bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving early infant diagnosis for HIV-exposed infants using unmanned aerial vehicles versus motorcycles for blood sample in Conakry, Guinea: a comparative cost-effectiveness analysis
Authors: Inghels Maxime , Mee Paul , Diallo Oumou Hawa , Cissé Mohamed , Nelson David , Tanser Frank , Asghar Zahid , Koita Youssouf , Laborde-Balen Gabrièle , Breton Guillaume
Published: June 2023

Background

Early infant diagnosis (EID) for HIV-exposed infants is essential due to high mortality during the first months of their lives. In Conakry (Guinea) timely EID is difficult as traffic congestion prevents the rapid transport of blood samples to the central laboratory. We investigated the cost-effectiveness of transporting EID blood samples by unmanned aerial vehicles (UAV), also known as drones.

Methods and Findings

We conducted a cost-effectiveness comparative analysis between EID blood samples transportation by UAV compared to motorcycle using Monte Carlo simulations. Incremental cost-effectiveness ratio (ICER) per life-year gained was computed with local annual GDP per capita (US$1,194) set as the threshold. Simulation models included parameters such as consultation timing (e.g. time of arrival), motorcycle and UAV characteristics, weather and traffic conditions. Sensitivity analyses were conducted. Over a 5-year program and 778 HIV-exposed infants seen in consultation on average every year, the UAV transport strategy was able to save 49.6 life-years [90% PI: -1.3 –100.5]. The UAV strategy costs an additional of $12.4 [10.2 –14.6] per infant tested compared to the motorcycle one. With an ICER of $979 per life-year gained, the UAV transportation strategy was below the cost-effectiveness threshold. The ICER is primarily sensitive to weather-related downtime, UAV loss risk, number of HIV-infected infants and travel time saved by UAV.

Conclusion

The transportation of EID blood samples by UAVs in Conakry was found to be cost effective in that context. EID blood samples transportation by UAV could be a cost-effective strategy in other countries with traffic congestion and low rate of EID.

What is already known on this topic

The cost-effectiveness of Unmanned aerial vehicles—UAV (drones) transportation for blood products remains limited in the Global South.

We aimed to investigate the cost-effectiveness of urgent blood sample transportation for early HIV infant diagnosis (EID) by UAV compared to motorcycle in the region of Conakry, Guinea.

What this study adds

We found that UAV transportation for EID was faster, saved more lives than motorcycles and was cost-effective (Incremental cost-effectiveness ratio: US$979 per life-year gained)

The effectiveness of the drone strategy was primarily sensitive to weather-related downtime, UAV loss risk, number of HIV-infected infants and travel time saved by UAV.

How this study might affect research, practice or policy

Our study suggests that the transportation of EID blood could be cost-effective in the Conakry region. Other low-or middle-income cities experiencing important traffic congestion with low EID could benefit from this strategy.
Viraemia and HIV drug resistance among people receiving dolutegravir versus efavirenz-based first-line antiretroviral therapy
Authors: Dorward Jienchi , Sookrajh Yukteshwar , Lessells Richard , Bulo Elliot , Bodley Nicola , Singh Lavanya , Moodley Pravikrishnen , Samsunder Natasha , Drain Paul K. , Hayward Gail , Butler Christopher C , Garrett Nigel
Published: June 2023

Limited data exists to inform management of viraemia among people receiving dolutegravir-based first-line ART in low- and middle-income countries. Among South-Africans with viraemia ≥1000copies/mL receiving dolutegravir (n=43) and efavirenz (n=37), we found no dolutegravir resistance, but high efavirenz resistance (66.7%). 12-week resuppression was higher with dolutegravir (85%) versus efavirenz (38%).
Development and validation of a neural network-based survival model for mortality in ischemic heart disease
Authors: Holm Peter C. , Haue Amalie D. , Westergaard David , Röder Timo , Banasik Karina , Tragante Vinicius , Christensen Alex H. , Thomas Laurent , Nøst Therese H. , Skogholt Anne-Heidi , Iversen Kasper K. , Pedersen Frants , Høfsten Dan E. , Pedersen Ole B. , Ostrowski Sisse Rye , Ullum Henrik , Svendsen Mette N. , Gjødsbøl Iben M. , Gudnason Thorarinn , Guðbjartsson Daníel F. , Helgadottir Anna , Hveem Kristian , Køber Lars V. , Holm Hilma , Stefansson Kari , Brunak Søren , Bundgaard Henning
Published: June 2023

Background

Current risk prediction models for ischemic heart disease (IHD) use a limited set of established risk factors and are based on classical statistical techniques. Using machine-learning techniques and including a broader panel of features from electronic health records (EHRs) may improve prognostication.

Objectives

Developing and externally validating a neural network-based time-to-event model (PMHnet) for prediction of all-cause mortality in IHD.

Methods

We included 39,746 patients (training: 34,746, test: 5,000) with IHD from the Eastern Danish Heart Registry, who underwent coronary angiography (CAG) between 2006-2016. Clinical and genetic features were extracted from national registries, EHRs, and biobanks. The feature-selection process identified 584 features, including prior diagnosis and procedure codes, laboratory test results, and clinical measurements. Model performance was evaluated using time-dependent AUC (tdAUC) and the Brier score. PMHnet was benchmarked against GRACE Risk Score 2.0 (GRACE2.0), and externally validated using data from Iceland (n=8,287). Feature importance and model explainability were assessed using SHAP analysis.

Findings

On the test set, the tdAUC was 0.88 (95% CI 0.86-0.90, case count, cc=196) at six months, 0.88(0.86-0.90, cc=261) at one year, 0.84(0.82-0.86, cc=395) at three years, and 0.82(0.80-0.84, cc=763) at five years. On the same data, GRACE2.0 had a lower performance: 0.77 (0.73-0.80) at six months, 0.77(0.74-0.80) at one year, and 0.73(0.70-0.75) at three years. PMHnet showed similar performance in the Icelandic data.

Conclusion

PMHnet significantly improved survival prediction in patients with IHD compared to GRACE2.0. Our findings support the use of deep phenotypic data as precision medicine tools in modern healthcare systems.
Real-World Evaluation of an Automated Algorithm to Detect Patients with Potentially Undiagnosed Hypertension in an Ethnically Diverse, Large Health System in Hawaiʻi
Authors: Thompson Mika D. , Wu Yan Yan , Nett Blythe , Ching Lance K. , Taylor Hermina , Lemmen Tiffany , Sentell Tetine L. , McGurk Meghan D. , Pirkle Catherine M.
Published: June 2023

Objective

This real-world evaluation considers an algorithm designed to detect patients with potentially undiagnosed hypertension, receiving routine care, in a large health system in Hawaiʻi. It quantifies patients identified as potentially undiagnosed with hypertension, summarizes the individual, clinical, and health system factors associated with undiagnosed hypertension, and examines if the COVID-19 pandemic impacted detection.

Methods

We analyzed the electronic health records (EHR) of patients treated across 6 clinics from 2018-2021. We calculated total patients with potentially undiagnosed hypertension and compared patients flagged for undiagnosed hypertension to those with diagnosed hypertension and to the full patient panel across individual characteristics, clinical and health system factors (e.g., clinic of care), and timing. Modified Poisson regression was used to calculate crude and adjusted risk ratios.

Results

Among the eligible patients (N=13,364), 52.6% had been diagnosed with hypertension, 2.7% were flagged as potentially undiagnosed, and 44.6% had no evidence of hypertension. Factors associated with a higher risk of potentially undiagnosed hypertension included: individual characteristics (ages 40-84 compared to 18-39 years), clinical (lack of diabetes diagnosis) and health system factors (clinic site and being a Medicaid versus a Medicare beneficiary), and timing (readings obtained after the COVID-19 Stay-At-Home Order in Hawaiʻi).

Conclusions

This evaluation provided evidence that a clinical algorithm implemented within a large health systems’s EHR could detect patients in need of follow-up to determine hypertension status, and it identified key individual characteristics, clinical and health system factors, and timing considerations that may contribute to undiagnosed hypertension among patients receiving routine care.
Collective synchrony of mating signals modulated by ecological cues and social signals in bioluminescent sea fireflies
Authors: Hensley Nicholai M. , Rivers Trevor J. , Gerrish Gretchen A. , Saha Raj , Oakley Todd H.
Published: June 2023

Individuals often employ simple rules that can emergently synchronise behaviour. Some collective behaviours are intuitively beneficial, but others like mate signalling in leks occur across taxa despite theoretical individual costs. Whether disparate instances of synchronous signalling are similarly organised is unknown, largely due to challenges observing many individuals simultaneously. Recording field collectives andex situplayback experiments, we describe principles of synchronous bioluminescent signals produced by marine ostracods (Crustacea; Luxorina) that seem behaviorally convergent with terrestrial fireflies, and with whom they last shared a common ancestor over 500 mya. Like synchronous fireflies, groups of signalling males use visual cues (intensity and duration of light) to decide when to signal. Individual ostracods also modulate their signal based on the distance to nearest neighbours. During peak darkness, luminescent “waves” of synchronous displays emerge and ripple across the sea floor every ∼60 seconds, but such periodicity decays within and between nights after the full moon. Our data reveal these bioluminescent aggregations are sensitive to both ecological and social light sources. Because the function of collective signals is difficult to dissect, evolutionary convergence, like in the synchronous visual displays of diverse arthropods, provides natural replicates to understand the generalities that produce emergent group behaviour.
The effect of Vitamin D (1,25-(OH)2-D3) on human theca and granulosa cell function
Authors: Seaward Brain Henrietta Philippa , Georgiou Christiana , Mason Helen D , Rice Suman
Published: June 2023

Numerous observational and interventional studies have investigated the link between Vitamin D (VD) deficiency and reproductive outcomes, with contradictory results. VD is known to regulate steroidogenic enzymes crucial for human granulosa and cumulus cell function and genes that play a critical role in folliculogenesis have a vitamin D response element (VDRE) on their promoters. This study investigated whether deficient levels of 1,25-(OH)2-D3 altered ovarian cell function; and if the ovary could obtain bioactive 1,25-(OH)2-D3 via local enzymatic expression ofCYP27B1, to counteract systemic deficiency. A variety of cells and tissues were used for thein vitroexperiments as practicable.

We have shown for the first time an increase in VDR expression inthecaof larger compared to smaller follicles, which along with the ability of 1,25-(OH)2-D3 to decrease Anti-Mullerian hormone (AMH) expression, supports a role for 1,25-(OH)2-D3 in theca and granulosa cell function. Conversely, we have shown that very levels of 1,25-(OH)2-D3 equivalent to hypovitaminosis, inhibited thecal production of androstenedione and cAMP-driven E2 production. Human thecal and unluteinised GC are incredibly hard to obtain for research purposes, highlighting the uniqueness of our data set. For the first time we have demonstrated that deficient levels of 1,25-(OH)2-D3 also down-regulated insulin receptor expression, potentially reducing insulin sensitivity. We have shown that the ovary expressesCYP27B1allowing it to make local bioactive 1,25-(OH)2-D3 which along with the upregulation in VDR expression in all ovarian cellular compartments, could be protective locally in counteracting systemic VD deficiency. To conclude a severely deficient VD environment (<2nM or <1ng/ml) could contribute to impaired ovarian cell function and hence potentially affect folliculogenesis/ovulation, but levels associated with mild deficiency may have less impact, apart from in the presence of hyperinsulinemia and insulin resistance.
ITPK1 regulates jasmonate-controlled root development inArabidopsis thaliana
Authors: Pullagurla Naga Jyothi , Shome Supritam , Yadav Ranjana , Laha Debabrata
Published: June 2023

Jasmonic acid (JA) is a plant hormone that regulates a plethora of physiological processes including immunity and development and is perceived by the F-Box protein, Coronatine-insensitive protein 1(COI1). The discovery of inositol phosphates (InsPs) in the COI1 receptor complex highlights their role in JA perception. InsPs are phosphate-rich signaling molecules that control many aspects of plant physiology. Inositol pyrophosphates (PP-InsPs) are diphosphate containing InsP species of which InsP7and InsP8are the best characterized ones. Different InsP and PP-InsP species are linked with JA-related plant immunity. However, role of PP-InsP species in regulating JA-dependent developmental processes are poorly understood. Recent identification of ITPK1 kinase responsible for the production of 5-InsP7from InsP6in plantaprovides a platform to interrogate possible involvement of ITPK-derived InsP species in JA-related plant development. Herein this study, we report that ITPK1-defective plants exhibit increased root growth inhibition to bioactive JA treatment. Theitpk1plants also show increased lateral root density when treated with JA. Notably, JA treatment does not induce ITPK1 protein level. Gene expression analyses revealed that JA-biosynthetic genes are not differentially expressed in the ITPK1-deficient plants. We further demonstrate that genes encoding different JAZ repressor proteins are severely downregulated in the ITPK1-defective plants. Taken together, our study highlights the role of ITPK1 in regulating JA-dependent root architecture development through controlling expression of different JAZ repressor proteins.
Intraspecies variability in plant and soil chemical properties in a common garden plantation of the energy cropPopulus
Authors: Craig Matthew E , Harman-Ware Anne E , Cope Kevin R , Kalluri Udaya C
Published: June 2023

Optimizing crops for synergistic soil carbon (C) sequestration represents a frontier approach toward CO2removal in food and bioenergy production systems. While the central roles of plants in biological C capture and storage belowground in soils is well known, we lack an understanding of how intraspecies variation in bioenergy plants affects soil biogeochemistry. This knowledge gap is exacerbated by spatial heterogeneity in soil and plant systems, and by the difficulty of characterizing belowground plant traits. Here, we sought to obtain first insights on the spatial variation of C and nutrients in soil and plant tissues from a common garden field site of diverse, natural variant,Populus trichocarpagenotypes—grown and characterized previously for aboveground biomass-to-biofuels research. Such field sites represent a potential resource for evaluating genotype-specific effects on soil C, but this usage may be complicated due to dense plantings of intermixed genotypes. Thus, we sampled soils at the scale of individual trees to determine whether it is feasible to detect soil property variation with different plant genotypes in this system. We additionally sampled stem and root tissues to evaluate the potential for inferring important belowground traits based on aboveground-belowground correlations. We found that substantial variation in soil properties could be explained at the scale of individual trees, suggesting that genetically diverse plantations can be used to assess plant-soil correlations. Though we did not observe genotype-specific patterns in soil C, other properties such as soil acid-base chemistry (soil pH and base cations) and bulk density showed genotype-specific correlations. Stem and root nutrient levels were generally not correlated, suggesting that belowground traits should be measured directly. In conclusion, our pilot study suggests that long-term common gardens of genome-wide association study populations represent useful resources for understanding plant genotypic relationships with soil properties inPopulusfield study test plots. These resources could be used to develop verified plant species, geographic region-specific standardized sampling methods, and baseline data. Such context-specific, empirically verified data and models will be necessary for informing applied research strategies in selecting high aboveground productivity genotypes for enhanced soil C storage in managed, commercial scale, woody bioenergy crop plantation systems.
Loss of chromosome Y in regulatory T cells
Authors: Mattisson Jonas , Halvardson Jonatan , Davies Hanna , Bruhn-Olszewska Bożena , Olszewski Paweł , Danielsson Marcus , Bjurling Josefin , Lindberg Amanda , Zaghlool Ammar , Rychlicka-Buniowska Edyta , Dumanski Jan P. , Forsberg Lars A.
Published: June 2023

Mosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4+ T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4+ T lymphocytes are particularly affected by LOY. Studying publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from cancer patients, we found that regulatory T cells (Tregs) had significantly more LOY than any other T lymphocytes studied. To validate these findings, we generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4+ T lymphocytes enriched samples. We observed an increased ratio of Tregs with LOY compared with other CD4+ cells, supported by developmental trajectory analysis of CD4+ T lymphocytes culminating in the Treg subtype. Furthermore, we identify dysregulation of 465 genes in Tregs with Y loss, many involved in the immunosuppressive functions and development of Tregs. Considering that Tregs plays a critical role in the process of immunosuppression; this enrichment for Tregs with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.
SMaRT-PCR: Sampling with Mask and Reverse Transcriptase PCR, a promising non-invasive diagnostic tool for paediatric pulmonary tuberculosis
Authors: Shaikh Ambreen , Sriraman Kalpana , Vaswani Smriti , Shah Ira , Poojari Vishrutha , Oswal Vikas , Mane Sushant , Rajagara Sakina , Mistry Nerges
Published: June 2023

Purpose

Diagnostic challenges in pediatric TB, like difficulties obtaining sputum, need for invasive sampling, and suboptimal sensitivity of existing detection tools, advocate for sputum-free, child-friendly, and diagnostically accurate methods. This proof-of-concept study evaluates the diagnostic potential of non-invasivelysampling patient bioaerosols using a mask combined with reverse transcriptase (RT)PCR (SMaRT-PCR) for pediatric TB detection.

Methods

In this case-control study, we recruited 51 children (30 confirmed TB and 21 without TB) aged 2-15. Exhaled bioaerosols were captured on gelatin membrane-layered N-95 masks in a 10-minute process that involved talking, coughing, and breathing. Two mask samples were consecutively collected from children with TB and tested using GeneXpert and in-house RT-PCR for16sandrpoBRNA. The control cohort underwent single mask sampling and testing with RT-PCR. Mask sampling acceptability was assessed using a questionnaire and a Likert-scale.

Results

The sensitivity and specificity of SMaRT-PCR for detecting16sandrpoBamong 24 treatment naïve patients were 75% and 95%, respectively, comparable to GeneXpert testing in standard samples from the same patients. Mask sampling with GeneXpert had sensitivity of only 13%. Over 90% of children were comfortable with mask sampling, and > 80% were happy or very happy on the Likert scale with the procedure.

Conclusion

This is the first study to provide evidence for testing patient bioaerosols as a promising alternative for detecting pediatric TB. SMaRT-PCR has potential in a hub-and-spoke model, where samples collected from remote locations can be centrally tested by RT-PCR at district-level laboratories, enabling equitable access to diagnostic care.
Referral for Cardiac Amyloidosis in Patients who underwent Transcatheter Aortic Valve Replacement: Result of Quality Outcome Project
Authors: Lee Dae Hyun , Eichelberger Gerry , Patel Vandan , Chhaya Ronak , Khadilkar Arjun , Bishops Jennifer , Bezerra Hiram , Oliveira Guilherme , Matar Fadi , Mohanty Bibhu , Fernandez Joel
Published: June 2023

Introduction

Transthyretin cardiac amyloidosis (ATTR) is important comorbidity present in 10-15% of severe aortic stenosis (AS). The purpose of this study was to raise awareness of ATTR in patients who underwent transcatheter aortic valve replacement (TAVR) for severe AS among healthcare providers and patients.

Methods

We reviewed 197 consecutive TAVR cases performed from 2019-2020. Based on the presence of predefined high-risk features for ATTR based on prior literature, we subsequently contacted the patients to discuss our clinical suspicion of ATTR and offered a referral to a cardiac amyloid specialist.

Results

We have identified 125 patients (69.4%) who had high-risk features of ATTR. Of the 105 patients who we were able to contact, 44 patients agreed to referral, 46 patients were not able to be contacted after several attempts, and 15 patients declined referral. Of the 44 patients who agreed to referral, 20 patients completed the evaluation for cardiac amyloidosis, all of which were negative for transthyretin and light chain cardiac amyloidosis.

Conclusion

In conclusion, our attempt to detect ATTR in prior TAVR patients was unsuccessful after 2-3 years post-TAVR. We believe that early detection of cardiac amyloidosis close to the timing of TAVR is important and the most effective means.
Mapping the landscape of transcription factor promoter activity during vegetative development in Marchantia
Authors: Romani Facundo , Sauret-Güeto Susanna , Rebmann Marius , Annese Davide , Bonter Ignacy , Tomaselli Marta , Dierschke Tom , Delmans Mihails , Frangedakis Eftychios , Silvestri Linda , Rever Jenna , Bowman John L. , Romani Ignacio , Haseloff Jim
Published: June 2023

Transcription factors (TFs) are essential for the regulation of gene expression and cell fate determination. Characterising the transcriptional activity of TF genes in space and time is a critical step towards understanding complex biological systems. The vegetative gametophyte meristems of bryophytes share some characteristics with the shoot-apical meristems of flowering plants. However, the identity and expression profiles of TFs associated with gametophyte organization are largely unknown. With only ∼450 TF genes,Marchantia polymorphais an outstanding model system for plant systems biology. We have generated a near-complete collection of promoter elements derived from Marchantia TF genes. We experimentally testedin plantareporter fusions for all the TF promoters in the collection and systematically analysed expression patterns in Marchantia gemmae. This allowed us to build a map of precise expression domains and identify a unique set of TFs expressed in the stem-cell zone, providing new insight into the dynamic regulation of the gametophytic meristem and its evolution. In addition, we provide an online database of expression patterns for all promoters in the collection. We expect that the promoter elements characterised here will be useful for cell-type specific expression, synthetic biology applications, and functional genomics.
Evolutionary innovations in germline biology of placental mammals revealed by transcriptomics of first wave spermatogenesis in opossum
Authors: Marshall Kira L , Stadtmauer Daniel J , Maziarz Jamie , Wagner Günter P , Lesch Bluma J
Published: June 2023

Mammalian spermatogenesis is a deeply conserved developmental program that is essential for fitness. Paradoxically, spermatogenic development also allows rapid divergence in gene expression and is thought to be a source of evolutionary novelty and gene birth. How mammalian spermatogenic cells protect a conserved developmental program while enabling exceptionally rapid divergence in gene expression and function is unknown. Here, we comprehensively profile the spermatogenic gene expression program in grey short-tailed opossum (Monodelphis domestica, a model marsupial) and compare it to equivalent data from the mouse (Mus musculus, a model placental mammal) to discover contrasting forces underlying the unique evolutionary dynamics of gene expression during mammalian spermatogenesis. For the first time, we describe the timing of the ‘first wave’ of opossum spermatogenesis, and we combine bulk transcriptomic data from first-wave juvenile testes with single-cell transcriptomic data from adult testes to define conserved and divergent gene expression programs across the placental-marsupial split. We substantiate and extend our findings using genome-wide chromatin and multi-species transcriptome data and identify three classes of genes with different evolutionary trajectories: a deeply conserved central gene regulatory program governing spermatogenic progression; a separate class of spermatogenic genes exhibiting dynamic expression across placental mammals; and a third set of genes with evidence for directional selection in the placental mammal ancestor and constraint on expression levels within the placental mammalian lineage, representing placental innovations in germline gene expression and including biologically critical modules such as the DNA recombination and repair machinery.
Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: A systematic review and meta-analysis
Authors: Elias Karen M , Khan Shanchita R , Stadler Eva , Schlub Timothy E , Cromer Deborah , Polizzotto Mark N , Kent Stephen J , Turner Tari , Davenport Miles P , Khoury David S
Published: June 2023

Background

Surrogates of antiviral efficacy are needed for COVID-19. We investigated the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in unvaccinated outpatients treated for mild to moderate COVID-19.

Methods

We searched PubMed, Scopus and medRxiv from inception to 27thSeptember 2022, for randomised controlled trials (RCTs) which tested potential treatments for COVID-19 in non-hospitalized patients. We included studies that reported both clinical and virological outcomes. Clinical outcomes were the rate of disease progression (generally hospitalization or death within 28 days of commencing treatment) and virological outcomes were viral load (viral RNA copies in upper respiratory tract swabs) within the first 7 days of treatment. Studies were excluded if they did not report on the outcome of a primary randomised controlled trial, or if results were reported in a more complete form in another publication. Risk of Bias assessment was performed using the RoB 2.0 tool. We used generalised linear models with random effects to assess the association between outcomes and account for study heterogeneity.

Findings

We identified 1372 unique studies of which 14 (with a total of 9257 participants) met inclusion criteria. Larger virological treatment effects at both day 3 and day 5 were associated with decreased odds of progression to hospitalisation or death in unvaccinated ambulatory subjects. The odds ratio (OR) for each extra two-fold reduction in viral load in treated compared to control subjects was 0.54 on both days 3 and 5 post treatment (day 3 95% CI 0.38 to 0.74, day 5 95%CI 0.41 to 0.72). There was no relationship between the odds of hospitalisation or death and virological treatment effect at day 7 (OR 0.91, 95%CI 0.74 to 1.13).

Interpretation

This review provides evidence that treatment-induced acceleration of viral clearance within the first 5 days after treatment is a surrogate of clinical efficacy to prevent hospitalisation with COVID-19. Limitations included the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes. These findings support the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy.

Funding

The authors were supported by the Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council and the University of New South Wales.
Machine learning to increase the efficiency of a literature surveillance system: a performance evaluation
Authors: Lokker Cynthia , Abdelkader Wael , Bagheri Elham , Parrish Rick , Cotoi Chris , Navarro Tamara , Germini Federico , Linkins Lori-Ann , Haynes R. Brian , Chu Lingyang , Afzal Muhammad , Iorio Alfonso
Published: June 2023

Background

Given suboptimal performance of Boolean searching to identify methodologically sound and clinically relevant studies in large bibliographic databases such as MEDLINE, exploring the performance of machine learning (ML) tools is warranted.

Objective

Using a large internationally recognized dataset of articles tagged for methodological rigor, we trained and tested binary classification models to predict the probability of clinical research articles being of high methodologic quality to support a literature surveillance program.

Materials and Methods

Using an automated machine learning approach, over 12,000 models were trained on a dataset of 97,805 articles indexed in PubMed from 2012-2018 which were manually appraised for rigor by highly trained research associates with expertise in research methods and critical appraisal. As the dataset is unbalanced, with more articles that do not meet criteria for rigor, we used the unbalanced dataset and over- and under-sampled datasets. Models that maintained sensitivity for high rigor at 99% and maximized specificity were selected and tested in a retrospective set of 30,424 articles from 2020 and validated prospectively in a blinded study of 5253 articles.

Results

The final selected algorithm, combining a model trained in each dataset, maintained high sensitivity and achieved 57% specificity in the retrospective validation test and 53% in the prospective study. The number of articles needed to read to find one that met appraisal criteria was 3.68 (95% CI 3.52 to 3.85) in the prospective study, compared with 4.63 (95% CI 4.50 to 4.77) when relying only on Boolean searching.

Conclusions

ML models improved by approximately 25% the efficiency of detecting high quality clinical research publications for literature surveillance and subsequent dissemination to clinicians and other evidence users.
Decreasing alpha flow releases task-specific processing paths
Authors: Hanna Jevri , Kim Cora , Rampp Stefan , Buchfelder Michael , Müller-Voggel Nadia
Published: June 2023

Directing and maintaining attention toward relevant information and away from non-relevant information is a critical competence of higher-order nervous systems. Here, we used directed connectivity to investigate how the human brain prioritizes appropriate processing paths when participants are performing a behavioral task requiring attention in the visual or the auditory modality. We show that the efficient transfer of information relevant for the task is mediated by a region- and task-specific decrease of alpha band connectivity from parietal and, in case a motor response is required, motor cortex to the relevant sensory cortices. Further, alpha-band connectivity modulations reliably predict alpha power modulations in the task-related sensory cortices, particularly where the task-irrelevant cortex is inhibited via local alpha power increases. We suggest that the task- and region-specific modulation of alpha-band connectivity in the present study is a basic neuronal mechanism orchestrating the allocation of task-relevant neuronal resources related to and possibly underlying the previously reported sensory alpha power modulations in association with the allocation of competing attentional resources.
Dysregulated Platelet Function in Patients with Post-Acute Sequelae of COVID-19
Authors: Aggarwal Anu , Singh Tamanna K. , Pham Michael , Godwin Matthew , Chen Rui , McIntyre Thomas M. , Scalise Alliefair , Chung Mina K. , Jennings Courtney , Ali Mariya , Park Hiijun , Englund Kristin , Khorana Alok A. , Svensson Lars G. , Kapadia Samir , McCrae Keith R. , Cameron Scott J.
Published: June 2023

Background

Post-acute sequelae of COVID-19 (PASC), also referred as Long-COVID, sometimes follows COVID-19, a disease caused by SARS-CoV-2. While SARS-CoV-2 is well-known to promote a prothrombotic state, less is known about the thrombosis risk in PASC.

Aim

Our objective was to evaluate the platelet function and thrombotic potential in patients following recovery from SARS-CoV-2 with clear symptoms of PASC.

Methods

PASC patients and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by Light Transmission Aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions.

Results

A mild increase in platelet aggregation in PASC patients through the thromboxane receptor was observed and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in PASC patients compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in PASC patients. Plasma from PASC patients was an extremely potent activator of washed, healthy platelets – a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals.

Conclusions

PASC patients show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exists in PASC patients to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.
Comprehensive Assessment of Sleep Duration, Insomnia and Brain Structure within the UK Biobank Cohort
Authors: Stolicyn Aleks , Lyall Laura M. , Lyall Donald M. , Høier Nikolaj , Adams Mark J. , Shen Xueyi , Cole James H. , McIntosh Andrew M. , Whalley Heather C. , Smith Daniel J.
Published: June 2023

Study Objectives

To assess for associations between sleeping more than or less than recommended by the National Sleep Foundation (NSF), and self-reported insomnia, with brain structure.

Methods

Data from the UK Biobank cohort were analysed (Nbetween 9K and 32K, dependent on availability, aged 44 to 82 years). Sleep measures included self-reported adherence to NSF guidelines on sleep duration (sleeping between 7 and 9 hours per night), and self-reported difficulty falling or staying asleep (insomnia). Brain structural measures included global and regional cortical or subcortical morphometry (thickness, surface area, volume), global and tract-related white matter microstructure, brain age gap (difference between chronological age and age estimated from brain scan), and total volume of white matter lesions.

Results

Longer-than-recommended sleep duration was associated with lower overall grey and white matter volumes, lower global and regional cortical thickness and volume measures, higher brain age gap, higher volume of white matter lesions, higher mean diffusivity globally and in thalamic and association fibers, and lower volume of the hippocampus. Shorter-than-recommended sleep duration was related to higher global and cerebellar white matter volumes, lower global and regional cortical surface areas, and lower fractional anisotropy in projection fibers. Self-reported insomnia was associated with higher global grey and white matter volumes, and with higher volumes of the amygdala, hippocampus and putamen.

Conclusions

Sleeping longer than recommended by the NSF is associated with a wide range of differences in brain structure, potentially indicative of poorer brain health. Sleeping less than recommended is distinctly associated with lower cortical surface areas. Future studies should assess the potential mechanisms of these differences and investigate long sleep duration as a putative marker of brain health.
Brain flexibility increases during the peri-ovulatory phase of the menstrual cycle
Authors: Liparoti Marianna , Cipriano Lorenzo , Lopez Emahnuel Troisi , Polverino Arianna , Minino Roberta , Sarno Laura , Sorrentino Giuseppe , Lucidi Fabio , Sorrentino Pierpaolo
Published: June 2023

The brain operates in a flexible dynamic regime, generating complex patterns of activity (i.e neuronal avalanches). This study aimed to describe how brain dynamics change according to menstrual cycle (MC) phases.

Brain activation patterns were estimated from resting state magnetoencephalography (MEG) scans, acquired women at early follicular (T1), peri-ovulatory (T2) and mid-luteal (T3) phases of MC. We investigated the functional repertoire (number of ways in which large bursts of activity spread through the brain) and the region-specific influence on large-scale dynamics across MC. Finally, we assessed the relationship between sex hormones and changes in brain dynamics.

A significantly larger number of visited configuration patterns, in T2 than in T1, in the beta frequency band was observed. No relationship between changes in brain dynamics and sex hormones was showed. Finally, we showed that, in the beta band, the left posterior cingulate gyrus and the right insula were more present in the functional repertoire in T2 than in T1, while the right pallidum was more present in T1 than in T2.

In summary, we showed a hormone independent increase of brain dynamics during the ovulatory phase. Moreover, we demonstrated that several specific brain regions play a key role in determining this change.
Epidemiological impact and cost-effectiveness of expanding formal PrEP provision to PrEP-eligible MSM expressing PrEP-intention in the Netherlands
Authors: Wang Haoyi , Popping Stephanie , van de Vijver David , Jonas Kai. J.
Published: June 2023

Objective

Reimbursed pre-exposure prophylaxis (PrEP) access in the Netherlands has reached its maximum capacity with a waiting-list of 3,000 men-who-have-sex-with-men (MSM) and 19,500 PrEP-eligible/intending MSM. This study models the epidemiological impact and cost-effectiveness of expanding PrEP provision to waiting-list and PrEP-eligible/intending MSM in the Netherlands, given the imminent national evaluation of the current PrEP programme in July 2023.

Methods

We calibrated a deterministic transmission model of HIV among MSM. Expanded PrEP provision was seeded in 01/2022, to achieve the coverage (varied at 25%,50%,75%, and 100%) for the waiting-list (n=3,000), and PrEP-eligible/intending group (n=19,500) by 01/2024. The epidemiological impact was modelled until 2030, while cost-effectiveness and the budget impact were calculated from a payer’s perspective over 40-years, and five-years, starting from 2022, respectively.

Results

Expanding PrEP provision leads to further reductions in HIV infections among MSM. Covering waiting-list and PrEP-eligible/intending MSM can avert a total of 11 (2.5%) up to 192 (45.1%) new infections by 2030. Expanding PrEP provision to over-75% of PrEP-eligible/intending MSM offers the possibility of ending the HIV epidemic by 2030. However, achieving this milestone comes with significant costs, with an incremental-cost-effectiveness-ratio of €164,100 per quality-adjusted-life-year and short-term costs of €1,074 million over five-years.

Conclusions

This study provides timely evidence for the upcoming national evaluation of the PrEP program in the Netherlands, supporting its continuation and further expansion. While expanding PrEP provision holds promise for HIV elimination, given the associated significant costs, careful consideration is crucial to balance efforts to end the HIV epidemic and the available resources.
The relationship between genotype- and phenotype-based estimates of genetic liability to psychiatric disorders, in practice and in theory
Authors: Dybdahl Krebs Morten , Appadurai Vivek , Georgii Hellberg Kajsa-Lotta , Ohlsson Henrik , Steinbach Jette , Pedersen Emil ,   iPSYCH Study Consortium, Werge Thomas , Sundquist Jan , Sundquist Kristina , Cai Na , Zaitlen Noah , Dahl Andy , Vilhjalmsson Bjarni , Flint Jonathan , Bacanu Silviu-Alin , Schork Andrew J. , Kendler Kenneth S.
Published: June 2023

Genetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation within individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, like polygenic scores, as the future of breeding programs or precision medicine and genetic epidemiology. However, unlike in agriculture, there is an emerging consensus that family variables act nearly independent of genotypes in models of human disease. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the iPSYCH2015 case-cohort study to show that state-of-the-field genotype- and phenotype-based genetic instruments explain largely independent components of liability to psychiatric disorders. We support these empirical results with novel theoretical analysis and simulations to describe, in a human biomedical context, parameters affecting current and future performance of the two approaches, their expected interrelationships, and consistency of observed results with expectations under simple additive, polygenic liability models of disease. We conclude, at least for psychiatric disorders, that phenotype- and genotype-based genetic instruments are likely noisy measures of the same underlying additive genetic liability, should be seen for the near future as complementary, and integrated to a greater extent.
Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair
Authors: Aubé Fabien , Fontrodona Nicolas , Guiguettaz Laura , Vallin Elodie , Lapendry Audrey , Ricci Emiliano P. , Auboeuf Didier
Published: June 2023

Amino acid bioavailability impacts mRNA translation in a codon depending manner. Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This results in the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate- and glutamate-rich proteins mostly involved in DNA metabolism. Consequently, cells that survive to MAPKi degrade aspartate and glutamate to generate energy, which simultaneously decreases their needs in amino acids owing to the downregulation of aspartate- and glutamate-rich proteins involved in cell proliferation. Concomitantly, the downregulation of aspartate- and glutamate-rich proteins involved in DNA repair increases DNA damage loads. Thus, DNA repair defects, and therefore mutations, are, at least in part, a secondary effect of the metabolic adaptation of cells exposed to MAPKi.
Integrative metabolomics and proteomics allow the global intracellular characterization of Bacillus subtilis cells and spores.
Authors: Huang Yixuan , Swarge Bhagyashree N , Roseboom Winfried , Bleeker Jurre D. , Brul Stanley , Setlow Peter , Kramer Gertjan
Published: June 2023

Reliable and comprehensive multi-omics analysis is essential for researchers to understand and explore complex biological systems more completely. Bacillus subtilis is a model organism for Gram-positive spore-forming bacteria, and in-depth insight into the physiology and molecular basis of spore formation and germination in this organism requires advanced multilayer molecular datasets generated from the same sample. In this study, we evaluated two monophasic methods for polar and nonpolar compound extraction (acetonitrile/methanol/water; isopropanol/water, and 60% ethanol), and two biphasic methods (chloroform/methanol/water, and methyl tert-butyl ether/methanol/water) on coefficients of variation of analytes, identified metabolite composition and the quality of proteomics profiles. The analytical workflow comprises (1) parallel metabolite and protein extraction, (2) monophasic or biphasic sample extraction, (3) proteomics comparison and (4) multi-omics-based data visualization. The 60% EtOH protocol proved to be the easiest in sample processing and more amenable to automation. Collectively, we annotated 505 and 484 metabolites and identified 1665 and 1562 proteins in B. subtilis vegetative cells and spores, respectively. We also show differences between vegetative cells and spores from a multi-omics perspective and demonstrated that an integrative multi-omics analysis can be implemented from one sample using the 60% EtOH protocol. Correlation analysis further demonstrated that the metabolome and proteome datasets were highly correlated in content for components annotated to be part of the pyrimidine metabolism pathway. The results obtained by the 60% EtOH protocol provide a comprehensive insight into differences in the metabolic and protein makeup of B. subtilis vegetative cells and spores.
Bimodular architecture of bacterial effector SAP05 drives ubiquitin-independent targeted protein degradation
Authors: Liu Qun , Maqbool Abbas , Mirkin Federico G. , Singh Yeshveer , Stevenson Clare E. M. , Lawson David M. , Kamoun Sophien , Huang Weijie , Hogenhout Saskia A.
Published: June 2023

In eukaryotes, targeted protein degradation (TPD) typically depends on a series of interactions among ubiquitin ligases that transfer ubiquitin molecules to substrates leading to degradation by the 26S proteasome. We previously discovered that the bacterial effector protein SAP05 mediates ubiquitin-independent TPD. SAP05 forms a ternary complex via interactions with the von Willebrand Factor Type A (vWA) domain of the proteasomal ubiquitin receptor Rpn10 and the Zinc-finger (ZnF) domains of the SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) and GATA BINDING FACTOR (GATA) transcription factors (TFs). This leads to direct TPD of the TFs by the 26S proteasome. Here, we report the crystal structures of the SAP05-vWA complex at 2.17 Å resolution and of the SAP05-ZnF(SPL5) complex at 2.20 Å resolution. Structural analyses revealed that SAP05 displays a unique bimodular architecture with two distinct non-overlapping surfaces, a ‘loop surface’ with three protruding loops that form electrostatic interactions with ZnF, and a ‘sheet surface’ featuring two β-sheets, loops and ⍺-helices that establish polar interactions with vWA. SAP05 binding to ZnF TFs involves single amino acids responsible for multiple contacts, while SAP05 binding to vWA is more stable due to the necessity of multiple mutations to break the interaction. In addition, positioning of the SAP05 complex on the 26S proteasome points to a mechanism of protein degradation. Collectively, our findings demonstrate how a small bacterial bimodular protein can bypass the canonical UPS cellular proteolysis pathway, enabling ubiquitin-independent TPD in eukaryotic cells. This knowledge holds significant potential for the creation of novel TPD technologies.