (VR) exercise paradigm, we investigated whether manipulating an individual’s expectation of effort (determined by a virtual hill gradient) may alter their perception of breathlessness, independent from actual effort (the physical effort of cycling).

Methods

Nineteen healthy volunteers completed a single experimental session where they exercised on a cycle ergometer while wearing a VR headset. We created an immersive virtual cycle ride where participants climbed up 100 m hills with virtual gradients of 4%, 6%, 8%, 10% and 12%. Each virtual hill gradient was completed twice: once with a 4% cycling ergometer resistance and once with a 6% resistance, allowing us to dissociate expected effort (virtual hill gradient) from actual effort (physical effort of pedalling). At the end of each hill, participants reported their perceived breathlessness. Linear mixed effects models were used to examine the independent contribution of actual effort and expected effort to ratings of breathlessness (0-10 scale).

Results

Expectation of effort (effect estimate ± std. error, 0.63 ± 0.11,p<0.001) and actual effort (0.81 ± 0.21,p<0.001) independently explained subjective ratings of breathlessness, with comparable contributions of 19% and 18%, respectively. Additionally, we found that effort expectation accounted for 6% of participants’ physical effort of pedalling and was a significant, independent predictor (0.09 ± 0.03;p=0.001).

Conclusions

An individuals’ expectation of effort is equally important for forming perceptions of breathlessness as the actual effort required to cycle. A new VR paradigm enables this to be experimentally studied and could be used to re-align breathlessness and enhance training programmes.
Three Imaging Endophenotypes Characterize Neuroanatomical Heterogeneity of Autism Spectrum Disorder
Authors: Hwang Gyujoon , Wen Junhao , Sotardi Susan , Brodkin Edward S. , Chand Ganesh B. , Dwyer Dominic B. , Erus Guray , Doshi Jimit , Singhal Pankhuri , Srinivasan Dhivya , Varol Erdem , Sotiras Aristeidis , Dazzan Paola , Kahn Rene S. , Schnack Hugo G. , Zanetti Marcus V. , Meisenzahl Eva , Busatto Geraldo F. , Crespo-Facorro Benedicto , Pantelis Christos , Wood Stephen J. , Zhuo Chuanjun , Shinohara Russell T. , Shou Haochang , Fan Yong , Koutsouleris Nikolaos , Gur Raquel E. , Gur Ruben C. , Satterthwaite Theodore D. , Wolf Daniel H. , Davatzikos Christos
Published: June 2022

Autism spectrum disorder (ASD) is associated with high structural heterogeneity in magnetic resonance imaging (MRI). This work uncovers three neuroanatomical dimensions of ASD (N=307) using machine learning methods and constructs their characteristic MRI signatures. The presence of these signatures, along with their clinical profiles and genetic architectures, are investigated in the general population. High expression of the first dimension (A1, “aging-related”) is associated with globally reduced brain volume, cognitive dysfunction, and aging-related genetic variants. The second dimension (A2, “schizophrenia-like”) is characterized by enlarged subcortical volume, antipsychotic medication use, and partially overlapping genetic underpinnings to schizophrenia. The third dimension (A3, “classical ASD”) is distinguished by enlarged cortical volume, high non-verbal cognitive performance, and genes and biological pathways implicating brain development and abnormal apoptosis. Thus, we propose a three-dimensional endophenotypic representation to construe the heterogeneity in ASD, which can support precision medicine and the discovery of the biological mechanisms of ASD.
Admixture mapping screening of CKD traits and risk factors in U.S. Hispanic/Latino individuals from Central America country-of-origin
Authors: Horimoto Andrea R.V.R. , Sun Quan , Lash James P. , Daviglus Martha L. , Cai Jianwen , Haack Karin , Cole Shelley A , Thornton Timothy A. , Browning Sharon R. , Franceschini Nora
Published: June 2022

Chronic kidney disease (CKD) is prevalent in Central America and ancestry-specific factors may contribute to CKD risk. To understand the genetic ancestry influences on CKD susceptibility, we conducted an admixture mapping of CKD traits and risk factors on 1,023 participants of the Hispanic Community Health Study/Study of Latinos who reported four-grandparents originating from the same Central America country. Admixture mapping signals were validated on 8,191 African Americans from the Women’s Health Initiative, 3,141 American Indians from the Strong Heart Study and 197,272 White individuals from the Million Veterans Program. We identified five novel ancestry-derived loci on chromosomes: 14 for albuminuria; 2, 6 and 9 for CKD; and 3 for type 2 diabetes (T2D). The 14q24.2 locus was validated in American Indians and consisted of two regions spanning theRGS6gene, in which the European (risk) and Native American (protective) ancestries had opposite effects for albuminuria. This locus was also identified using the traditional association mapping. Among the three CKD loci, the 6q25.3 African ancestry-derived locus atARID1Bgene, associated with increased risk for CKD, was validated in African Americans. The T2D locus at 3q22.2 encompasses theEPHB1andKYgenes and was validated in White individuals. U.S. Hispanic/Latino populations are culturally and genetically diverse. Our strategy of using grandparent country-of-origin for selection of a more genetically similar group likely helped the gene discovery. This study of CKD traits and risk factors in individuals from Central America country-of-origin provides new insights into the ancestry-of-origin influences on CKD in this population.
Enormity of anaemia and its determinant factors among lactating mothers in Northern Ghana: A case of nanton district
Authors: Yidaana Adadow , Weyori Enoch Weikem , Wemah Khadijah , Bernard Nkrumah , Abubakari Braimah Baba , Eugene Kuugbee Dogkotenge , Nuertey Benjamin , Yakubu Etowi Boye , Cheba Valentine Koyiri , Kujo Adatsi Richard
Published: June 2022

Background

Anemia remains one of the most severe and common public health conditions that predominantly affects children and women across the globe. It is defined as a condition in which the hemoglobin (Hb) concentration is less than 11.0 g/dl particularly in women. The World health organization report indicated that 20–50% of the world population was affected by iron deficiency anemia.

Method

An institutional cross-sectional study design was the method used through the data collection and management. Information was sought from four selected health centres across the nanton district with systematic sampling deployed to select respondents of interest. A sample of 420 respondents were obtained and processed for analysis. A bi-variate and multivariate analysis uncovered the associated factors and its predictiveness.

Results

The prevalence of anaemia in totality was 56.0% (95% CI 51.3%, 60.8%). The divergence of the blood concentration levels between the means of the anaemic and non anaemic group was statistically significance (F-stat=68.233, t-stat=-35.697, p<0.01). The multivariate statistical model showed that, lactating mothers who have suffered malaria episode(s) after delivery had a 94% chance of being anaemic [AOR = 0.054; (95% CI: 0.025, 0.119)]. Lack of post-partum iron supplementation increased the risk of having anaemia [AOR = 15.336; (95% CI: 6.112, 38.483)], and lactating mothers had higher risk [AOR = 1.927, (95% CI: 1.031, 3.602)] of developing anaemia with increasing ‘child’s age beyond three (3) months.

Conclusion

Anaemia remains very high in lactating mothers attributable to episodes of postpartum malaria, iron supplementation, and increasing ‘child’s age beyond 3 months. There is the need for public health interventions and measures such as extension of folic acid distribution and Intermittent Preventive Therapy (IPT) for malaria program to mothers at postnatal care and child welfare clinics across the region.
Corticosteroid Prescribing Practices at Dermatology Outpatient Departments of Tertiary Care Hospitals: A Multicenter, Cross Sectional Study
Authors: Sultana Nagina , Ferdoush Jannatul , Sarwar Wafa , Towfiq Hossain Sharif Mohammad , Hossain Arifa , Asma Mosammat
Published: June 2022

Background

In dermatology, corticosteroids are the most frequently prescribed medication group. The goal of this study was to examine the prescription pattern of glucocorticoids in patients with skin diseases in outpatient dermatology departments (OPD) in tertiary care hospitals.

Methods

A prospective, multi-centered, cross-sectional study was undertaken in the dermatology department of government affiliated private medical College hospitals in Chittagong, Bangladesh, from March 2021 to April 2022. A total of 450 prescriptions from dermatology out-patient department patients with skin diseases were obtained and evaluated for demographics, skin diseases, and corticosteroid use patterns.

Result

Out of 450 patients, majority belonged to the age group 21-40 years (44%) and were female (56%). The most frequent indication for prescribing corticosteroids were eczema (20%) urticaria (17%) and allergic Contact dermatitis (7%) and psoriasis (7%). The commonest corticosteroids used were betamethasone (19%) and Clobetasol proprionate (17%), Deflazacort (15%). Use of topical steroid combinations with Fusidic acid and Miconazole nitrate were prevalent, (4%) and (5%), respectively. Highly potent steroids were used in 51% cases whereas only 21% were given low potency steroids.

Conclusion

Physicians prefer highly potent corticosteroids, according to this study. To improve prescribing, physicians should receive ongoing medical education and be made aware of the irrational use of steroids. Researchers and policymakers can use the baseline data acquired in these studies to enhance judicial prescribing practices. Keywords: Corticosteroids, dermatology, prescribing pattern.
Persistent and reversible impacts of smoking on resting-state EEG in chronic smokers and successful long-term abstainers
Authors: Lee Hyeji , Jeon Yoonji , Yoo Cheolin , Seon HeeYoung , Park Jiwon , Hwang Minho , Baek Kwangyeol , Chung Dongil
Published: June 2022

Smoking is a severe addictive health risk behavior and notorious for the high likelihood of relapse after attempted cessation. Such an addictive pattern in smoking has been associated with neurobiological changes in the brain. However, little is known whether the neural changes associated with chronic smoking persist after a long period of successful abstinence. To address this question, we examined resting state EEG (rsEEG) in heavy smokers who have been smoking for 20 years or more, past-smokers who have been successfully abstaining for 20 years or more, and non-smokers. Compared with chronic current- or past-smokers, non-smokers showed higher relative power in theta frequency band, showcasing long-lasting effects of smoking on the brain. A few rsEEG features in alpha frequency band also revealed reversible impacts of smoking, such that only current-smokers, but not past-smokers, showed distinctively higher patterns than non-smokers in their relative power, EEG reactivity—power changes between eyes-closed and eyes-open conditions—, and coherence between channels. Furthermore, rsEEG feature differences between current- and past-smokers were accounted for by individuals’ self-reported smoking history and nicotine dependence. These data suggest long-lasting impacts of chronic smoking on the brain that are dissociable from the neural changes reversible with long-term abstinence.
A method for rapid machine learning development for data mining with Doctor-In-The-Loop
Authors: Bull Neva J , Honan Bridget , Spratt Neil J. , Quilty Simon
Published: June 2022

Classifying free-text from historical databases into research-compatible formats is a barrier for clinicians undertaking audit and research projects. The aim of this study was to evaluate the accuracy and speed of an interactive active machine-learning model training methodology for classifying free text from clinical notes into customised researcher-defined categories. A user interface for medical experts to train and evaluate the algorithm was created. Data requiring coding in the form of two databases of free-text clinical notes. Medical experts defined categories relevant to research projects and performed ‘label-train-evaluate’ loops on the training data set. A separate dataset was used for validation, with the medical experts blinded to the label given by the algorithm.

The first dataset was 32,034 death certificate records from Northern Territory Births Deaths and Marriages, which were coded into 3 categories: haemorrhagic stroke, ischaemic stroke or no stroke. The second dataset was 12,039 recorded episodes of aeromedical retrieval from two prehospital and retrieval services in Northern Territory, Australia, which were coded into 5 categories: medical, surgical, trauma, obstetric or psychiatric.

For the first dataset, macro-accuracy of the algorithm was 94.7%. For the second dataset, macro-accuracy was 92.4%. The time taken to develop and train the algorithm was 124 minutes for the death certificate coding, and 144 minutes for the aeromedical retrieval coding. This machine-learning training method was able to classify free-text clinical notes quickly and accurately from two different health datasets into categories of relevance to clinicians undertaking health service research.
Risdiplam in adult non-sitter patients with 5q spinal muscular atrophy: a non-interventional, single centre, observational cohort study
Authors: Ñungo Garzón Nancy Carolina , Castellano Inmaculada Pitarch , Sevilla Teresa , Vázquez-Costa Juan F
Published: June 2022

Objective

To describe the safety and efficacy of risdiplam in non-sitter adult patients with 5q spinal muscular atrophy (SMA).

Methods

Type 2 SMA adult patients, who were not eligible for nusinersen, were offered risdiplam through the expanded access program. Patients were followed up with a battery of scales and clinical measures.

Results

Six non-sitter patients (17 – 46 years old) were treated with risdiplam. One patient reported mild adverse events (dyspepsia and headache). After one year of treatment, all patients showed clinically meaningful improvements in at least one scale and none of them showed any clinically meaningful deterioration. Two patients showed a clinically significant increase in the body mass index and other two in the revised upper limb module. Moreover, clinically meaningful improvements were found in motor (axial and upper limbs), bulbar (speech and swallowing) and respiratory (coughing) domains of functional scales, in five patients. Four subjects achieved at least one of the goals set with the goal attainment scale (GAS).

Discussion

This series suggests the safety and efficacy of risdiplam in non-sitter adult SMA patients. In these patients, functional scales and GAS are more appropriate than motor scales to detect changes, because they include axial, bulbar and respiratory domains.
Confidence-based laboratory test reduction recommendation algorithm
Authors: Huang Tongtong , Li Linda T. , Bernstam Elmer V. , Jiang Xiaoqian
Published: June 2022

Unnecessary laboratory tests present health risks and increase healthcare costs. We propose a new deep learning model to identify unnecessary hemoglobin (Hgb) tests for patients admitted to the hospital. Machine learning models might generate less reliable results due to noisy inputs containing low-quality information. We estimate prediction confidence to measure reliability of predicted results. Using a “select and predict” design philosophy, we aim to maximize prediction performance by selectively considering samples with high prediction confidence for recommendations. We use a conservative definition of unnecessary laboratory tests, which we define as stable and below the lower normal bound (LBNR). Our model accommodates irregularly sampled observational data to make full use of variable correlations (i.e., with other laboratory test values) and temporal dependencies (i.e., previous observations) in order to select candidates for training and prediction. Using data collected from a teaching hospital in Houston, our model achieves Hgb prediction performance with a normality AUC at 95.89% and a Hgb stability AUC at 95.94%, while recommending a reduction of 9.91% of Hgb tests that were deemed unnecessary.
Neural fingerprints of Alice in Wonderland Syndrome in patients with migraine with aura
Authors: Mastria Giulio , Mancini Valentina , Viganò Alessandro , Piervincenzi Claudia , Petsas Nikolaos , Puma Marta , Giannì Costanza , Pantano Patrizia , Di Piero Vittorio
Published: June 2022

Background

the Alice in Wonderland syndrome (AIWS) is a transient neurological disturbance characterized by visual and somatosensory misperceptions most frequently associated with migraine. The heterogeneity of the etiologies and techniques applied to investigate the reported cases have so far prevented to draw strong conclusions about the origin of AIWS symptoms. Some lines of evidence suggest that AIWS and migraine might share common pathophysiological mechanisms, therefore we set out to investigate the common and distinct neurophysiological alterations associated with these conditions in a population of migraineurs.

Methods

we acquired resting-state fMRI data from 12 migraine patients with AIWS, 12 patients with migraine with typical aura (MA) and 24 age-matched healthy controls (HC). We then compared the interictal thalamic seed-to-voxel and ROI-to-ROI cortico-cortical resting-state functional connectivity between the 3 groups.

Results

we found a common pattern of altered thalamic connectivity in MA and AIWS, compared to HC, with more profound and diffuse alterations observed in AIWS. The ROI-to-ROI functional connectivity analysis highlighted an increased connectivity between a lateral occipital region corresponding to area V3 and the posterior part of the superior temporal sulcus (STS) in AIWS, compared to both MA and HC. The posterior STS is a multisensory integration area, while area V3 is considered the starting point of the cortical spreading depression (CSD), the neural correlate of migraine aura. This interictal hyperconnectivity might increase the probability of the CSD to directly diffuse to the posterior STS or trigger a diaschisis phenomenon causing the AIWS symptoms during the ictal phase.

Conclusions

taken together, these results suggest that AIWS in migraineurs might be a form of complex migraine aura, characterized by the involvement of associative and multisensory integration areas. The altered connectivity between early visual and multisensory associative areas provides a model for the pathophysiology of AIWS associated with other transient neurological conditions or with a structural etiology.
Mediators of the association between childhood BMI and educational attainment: analysis of a UK prospective cohort study
Authors: Bowman Kirsty , Cadman Tim , Robinson Oliver , Hughes Amanda , Heron Jon , Segal Alexa Blair , Huerta Maria Carmen , Howe Laura D
Published: June 2022

Background

Higher BMI in childhood is associated with lower academic achievement.

Objective

To explore potential pathways linking childhood BMI with educational attainment.

Methods

In the Avon Longitudinal Study of Parents and Children prospective cohort study (N=6234), we used structural equation models to assess the association between BMI z-scores at 11.7 years and educational attainment at 16 (General Certificate of Secondary Education (GCSE) results). Depressive symptoms, externalising symptoms, bullying, pressure to lose weight, and school enjoyment were considered as potential mediators.

Results

Higher BMI z-scores were associated with lower GCSE scores (total effect: females β = -3.20 95% CI -5.15, -1.26; males β = -2.98 95% CI -5.12, -0.84). Depressive symptoms and externalising symptoms partially mediated this association in females (indirect effect: β = -0.35 95% CI -0.63, -0.06, proportion mediated = 11%; β = -0.84 95% CI -1.77, 0.10, proportion mediated = 26%, respectively). In males, there was some evidence that the association was partially mediated by bullying (indirect effect β = -0.35 95% CI -0.74, 0.03, proportion mediated = 12%).

Conclusions

The association between childhood BMI and educational attainment may be partially mediated by depressive symptoms and externalising symptoms in females, and by bullying in males.
Multiple cohort study of hospitalized SARS-CoV-2 in-host infection dynamics: parameter estimates, sensitivity and the eclipse phase profile
Authors: Korosec Chapin S. , Betti Matthew I. , Dick David W. , Ooi Hsu Kiang , Moyles Iain R. , Wahl Lindi M. , Heffernan Jane M.
Published: June 2022

Within-host SARS-CoV-2 modelling studies have been published throughout the COVID-19 pandemic. These studies contain highly variable numbers of individuals and capture varying timescales of pathogen dynamics; some studies capture the time of disease onset, the peak viral load and subsequent heterogeneity in clearance dynamics across individuals, while others capture late-time post-peak dynamics. In this study, we curate multiple previously published SARS-CoV-2 viral load data sets, fit these data with a consistent modelling approach, and estimate the variability of in-host parameters including the basic reproduction number, R0. We find that fitted dynamics can be highly variable across data sets, and highly variable within data sets, particularly when key components of the dynamic trajectories (e.g. peak viral load) are not represented in the data. Further, we investigated the role of the eclipse phase time distribution in fitting SARS-CoV-2 viral load data. By varying the shape parameter of an Erlang distribution, we demonstrate that models with either no eclipse phase, or with an exponentially-distributed eclipse phase, offer significantly worse fits to these data, whereas models with less dispersion around the mean eclipse time (shape parameter two or more) offered the best fits to the available data.
Contemporary social context and patterns of prenatal cannabis use in Canada following legalization: a secondary analysis of prospective cohort data
Authors: Chaput Kathleen H. , Sanghera Harleen , Sekandary Sanam , McMorris Carly , Metcalfe Amy , Wood Stephen , McNeil Deborah , McDonald Sheila
Published: June 2022

Background

The epidemiology of prenatal cannabis use in Canada following legalization remains unknown despite increasing evidence for associated health risks. Our study aimed to identify current risk factors for, and patterns of, prenatal cannabis use and second-hand cannabis exposure in Alberta.

Methods

We conducted a secondary analysis of prospective data from a 2019 study in Calgary AB, of 153 pregnant (<28 weeks gestation at enrollment), English-speaking Alberta residents. We conducted descriptive analyses of prenatal cannabis use patterns (timing, frequency, dose, modes and reasons for use) and logistic regression to identify risk factors for direct use and second-hand exposure.

Results

Odds of prenatal cannabis use were significantly higher among those who did not own their home (Odds Ratio (OR) 3.1; 95% CI:1.6-9.6), smoked tobacco prenatally (OR 3.3,95% CI:1.2-9.3) and used illicit substances in the past (OR 3.2; 95% CI:1.7-9.9), and lower for those consuming alcohol prenatally (OR 0.3, 0.12-0.89). Among the 90 (58%) participants who used cannabis prenatally, the majority used for medicinal reasons (96%), at least daily (67%), by smoking (88%), in all trimesters of pregnancy (66%). Although reported dose-per-use was commonly low, cumulative doses over pregnancy were high.

Interpretation

Our study finds marked differences in prenatal cannabis use risk factors, and patterns of more frequent use sustained throughout pregnancy with perceived medicinal indications than pre-legalization studies. Prenatal care providers should include cannabis explicitly in medication counselling. Further prospective studies are needed as the impacts of prenatal cannabis on maternal and infant health in Canada may currently be underestimated.
The burden of RSV-associated illness in children aged <5 years, South Africa, 2011 to 2016
Authors: Moyes Jocelyn , Tempia Stefano , Walaza Sibongile , McMorrow Meredith L. , Treurnicht Florette , Wolter Nicole , von Gottberg Anne , Kahn Kathleen , Cohen Adam L , Dawood Halima , Variava Ebrahim , Cohen Cheryl
Published: June 2022

Background

Vaccines and monoclonal antibodies to protect the very young infant against respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost effectiveness analyses.

Methods

We combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged <5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the <1-year age group, by 3-month intervals until 2 years and then 12 monthly intervals to <5 years for medically and non-medically attended illness.

Results

We estimated a mean annual total (medically and non-medically attended) of 264,112 (95% Confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) cases of RSV-associated SARI (4.7% and 1.7% of the population aged <5 years, respectively). RSV-associated ARI incidence was highest in 2 month-old infants (18,361/100,000 population, 95% CI 9,336-28,466). The highest incidence of RSV-associated SARI was in the <1-month age group 14,674/100,000 (95% CI 11,175-19,645). RSV-associated deaths were highest in the first and second month of life (8.7 deaths/100 000 (95% CI 6.3-11.2) and 8.7 deaths/100 000 (95% CI 6.4-11.4), respectively).

Conclusion

Due to the high burden of RSV-associated illness, specifically SARI cases in young infants, maternal vaccination and monoclonal antibody products delivered at birth could prevent significant RSV-associated disease burden.
Synthetic regulatory genomics uncovers enhancer context dependence at the Sox2 locus
Authors: Brosh Ran , Coelho Camila , Ribeiro-dos-Santos André M. , Ellis Gwen , Hogan Megan S. , Ashe Hannah J. , Somogyi Nicolette , Ordoñez Raquel , Luther Raven D. , Huang Emily , Boeke Jef D. , Maurano Matthew T.
Published: June 2022

Expression of Sox2 in mouse embryonic stem cells (mESCs) depends on a distal regulatory cluster of DNase I hypersensitive sites (DHSs), but their individual contributions and degree of independence remain a mystery. Here, we comprehensively analyze the regulatory architecture of Sox2 at its endogenous locus using Big-IN to scarlessly integrate DNA payloads ranging up to 143 kb. We analyzed 83 payloads incorporating deletions, rearrangements, and inversions affecting single or multiple DHSs, as well as surgical alterations to transcription factor (TF) recognition sequences. Multiple mESC clones were derived for each payload, sequence-verified, and analyzed to establish the necessity and sufficiency of genomic features for Sox2 expression. We found that two LCR DHSs comprising a handful of key TF recognition sequences were each sufficient to autonomously sustain significant expression in mESCs. However, three additional LCR DHSs were entirely context-dependent, in that they showed no activity alone but could dramatically augment activity of the core DHSs. Our synthetic regulatory genomics approach demonstrates that composite regulatory elements can be reduced to a tractable set of essential sequence features, and is readily scalable to investigate regulatory architecture at other key loci genome-wide.
Tailoring and optimizing fatty acid production by oleaginous yeasts through the systematic exploration of their physiological fitness
Authors: Duman-Özdamar Zeynep Efsun , Martins dos Santos Vitor A.P. , Hugenholtz Jeroen , Suarez-Diez Maria
Published: June 2022

Background

The use of palm oil for our current needs is unsustainable. Replacing palm oil with oils produced by microbes through the conversion of sustainable feedstocks is a promising alternative. However, there are major technical challenges that must be overcome to enable this transition. Foremost among these challenges is the stark increase in lipid accumulation and production of higher content of specific fatty acids. Therefore, there is a need for more in-depth knowledge and systematic exploration of the oil productivity of the oleaginous yeasts. In this study, we cultivated Cutaneotrichosporon oleaginosus and Yarrowia lipolytica at various C/N ratios and temperatures in a defined medium with glycerol as carbon source and urea as nitrogen source. We ascertained the synergistic effect between various C/N ratios of a defined medium at different temperatures with Response Surface Methodology (RSM) and explored the variation in fatty acid composition through Principal Component Analysis.

Results

By applying RSM, we determined a temperature of 30 °C and a C/N ratio of 175 g/g to enable maximal oil production by C. oleaginosus and a temperature of 21 °C and a C/N ratio of 140 g/g for Y. lipolytica. We increased production by 71 % and 66 % respectively for each yeast compared to the average lipid accumulation in all tested conditions. Modulating temperature enabled us to steer the fatty acid compositions. Accordingly, switching from higher temperature to lower cultivation temperature shifted the production of oils from more saturated to unsaturated by 14 % in C. oleaginosus and 31 % in Y. lipolytica. Higher cultivation temperatures resulted in production of even longer saturated fatty acids, 3 % in C. oleaginosus and 1.5 % in Y. lipolytica.

Conclusions

In this study, we provided the optimum C/N ratio and temperature for C. oleaginosus and Y. lipolytica by RSM. Additionally, we demonstrated that lipid accumulation of both oleaginous yeasts was significantly affected by the C/N ratio and temperature. Furthermore, we systematically analyzed the variation in fatty acids composition and proved that changing the C/N ratio and temperature steer the composition. We have further established these oleaginous yeasts as platforms for production of tailored fatty acids.
Differences in neurotoxic outcomes of organophosphorus pesticides revealed via multi-dimensional screening in adult and regenerating planarians
Authors: Ireland Danielle , Zhang Siqi , Bochenek Veronica , Hsieh Jui-Hua , Rabeler Christina , Meyer Zane , Collins Eva-Maria S.
Published: June 2022

Organophosphorus pesticides (OPs) are a chemically diverse class of commonly used insecticides. Epidemiological studies suggest that low dose chronic prenatal and infant exposures can lead to life-long neurological damage and behavioral disorders. While inhibition of acetylcholinesterase (AChE) is the shared mechanism of acute OP neurotoxicity, OP-induced developmental neurotoxicity (DNT) can occur independently and/or in the absence of significant AChE inhibition, implying that OPs affect alternative targets. Moreover, different OPs can cause different adverse outcomes, suggesting that different OPs act through different mechanisms. These findings emphasize the importance of comparative studies of OP toxicity. Freshwater planarians are an invertebrate system that uniquely allows for automated, rapid and inexpensive testing of adult and developing organisms in parallel to differentiate neurotoxicity from DNT. Effects found only in regenerating planarians would be indicative of DNT, whereas shared effects may represent neurotoxicity. We leverage this unique feature of planarians to investigate potential differential effects of OPs on the adult and developing brain by performing a comparative screen to test 7 OPs (acephate, chlorpyrifos, dichlorvos, diazinon, malathion, parathion and profenofos) across 10 concentrations in quarter-log steps. Neurotoxicity was evaluated using a wide range of quantitative morphological and behavioral readouts. AChE activity was measured using an Ellman assay. The toxicological profiles of the 7 OPs differed across the OPs and between adult and regenerating planarians. Toxicological profiles were not correlated with levels of AChE inhibition. Twenty-two “mechanistic control compounds” known to target pathways suggested in the literature to be affected by OPs (cholinergic neurotransmission, serotonin neurotransmission, endocannabinoid system, cytoskeleton, adenyl cyclase and oxidative stress) and 2 negative controls were also screened. When compared with the mechanistic control compounds, the phenotypic profiles of the different OPs separated into distinct clusters. The phenotypic profiles of adult vs regenerating planarians exposed to the OPs clustered differently, suggesting some developmental-specific mechanisms. These results further support findings in other systems that OPs cause different adverse outcomes in the (developing) brain and build the foundation for future comparative studies focused on delineating the mechanisms of OP neurotoxicity in planarians.
Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons
Authors: Venkatesan Sridevi , Chen Tianhui , Liu Yupeng , Turner Eric E , Tripathy Shreejoy , Lambe Evelyn K
Published: June 2022

Attention depends on cholinergic excitation of prefrontal neurons but is sensitive to perturbation of α5-containing nicotinic receptors encoded byChrna5. However,Chrna5-expressing (Chrna5+) neurons remain enigmatic, despite their potential as a target to improve attention. Here, we generate complex transgenic mice to probe Chrna5+ neurons and their sensitivity to endogenous acetylcholine. Through opto-physiological experiments, we discover that Chrna5+ neurons contain a distinct population of acetylcholine super-responders. Leveraging single-cell transcriptomics, we discover molecular markers conferring subplate identity on this subset. We determine that Chrna5+ super-responders express a unique complement of GPI-anchored lynx prototoxin genes (Lypd1, Ly6g6e, andLypd6b), predicting distinct nicotinic receptor regulation. To manipulate lynx regulation of endogenous nicotinic responses, we developed a pharmacological strategy guided by transcriptomic predictions. Overall, we revealChrna5-Cre mice as a transgenic tool to target the diversity of subplate neurons in adulthood, yielding new molecular strategies to manipulate their cholinergic activation relevant to attention disorders.
From Easy to Hopeless - Predicting the Difficulty of Phylogenetic Analyses
Authors: Haag Julia , Höhler Dimitri , Bettisworth Ben , Stamatakis Alexandros
Published: June 2022

Phylogenetic analyses under the Maximum Likelihood model are time and resource intensive. To adequately capture the vastness of tree space, one needs to infer multiple independent trees. On some datasets, multiple tree inferences converge to similar tree topologies, on others to multiple, topologically highly distinct yet statistically indistinguishable topologies. At present, no method exists to quantify and predict this behavior. We introduce a method to quantify the degree of difficulty for analyzing a dataset and present Pythia, a Random Forest Regressor that accurately predicts this difficulty. Pythia predicts the degree of difficulty of analyzing a datasetpriorto initiating Maximum Likelihood based tree inferences. Pythia can be used to increase user awareness with respect to the amount of signal and uncertainty to be expected in phylogenetic analyses, and hence inform an appropriate (post-)analysis setup. Further, it can be used to select appropriate search algorithms for easy-, intermediate-, and hard-to-analyze datasets.
(-)-Gossypol inhibition of musashi-mediated forgetting improves memory and age-dependent memory decline in Caenorhabditis elegans
Authors: Mastrandreas Pavlina , Arnold Andreas , Boglari Csaba , de Quervain Dominique J.-F. , Stetak Attila , Papassotiropoulos Andreas
Published: June 2022

Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that MSI1 actively promotes forgetting upon associative learning via a 3’UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human MSI1 and MSI2 under the endogenous musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (−)-gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy we found no changes in MSI-1 protein abundance following (−)-gossypol treatment, suggesting that musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (−)-gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (−)-gossypol can regulate the musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (−)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of musashi might represent a promising approach for memory modulation.
Bcmap: fast alignment-free barcode mapping for linked-read sequencing data
Authors: Lüpken Richard , Krannich Thomas , Kehr Birte
Published: June 2022

The bottleneck for genome analysis will soon shift from sequencing cost to computationally expensive read alignment. Here, we propose to circumvent full read alignment computation on linked-read sequencing data when only portions of the genome are of interest. Our novel barcode mapping approach ‘bcmap’ indexes and places barcoded read sets on the reference genome, thereafter allowing the extraction of reads originating from genomic regions of interest directly from FASTQ files. We demonstrate that bcmap is accurate and an order of magnitude faster than full read alignment. As example application, we use bcmap to locally assemble a known variant region.
Flower patterns improve foraging efficiency in bumblebees independent of nectary guidance
Authors: Richter Robin , Dietz Alexander , Foster James , Spaethe Johannes , Stöckl Anna
Published: June 2022

Colourful patterns on flowers are thought to benefit both pollinators and the plants they visit, by increasing the plants’ pollination success via an improved foraging efficiency of its pollinators. This increased efficiency is thought to result from a guidance effect of the flower patterns, correspondingly termed ‘nectar guides’, which indicate the position of the nectary to visiting pollinators. While it is well established that flower patterns play an important role in flower choice, the mechanisms underlying their function for flower-visiting insects remain poorly understood. In this study, we quantified the contributions of patterns to all phases of flower interaction in the buff-tailed bumblebee (Bombus terrestris). We analysed their flight paths, as well as landing positions and walking tracks on artificial flowers with different pattern types. We reveal that flower patterns improved the overall foraging efficiency of the bees by up to 30%, by guiding their approach flight, landing positions, and departure decisions. Surprisingly, these effects were not related to nectary guidance. Since we conducted the experiments with experienced foragers, which represent the majority of insect pollinators active in nature, the newly described nectary-independent guidance effects of flower patterns are of fundamental importance to plant-pollinator interactions under natural conditions.
Variability of functional and biodiversity responses to perturbations is predictable and informative
Authors: Orr James A. , Piggott Jeremy J. , Jackson Andrew L. , Jackson Michelle C. , Arnoldi Jean-François
Published: June 2022

Perturbations such as climate change, invasive species and pollution, impact the functioning and diversity of ecosystems. But because there is no unique way to measure functioning and diversity, this leads to a ubiquitous and overwhelming variability in community-level responses, that is often seen as a barrier to prediction in ecology. Here, we show that this variability can instead provide insights into hidden features of a community’s functions and responses to perturbations. By first analysing a dataset of global change experiments in microbial soil systems we show that variability of functional and diversity responses to a given perturbation is not random: aggregate properties that are thought to be mechanistically similar tend to respond similarly. We then formalise this intuitive observation to demonstrate that the variability of community-level responses to perturbations is not only predictable, but that it can also be used to access hidden and useful information about population-level responses to perturbations (i.e., response diversity and scaling by species biomass). Our theory offers a baseline expectation for the variability of community-level responses to perturbations and helps to explain the complexity of ecological responses to global change.

Significance Statement

Measures of biodiversity and ecosystem functioning show highly variable responses to a given perturbation. This variability is traditionally thought of as reflecting our inability to predict ecological responses to global change. Our work, however, finds that variability of community-level responses is itself predictable and can even be used to gain insights about how species respond to perturbations and collectively contribute to ecosystem functions.