bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug-Related Problems and associated factors among hospitalized pediatric patients at the University of Gondar Comprehensive and Specialized Hospital
Authors: Amsalu Atalay , Baraki Adhanom Gebreegziabher , Muche Esileman Abdela
Published: September 2022

Introduction

Drug-related problem is any event involving drug therapy that interferes with a patient’s desired clinical outcome. Hospitalized pediatric patients are particularly prone to drugrelated problems. Thus, this study aimed to assess drug-related problems and associated factors among patients admitted to the pediatric ward of the University of Gondar Comprehensive and Specialized Hospital, Ethiopia.

Methods

A hospital-based cross-sectional study was conducted among pediatric patients admitted to the University of Gondar Comprehensive and Specialized Hospital from May 1, to July 30, 2021. A Simple random sampling technique was employed to select study participants. Odds ratio with 95% confidence interval was computed for each variable for the corresponding P-value to see the strength of association. Those variables which have a P-value of < 0.25 in Bivariable analysis were entered in Multivariable analysis to determine factors associated with drug related problems.

Results

A total of 180 drug-related problems were identified in 145 participants with an overall prevalence of 40.2% [95% CI (35.5-45.4)]. Dose too low (35.56%), needs additional drug (28.89%) and dose too high (21%) were the commonest type of drug-related problems identified. The most important interventions made were dose adjustment (52%) and the addition of drugs (30%). The presence of comorbidity [AOR = 3.32, 95% CI (1.88-5.88)], polypharmacy [AOR = 4.22, 95% CI (2.21-8.10)], and more than 6 days stay in the hospital [AOR =7.59, 95% CI (3.76-15.33)] were independent predictors for the occurrence of drug-related problems.

Conclusion

Drug-related problems are common among hospitalized pediatrics at the University of Gondar Comprehensive and Specialized Hospital. The presence of comorbidity, polypharmacy and prolonged hospital stay were predictors of drug-related problems. Therefore, health care providers have to work in collaboration with clinical pharmacists and give due attention to those patients with comorbidity, polypharmacy and patients who stayed longer days in the hospital.
Real-world Use of Nirmatrelvir-Ritonavir in COVID-19 Outpatients During the Emergence of Omicron Variants BA.2/BA2.12.1
Authors: Aggarwal Neil R. , Molina Kyle C. , Beaty Laurel E. , Bennett Tellen D. , Carlson Nichole E. , Ginde Adit A.
Published: September 2022

Background

Ritonavir-boosted Nirmatrelvir (NMV-r), a protease inhibitor with in vitro activity against SARS-CoV-2, has been shown to reduce risk of progression to severe COVID-19 among high-risk individuals during the Delta-variant phase. We sought to determine the effectiveness of NMV-r against Omicron lineage variants BA.2/BA2.12.1, and assess for evidence of a clinical rebound effect.

Methods

We conducted a retrospective observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from March 26th, 2022 to June 23rd, 2022, using records from a statewide health system linked to vaccine and mortality data. Propensity score matching was performed on NMV-r treated outpatients with outpatients not treated with antiviral therapy. The primary outcome was 28-day all-cause hospitalization; secondary outcomes were COVID-19-related hospitalization, 28-day all-cause mortality, and 28-day ED visits. Logistic regression was used to determine NMV-r treatment effectiveness; subgroup analyses were performed to assess for heterogeneity in treatment effect.

Results

Of 14,953 SARS-CoV-2 infected outpatients, 3,614 NMV-r treated patients were matched to 4,835 untreated outpatients. NMV-r was associated with significantly lower odds of 28-day all-cause hospitalization as compared to no antiviral treatment [31 (0.9%) vs. 64 (1.3%), adjusted odds ratio (aOR): 0.48 (95% CI 0.31-0.75)]. NMV-r was also associated with lower odds of COVID-19 related hospitalization [aOR (95% CI): 0.42 (0.25-0.68)] and 28-day all-cause mortality [aOR (95% CI): 0.05 (0.00-0.38)]. Using ED visits within 28 days as a surrogate for rebound symptoms, we observed no clinically evident rebound effect with NMV-r treatment [140 (3.9%) vs 205 (4.2%), aOR: 0.81 (95% CI 0.65-1.02), p = 0.075].

Conclusion

Real-world evidence during an Omicron BA.2/BA2.12.1 predominant period demonstrated an association of NMV-r treatment with reduced 28-day hospitalization and all-cause mortality, and without an increase in rebound symptoms as assessed by ED visits within 28 days after treatment.
Drought, armed conflict and population mortality in Somalia, 2014-2018: a statistical analysis
Authors: Warsame Abdihamid , Frison Séverine , Checchi Francesco
Published: September 2022

Background

During 2010-2012, extreme food insecurity and famine in Somalia were estimated to account for 256,000 deaths. Since 2014 Somalia has experienced recurrent below-average rainfall, with consecutive failed rains in late 2016 and 2017 leading to large-scale drought, displacement and epidemics. We wished to estimate mortality across Somalia from 2014 to 2018, and measure the excess death toll attributable to the 2017-2018 drought-triggered crisis.

Methods

We used a statistical approach akin to small-area estimation, and relying solely on existing data. We identified and re-analysed 91 household surveys conducted at the district level and estimating the crude (CDR) and under 5 years death rate (U5DR) over retrospective periods of 3-4 months. We captured datasets of candidate predictors of mortality with availability by district and month. We also reconstructed population denominators by district-month combining alternative census estimates and displacement data. We combined these data inputs into predictive models to estimate CDR and U5DR and combined the predictions with population estimates to project death tolls. Excess mortality was estimated by constructing counterfactual no-crisis scenarios.

Results

Between 2013 and 2018, Somalia’s population increased from 12.0 to 13.5 million, and internally displaced people or returnees reached 20% of the population. We estimated an excess death toll of 44,700 in the most likely counterfactual scenario, and as high as 163,800 in a pessimistic scenario. By contrast to 2010-2012, excess deaths were widespread across Somalia, including central and northern regions.

Conclusion

This analysis suggests that the 2017-2018 crisis had a lower, albeit still very substantial, mortality impact than its 2010-2012 predecessor. Despite modest elevations in death rate, crisis conditions were widespread and affected a population of millions. Humanitarian response to drought-related crises in Somalia needs to be strengthened, target the most vulnerable and emphasise very early interventions.
Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study
Authors: Ho Peh Joo , Tan Iain Bee Huat , Chong Dawn Qingqing , Khor Chiea Chuen , Yuan Jian-Min , Koh Woon-Puay , Dorajoo Rajkumar , Li Jingmei
Published: September 2022

Background

To evaluate the utility of polygenic risk scores (PRS) in identifying high-risk individuals, different publicly available PRS for breast (n=65), prostate (n=26), colorectal (n=12) and lung cancers (n=7) were examined in a prospective study of 21,694 Chinese adults.

Methods

We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals [CI] of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.

Results

A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best performing site-specific PRS were 0.61 (PGS000004, breast), 0.66 (PGS00586, prostate), 0.58 (PGS000148, female-colorectal), 0.60 (PGS000734, male-colorectal) and 0.55 (PGS000740, female-lung), and 0.55 (PGS000392, male-lung), respectively. Compared to the middle quintile, individuals in the highest PRS quintile were 67% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest PRS quintile was associated with 31-45% decreased risk compared to the middle quintile. In contrast, the hazard ratios observed for quintiles 4 (female-lung: 0.91 [0.58-1.44]; male-lung: 1.01 [0.74-1.38]) and 5 (female-lung: 1.00 [0.64-1.56]; male-lung: 1.07 [0.79-1.45]) were not significantly different from that for the middle quintile.

Conclusions

Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.

Funding

This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).

The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health [NIH] (R01 CA144034 and UM1 CA182876).
The Incidence, Predictors, and Mortality Impact of Ventricular Pacing Dependency after Transcatheter Aortic Valve Replacement: A Prospective Cohort
Authors: Apiyasawat Sirin , Chandavimol Mann , Soontornmanokati Natcha , Sirikhamkorn Chulaporn
Published: September 2022

Background

Atrioventricular conduction disturbance occurs in a significant number of patients underwent transcatheter aortic valve replacement (TAVR). However, not all of the cases persistently depend on ventricular pacing.

Objective

To study the incidence, predictors, and outcomes of new ventricular pacing dependency (VpDep) after TAVR.

Design

Prospective, single-center, cohort trial

Methods

The first 130 consecutive transfemoral TAVR cases, except 3 with prior cardiac electronic implantable devices (CIEDs) who depended on ventricular pacing, were analyzed. The endpoints were VpDep at 1 month and all-cause mortality at the end of follow-up in 2021. The effects of variables on VpDep and all-cause mortality were evaluated using multivariate binary logistic regression and Cox-regression analysis, respectively. First degree atrioventricular block (AVB) was considered severe when PR interval > 300 ms.

Results

Out of 127 patients in the analysis (mean age 82 years, SD 6.3; 62.2% female sex; 67.7% Balloon-expandable device), 7 patients (5.5%) had implanted with CIEDs before TAVR but not ventricular pacing dependent. The incidence of VpDep at 1 month was 7.9% (n=10) among all patients and 34.5% among patients with CIEDs (n=29). VpDep was likely to occur in patients with pre-existing right bundle branch block (OR 21.38; 95% CI 3.25-139.33; P=.001) and severe 1st degree or Mobitz I AVB (OR 14.79; 95% CI 1.65-132.74; P=.016). After a mean follow-up of 25.8 months (SD 21.2), death from any causes occurred in 18 patients (14.2%). VpDep was not associated with excess mortality.

Conclusion

VpDep at 1 month occurred in 7.9% of all patients underwent TAVR. Pre-existing conduction abnormalities were significantly associated with higher risk of VpDep. Mortality was similar between patients with and without VpDep.

Clinical Trial Registration

Thai Clinical Trial Registration; Study ID: TCTR20220726005
FASDetect – A machine learning-based app to screen for the risk of fetal alcohol-spectrum disorder in youth with attention-deficit/hyperactivity disorder symptoms
Authors: Ehrig Lukas , Wagner Ann-Christin , Wolter Heike , Correll Christoph U. , Geisel Olga , Konigorski Stefan
Published: September 2022

Fetal alcohol-spectrum disorder (FASD) is underdiagnosed and often misdiagnosed as attention-deficit/hyperactivity disorder (ADHD). Here, we developed a screening tool for FASD in youth with ADHD symptoms. To develop the prediction model, medical record data from a German University outpatient unit were assessed including 275 patients aged 0-19 years old with FASD with or without ADHD and 170 patients with ADHD without FASD aged 0-19 years old. We trained 6 machine learning models based on 13 selected variables and evaluated their performance. Random forests yielded the best prediction models with a cross-validated AUC of 0.92 (95% confidence interval [0.84, 0.99]). Follow-up analyses indicated that a random forest model with 6 variables – body length and head circumference at birth, IQ, socially intrusive behaviour, poor memory and sleep disturbance – yielded equivalent predictive accuracy. We implemented the prediction model in a web-based app called FASDetect – a user-friendly, clinically scalable FASD risk calculator that is freely available at https://fasdetect.dhc-lab.hpi.de.
Human Adult Neurogenesis Loss Underlies Cognitive Decline During Epilepsy Progression
Authors: Ammothumkandy Aswathy , Corona Luis , Ravina Kristine , Wolseley Victoria , Nelson Jeremy , Atai Nadiya , Abedi Aidin , Jimenez Nora , Armacost Michelle , D'Orazio Lina M , Zuverza-Chavarria Virginia , Cayce Alisha , McCleary Carol , Nune George , Kalayjian Laura , Lee Darrin , Lee Brian , Heck Christianne , Chow Robert H , Russin Jonathan J , Liu Charles Y , Smith Jason AD , Bonaguidi Michael A
Published: September 2022

Mesial temporal lobe epilepsy (MTLE) is a syndromic disorder presenting with seizures and cognitive comorbidities. While seizure etiology is increasingly understood, the pathophysiological mechanisms contributing to cognitive decline and epilepsy progression remain less recognized. We have previously shown that adult hippocampal neurogenesis, a process contributing to visual spatial learning and memory in rodents, dramatically declines in MTLE patients with increased disease duration. Here, we investigate when multiple cognitive domains become effected by epilepsy disease duration and how human neurogenesis levels contribute to it. We find that intelligence, and verbal learning and memory decline at a critical period of 20 years disease duration. Surprisingly, the number of human immature neurons positively associate with auditory verbal, rather than visuospatial, learning and memory. Moreover, we uncover cognitive functions enriched to either immature or mature granule neurons and functions shared between them. Our study provides cellular evidence of how adult neurogenesis contributes to human cognition, and signifies an opportunity to advance regenerative medicine for patients with MTLE and other cognitive disorders.
RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects: Therapeutic implications
Authors: Lee Kiwon , Ahn Hyun Sook , Estevez Brian , Poncz Mortimer
Published: September 2022

Heterozygous defects in runt-related transcription factor-1 (RUNX1) are causative of a familial platelet disorder with associated myeloid malignancy (FPDMM). Since RUNX1-deficient animal models do not mimic FPDMM’s bleeding disorder or leukemic risk, establishment of a proper model system is critical to understand the underlying mechanisms of the observed phenotype and to identify therapeutic interventions. We previously reported an in vitro-megakaryopoiesis system using human CD34+-hematopoietic stem and progenitor cells that recapitulated the FPDMM quantitative megakaryocyte defect by decreasing RUNX1 expression using a lentiviral short-hairpin RNA (shRNA for RUNX1 or shRX) strategy. We now show that shRX-megakaryocytes have a marked reduction in agonist responsiveness. We then infused shRX-megakaryocytes into immunocompromised NOD-SCID gamma (NSG) mice and demonstrated that these megakaryocytes released fewer platelets than megakaryocytes transfected with a non-targeting shRNA, and these platelets had a diminished half-life. The platelets were also poorly responsive to agonists, unable to correct thrombus formation in NSG mice homozygous for a R1326H mutation in von Willebrand Factor (VWFR1326H), which switches species-binding specificity of the VWF from mouse to human glycoprotein Ibα. A small-molecule inhibitor RepSox, which blocks the transforming-growth factor beta pathway, and which rescued defective megakaryopoiesis in vitro, corrected the thrombopoietic defect, platelet half-life and agonist response, and thrombus formation in NSG/VWFR1326H mice. Thus, this model recapitulates the defect in FPDMM megakaryocytes and platelets, identifies previously unrecognized defects in thrombopoiesis and platelet half-life, and demonstrates, for the first time, reversal of RUNX1 deficiency’s hemostatic defects by a drug.

Key Points

RUNX1-deficient megakaryocytes exhibit thrombopoietic and platelet defects in NSG/VWFR1326H mice.

Pre-exposure of RUNX1-deficient megakaryocytes to a TGFβ1-pathway inhibitor ameliorated both defects, correcting hemostasis.
Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation
Authors: Das Priyojit , San Martin Rebeca , McCord Rachel Patton
Published: September 2022

Interactions of chromatin with the nuclear lamina play a significant role in properly organizing the genome in 3D space and in regulating gene expression. Genome wide studies have inferred the global association between the lamina, heterochromatin, gene repression and the B genomic compartment, and repositioning genes to the lamina can result in their repression. However, there are scenarios in which these features are discordant and, in those cases, the relative contribution to gene regulation of genomic compartment, chromatin, and lamin association status can be examined. Here we compared datasets from cell lines representing different states of differentiation across different cell type lineages to examine the relationships between changes in genomic compartmentalization, lamin association, and gene expression. With these data, we could examine, for example, what gene expression changes occur when a B compartment region is moved from the nuclear interior to the nuclear lamina and what differences exist between lamin associated and internal A compartment regions. In general, we observed an additive rather than redundant effect in which lamin association and compartment status both contribute to gene expression state. However, we found that cell type lineages differed in whether compartment status or lamin association had a dominant influence on gene expression. Finally, we identified conserved trends of how compartment and lamin association status influence the likelihood that gene expression will be induced or repressed in response to a physiochemical treatment.
Environment-wide and epigenome-wide association study of adiposity in “Children of 1997” birth cohort
Authors: Zhao Jie V , Fan Bohan , Huang Jian , Cowling BJ , Au Yeung SL , Baccarelli Andrea , Leung GM , Schooling C Mary
Published: September 2022

Background

Increasing childhood adiposity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of adiposity at the onset and end of puberty in Hong Kong the most economically developed major Chinese city.

Methods

We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of adiposity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kong’s population-representative “Children of 1997” birth cohort. Univariable linear regression was used to select exposures related to adiposity at ~11.5 years (BMI n≤7,119, WHR n=5,691) and ~17.6 years (n = 3,618) at Bonferroni-corrected significance, and multivariable linear regression to adjust for potential confounders followed by replication (n=308) and CpG by CpG analysis (n=286) at ~23 years. Findings were compared with evidence from randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.

Results

At ~11.5 and ~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as seven and 12 associated with WHR respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with adiposity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, binge eating, and possibly earlier puberty are consistent with available evidence from RCTs or MR studies We found 21 CpGs related to BMI and 18 to WHR.

Conclusions

These novel insights into potentially modifiable factors associated with adiposity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings.

Funding

This study was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction was supported by CFS-HKU1.
A Systems Biology Approach to Pathogenesis of Gastric Cancer: Gene Network Modeling and Pathway Analysis
Authors: Mottaghi-Dastjerdi Negar , Ghorbani Abozar , Montazeri Hamed
Published: September 2022

Introduction

Gastric cancer (GC) ranks among the most common malignancies worldwide. In our previous study, we found overexpressed genes in GC clinical samples. The goal of the current study was to find critical genes and key pathways involved in the pathogenesis of GC.

Methods

Gene interactions were analyzed using STRING, and Cytoscape was used to visualize the molecular interaction network. CytoHubba was used for drawing the PPI network and identifying hub proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) at STRING were used for the enrichment analysis of the hub genes. Cluster analysis of the network was done using CytoCluster. MEME Suite was used for promoter analysis of the hub genes using Tomtom and GoMo tools.

Results and Discussion

Our results showed that the most affected processes in GC are the metabolic processes. The OXPHOS pathway was also considerably enriched in our analyses. These results showed the significant role of mitochondria in GC pathogenesis. Although many investigations have focused on the mitochondrial role in the pathogenesis of various cancers, the characteristics of respiratory and metabolic changes in GC have not been fully elucidated. Our results also showed that most of the affected pathways in GC were the pathways also involved in neurodegenerative diseases. Also, promoter analysis showed that negative regulation of signal transduction might play an important role in GC pathogenesis. The results of this study might open up new insights into GC pathogenesis. The identified genes might be novel diagnostic or prognostic biomarkers or potential therapeutic targets for GC. Nonetheless, these results were obtained by bioinformatics analysis and require further clinical validation.
Multiscale compression-induced restructuring of stacked lipid bilayers: from buckling delamination to molecular packing
Authors: Porras-Gómez Marilyn , Kim Hyunchul , Dronadula Mohan Teja , Kambar Nurila , Metellus Christopher J.B. , Aluru Narayana R. , van der Zande Arend , Leal Cecília
Published: September 2022

Lipid membranes in nature adapt and reconfigure to changes in composition, temperature, humidity, and mechanics. For instance, the oscillating mechanical forces on lung cells and alveoli influence membrane synthesis and structure during breathing. However, despite advances in the understanding of lipid membrane phase behavior and mechanics of tissue, there is a critical knowledge gap regarding the response of lipid membranes to micromechanical forces. Most studies of lipid membrane mechanics use supported lipid bilayer systems missing the structural complexity of pulmonary lipids in alveolar membranes comprising multi-bilayer interconnected stacks. Here, we elucidate the collective response of the major component of pulmonary lipids to strain in the form of multi-bilayer stacks supported on flexible elastomer substrates. We utilize X-ray diffraction, scanning probe microscopy, confocal microscopy, and molecular dynamics simulation to show that lipid multilayered films both in gel and fluid states evolve structurally and mechanically in response to compression at multiple length scales. Specifically, compression leads to increased disorder of lipid alkyl chains comparable to the effect of cholesterol on gel phases as a direct result of the formation of nanoscale undulations in the lipid multilayers, also inducing buckling delamination and enhancing multi-bilayer alignment. We propose this cooperative short- and long-range reconfiguration of lipid multilayered films under compression constitutes a mechanism to accommodate stress and substrate topography. Our work raises fundamental insights regarding the adaptability of complex lipid membranes to mechanical stimuli. This is critical to several technologies requiring mechanically reconfigurable surfaces such as the development of electronic devices interfacing biological materials.
Dispensing with unnecessary assumptions in population genetics analysis
Authors: Labayle Pabet Olivier , Tetley-Campbell Kelsey , van der Laan Mark J. , Ponting Chris P. , Beentjes Sjoerd Viktor , Khamseh Ava
Published: September 2022

Parametric assumptions in population genetics analysis – including linearity, sources of population stratification and additivity of variance as part of a Gaussian noise – are often made, yet their (approximate) validity depends on variant and traits of interest, as well as genetic ancestry and population dependence structure of the sample cohort. We present a unified statistical workflow, called TarGene, for targeted estimation of effect sizes, as well as two-point and higher-order epistatic interactions of genomic variants on polygenic traits, which dispenses with these unnecessary assumptions. Our approach is founded on Targeted Learning, a framework for estimation that integrates mathematical statistics, machine learning and causal inference. TarGene maximises power whilst simultaneously maximising control over false discoveries by: (i) guaranteeing optimal bias-variance trade-off, (ii) taking into account potential covariate non-linearities, sources of population stratification and dependence structure, and (iii) detecting genetic non-linearities. The necessity of this model-independent approach is demonstrated via extensive simulations. We validate the effectiveness of our method by reproducing previously verified effect sizes on UK Biobank data, whilst simultaneously discovering non-linear effect sizes of additional allelic copies on trait or disease, in a PheWAS study involving 781 traits. Specifically, we demonstrate genetic non-linearity at the FTO locus is significant for 54 traits in this study. We further find three pairs of epistatic loci associated with skin color that have been previously reported to be associated with hair color. Finally, we illustrate how TarGene can be used to investigate higher-order interactions using three variants linked to the vitamin D receptor complex. TarGene provides a platform for comparative analyses across biobanks, or integration of multiple biobanks and heterogeneous populations to simultaneously increase power and control for type I errors, whilst taking into account population stratification and complex dependence structures.
Mathematical reconstruction of the metabolic network in anin-vitromultiple myeloma model
Authors: Vera-Siguenza Elias , Escribano-Gonzalez Cristina , Serrano-Gonzalo Irene , Eskla Kattri-Liis , Spill Fabian , Tennant Daniel
Published: September 2022

It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies that exclusively utilisein-vitromono-culture models could prove to be limited for uncovering novel metabolic targets that can translate into clinical therapies. Although this is increasingly recognised, and work addressing this is becoming routinary in a rapidly emerging field, much remains unknown.

This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellularin-silicomodel that facilitates the qualitative and quantitative analysis of the metabolic network spawned by anin-vitroco-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE & Metabotools algorithms, the novel redHuman algorithm, along with13C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating ourin-silicomodel against the in-vitro model, we found that thein-silicomodel successfully reproduces vital metabolic behaviours of itsin-vitrocounterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells. Together, our methodology and its results provide yet another step toward the relevance of studies of this type in the field.
Histone chaperone ASF1 mediates H3.3-H4 deposition in Arabidopsis
Authors: Zhong Zhenhui , Wang Yafei , Wang Ming , Yang Fan , Thomas Quentin Angelo , Xue Yan , Zhang Yaxin , Liu Wanlu , Jami-Alahmadi Yasaman , Xu Linhao , Feng Suhua , Marquardt Sebastian , Wohlschlegel James A. , Ausin Israel , Jacobsen Steven E.
Published: September 2022

Histone chaperones and chromatin remodelers control nucleosome dynamics, which are essential for transcription, replication, and DNA repair. The histone chaperone Anti-Silencing Factor 1 (ASF1) plays a central role in facilitating CAF-1-mediated replication-dependent H3.1 deposition and HIRA-mediated replication-independent H3.3 deposition in yeast and metazoans. Whether ASF1 function is evolutionarily conserved in plants is unknown. Here, we show that Arabidopsis ASF1 proteins display a preference for the HIRA complex. Simultaneous mutation of both Arabidopsis ASF1 genes caused a decrease in chromatin density and ectopic H3.1 occupancy at loci typically enriched with H3.3. Genetic, transcriptomic, and proteomic data indicate that ASF1 proteins strongly prefers the HIRA complex over CAF-1. asf1 mutants also displayed an increase in spurious Pol II transcriptional initiation and showed defects in the maintenance of gene body CG DNA methylation and in the distribution of histone modifications. Furthermore, ectopic targeting of ASF1 caused excessive histone deposition, less accessible chromatin, and gene silencing. These findings reveal the importance of ASF1-mediated histone deposition for proper epigenetic regulation of the genome.
PhysiPKPD: A pharmacokinetics and pharmacodynamics module for PhysiCell
Authors: Bergman Daniel , Marazzi Lauren , Chowkwale Mukti , Maheshvare M Deepa , Bidanta Supriya , Mapder Tarunendu , Li Jialun
Published: September 2022

Pharmacokinetics and pharmacodynamics are key considerations in any study of molecular therapies. It is thus imperative to factor their effects in to any in silico model of biological tissue involving such therapies. Furthermore, creation of a standardized and flexible framework will benefit the community by increasing access to such modules and enhancing their communicability. PhysiCell is an open source physics-based cell simulator, i.e. a platform for modeling biological tissue, that is quickly being adopted and utilized by the mathematical biology community. We present here PhysiPKPD, an open source PhysiCell-based package that allows users to include PKPD in PhysiCell models.

Availability & Implementation

The source code for PhysiPKPD is located here: https://github.com/drbergman/PhysiPKPD.
Phenotypic profiling of macrocyclic lactones on parasitic Schistosoma flatworms
Authors: Ryan Kaetlyn T. , Wheeler Nicolas J. , Kamara Isaac K. , Johnson Hailey , Humphries Judith E , Zamanian Mostafa , Chan John D.
Published: September 2022

Macrocyclic lactones are front-line therapies for parasitic roundworm infections, but there are no comprehensive studies on the activity of this drug class against parasitic flatworms. Ivermectin is well known to be inactive against flatworms. However, the structure-activity relationship of macrocyclic lactones may vary across phyla, and it is entirely possible other members of this drug class do in fact show antiparasitic activity on flatworms. For example, there are several reports hinting at the anti-schistosomal activity of doramectin and moxidectin. To explore this class further, we developed an automated imaging assay combined with measurement of lactate levels from worm media. This assay was applied to the screening of 21 macrocyclic lactones (avermectins, milbemycins and others such as spinosyns) against adult schistosomes. These in vitro assays identified several macrocyclic lactones (emamectin, milbemycin oxime, and the moxidectin metabolite 23-ketonemadectin) that caused contractile paralysis and lack of lactate production. Several of these were also active against miracidia, a juvenile life cycle stage of the parasite. Hits prioritized from these in vitro assays were administered to mice harboring patent schistosome infections. However, no reduction in worm burden was observed. Nevertheless, these data show the utility of a multiplexed in vitro screening platform to quantitatively assess drug action and prioritize hits in a chemical series for in vivo studies. While the prototypical macrocyclic lactone ivermectin displays minimal activity against adult Schistosoma mansoni, this family of compounds does contain schistocidal compounds which may serve as a starting point for development of new anti-flatworm chemotherapies.
Life expectancy, quality of life, and hope among Japanese patients receiving home medical care
Authors: Yasunaka Masakazu , Tsugihashi Yukio , Hayashi Shinu , Iida Hidekazu , Hirose Misaki , Shirahige Yutaka , Kurita Noriaki ,   the ZEVIOUS group
Published: September 2022

Background

Spiritual care should be included in home medical care for patients with limited life expectancy. However, the effect of shortened life expectancy on patients’ quality of life (QOL) and hopes is poorly understood.

Methods

This multicenter cross-sectional study involved 29 home medical care centers in Japan. Exposures were life expectancy (≥ one year / ≥ six months to < one year / < six months) as assessed by home medical care physicians. The outcomes were QOL in home medical care measured via the Quality-of-Life Scale for Elderly Patients Receiving Professional Home Care (QOL-HC), the domain scores of health-related hope (“health,” “role and connectedness,” and “something to live for”), and decrease in life functioning measured using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Linear mixed models were fitted for analyses, with the facilities treated as clusters.

Results

Shorter life expectancy was associated with higher WHODAS 2.0 scores and significantly lower “something to live for” scores (< six months vs. ≥ one year). In contrast, “role and connectedness” scores did not change remarkably with decreased life expectancy, whereas QOL-HC scores were significantly higher with shorter life expectancy.

Conclusion

Home medical care physicians who engage in spiritual care should facilitate thoughtful dialogue with their patients by recognizing declines in life functions and hope for fulfillment, which are associated with short life expectancy.
Pregnant women’s attitudes and behaviours towards antenatal vaccination against Influenza and COVID-19 in the Liverpool City Region, United Kingdom: cross-sectional survey
Authors: Kilada Samantha , French Neil , Perkins Elizabeth , Hungerford Dan
Published: September 2022

Objective

Influenza poses a serious health risk to pregnant women and their babies. Despite this risk, influenza vaccine uptake in pregnant women in the UK is less than 50%. Little is known about how COVID-19 affects pregnant women, but its management may affect attitudes and behaviours towards vaccination in pregnancy. The study objectives were to establish attitudes and knowledge of pregnant women towards influenza disease and influenza vaccination and to compare these to attitudes and knowledge about COVID-19 and COVID-19 vaccination.

Design

A cross-sectional survey was conducted using an online questionnaire distributed through local advertisement and social media outlets. Information was sought on attitudes and knowledge of influenza and COVID-19 and their respective vaccines.

Participants and setting

Pregnant women residing in Liverpool City Region, UK

Results

Of the 237 respondents, 73.8% reported receiving an influenza vaccine. Over half (56.5%) perceived themselves to be at risk from influenza, 70.5% believed that if they got influenza, their baby would get ill, and 64.6% believed getting influenza could hurt their baby, 60.3% believed that the influenza vaccine would prevent their baby from getting ill, and 70.8% believed it would protect their baby. Only 32.9% of respondents stated they would receive the COVID-19 vaccine if it were available to them. However, 80.2% stated they would receive a COVID-19 vaccine if they were not pregnant. Most of the women stated that they would accept a vaccine if recommended to them by healthcare professionals.

Conclusions

Acceptance of the influenza and COVID-19 vaccines during pregnancy seems to be more related to the safety of the baby rather than the mother. Women perceived their child to be more at risk than themselves. Information about influenza and COVID-19 vaccine safety as well as healthcare provider recommendations play an important role in vaccine uptake in pregnant women.

Strengths and limitations of this study

The study provides information on how a pandemic affects vaccine attitudes and behaviours during pregnancy.

The study compares and contrasts attitudes and behaviours towards influenza and COVID-19 vaccines.

The study provides new information relating to barriers to COVID-19 vaccine acceptance and provides insights into mechanisms for improving uptake.

The sample size is small and self-selected which might lead to an over-representation of women likely to accept or have strong opinions on vaccinations.

Responses to the questions on vaccine status are self-reported, not provided from healthcare records.
Real-time intelligent classification of COVID-19 and thrombosis via massive image-based analysis of platelet aggregates
Authors: Zhang Chenqi , Herbig Maik , Zhou Yuqi , Nishikawa Masako , Shifat-E-Rabbi Mohammad , Kanno Hiroshi , Yang Ruoxi , Ibayashi Yuma , Xiao Ting-Hui , Rohde Gustavo K. , Sato Masataka , Kodera Satoshi , Daimon Masao , Yatomi Yutaka , Goda Keisuke
Published: September 2022

Microvascular thrombosis is a typical symptom of COVID-19 and shows similarities to thrombosis. Using a microfluidic imaging flow cytometer, we measured the blood of 181 COVID-19 samples and 101 non-COVID-19 thrombosis samples, resulting in a total of 6.3 million bright-field images. We trained a convolutional neural network to distinguish single platelets, platelet aggregates, and white blood cells and performed classical image analysis for each subpopulation individually. Based on derived single-cell features for each population, we trained machine learning models for classification between COVID-19 and non-COVID-19 thrombosis, resulting in a patient testing accuracy of 75%. This result indicates that platelet formation differs between COVID-19 and non-COVID-19 thrombosis. All analysis steps were optimized for efficiency and implemented in an easy-to-use plugin for the image viewer napari, allowing the entire analysis to be performed within seconds on mid-range computers, which could be used for real-time diagnosis.
Utilizing Metabolomics to Identify Potential Biomarkers and Perturbed Metabolic Pathways in Osteoarthritis: A Systematic Review
Authors: Pevenage Peyton Van , Birchmier Jaedyn T. , June Ronald K.
Published: September 2022

Purpose

Osteoarthritis (OA) is a joint disease that is clinically diagnosed using components of history, physical exam, and radiographic evidence of joint space narrowing. Currently, there are no laboratory findings that are specific to a diagnosis of OA. The purpose of this systematic review is to evaluate the state of current studies of metabolomic biomarkers that can aid in the diagnosis and treatment of OA.

Methods

Articles were gathered from PubMed and Web of Science using the search terms “osteoarthritis” and “biomarkers” and “metabolomics”. Last search of databases took place July 20th, 2021. Duplicates were manually screened, along with any other results that were not original journal articles. Only original reports involving populations with diagnosed primary or secondary OA (human participants) or surgically induced OA (animal participants) and a healthy control group for comparison were considered for inclusion. Metabolites and metabolic pathways reported in included articles were then manually extracted and evaluated for significance based on reported a priori p-values and/or area under the receiver-operator curve (AUC).

Results

Of the 129 results that were returned in the database searches, 36 unique articles met the inclusion criteria. Articles were categorized based on body fluid analyzed: 6 studies on urine samples, 12 studies on plasma samples, 9 studies on synovial fluid (SF) samples, 8 studies on serum samples, and 1 study that involved both plasma and synovial fluid. To synthesize results, individual metabolites, as well as metabolic pathways that involve frequently reported metabolites, are presented for each study. Indications as to whether metabolite levels were increased or decreased are also included if this data was included in the original articles.

Conclusions

These studies clearly show that there are a wide range of metabolic pathways perturbed in OA. For this period, there was no consensus on a single metabolite, or panel of metabolites, that would be clinically useful in early diagnosis of OA or distinguishing OA from a healthy control. However, many common metabolic pathways were identified in the studies, including TCA cycle, fatty acid metabolism, amino acid metabolism (notably BCAA metabolism and tryptophan metabolism via kynurenine pathway), nucleotide metabolism, urea cycle, cartilage metabolism, and phospholipid metabolism. Future research is needed to define effective clinical biomarkers of osteoarthritis from metabolomic and other data.
Increasing Cases of SARS-CoV-2 Omicron Reinfection Reveals Ineffective Post-COVID-19 Immunity in Denmark and Conveys the Need for Continued Next-Generation Sequencing
Authors: Burkholz Scott , Rubsamen Michael , Blankenberg Luke , Carback Richard T. , Mochly-Rosen Daria , Harris Paul E.
Published: September 2022

SARS-CoV-2 has extensively mutated creating variants of concern (VOC) resulting in global infection surges. The Omicron VOC reinfects individuals exposed to earlier variants of SARS-CoV-2 at a higher frequency than previously seen for non-Omicron VOC. An analysis of the sub-lineages associated with an Omicron primary infection and Omicron reinfection reveals that the incidence of Omicron-Omicron reinfections is occurring over a shorter time interval than seen after a primary infection with a non-Omicron VOC. Our analysis suggests that a single infection from SARS-CoV-2 may not generate the protective immunity required to defend against reinfections from emerging Omicron lineages. This analysis was made possible by Next-generation sequencing (NGS), specifically of a Danish cohort with clinical metadata on both infections occurring in the same individual. We suggest that the continuation of COVID-19 NGS and inclusion of clinical metadata is necessary to ensure effective surveillance of SARS-CoV-2 genomics, assist in treatment and vaccine development, and guide public health recommendations.
The persistent homology of mitochondrial ATP synthases
Authors: Sinha Savar D. , Wideman Jeremy G.
Published: September 2022

While mitochondrial ATP synthase has been thoroughly studied in animals and fungi, relatively little is known about the structures of protists. Among those that have been studied, protist ATP synthases possess divergent structures distinct from those of yeast or animals. Therefore, we aimed to clarify the subunit composition and evolution of ATP synthase across all major eukaryotic lineages. We used sensitive homology detection methods and molecular modelling tools to demonstrate the persistence of a near-complete ancestral set of 17 subunits in most major eukaryotic taxa even despite major divergence. These data demonstrate that most eukaryotes possess an ancestral-like ATP synthase structure similar to those of animals, fungi, and plants, but a number have diverged drastically (e.g., ciliates, myzozoans, euglenozoans, and likely retarians and heteroloboseans). In addition, we identified the first synapomorphy of the SAR (stramenopile, alveolate, rhizaria) supergroup – a ~1 billion-year-old gene fusion between ATP synthase stator subunits. Our comparative approach highlights the persistence of ancestral subunits even amidst major structural changes. We conclude by urging that more ATP synthase structures (e.g., from jakobids, heteroloboseans, stramenopiles, rhizarians) are needed to provide a complete picture of the evolution of structural diversity of this ancient and essential complex.