bluuebunny/crossref_metadata_2025 huggingface dataset:
Phylogeography and transmission ofM. tuberculosisspanning prisons and surrounding communities in Paraguay
Authors: Sanabria Gladys Estigarribia , Sequera Guillermo , Aguirre Sarita , Méndez Julieta , dos Santos Paulo César Pereira , Gustafson Natalie Weiler , Ortiz Analía , Cespedes Cynthia , Martínez Gloria , García-Basteiro Alberto L. , Andrews Jason R. , Croda Julio , Walter Katharine S.
Published: August 2022

Recent rises in incident tuberculosis (TB) cases in Paraguay and the increasing concentration of TB within prisons highlight the urgency of targeting strategies to interrupt transmission and prevent new infections. However, whether specific cities or carceral institutions play a disproportionate role in transmission remains unknown. We conducted prospective genomic surveillance, sequencing 471M. tuberculosisgenomes, from inside and outside prisons in Paraguay’s two largest urban areas, Asunción and Ciudad del Este, from 2016 to 2021. We found genomic evidence of frequent recent transmission within prisons and transmission linkages spanning prisons and surrounding populations. We identified a signal of frequentM. tuberculosisspread between urban areas and marked recent population size expansion of the three largest genomic transmission clusters. Together, our findings highlight the urgency of strengthening TB control programs to reduce transmission risk within prisons, where, in Paraguay, incidence was 70 times that outside prisons in 2021.

Financing agencies

National Institutes of Health grants R01 AI130058 (JRA) and R01 AI149620 (JRA and JC). Paraguay National Commission of Science and Technology grant CONACYT PIN 15-705 (GES and GS).
Air filtration mitigates aerosol levels both during and after OGD procedures
Authors: Phillips Frank , Crowley Jane , Warburton Samantha , Parra-Blanco Adolfo , Gordon George S.D.
Published: August 2022

Objectives

Upper GI endoscopies are aerosol generating procedures (AGPs), increasing risk of spreading airborne pathogens. We aim to quantify mitigation of airborne particles via improved ventilation, specifically laminar flow theatres and portable HEPA filters, during and after upper GI endoscopies.

Methods

This observational study included patients undergoing routine oral gastroscopy in a standard endoscopy room with 15-17 air changes per hour, a standard endoscopy room with portable HEPA filtration unit, and a laminar flow theatre with 300 air changes per hour. A particle counter (diameter range 0.3µm-25µm) took measurements 10cm from the mouth. Three analyses were performed: whole procedure particle counts, event-based counts and air clearance estimation using post-procedure counts.

Results

Compared to a standard endoscopy room, for whole procedures we observe a 28.5x reduction in particle counts in laminar flow (p<0.001) but no significant effect of HEPA filtration (p=0.50). For event analysis we observe for lateral flow theatres reduction in particles >5µm for oral extubation (12.2x, p<0.01), reduction in particles <5µm for coughing/gagging (6.9x, p<0.05) and reduction for all sizes in anaesthetic throat spray (8.4x, p<0.01) but no significant effect of HEPA filtration. However, we find that in the fallow period between procedures HEPA filtration reduces particle clearance times by 40%.

Conclusions

Laminar flow theatres are highly effective at dispersing aerosols immediately after production and should be considered for high-risk cases where patients are actively infectious or supply of PPE is limited. Portable HEPA filers can safely reduce fallow time between procedures by 40%.
Self-Management of Diabetic Patients from the Urban Areas in Bangladesh
Authors: Hossain Md. Jubayer , Towhid Syeda Tasneem , Akter Sumona , Shahjahan Muhibullah , Roy Tilottoma , Akter Bithi , Nodee Tanjum Ahmed
Published: August 2022

Background

This study aimed to determine the knowledge about self-management and the effects of diabetes on the daily activities among adult patients with Type 1 and Type 2 diabetes in Bangladesh.

Methodology

A cross-sectional study was conducted from April to August 2021 on diabetic patients from Dhaka and the Rangpur district in Bangladesh. A structured questionnaire was used to collect data from study participants. This study’s researchers collected data via phone interview. The collected data was analyzed using Python (Version 3.8), Pandas, and ResearchPy (A Python package for research data analysis).

Results

Out of the 303 participants, all are middle-class service holders with an urban sedentary lifestyle. 69.64% and 30.3% are male and female, respectively, with 66% having post-secondary education and 35% having smoking habits. Most (68.32%) had onset of diabetic symptoms between 36-50 years, 23.43% with Type I and 41.9% with Type II diabetes. However, 34.65% of participants couldn’t answer about their ailment definitively. 22.44% of participants were on regular insulin shots within 3 months of the first diagnosis, and 90% were satisfied with managing diabetes. However, 54.46% admitted to adopting an altered lifestyle after becoming diabetic. Males and females with both types of diabetes showed significantly different comorbidities in a paired 2-tailed t-test (0.012 and 0.02 for Type I and Type II, respectively). The male participants showed higher incidences of cardiac issues, while females showed a higher propensity to hypertension. 85% of participants were confident about their medication, course of management, prognosis, diet, and lifestyle for controlling diabetes.

Conclusions

The disparity in the number of male and female participants and the high percentage of participants with no factual information about their prognosis need to be targeted for further study, and a patient-friendly engagement/ information dissemination action plan should be helpful.
Use of human albumin solution in a secondary hospital: an observational, retrospective, cross-sectional study
Authors: Rodriguez Mauriz Rosa , Monzó Patricia , Rudi Sola Nuria , Villagrasa Ares , Borràs Trias Laura
Published: August 2022

Human albumin solution (HAS) is a plasma-derived product used for a wide variety of clinical indications, although only some of these are supported by solid scientific evidence.

Objectives

The primary aim of this study was to analyze the level of evidence supporting the clinical indications for which HAS is used at a secondary care hospital. Secondary objectives were to evaluate dosing appropriateness and perform a subanalysis of the internal medicine department.

Methods

Retrospective, observational, multidisciplinary study of adults who received at least one dose of HAS during 2019. We analyzed sociodemographic, clinical, laboratory, and pharmacotherapy variables. The indications for which HAS was used were classified into the four evidence-based categories established by the American Society for Apheresis: high priority (category I), reasonable evidence (II), weak evidence (III), and treatment not recommended (IV). Clinical guideline recommendations were used to evaluate dosing appropriateness.

Results

The study population comprised 142 patients (41% women), mean (SD) age of 66 (14) years. The main admission diagnoses were decompensated cirrhosis (32%) and septic shock (31%). In total, 223 courses of HAS were prescribed. The main indications were treatment of anasarca and hypoalbuminemia (32%), prevention of paracentesis-induced circulatory dysfunction after large-volume paracentesis (17%), resuscitation in septic shock (13%), and treatment of protein malnutrition (9%). Just 26% of hospital-wide indications were supported by strong evidence (category I); 13% category II, 8% category III, and 53% category IV. In the internal medicine department, 36% of indications were in category I, 16% in category III, 48% in category IV. An appropriate dosing regimen was used in just four category I indications.

Conclusions

A large proportion of HAS indications at our hospital are supported by weak evidence. Training to promote the rational use of HAS is needed. Protocols and local clinical guidelines could help standardize and optimize its use.
Isoform-level transcriptome-wide association uncovers extensive novel genetic risk mechanisms for neuropsychiatric disorders in the human brain
Authors: Bhattacharya Arjun , Vo Daniel D. , Jops Connor , Kim Minsoo , Wen Cindy , Hervoso Jonatan L. , Pasaniuc Bogdan , Gandal Michael J.
Published: August 2022

Integrative methods, like colocalization and transcriptome-wide association studies (TWAS), identify transcriptomic mechanisms at only a fraction of trait-associated genetic loci from genome-wide association studies (GWAS). Here, we show that a reliance on reference functional genomics panels of only total gene expression greatly contributes to this reduced discovery. This is particularly relevant for neuropsychiatric traits, as the brain expresses extensive, complex, and unique alternative splicing patterns giving rise to multiple genetically-regulated transcript-isoforms per gene. Integrating highly correlated transcript-isoform expression with GWAS requires methodological innovations.

We introduce isoTWAS, a multivariate framework to integrate genetics, isoform-level expression, and phenotypic associations in a step-wise testing framework, and evaluate it using data from the Genotype-Tissue Expression (GTEx) Project, PsychENCODE Consortium, and other sources. isoTWAS shows three main advantages. First, joint, multivariate modeling of isoform expression fromcis-window SNPs improves prediction by ∼1.8-2.4 fold, compared to univariate modeling. Second, compared to gene-level TWAS, these improvements in prediction lead to ∼1.9-2.5-fold increase in the number of testable genes and a median of 25-70% increase in cross-validated prediction of total gene expression, with the added ability to jointly capture expression and splicing mechanisms. In external validation, isoform-centric models predicted gene expression at percent variance explained >1% for 50% more genes than gene-centric models. Third, across 15 neuropsychiatric traits, isoTWAS increased discovery of trait associations within GWAS loci over TWAS, capturing ∼60% more unique loci and 95% of loci detected by TWAS. Results from extensive simulations showed no increase in false discovery rate and reinforce isoTWAS’s advantages in prediction and trait mapping power over TWAS, especially when genetic effects on expression vary across isoforms of the same gene. We illustrate multiple biologically-relevant isoTWAS-identified trait associations undetectable by gene-level methods, including isoforms ofAKT3,CUL3, andHSPD1with schizophrenia risk, andPCLOwith multiple disorders.

The isoTWAS framework addresses an unmet need to consider the transcriptome on the transcript-isoform level to increase discovery of trait associations, especially for brain-relevant traits.
A Census of Clinical Trials Conducted Under the US Exception from Informed Consent Rule
Authors: Snyder Krista L. , Merz Jon F.
Published: August 2022

Background

The US Food and Drug Administration and National Institutes of Health adopted the Exception from Informed Consent (EFIC) rule in 1996, permitting waiver of informed consent for certain emergency research, including trials funded by the federal government. The rule requires that prospective consent be sought when practicable from patients or their Legally Authorized Representative(s) (LAR), and for those enrolled without consent, the patient or their LAR must be given information and an opportunity to opt-out from continued participation at the earliest opportunity. We sought to census the trials conducted under the EFIC rule to facilitate research to better understand how the rule is being used.

Methods

We conducted a multi-pronged search to try and identify all trials conducted under the EFIC rule, drawing on numerous reviews, Medline and Google searches (including of theclinicaltrials.govregistry), examination of the FDA’s docket, posting an inquiry on the IRB Forum, and email requests to lead authors of all published EFIC trials and related review articles. We describe the trials, when they were started and completed, and whether they were terminated early.

Results

We identified a total of 105 trials as of April 1, 2022: 77 complete, 10 recruiting, 10 registered onclinicaltrials.govbut not yet recruiting, 5 trials that were abandoned before enrolling any subjects, and 3 trials in early planning. Nine of the 77 completed trials were pilot or feasibility trials. Of 68 completed full trials, 30 (44.1%) were terminated early. The most common reason for early termination was futility or safety (17 trials, 25.0%) followed by poor recruitment (9 trials, 13.2%). The rate of conduct of trials has been remarkably constant since 2001, with roughly 18 trials started in each 5-year period.

Conclusions

The rate of early termination of EFIC trials for futility or safety appears higher than for other kinds of clinical research. We provide the list of trials in a Supplement for further in-depth data collection and analysis of this set of trials.
Correlated variation between the splanchnocranium and basicranium in the Toy rabbit
Authors: Parés-Casanova Pere M.
Published: August 2022

The aim of this study was to explore and compare patterns of morphological covariation, including symmetrical deviations, between splanchnocranium and the basicranium in Toy rabbit, a type of paedomorphic rabbit. A sample of 32 skulls of adult Toy rabbits was studied on digital pictures on ventral aspects by means of geometric morphometric methods. A set of 7 landmarks were located on the horizontal plane of the splanchnocranial ventral bones (palatine process of the maxillary bone [processus palatinus maxillae] + palatine bone [lamina horizontalis ossis palatini]), and a set of 8 landmarks were on the basicranium (sphenoid [os sphenoidale] + basilar part of the occipital bone [pars basilaris] + bulla tympanica). Both fluctuating and directional asymmetries were detected on both blocks, being the asymmetry more important among splanchnocranial bones. It appeared also a significant relationship (allometry) between size and shape, especially in the basicranium, as well a significant relationship between the two blocks. From results we deduce that, although normally cranial base usually reaches adult size before the face, in paedomorphic animals the face stops its growth earlier than basicranium, resulting in their proportionally reduced splanchnocranium, the typical brachyfacial morphology for paedomorphy. In other words, our results support the hypothesis of an early stop of facial pattern development in neoteny -the retention of juvenile characteristics into adulthood-, which can affect vital structures. So, further research should expand on clinical data of paedomorphic animals in order to advance in the understanding of pathological results of this growth anomaly.
Development of an adenosquamous carcinoma histopathology-selective lung cancer graft model
Authors: Lähdeniemi I.A.K. , Devlin J.R. , Nagaraj A.S. , Talwelkar S.S. , Bao J. , Linnavirta N. , Şeref Vujaklija C. , Kiss E.A. , Hemmes A. , Verschuren E.W.
Published: August 2022

Preclinical tumor models with native tissue microenvironments provide essential tools to understand how heterogeneous tumor phenotypes relate to drug response. Here, we present syngeneic graft models of aggressive, metastasis-prone histopathology-specific NSCLC tumor types driven by KRAS mutation and loss of LKB1 (KL): adenosquamous carcinoma (ASC) and adenocarcinoma (AC). We show that subcutaneous injection of primary KL-ASC cells results in squamous cell carcinoma (SCC) tumors with high levels of stromal infiltrates, lacking the source heterogeneous histotype. Despite forming subcutaneous tumors, intravenously injected KL-AC cells were unable to form lung tumors. In contrast, intravenous injection of KL-ASC cells leads to their lung re-colonization and lesions recapitulating the mixed AC and SCC histopathology, tumor immune suppressive microenvironment and oncogenic signaling profile of source tumors, demonstrating histopathology-selective phenotypic dominance over genetic drivers. Pan-ERBB inhibition increased survival, while selective ERBB1/EGFR inhibition did not, suggesting a role of ERBB network crosstalk in resistance to ERBB1/EGFR. This immunocompetent NSCLC lung colonization model hence phenocopies key properties of the metastasis-prone ASC histopathology, and serves as a preclinical model to dissect therapy responses and metastasis-associated processes.
A cosmic view of ‘tundra gardens’: satellite imagery provides a landscape-scale perspective of Arctic fox ecosystem engineering
Authors: Johnson-Bice Sean M. , Roth James D. , Markham John H.
Published: August 2022

Animal ecology has benefitted greatly from advancements in remote sensing technology and data availability in recent decades. Most animal ecology studies using remote sensing data have focused on assessing how environmental characteristics shape animal abundance, distribution, or behavior. But the growing availability of high-resolution remote sensing data offers new opportunities to study how animals, in turn, shape ecosystems. We use high-spatiotemporal resolution Sentinel-2 satellite imagery to evaluate the effects of Arctic fox (Vulpes lagopus) denning activity on vegetation. Arctic fox dens are characterized with unique vegetation relative to the surrounding area, presumably due to decades of nutrient accumulation and bioturbation. We use an imagery-derived metric (NDVI) to compare maximum plant productivity and plant phenology patterns on Arctic fox dens vs. reference sites, i.e., points generated within areas of preferred denning habitat as predicted from a habitat selection analysis. We show that high-resolution satellite imagery can be used effectively to quantify the effects of Arctic fox denning activity on vegetation. Plant productivity and the rate of green up were both greater on fox dens compared to reference sites. Productivity on these preferred-habitat (reference) sites was lower than average productivity on the tundra (i.e., random sites), indicating that foxes primarily establish dens in low-productivity areas. Our findings support previous studies that proposed Arctic foxes function as ecosystem engineers in low Arctic ecosystems by converting sites of low productivity into sites of high productivity through their denning activity. Plant productivity was unrelated to recent den occupancy patterns, indicating fox denning activity has long-term legacy effects on plants that last well beyond the lifetime of foxes. We add to the growing body of literature that recognizes predators can be drivers of landscape heterogeneity and influence ecosystem dynamics through patch-scale pathways, such as by concentrating nutrients into localized areas. Our study demonstrates the efficacy of using remote sensing technologies to advance our understanding of the functional roles that predators specifically, and animals generally, occupy in ecosystems.
A novel method for investigating fish social behaviour in the field
Authors: Clark Molly A , Ioannou Christos C
Published: August 2022

Field studies of social behaviour are challenging due to having to observe multiple individuals simultaneously. In aquatic environments, these challenges are often amplified by environmental conditions such as habitat complexity, turbidity or darkness, which are often the conditions of interest in the context of studying anthropogenic impacts. Many fish species rely on social interactions for at least part of their life cycle, and while these interactions are known from laboratory studies to be impacted by environmental factors, approaches to quantify social behaviour under natural conditions are limited. Here, we present a novel method whereby multiple funnel traps are deployed simultaneously within a pond to quantify the aggregation and assortment of wild fish populations, using three-spine sticklebacks (Gasterosteus aculeatus) as a model species. The number of sticklebacks caught decreased in lower temperatures and through the seasons, from May to November. There was some evidence for decreases in fish numbers with reduced light intensity and higher dissolved oxygen levels. No effect of turbidity was found. The only evidence for changes in aggregation was related to the proportion of breeding males caught, where sticklebacks were less aggregated during the breeding season. These trends are expected based on previous work and knowledge about stickleback biology, validating the method. However, in contrast to previous studies, we found little evidence for phenotypic assortment. This study establishes a new cost-effective technique for investigating the social behaviour of wild fish, with some important benefits over existing techniques.
Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan
Authors: Grzegorzewski Jan , Brandhorst Janosch , König Matthias
Published: August 2022

The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO+DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.
Identifying Optimal Neuroinflammation Treatment Using Nanoligomer™ Discovery Engine
Authors: Sharma Sadhana , Borski Curtis , Hanson Jessica , Garcia Micklaus A. , Link Christopher D. , Hoeffer Charles , Chatterjee Anushree , Nagpal Prashant
Published: August 2022

Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury. However, chronic neuroinflammation leads to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and is causally linked to a range of neurodegenerative diseases such as Alzheimer’s diseases (AD), Multiple Sclerosis (MS), Parkinson’s diseases (PD), and many others. While neuroinflammation is a key target for a range of neuropathological diseases, there is a lack of effective countermeasures to tackle it, and existing experimental therapies require fairly invasive intracerebral and intrathecal delivery due to difficulty associated with the therapeutic crossover between the blood-brain barrier (BBB), making such treatments impractical to treat neuroinflammation long-term. Here, we present the development of an optimal neurotherapeutic using our Nanoligomer™ discovery engine, by screening downregulation of several proinflammatory cytokines (e.g., Interleukin-1β or IL-1β, tumor necrosis factor-alpha or TNF-α, TNF receptor 1 or TNFR1, Interleukin 6 or IL-6), inflammasomes (e.g., NLRP1), key transcription factors (e.g., nuclear factor kappa-B or NF-κβ) and their combinations, as upstream regulators and canonical pathway targets, to identify and validate the best-in-class treatment. Using our high-throughput drug discovery, target validation, and lead molecule identification via a bioinformatics and AI-based ranking method to design sequence-specific peptide molecules to up-or down-regulate gene expression of the targeted gene at will, we used our discovery engine to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse neuroinflammation. The lead neurotherapeutic was a combination of Nanoligomers™ targeted to NF-κβ (SB.201.17D.8_ NF-κβ1) and TNFR1 (SB.201.18D.6_TNFR1), which were identified usingin vitrocell-based screening in donor-derived human astrocytes, and further validatedin vivousing a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation. The combination treatment SB_NI_111 was delivered without any special formulation using a simple intraperitoneal injection of low-dose (5mg/kg) and was found to significantly suppress the expression of LPS-induced neuroinflammation in mouse hippocampus. These results point to the broader applicability of this approach towards the development of therapies for chronic neuroinflammation-linked neurodegenerative diseases, sleep countermeasures, and others, and the potential for further investigation of the lead neurotherapeutic molecule as reversible gene therapy.
Spiders as surrogates of biodiversity in a geothermal area of northern Puebla, México
Authors: Hernández-Salgado Luis Carlos , Romero Guillermo , Rodriguez-Canseco Jesus , Gonzalez-Estupiñan Krystal
Published: August 2022

The word biodiversity has gained popularity for more than 30 years; and we used this term for all aspects of biological diversity, from the richness of taxa, genetic variation, and ecosystem complexity. Thoroughly measuring biodiversity would be impractical due to many existing species and the effort that their identification would represent. Therefore, we need to find suitable surrogates or substitute taxa, which we can monitor because they represent broader biodiversity, helping us in ecological monitoring or conservation program planning. We tested the richness of spiders to measure their ability to estimate total spider richness at a site with geothermal influence. We use data from six locations with geothermal effect in the northern highlands of Puebla, Mexico. The genera richness of spiders was a good substitute for the total species richness, and the opposite happened with the family richness. Therefore, we recommend using this taxonomic level as a substitute to predict spider species richness or to evaluate and classify sites according to their importance for conservation. Here, we present the first spiders biodiversity data of a geothermal area and the use of spiders as surrogates in sites with geothermal condition.
SlowMoMan: A web app for discovery of important features along user-drawn trajectories in 2D embeddings
Authors: Deol Kiran , Weber Griffin M. , Yu Yun William
Published: August 2022

Nonlinear low-dimensional embeddings allow humans to visualize high-dimensional data, as is often seen in bioinformatics, where data sets may have tens of thousands of dimensions. However, relating the axes of a nonlinear embedding to the original dimensions is a nontrivial problem. In particular, humans may identify patterns or interesting subsections in the embedding, but cannot easily identify what those patterns correspond to in the original data. Thus, we present SlowMoMan (SLOW Motions on MANifolds), a web application which allows the user to draw a 1-dimensional path onto a 2-dimensional embedding. Then, by back-projecting the manifold to the original, high-dimensional space, we sort the original features such that those most discriminative along the manifold are ranked highly. We show a number of pertinent use cases for our tool, including trajectory inference, spatial transcriptomics, and automatic cell classification.

Software availability

https://yunwilliamyu.github.io/SlowMoMan/

Code availability

https://github.com/yunwilliamyu/SlowMoMan
Exploring masses and internal mass distributions of single carboxysomes in free solution using fluorescence and interferometric scattering in an anti-Brownian trap
Authors: Lavania Abhijit A. , Carpenter William B. , Oltrogge Luke M. , Perez Davis , Borden Julia S. , Savage David F. , Moerner W. E.
Published: August 2022

Carboxysomes are self-assembled bacterial microcompartments that facilitate carbon assimilation by co-localizing the enzymes of CO2 fixation within a protein shell. These microcompartments can be highly heterogeneous in their composition and filling, so measuring the mass and loading of an individual carboxysome would allow for better characterization of its assembly and function. To enable detailed and extended characterizations of single nanoparticles in solution, we recently demonstrated an improved Interferometric Scattering Anti-Brownian ELectrokinetic (ISABEL) trap, which tracks the position of a single nanoparticle via its scattering of a near-infrared beam and applies feedback to counteract its Brownian motion. Importantly, the scattering signal can be related to the mass of nanoscale proteinaceous objects, whose refractive indices are well-characterized. We calibrate single-particle scattering cross-section measurements in the ISABEL trap and determine individual carboxysome masses in the 50-400 MDa range by analyzing their scattering cross-sections with a core-shell model. We further investigate carboxysome loading by combining mass measurements with simultaneous fluorescence reporting from labeled internal components. This method may be extended to other biological objects, such as viruses or extracellular vesicles, and can be combined with orthogonal fluorescence reporters to achieve precise physical and chemical characterization of individual nanoscale biological objects.

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New Insights into How JUUL™ Electronic Cigarette Aerosols and Aerosol Constituents Affect SARS-CoV-2 Infection of Human Bronchial Epithelial Cells
Authors: Phandthong Rattapol , Wong Man , Song Ann , Martinez Teresa , Talbot Prue
Published: August 2022

Background

The relationship between the use of tobacco products and SARS-CoV-2 infection is poorly understood and controversial. Most studies have been done with tobacco cigarettes, while few have examined the effect of electronic cigarettes (ECs) on SARS-CoV-2 infection. We tested the hypothesis that EC fluids and aerosols with high concentrations of nicotine promote SARS-COV-2 infection by increasing viral entry into human respiratory epithelial cells.

Methods

Responses of BEAS-2B cells to authentic JUUL™ aerosols or their individual constituents (propylene glycol (PG)/vegetable glycerin (VG) and nicotine) were compared using three exposure platforms: submerged culture, air-liquid-interface (ALI) exposure in a cloud chamber, and ALI exposure in a Cultex® system, which produces authentic heated EC aerosols. SARS-CoV-2 infection machinery was assessed using immunohistochemistry and Western blotting. Specifically, the levels of the SARS-CoV-2 receptor ACE2 (angiotensin converting enzyme 2) and a spike modifying enzyme, TMPRSS2 (transmembrane serine protease 2), were evaluated. Following each exposure, lentivirus pseudoparticles with spike protein and a green-fluorescent reporter were used to test viral penetration and the susceptibility of BEAS-2B cells to infection.

Results

Nicotine, EC fluids, and authentic JUUL™ aerosols increased both ACE2 levels and TMPRSS2 activity, which in turn increased viral particle entry into cells. While most data were in good agreement across the three exposure platforms, cells were more responsive to treatments when exposed at the ALI in the Cultex system, even though the exposures were brief and intermittent. In the Cultex system, PG/VG, PG/VG/nicotine, and JUUL™ aerosols significantly increased infection above clean air controls. However, both the PG/VG and JUUL™ treatments were significantly lower than nicotine/PG/VG. PG/VG increased infection only in the Cultex® system, which produces heated aerosol.

Conclusion

Our data are consistent with the conclusion that authentic JUUL™ aerosols or their individual constituents (nicotine or PG/VG) increase SARS-CoV-2 infection. The strong effect produced by nicotine was modulated in authentic JUUL aerosols, demonstrating the importance of studying mixtures and aerosols from actual EC products. These data support the idea that vaping increases the likelihood of contracting COVID-19.
Downregulated NPAS4 in multiple brain regions is associated with Major Depressive Disorder
Authors: Selçuk Berkay , Aksu Tuana , Dereli Onur , Adebali Ogun
Published: August 2022

Major Depressive Disorder (MDD) is a commonly observed psychiatric disorder that affects more than 2% of the world population with a rising trend. However, disease-associated pathways and biomarkers are yet to be fully comprehended. In this study, we analyzed previously generated RNA-seq data across seven different brain regions from three distinct studies to identify differentially and co-expressed genes for patients with MDD. Differential gene expression (DGE) analysis revealed that NPAS4 is the only gene downregulated in three different brain regions. Furthermore, co-expressing gene modules responsible for glutamatergic signaling are negatively enriched in these regions. We used the results of both DGE and co-expression analyses to construct a novel MDD-associated pathway. In our model, we propose that disruption in glutamatergic signaling-related pathways might be associated with the downregulation of NPAS4 and many other immediate-early genes (IEGs) that control synaptic plasticity. In addition to DGE analysis, we identified the relative importance of KEGG pathways in discriminating MDD phenotype using a machine learning-based approach. We anticipate that our study will open doors to developing better therapeutic approaches targeting glutamatergic receptors in the treatment of MDD.
Primary postpartum haemorrhage and longer-term physical, psychological, and psychosocial health outcomes for women and their partners: a mixed-methods systematic review
Authors: Latt Su Mon , Alderdice Fiona , Elkington Madeline , Shar Mahkawnghta Awng , Kurinczuk Jennifer J , Rowe Rachel
Published: August 2022

Objectives

Most research about outcomes following postpartum haemorrhage (PPH) has focused on immediate outcomes. There are fewer studies investigating longer-term maternal morbidity following PPH, resulting in a significant knowledge gap. This review aimed to synthesize the evidence about the longer-term physical and psychological consequences of primary PPH for women and their partners from high income settings.

Methods

The review was registered with PROSPERO and five electronic databases were searched. Studies were independently screened against the eligibility criteria by two reviewers and data were extracted from both quantitative and qualitative studies that reported non-immediate health outcomes of primary PPH.

Results

Data were included from 24 studies, of which 16 were quantitative, five were qualitative and three used mixed-methods. The included studies were of mixed methodological quality. Of the nine studies reporting outcomes beyond five years after birth, only two quantitative studies and one qualitative study had a follow-up period longer than ten years. Seven studies reported outcomes or experiences for partners. The evidence indicated that women with PPH were more likely to have persistent physical and psychological health problems after birth compared with women who did not have a PPH. These problems, including PTSD symptoms and cardiovascular disease, may be severe and extend for many years after birth and were more pronounced after a severe PPH, as indicated by a blood transfusion or hysterectomy. There was limited evidence about outcomes for partners after PPH, but conflicting evidence of association between PTSD and PPH among partners who witnessed PPH.

Conclusion

This review explored existing evidence about longer-term physical and psychological health outcomes among women who had a primary PPH in high income countries, and their partners. While the evidence about health outcomes beyond five years after PPH is limited, our findings indicate that women can experience long lasting negative impacts after primary PPH, including PTSD symptoms and cardiovascular disease, extending for many years after birth.

PROSPERO registration number

CRD42020161144
Optimal Respiratory Syncytial Virus intervention programmes using Nirsevimab in England and Wales
Authors: Hodgson David , Koltai Mihaly , Krauer Fabienne , Flasche Stefan , Jit Mark , Atkins Katherine E.
Published: August 2022

Introduction

Respiratory Syncytial Virus (RSV) is a major cause of acute lower respiratory tract infections (ALRI) in infants. There are no licensed vaccines and only one monoclonal antibody available to protect infants from disease. A new and potentially longer-lasting monoclonal antibody, Nirsevimab, showed promising results in phase IIb/III trials. We evaluate the cost-effectiveness of Nirsevimab intervention programmes in England and Wales

Methods

We used a dynamic model for RSV transmission, calibrated to data from England and Wales. We considered a suite of potential Nirsevimab programmes, including administration to all neonates (year-round); only neonates born during the RSV season (seasonal); or neonates born during the RSV season plus infants less than six months old before the start of the RSV season (seasonal + catch-up).

Results

If administered seasonally to all infants at birth, we found that Nirsevimab would have to be priced less than £63 per dose for at least 50% certainty that it could cost-effectively replace the current Palivizumab programme, using an ICER threshold of £20,000/QALY. An extended seasonal programme which includes a pre-season catch-up becomes the optimal strategy below a £34/dose purchasing price for at least 50% certainty. At a purchasing price per dose of £5-32, the annual implementation costs of a seasonal programme could be as high as £2 million before a switch to a year-round strategy would be optimal.

Discussion

Nirsevimab has the potential to be cost-effective in England and Wales not only for use in high-risk infants.
Dynamics of anti-S IgG antibodies titers after the second dose of COVID 19 mRNA and non-mRNA vaccines in the manual and craft worker population of Qatar
Authors: Bansal Devendra , Atia Hassan , Badr Mashael Al , Nour Mohamed , Abdulmajeed Jazeel , Hasan Amal , Al-Hajri Noora , Ahmed Lina , Ibrahim Rumissa , Zamel Reham , Mohamed Almuthana , Pattalaparambil Hamad , Daraan Faisal , Chaudhry Adil , Oraby Sahar , El-Saleh Sahar , El-Shafie Sittana S , Al-Farsi Affra Faiz , Paul Jiji , Ismail Ahmed , Al-Romaihi Hamad E. , Al-Thani Mohammed H , Doi Suhail A.R. , Zughaier Susu M , Cyprian Farhan , Farag Elmobashar , Farooqui Habib Hasan
Published: August 2022

Background

There is limited seroepidemiological evidence on the magnitude and long-term durability of antibody titers of mRNA and non-mRNA vaccines in the Qatari population. This study was conducted to generate evidence on long-term anti-S IgG antibodies titers and their dynamics in individuals who have completed a primary COVID-19 vaccination schedule.

Methods

A total of 300 participants who received any of the following vaccines BNT162b2/Comirnaty or mRNA-1273 or ChAdOx1-S/Covishield or COVID-19 Vaccine Janssen/Johnson or BBIBP-CorV or Covaxin were enrolled in our study. All sera samples were tested by chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of IgG antibodies to SARS-CoV-2, receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. Antibodies against SARS-CoV-2 nucleocapsid (SARS-CoV-2 N-protein IgG) were also determined. Kaplan–Meier survival curves were used to compare the time from the last dose of the primary vaccination schedule to the time by which anti-S IgG antibodies titers fell into the lowest quartile (range of values collected) for the mRNA and non-mRNA vaccines.

Results

Participants vaccinated with mRNA vaccines had higher median anti-S IgG antibody titers. Participants vaccinated with the mRNA-1273 vaccine had the highest median anti-S-antibody level of 13720.9 AU/mL (IQR 6426.5 to 30185.6 AU/mL) followed by BNT162b2 (median, 7570.9 AU/ml; IQR, 3757.9 to 16577.4 AU/mL); while the median anti-S antibody titer for non-mRNA vaccinated participants was 3759.7 AU/mL (IQR, 2059.7-5693.5 AU/mL). The median time to reach the lowest quartile was 3.53 months (IQR, 2.2-4.5 months) and 7.63 months (IQR, 6.3-8.4 months) for the non-mRNA vaccine recipients and Pfizer vaccine recipients, respectively. However, more than 50% of the Moderna vaccine recipients did not reach the lowest quartile by the end of the follow-up period.

Conclusions

This evidence on anti-S IgG antibody titers, their durability and decay over time should be considered for the utility of these assays in transmission dynamics after the full course of primary vaccination.
An idiosyncratic, zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver
Authors: Fernández Moro Carlos , Harrizi Sara , Hamidi Yousra , Geyer Natalie , Kuznyecov Danyil , Tidholm-Qvist Evelina , Salmonson Schaad Media , del Valle Andrea C. , Söderqvist Sara , Bozóky Lorand , Sparrelid Ernesto , Dirix Luc , Vermeulen Peter B , Bozóky Béla , Engstrand Jennie , Gerling Marco
Published: August 2022

Colorectal cancer liver metastases (CRLM) grow in two major patterns defined by the histomorphology of the invasion front, replacement or desmoplastic. The desmoplastic pattern, in which a stromal rim separates tumor cells and liver parenchyma is a strong positive prognostic factor, implying favorable biological features. However, the origin of the perimetastatic stroma is unknown and the underlying biological mechanisms are unclear. Here, we created spatial growth pattern maps of resected CRLM at cell-level resolution using digital pathology and quantified growth pattern heterogeneity at unprecedented resolution. We manually generated > 60’ 000 individual digital annotations on 543 metastases from 263 consecutive patients. We found that, in contrast to standard growth pattern assessments, high-resolution scoring revealed the prognostic outcome to be dependent on growth pattern proportions, such that survival improved with increasing fractions of desmoplastic encapsulation. The desmoplastic pattern was coupled to decreased tumor viability and to preoperative chemotherapy, hinting at a potentially causative connection of tumor viability and fibrotic encapsulation. Analyses of the cellular constituents of the rim revealed previously unrecognized liver parenchymal remnants. Spatial quantitation of liver remnants in the rim uncovered its gradual zonation from benign-like fibrosis at the liver side to tumor-associated stroma at the metastasis edge. Together, our data suggest that the perimetatstic “desmoplastic” capsule primarily results from a reparative hepatic process in conjunction with inefficient tumor cell colonization of liver plates, rather than from actively induced desmoplasia. We posit a model in which efficient replacement-type growth that precludes a mature hepatic injury reaction determines prognosis. Our results underscore tumor-cell replacement of hepatocytes as key for liver metastatic progression and suggest that the spatial heterogeneity of tumor invasion can be leveraged to understand fundamental mechanisms of metastatic growth.
Aberrant oscillatory activity in Neurofibromatosis Type 1: An EEG study of resting state and working memory
Authors: Booth Samantha J. , Garg Shruti , Brown Laura J. E. , Green Jonathan , Pobric Gorana , Taylor Jason R.
Published: August 2022

Background

Neurofibromatosis Type 1 (NF1) is a genetic neurodevelopmental disorder commonly associated with impaired cognitive function. Despite the well-explored functional roles of neural oscillations in neurotypical populations, only a limited number of studies have investigated oscillatory activity in the NF1 population.

Methods

We compared oscillatory spectral power and theta phase coherence in a paediatric sample with NF1 (N=16; mean age: 13.03 years; female: n=7) to an age/sex-matched typically-developing control group (N=16; mean age: 13.34 years; female: n=7) using electroencephalography measured during rest and during working memory task performance.

Results

Relative to typically-developing children, the NF1 group displayed higher resting state slow wave power and a lower peak alpha frequency. Moreover, higher theta power and frontoparietal theta phase coherence were observed in the NF1 group during working memory task performance, but these differences disappeared when controlling for baseline (resting state) activity.

Conclusions

Overall, results suggest that NF1 is characterised by aberrant resting state oscillatory activity that may contribute towards the cognitive impairments experienced in this population.

Trial registration

ClinicalTrials.gov identifier: NCT03310996 (first posted: October 16 2017).
Neonatal transport practices and effectiveness of the use of low-cost interventions on the morbidity and mortality of transported neonates in Sub-Saharan Africa: A systematic review protocol
Authors: Okai Emmanuel , Soltani Hora , Fair Frankie J
Published: August 2022

Objectives

Poor pre-transport and intra-transport care are associated with early neonatal morbidity and mortality. The objective of this study is to produce a critical overview of research on neonatal transport practices, the use of any low-cost interventions, including Kangaroo mother care (KMC) employed in neonatal transport on the outcomes of neonates transported for specialized care in Sub-Saharan Africa, through a systematic review and narrative synthesis.

Study design

The study design is a protocol for systematic review

Methods

A comprehensive literature search will be conducted using the electronic databases of CINAHL, EMBASE, MEDLINE, Web of Science, as well as Google Scholar. A manual search will be carried out of the reference lists of eligible studies for relevant papers. The search strategy will include combining three key blocks of terms, namely: ‘neonates’, ‘transport’ and ‘Sub Saharan Africa,’ using database-specific subject headings and text words. Two independent reviewers will screen and assess data quality and extraction for synthesis. Any disagreements during the data extraction and quality assessment stages will be determined by consensus with the involvement of a third reviewer. Study quality will be assessed using the Mixed-Methods Appraisal Tool (MMAT); a narrative synthesis will be undertaken to integrate and summarise findings. Subgroup analysis will be done where data is available within countries with different groups of neonates and modes of transportation.

Ethics and dissemination

Approval by a research ethics committee is not required for this study since the review only includes published and publicly accessible data. Findings from this review will inform research into the use of Kangaroo Mother Care (KMC) in neonatal transport in Ghana. We will publish our findings in a peer-reviewed journal as per Preferred Reporting for Systematic Review and Meta-analysis (PRISMA) 2020 Guidance

Registration

PROSPERO registration CRD42022352401