Search

Abstract Background The human microbiome plays a vital role in human health, mediated by the gut–brain axis, with a large diversity of functions and physiological benefits. The dynamics and mechanisms of meditations on oral and gut microbiome modulations are not well understood. This study investigates the short-term modulations of the gut and oral microbiome during an Arhatic Yoga meditation retreat as well as on the role of microbiome in improving well-being through a possible gut-brain axis. Methods A single-arm pilot clinical trial was conducted in a controlled environment during a 9-day intensive retreat of Arhatic Yoga meditation practices with vegetarian diet. Oral and fecal samples of 24 practitioners were collected at the start (Day0: T1), middle (Day3: T2), and end (Day9:T3) of the retreat. Targeted 16S rRNA gene amplicon sequencing was performed for both oral and gut samples. Functional pathway predictions was identified using phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2). DESeq2 was used to identify the differential abundant taxa. Various statistical analyses were performed to assess the significant changes in the data. Results Our findings revealed that Arhatic Yoga meditation together with a vegetarian diet led to changes in the oral and gut microbiome profiles within the 9-day retreat. Oral microbiome profile showed a significant (p

Abstract Background Health system disruptions since onset of the COVID-19 pandemic may have adversely impacted adherence to medications for common cardiovascular risk factors. Methods We examined adherence to and discontinuation of incident prescriptions for medications treating hypertension, dyslipidemia, diabetes, and atrial fibrillation in Ontario, Alberta, and Nova Scotia, Canada. We compared the recent period (April 1, 2020 through most recently available follow-up: September 30, 2021 for Ontario; March 31, 2021 for Alberta; and March 31, 2022 for Nova Scotia) to the baseline, pre-pandemic period (April 1, 2014 through March 31, 2019). In each province, people aged ≥66 years with a valid health number and corresponding incident prescription were included. For each medication class, adherence in the recent period, defined as ≥ 0.80 proportion-of-days-covered (PDC), was compared to the pre-pandemic period using modified Poisson regression with robust error variance, adjusted for patient characteristics. Similarly adjusted Cox proportional hazards models compared hazard of discontinuation over one year of follow-up between the two time periods. Results In the recent period, PDC ranged from 48.9% for dyslipidemia medications in Alberta to 82.2% for anticoagulants in Nova Scotia. Adherence was not different between periods, with the following exceptions: higher adherence in the recent period for antihypertensives (adjusted risk ratios [aRR] 1.08, 95% CI 1.06–1.10) and dyslipidemics (aRR 1.07, 95% CI 1.04–1.09) in Nova Scotia, and for antihyperglycemics (aRR 1.10, 95% CI 1.08–1.14) and anticoagulants (1.15, 95% CI 1.12, 1.18) in Alberta. Adherence was lower in the recent period only for antihypertensives in Alberta (aRR 0.95, 95% CI 0.93, 0.97). One-year rates of discontinuation ranged from 20.9% for anticoagulants in the Alberta recent period to 56.7% for antihypertensives in the Ontario baseline period. The adjusted hazard of discontinuation was lower or unchanged in the recent period for all medication classes. Conclusions Despite significant health system disruptions since 2020, recent adherence to incident cardiovascular prescriptions was similar or better than before and rates of medication discontinuation were lower. However, interventions are still needed to improve existing, suboptimal adherence.

Abstract Background There has been increased use of prehospital point-of-care ultrasound (PoCUS) by helicopter emergency medical services (HEMS) in recent years. Lack of governance structure and evidence of benefit have been described as major barriers to its implementation. This paper describes a novel approach to implementation of prehospital PoCUS and clinical governance framework in a UK HEMS. Methods A retrospective database review was undertaken at London’s Air Ambulance (LAA) from 1st September 2021 to 31st March 2023. All patients who had PoCUS examination were included. Scans were archived in a cloud-based server and reviewed weekly by expert clinicians. They were graded in adequacy, agreement between reviewer and clinician was recorded and fed back to the clinicians allowing continuous feedback learning. In-hospital diagnosis was sought for patients having the full Pump, Pleura and Pouring blood (PPPB) protocol. Cohen’s Kappa (ƙ) was calculated for inter-rater reliability. Sensitivity and specificity analysis was performed using 2 × 2 tables. Results LAA attended 3,068 missions. Our reviewers identified 701 PoCUS scanning encounters and 628 were included in the final analysis. Clinicians performed 420 scans for pneumothorax, 308 for free fluid and 305 pericardial effusions respectively. Majority of the population were male (85%) who sustained traumatic (93.5%) thoracic injuries (65%). Paramedics performed 29% of the scans. Reviewers deemed 83% of the scans of adequate quality. Inter-rater reliability between clinicians and reviewers was 0.6 for pericardial effusion, 0.67 for pneumothorax and 0.71 for free fluid respectively. A full PPPB protocol was performed in 52 patients out of which 46 were included. The sensitivity and specificity of PPPB protocol for diagnosis life-threatening injuries was 0.5 and 0.9 respectively. Conclusion Introduction of prehospital PoCUS in a HEM service utilizing high quality training, user-friendly workflow and image archiving system, robust governance framework and continuous feedback may be feasible allowing high quality ultrasound examinations. The bespoke PPPB protocol in prehospital may improve diagnosis of life-threatening injuries.

Abstract Sterile inflammation resulting in an altered immune response is a key determinant of renal injury in diabetic nephropathy (DN). In this investigation, we evaluated the hypothesis that hyperglycemic conditions augment the pro-inflammatory immune response in the kidney by promoting podocyte-specific expression of the stress response protein regulated in development and DNA damage response 1 (REDD1). In support of the hypothesis, streptozotocin (STZ)-induced diabetes increased REDD1 protein abundance in the kidney concomitant with renal immune cell infiltration. In diabetic mice, administration of the SGLT2 inhibitor dapagliflozin was followed by reductions in blood glucose concentration, renal REDD1 protein abundance, and immune cell infiltration. In contrast with diabetic REDD1+/+ mice, diabetic REDD1−/− mice did not exhibit albuminuria, increased pro-inflammatory factors, or renal macrophage infiltration. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1-dependent activation of NF-κB signaling. REDD1 deletion in podocytes attenuated both the increase in chemokine expression and macrophage chemotaxis under hyperglycemic conditions. Notably, podocyte-specific REDD1 deletion prevented the pro-inflammatory immune cell infiltration in the kidneys of diabetic mice. Furthermore, exposure of podocytes to hyperglycemic conditions promoted REDD1-dependent pyroptotic cell death, evidenced by an NLRP3-mediated increase in caspase-1 activity and LDH release. REDD1 expression in podocytes was also required for an increase in pyroptosis markers in the glomeruli of diabetic mice. The data support that podocyte-specific REDD1 is necessary for chronic NF-κB activation in the context of diabetes and raises the prospect that therapies targeting podocyte-specific REDD1 may be helpful in DN.

Objective: This study aimed to predict long-term growth-related changes in skeletal and dental relationships within the craniofacial complex using machine learning (ML) models. Materials and Methods: Cephalometric radiographs from 301 subjects, taken at pre-pubertal (T1, age 11) and post-pubertal stages (T2, age 18), were analysed. Three ML models—Lasso regression, Random Forest, and Support Vector Regression (SVR)—were trained on a subset of 240 subjects, while 61 subjects were used for testing. Model performance was evaluated using mean absolute error (MAE), intraclass correlation coefficients (ICCs), and clinical thresholds (2 mm or 2°). Results: MAEs for skeletal measurements ranged from 1.36° (maxilla to cranial base angle) to 4.12 mm (mandibular length), and for dental measurements from 1.26 mm (lower incisor position) to 5.40° (upper incisor inclination). ICCs indicated moderate to excellent agreement between actual and predicted values. The highest prediction accuracy within the 2 mm or 2° clinical thresholds was achieved for maxilla to cranial base angle (80%), lower incisor position (75%), and maxilla to mandible angle (70%). Pre-pubertal measurements and sex consistently emerged as the most important predictive factors. Conclusions: ML models demonstrated the ability to predict post-pubertal values for maxilla to cranial base, mandible to cranial base, maxilla to mandible angles, upper and lower incisor positions, and upper face height with a clinically acceptable margin of 2 mm or 2°. Prediction accuracy was higher for skeletal relationships compared to dental relationships over the 8-year growth period. Pre-pubertal values of the measurements and sex emerged consistently as the most important predictors of the post-pubertal values.

The successful adoption of additive manufacturing for the rapid prototyping of direct-write printed electronics requires the establishment of quantifiable metrics. These metrics should directly interrogate the fabrication quality of the device during the manufacturing process. This implies that the characterization technique should be nondestructive. One measure of fabrication performance is the adhesion strength between the substrate and printed film interface, which is critical since the strength of this interface can dictate the accuracy and reliability of the printed device. In this work, a noncontact laser-induced spallation technique has been used to estimate the adhesion of silver-printed films on aluminum alloy substrates. The laser-based method was compared to a standardized pull-off adhesion test, which provided baseline measurements of adhesion strength. These adhesion measurement techniques were compared against the sintering condition-dependent microstructure of the additive manufacturing films. The porous structure of the printed thin film was found to be an important factor that impacted adhesion tests that utilize adhesives (i.e., glue and resins) due to an enhanced interlocking to the adherend surface. Due to its noncontact nature and insensitivity to thin samples/films, laser spallation was found to be a more reliable indication of process parameter change. The methods and results described in this work support the establishment of process control steps that are necessary for quickly verifying the reliability of printed devices prior to their deployment in critical experiments.

Abstract Cilostazol has previously been shown to reduce liver steatosis and enhance hepatic perfusion. We investigated the effects of cilostazol after major hepatectomy in a steatotic rat model. Six weeks prior to surgery, Sprague–Dawley rats were fed with a high-fructose diet. The treatment group received daily 5 mg/kg cilostazol. Seven days following the cilostazol treatment, all animals underwent 70% liver resection (PHX). Analysis of hepatic blood flow and microcirculation and immunohistochemical examinations were conducted 30 min after PHX (postoperative day [POD] 0) as well as on POD 1, POD 3 and POD 7. The weight of cilostazol-treated animals was significantly reduced compared to untreated controls after completion of the 6-week high-FRC diet. Furthermore, 41% macrovesicular steatosis was found in the control group compared to 8% in the cilostazol group. Hepatic arterial and portal venous perfusion were increased in the cilostazol group on POD 7. Lower liver enzyme release was found postoperatively in cilostazol-treated animals. Moreover, apoptosis and neutrophil infiltration were reduced after cilostazol treatment. Proliferation of hepatocytes and liver regeneration after PHX were significantly increased in the cilostazol group. Consequently, cilostazol should be evaluated as a novel strategy to reduce the rate of liver failure after PHX in steatotic liver.

Abstract While animals readily adjust their behavior to adapt to relevant changes in the environment, the neural pathways enabling these changes remain largely unknown. Here, using multiphoton imaging, we investigate whether feedback from the piriform cortex to the olfactory bulb supports such behavioral flexibility. To this end, we engage head-fixed male mice in a multimodal rule-reversal task guided by olfactory and auditory cues. Both odor and, surprisingly, the sound cues trigger responses in the cortical bulbar feedback axons which precede the behavioral report. Responses to the same sensory cue are strongly modulated upon changes in stimulus-reward contingency (rule-reversals). The re-shaping of individual bouton responses occurs within seconds of the rule-reversal events and is correlated with changes in behavior. Optogenetic perturbation of cortical feedback within the bulb disrupts the behavioral performance. Our results indicate that the piriform-to-olfactory bulb feedback axons carry stimulus identity and reward contingency signals which are rapidly re-formatted according to changes in the behavioral context.

Abstract Biogenesis of human telomerase requires its RNA subunit (hTR) to fold into a multi-domain architecture that includes the template-pseudoknot (t/PK) and the three-way junction (CR4/5). These hTR domains bind the telomerase reverse transcriptase (hTERT) protein and are essential for telomerase activity. Here, we probe hTR structure in living cells using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and ensemble deconvolution analysis. Approximately 15% of the steady state population of hTR has a CR4/5 conformation lacking features required for hTERT binding. The proportion of hTR CR4/5 folded into the primary functional conformation is independent of hTERT expression levels. Mutations that stabilize the alternative CR4/5 conformation are detrimental to telomerase assembly and activity. Moreover, the alternative CR4/5 conformation is not found in purified telomerase RNP complexes, supporting the hypothesis that only the primary CR4/5 conformer is active. We propose that this misfolded portion of the cellular hTR pool is either slowly refolded or degraded, suggesting that kinetic RNA folding traps studied in vitro may also hinder ribonucleoprotein assembly in vivo.

Abstract: Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

Plant phylogenetics has been revolutionised in the genomic era, with target capture acting as the primary workhorse of most recent research in the new field of phylogenomics. Target capture (aka Hyb-Seq) allows researchers to sequence hundreds of genomic regions (loci) of their choosing, at relatively low cost per sample, from which to derive phylogenetically informative data. Although this highly flexible and widely applicable method has rightly earned its place as the field’s de facto standard, it does not come without its challenges. In particular, users have to specify which loci to sequence—a surprisingly difficult task, especially when working with non-model groups, as it requires pre-existing genomic resources in the form of assembled genomes and/or transcriptomes. In the absence of taxon-specific genomic resources, target sets exist that are designed to work across broad taxonomic scales. However, the highly conserved loci that they target may lack informativeness for difficult phylogenetic problems, such as that presented by the rapid radiation of Erica in southern Africa. We designed a target set for Erica phylogenomics intended to maximise informativeness and minimise paralogy while maintaining universality by including genes from the widely used Angiosperms353 set. Comprising just over 300 genes, the targets had excellent recovery rates in roughly 90 Erica species as well as outgroups from Calluna, Daboecia, and Rhododendron, and had high information content as measured by parsimony informative sites and Quartet Internode Resolution Probability (QIRP) at shallow nodes. Notably, QIRP was positively correlated with intron content, while including introns in targets—rather than recovering them via exon-flanking “bycatch”—substantially improved intron recovery. Overall, our results show the value of building a custom target set, and we provide a suite of open-source tools that can be used to replicate our approach in other groups (https://github.com/SethMusker/TargetVet).

Abstract Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to identify patient characteristics predictive of CIRT response. We utilized a panel of human PDAC cell lines with diverse genetic profiles to determine their sensitivity to CIRT compared to γ-rays, assessing relative biological effectiveness (RBE) at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity was linked to impaired DNA double-strand break (DSB) repair, particularly in cell lines with deficiencies in the homologous recombination (HR) repair pathway and/or elevated genomic instability from replication stress. Furthermore, pretreatment with the HR inhibitor B02 significantly enhanced CIRT sensitivity in a radioresistant PDAC cell line when irradiated in the spread-out Bragg peak but not at the entry position of the beam. These findings suggest that PDAC tumors with HR pathway mutations or high replication stress are more likely to benefit from CIRT while minimizing normal tissue toxicity.

Abstract We have developed the regionalpcs method, an approach for summarizing gene-level methylation. regionalpcs addresses the challenge of deciphering complex epigenetic mechanisms in diseases like Alzheimer’s disease. In contrast to averaging, regionalpcs uses principal components analysis to capture complex methylation patterns across gene regions. Our method demonstrates a 54% improvement in sensitivity over averaging in simulations, providing a robust framework for identifying subtle epigenetic variations. Applying regionalpcs to Alzheimer’s disease brain methylation data, combined with cell type deconvolution, we uncover 838 differentially methylated genes associated with neuritic plaque burden—significantly outperforming conventional methods. Integrating methylation quantitative trait loci with genome-wide association studies identified 17 genes with potential causal roles in Alzheimer’s disease risk, including MS4A4A and PICALM. Available in the Bioconductor package regionalpcs, our approach facilitates a deeper understanding of the epigenetic landscape in Alzheimer’s disease and opens avenues for research into complex diseases.

Abstract Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential to chromosomally unstable cells, we mined the Cancer Dependency Map for genes essential in tumor cells with high levels of copy number aberrations. We identify and validate KIF18A, a mitotic kinesin, as a vulnerability of chromosomally unstable cancer cells. Knockdown of KIF18A leads to mitotic defects and reduction of tumor growth. Screening of a chemical library for inhibitors of KIF18A enzymatic activity identified a hit that was optimized to yield VLS-1272, which is orally bioavailable, potent, ATP non-competitive, microtubule-dependent, and highly selective for KIF18A versus other kinesins. Inhibition of KIF18A’s ATPase activity prevents KIF18A translocation across the mitotic spindle, resulting in chromosome congression defects, mitotic cell accumulation, and cell death. Profiling VLS-1272 across >100 cancer cell lines demonstrates that the specificity towards cancer cells with chromosome instability differentiates KIF18A inhibition from other clinically tested anti-mitotic drugs. Treatment of tumor xenografts with VLS-1272 results in mitotic defects leading to substantial, dose-dependent inhibition of tumor growth. The strong biological rationale, robust preclinical data, and optimized compound properties enable the clinical development of a KIF18A inhibitor in cancers with high chromosomal instability.

Abstract Autonomous artificial intelligence (AI) for pediatric diabetic retinal disease (DRD) screening has demonstrated safety, effectiveness, and the potential to enhance health equity and clinician productivity. We examined the cost-effectiveness of an autonomous AI strategy versus a traditional eye care provider (ECP) strategy during the initial year of implementation from a health system perspective. The incremental cost-effectiveness ratio (ICER) was the main outcome measure. Compared to the ECP strategy, the base-case analysis shows that the AI strategy results in an additional cost of $242 per patient screened to a cost saving of $140 per patient screened, depending on health system size and patient volume. Notably, the AI screening strategy breaks even and demonstrates cost savings when a pediatric endocrine site screens 241 or more patients annually. Autonomous AI-based screening consistently results in more patients screened with greater cost savings in most health system scenarios.

Background: Acromial fractures are rare in the traumatic setting; however, they have recently gained attention due to the increase in incidence as a result of a postoperative complication of reverse total shoulder arthroplasty. While historically these fractures were routinely treated nonoperatively, there is evidence that surgery can improve outcomes. The study aims to evaluate clinical outcomes following surgical treatment of acromion fractures and compare outcomes among patients with an intact rotator cuff against those with a deficient rotator cuff or reverse shoulder arthroplasty. Methods: This is a retrospective review of patients with acromion fractures that were treated with open reduction internal fixation between January 2014 and March 2023. Patients were stratified into three cohorts as follows: 1) rotator cuff intact; 2) rotator cuff impaired; and 3) presence of reverse total shoulder arthroplasty. Results: Thirty-seven patients were included in the study with a mean follow-up of 9 months (range 0.5-77). The mechanism of injury was stress fracture (46%), high-energy trauma (32%), or low-energy falls (22%). The mean time to surgery was 6 months (0-24). Older age and female sex were associated with stress fractures (P

Abstract Plant genebanks contain large numbers of germplasm accessions that likely harbor useful alleles or genes absent in commercial plant breeding programs. Broadening the genetic base of commercial alfalfa germplasm with these valuable genetic variations can be achieved by screening the extensive genetic diversity in germplasm collections and enabling maximal recombination among selected genotypes. In this study, we assessed the genetic diversity and differentiation of germplasm pools selected in northern U.S. latitudes (USDA Plant Hardiness Zone 7 or below) originating from Eurasian germplasm. The germplasm evaluated included four BASE populations (C0) from different geographical origins (Central Asia, Northeastern Europe, Balkans-Turkey-Black Sea, and Siberia/Mongolia), 20 cycle-one populations (C1) derived from each of the four BASE populations selected across five locations in the U.S. and Canada, and four commercial cultivars. Using a panel of 3,000 Diversity Array Technologies (DArTag) marker loci, we retrieved 2,994 target SNPs and approximately 12,000 microhaplotypes. Microhaplotypes exhibited higher genetic diversity values than target SNPs. Principal component analysis and discriminant analysis of principal components revealed significant population structure among the alfalfa populations based on geographical origin, while the check cultivars formed a central cluster. Inbreeding coefficients (FIS) ranged from − 0.1 to 0.006, with 27 out of 28 populations showing negative FIS values, indicating an excess of heterozygotes. Interpopulation genetic distances were calculated using Rho pairwise distances (FST adapted for autotetraploid species) and analysis of molecular variance (AMOVA) parameters. All BASE populations showed lower Rho values compared to C1 populations and check cultivars. AMOVA revealed that most of the genetic diversity was among individuals within populations, especially in BASE populations (92.7%). This study demonstrates that individual plants in BASE populations possess high genetic diversity, low interpopulation distances, and minimal inbreeding, characteristics that are essential for base-broadening selection. The populations developed in this project serve as valuable sources of novel alleles for North American alfalfa breeding programs, offering breeders access to diverse, regionally adapted pools for improving various alfalfa traits.

Abstract Background Understanding factors associated with antimicrobial resistance (AMR) distribution across populations is a necessary step in planning mitigation measures. While associations between AMR and socioeconomic-status (SES), including employment and education have been increasingly recognized in low- and middle-income settings, connections are less clear in high-income countries where SES remains an important influence on other health outcomes. Methods We explored the relationship between SES and AMR in Calgary, Canada using spatially-resolved wastewater-based surveillance of resistomes detected by metagenomics across eight socio-economically diverse urban neighborhoods. Resistomes were established by shotgun-sequencing of wastewater pellets, and qPCR of targeted-AMR genes. SES status was established using 2021 Canadian census data. Conducting this comparison during the height of COVID-related international travel restrictions (Dec. 2020–Oct. 2021) allowed the hypotheses linking SES and AMR to be assessed with limited confounding. These were compared with sewage metagenomes from 244 cities around the world, linked with Human Development Index (HDI). Results Wastewater metagenomes from Calgary’s socioeconomically diverse neighborhoods exhibit highly similar resistomes, with no quantitative differences (p > 0.05), low Bray-Curtis dissimilarity, and no significant correlations with SES. By comparison, dissimilarity is observed between globally-sourced resistomes (p

Abstract Introduction Over the past three decades, more advanced pre-hospital systems have increasingly integrated physicians into targeted roles, forming interprofessional teams. These teams focus on providing early senior decision-making and advanced interventions while also ensuring rapid transport to hospitals based on individual patient needs. This paper aims to evaluate the benefits of an inter-professional care model compared to a model where care is delivered solely by paramedics. Methodology A meta-analysis and systematic review were conducted using the guidelines of PRISMA 2020. Articles were identified through a systematic search of three databases and snowballing references. A systematic review was conducted of articles that met the inclusion criteria, and a suitable subset was included in a meta-analysis. The survival and mortality outcomes from the studies were then pooled using the statistical software Review Manager (RevMan) Version 8.2.0. Results Two thousand two hundred ninety-six articles were found from the online databases and 86 from other sources. However, only 23 articles met the inclusion criteria of our study. A pooled analysis of the outcomes reported in these studies indicated that the mortality risk was significantly reduced in patients who received pre-hospital care from interprofessional teams led by physicians compared with those who received care from paramedics alone (AOR 0.80; 95% CI [0.68, 0.91] p = 0.001). The survival rate of critically ill or injured patients who received pre-hospital care from interprofessional teams led by physicians was increased compared to those who received care from paramedics alone (AOR 1.49; 95% CI [1.31, 1.69] P

In the medical diagnostics domain, pathology and histology are pivotal for the precise identification of diseases. Digital histopathology, enhanced by automation, facilitates the efficient analysis of massive amount of biopsy images produced on a daily basis, streamlining the evaluation process. This study focuses in Stain Color Normalization (SCN) within a Whole-Slide Image (WSI) cohort, aiming to reduce batch biases. Building on published graphical method, this research demonstrates a mathematical population or data-driven method that optimizes the dependency on the number of reference WSIs and corresponding aggregate sums, thereby increasing SCN process efficiency. This method expedites the analysis of color convergence 50-fold by using stain vector Euclidean distance analysis, slashing the requirement for reference WSIs by more than half. The approach is validated through a tripartite methodology: 1) Stain vector euclidean distances analysis, 2) Distance computation timing, and 3) Qualitative and quantitative assessments of SCN across cancer tumors regions of interest. The results validate the performance of data-driven SCN method, thus potential to enhance the precision and reliability of computational pathology analyses. This advancement is poised to enhance diagnostic processes, therapeutic strategies, and patient prognosis.

Purpose – Drawing primarily on the Japanese context, this study aims to highlight this setting to emphasise the potential for tertiary-level self-access language centres to develop lifelong global citizenship, self-reflection and cross-cultural collaboration. Design/methodology/approach – This inquiry calls on the community of practice approach to account for the shared interests motivating lifelong cross-cultural participation, the quality of social engagement between actors, and the material and cognitive tools called upon to realise global citizenship’s shared enterprise. Findings – As argued here, embracing various cultures and inclusive participation can lead to a broader understanding of global citizenship, avoiding narrow-minded views of globalism through shared knowledge and critical practices. Further, self-access provides a cost-effective, technology-mediated alternative to bilateral student mobility, whereby digital community-building occasions cross-cultural practice that may be extended throughout a learner’s life, irrespective of their financial status or place of study. Originality/value – This study is one of a select few drawing on the community of practice framework within the context of lifelong global citizenship. Nevertheless, such an approach remains primed for future development. With a social constructivist philosophy in view, the authors suggest complementary qualitative research approaches that highlight the socially situated nature of both disciplines.

Damages due to pitting corrosion of metals cost industry billions of dollars per year and can put human lives at risk. The design and implementation of an adaptive moving mesh method is provided for a moving boundary problem related to pitting corrosion. The adaptive mesh is generated automatically by solving a mesh PDE coupled to the nonlinear potential problem. The moving mesh approach is shown to enable initial mesh generation, provide automatic mesh adjustment (or recovery) and is able to smoothly tackle changing pit geometry. Materials with varying crystallography are considered. Changing mesh topology due to the merging of pits is also handled. The evolution of the pit shape, the pit depth, and the pit width are computed and compared to existing results in the literature. Mesh quality results are also included.

Abstract Case We present the case of a 73-year-old female with an acromioclavicular joint cyst associated with atypical, exquisite, progressive pain, and imaging findings concerning for neoplastic etiology. She underwent en bloc resection of the trapezium containing this cystic mass and distal clavicle. Surgical pathology demonstrated findings consistent with a large ganglion cyst without evidence of malignancy. Conclusion Our case serves to emphasize the importance of stepwise evaluation and appropriate treatment of such cysts while utilizing appropriate principles of oncologic resection in cases where a neoplastic etiology is considered.

Abstract Gilles de la Tourette Syndrome (GTS) is a chronic tic disorder, characterized by unwanted motor actions and vocalizations. While brain stimulation techniques show promise in reducing tic severity, optimal target networks are not well-defined. Here, we leverage datasets from two independent deep brain stimulation (DBS) cohorts and a cohort of tic-inducing lesions to infer critical networks for treatment and occurrence of tics by mapping stimulation sites and lesions to a functional connectome derived from 1,000 healthy participants. We find that greater tic reduction is linked to higher connectivity of DBS sites (N = 37) with action-related functional resting-state networks, i.e., the cingulo-opercular (r = 0.62; p

Abstract The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CB1R inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CB1R inhibitors while sparing the negative psychiatric effects. To understand the mechanism of binding and inhibition of CB1R by peripherally restricted antagonists, we developed a nanobody/fusion protein strategy for high-resolution cryo-EM structure determination of the GPCR inactive state, and used this method to determine structures of CB1R bound to either MRI-1867 or MRI-1891. These structures reveal how these compounds retain high affinity and specificity for CB1R’s hydrophobic orthosteric site despite incorporating polar functionalities that lead to peripheral restriction. Further, the structure of the MRI-1891 complex along with accompanying molecular dynamics simulations shows how differential engagement with transmembrane helices and the proximal N-terminus can propagate through the receptor to contribute to biased inhibition of β-arrestin signaling.

Abstract Where adopted, Autonomous artificial Intelligence (AI) for Diabetic Retinal Disease (DRD) resolves longstanding racial, ethnic, and socioeconomic disparities, but AI adoption bias persists. This preregistered trial determined sensitivity and specificity of a previously FDA authorized AI, improved to compensate for lower contrast and smaller imaged area of a widely adopted, lower cost, handheld fundus camera (RetinaVue700, Baxter Healthcare, Deerfield, IL) to identify DRD in participants with diabetes without known DRD, in primary care. In 626 participants (1252 eyes) 50.8% male, 45.7% Hispanic, 17.3% Black, DRD prevalence was 29.0%, all prespecified non-inferiority endpoints were met and no racial, ethnic or sex bias was identified, against a Wisconsin Reading Center level I prognostic standard using widefield stereoscopic photography and macular Optical Coherence Tomography. Results suggest this improved autonomous AI system can mitigate AI adoption bias, while preserving safety and efficacy, potentially contributing to rapid scaling of health access equity. ClinicalTrials.gov NCT05808699 (3/29/2023).

Abstract Objective This prospective clinical study examined the effects of fixed orthodontic appliances on oral hygiene and assessed changes in the oral microflora structure of orthodontic patients using high-throughput sequencing technology. Methods A total of 45 patients undergoing initial fixed orthodontic treatment were recruited from three hospitals in Beijing, China. Clinical parameters and oral hygiene habits questionnaire were recorded at pre-treatment (T0) and at a 6-month follow-up (T1). Saliva samples were collected for DNA extraction, PCR amplification, 16S rRNA gene sequencing, and bioinformatics analysis. Microbial diversity and structural changes in abundance were evaluated. Results After six months of orthodontic treatment, patients’ daily brushing frequency increased (P ≤ 0.01), while the plaque index and the debris index decreased. A total of 3,344,549 valid tags were obtained from 90 saliva samples. After the six-month follow-up, the microbial diversity in patients’ saliva samples increased significantly. High-throughput sequencing identified 3,662 amplicon sequence variants (ASVs), with the dominant phyla being Proteobacteria, Bacteroidota, Firmicutes, Actinobacteriota, Fusobacteriota, Patescibacteria, Campylobacterota and Spirochaetota. At the phylum level, the abundance of Firmicutes_C and Spirochaetota at T1 significantly increased compared to T0. Conclusion During fixed orthodontic treatment, although patients’ oral hygiene habits improved, significant changes in the oral microbiota structure were still observed, with an increase in anaerobic and pathogenic bacteria that may potentially impact oral health.

Abstract Electronic cigarettes (e-cigs) fundamentally differ from tobacco cigarettes in their generation of liquid-based aerosols. Investigating how e-cig aerosols behave when inhaled into the dynamic environment of the lung is important for understanding vaping-related exposure and toxicity. A ventilated artificial lung model was developed to replicate the ventilatory and environmental features of the human lung and study their impact on the characteristics of inhaled e-cig aerosols from simulated vaping scenarios. Compared to static conditions, normal breathing decreased peak particle number concentrations (PNCs) and area under the curve (AUC) by 40% and 70%, respectively, and increased particle decay rates fourfold. However, even with ventilation, intrapulmonary PNC levels exceeded 2 × 106 particles/mL in a 4-puff vaping session. Both respiratory rate and tidal volume modulated e-cig aerosol exposure in a manner inversely proportional to minute ventilation. The modeled lung environment (37 °C, 88% relative humidity) also significantly altered particle size distributions by facilitating aerosol transformations such as hygroscopic growth, which further impacted e-cig aerosol exposure and particle removal. This work highlights the dynamic nature of intrapulmonary exposures and underscores the need to account for lung physiology and environmental factors when assessing inhaled e-cig aerosols.

Abstract The genomes of human gut bacteria in the genus Bacteroides include numerous operons for biosynthesis of diverse capsular polysaccharides (CPSs). The first two genes of each CPS operon encode a locus-specific paralog of transcription elongation factor NusG (called UpxY), which enhances transcript elongation, and a UpxZ protein that inhibits noncognate UpxYs. This process, together with promoter inversions, ensures that a single CPS operon is transcribed in most cells. Here, we use in-vivo nascent-RNA sequencing and promoter-less in-vitro transcription (PIVoT) to show that UpxY recognizes a paused RNA polymerase via sequences in both the exposed non-template DNA and the upstream duplex DNA. UpxY association is aided by ‘pause-then-escape’ nascent RNA hairpins. UpxZ binds non-cognate UpxYs to directly inhibit UpxY association. This UpxY-UpxZ hierarchical regulatory program allows Bacteroides to generate subpopulations of cells producing diverse CPSs for optimal fitness.

Background: Patients requiring extracorporeal membrane oxygenation (ECMO) are at increased risk of malnutrition due to high rates of protein catabolism, unclear metabolic needs, and safety risks with both parenteral and enteral nutrition (EN). Malnourishment is associated with increased morbidity and mortality, and improved EN and protein intake are associated with decreased 60-day mortality. A standardized practice for nutrition therapy in this population is unestablished. We aim to provide an update on current nutritional practices in pediatric and neonatal patients receiving ECMO support. Subjects and Methods: An online survey was distributed to ECMO medical directors in the US and Canada who had previously participated in survey-based research and those who requested participation during a pediatric ECMO presentation of this study. Each medical director was asked to forward the survey to their center’s registered dietitians (RDs). Results: Of 100 institutions surveyed, 36 physicians and 19 RDs responded yielding a physician response rate of 36% and an RD response rate of 19%. Physicians report “always” providing nutrition parenterally 28% and enterally 17% of the time with 11% of institutions using a protocolized approach. Nutrition therapy aids reduction of morbidity and mortality; however, there is variability in its delivery. Conclusions: Compared to 2015, EN is reported to be less utilized (47% vs. 55%) with less protocol use (11% vs. 38%). These data support the need for the development of a stepwise nutritional support algorithm, which is congruent with the recommendations in the Extracorporeal Life Support Organization Nutrition Guidelines.

Abstract Objective To systematically evaluate which lesion‐based imaging features and methods allow for the best statistical prediction of poststroke deficits across independent datasets. Methods We utilized imaging and clinical data from three independent datasets of patients experiencing acute stroke (N1 = 109, N2 = 638, N3 = 794) to statistically predict acute stroke severity (NIHSS) based on lesion volume, lesion location, and structural and functional disconnection with the lesion location using normative connectomes. Results We found that prediction models trained on small single‐center datasets could perform well using within‐dataset cross‐validation, but results did not generalize to independent datasets (median R2N1 = 0.2%). Performance across independent datasets improved using large single‐center training data (R2N2 = 15.8%) and improved further using multicenter training data (R2N3 = 24.4%). These results were consistent across lesion attributes and prediction models. Including either structural or functional disconnection in the models outperformed prediction based on volume or location alone (P

Abstract Objective Temporal lobe encephaloceles (TLEN) have been implicated as a cause of temporal lobe epilepsy (TLE), the treatment which is primarily surgical; however, there is no clear consensus on the optimal surgical approach, because it is unclear whether TLE related to TLEN can be addressed by a restricted encephalocele resection or if a more extensive resection is required. The aim of the current article is to report the clinical and electrophysiological profile of patients with TLE secondary to TLEN who underwent stereotactic electroencephalography (SEEG) implantation to identify the epileptogenic network. Methods A retrospective review was performed of patients with TLE related to TLEN who underwent SEEG implantation. Medical charts were reviewed for demographic data, the results of noninvasive and invasive investigations, and operative details. Surgical outcomes were based on Engel classification with at least 6 months follow‐up. Results Nine patients were identified. The mean age at epilepsy onset was 28 years (range, 15–41 years), and 7/9 patients were female. Scalp EEG revealed interictal epileptiform activity most often maximum in the frontotemporal and/or temporal regions. A discrete TLEN was often not identified on initial imaging, but was identified during re‐review or at the time of surgery. Seizure onset zones during SEEG were localized to the mesial temporal structures, the temporal pole, or both. One patient became seizure‐free following SEEG and another refused further surgery. Of the 7 patients who underwent epilepsy surgery, 5/7 underwent an anterior temporal lobectomy—surgical outcomes were favorable, with 5/7 achieving Engel I outcomes. Significance Invasive SEEG monitoring demonstrated ictal onsets may not be restricted to the TLEN, and often the temporal pole and mesial structures are involved at seizure onset. Ictal propagation patterns vary significantly, which may be related to the underlying pathology and explain the variability in semiology. These findings may inform surgical treatment options. Plain language summary Temporal lobe encephaloceles can cause intractable epilepsy, although their presence may be missed on routine imaging. The management of encephaloceles is primarily surgical; however, the optimal surgical approach can be unclear. Invasive monitoring with SEEG may help characterize the epileptogenic network and result in more optimal surgical outcomes.

ABSTRACT: International trends of increasing dairy herd sizes coupled with scarcity of labor have necessitated the enhancement of labor efficiency for dairy production systems. This study quantified the effects of infrastructure, automation, and management practices on the milking and operator efficiency of herringbone and rotary parlors used on pasture-based farms in Ireland. Data were used from 592 milkings across 26 farms (16 herringbones and 10 rotaries). The metrics of cows milked per hour (cows/h), cows milked per operator per hour (cows/h per operator), and liters of milk harvested per hour (L/h) described milking efficiency. The metrics of total process time per cow (TPT, s/cow), milk process time per cow (MPT, s/cow), work routine time (WRT, s/cow), cluster time (CT, s/cluster), and attachment time per cow (ATC, s/cow) described operator efficiency. Automations investigated were backing gates, cluster flush, plant wash, cluster removers (ACR), feeders, entry gates, rapid exit, and teat spray. Additional operator presence at milking was also investigated. Herringbone and rotary parlors were assigned to quartiles from their cows/h per operator values to examine variations in infrastructure, automations, and management practices. Fourth quartile (Q4) herringbones based on cows/h per operator values averaged 93 cows/h per operator using average system sizes of 24 clusters with 5 parlor automations. The Q4 rotaries averaged 164 cows/h per operator using average system sizes of 47 clusters and an average CT of 13 s/cluster. Cows/h per operator values for Q4 herringbone and rotary parlors were 82% and 54% higher, respectively, than values observed on first quartile parlors, indicating the considerable potential to improve efficiency. To determine if infrastructure, automations, or additional operators at milking significantly affected operator efficiencies, general linear mixed models were developed. For parlor infrastructure, additional clusters had greater significance on operator efficiencies (MPT) for herringbones (−1.3 s/cow) as opposed to rotaries (−0.2 s/cow). Hence, increases in system size were likely to result in improved efficiencies for herringbones but less so for rotaries. For automations, ACR significantly reduced herringbone TPT, CT, and WRT values by 13.3 s/cow, 18.9 s/cluster, and 32.6 s/cow, respectively, whereas rapid exit significantly lowered CT by 18.6 s/cluster. We found no significant effect on rotary TPT, MPT, CT, or WRT values from the use of automatic teat sprayers. An additional operator at milking was found to significantly reduce herringbone TPT but not MPT or CT. For rotaries, a second operator had no significant effect on TPT, MPT, CT, or WRT values. We documented strong negative correlations between operator efficiencies (TPT, MPT) and milking efficiency (cows/h) for both herringbone (−0.91, −0.84) and rotaries (−0.98, −0.89). Strong negative correlations between the herringbone automation count and TPT (−0.80), MPT (−0.72), and CT (−0.75) suggested highly automated parlors were likely to achieve greater operator efficiencies than less automated parlors. The strong negative correlation (−0.81) between rotary milking efficiency (cows/h) and CT suggested that lower CT values (i.e., rotation speed) resulted in increased milking efficiency. Overall, our study quantified the effects of parlor infrastructure, automation, and management practices on the milking and operator efficiency of herringbone and rotary parlors.

Bacteria-related infections remain a leading cause of dental implant failures. Despite the successful history of titanium implants, naturally forming oxides lack antibacterial properties. Crystalline oxides, modified through anodization processes, have shown photocatalytic-induced antibacterial properties when exposed to sufficient energy sources such as UVA light. Chemically doping these oxides with some metallic and non-metallic elements has been shown to enhance their photocatalytic activity (PCA). The present study’s objectives were to assess the relative UVA and violet-light-irradiated PCA levels, bacterial attachment levels, and pre-osteoblast early cell viability levels of phosphorus-doped and phosphorus-and-silver-doped anatase-phase oxides. Each oxide revealed similar surface topographies and surface porosity levels. However, the phosphorus-and-silver-doped oxides exhibited significantly higher PCA levels compared to the phosphorus-doped oxide counterpart after irradiation with 365 nm UVA (p < 0.0001) or 410 nm violet (p = 0.007 and 0.03) light. The phosphorus-doped oxides and phosphorus-and-silver-doped oxides revealed similar Staphylococcus aureus attachment levels after 60 min of UVA irradiation. The phosphorus-and-silver-doped oxides exhibited significantly increased 7-day cell viability compared to their phosphorus-doped oxide counterparts. Thus, it was concluded that the silver doping additions to the oxides show much promise for biomaterials applications and warrant further exploration.

Background: Detection of the regional wall motion abnormalities (RWMA) on the transthoracic echocardiography (TTE) is commonly used to correlate with coronary artery disease (CAD) and often prompts a further workup, including cardiac computed tomography or cardiac catheterization. However, the RWMA do not consistently predict obstructive CAD. This study investigates the accuracy and reliability of the presence of the RWMA on the TTE at detecting significant CAD (≥70% vessel stenosis). Materials and Methods: A retrospective chart review was conducted on the adults seen by the Baylor Scott and White Temple Echocardiography Laboratory who received a resting TTE followed by a cardiac catheterization within 30 days over 4 years. The exclusion criteria included catheterization without coronary angiography and a prior history of CAD, percutaneous coronary intervention, or coronary artery bypass graft. We analyzed the RWMA on the TTE and atherosclerotic CAD on the cardiac catheterization to assess correlation. Results: Four hundred and thirty-five patients were included in the study, and 198 patients received ultrasound-enhancing agent (UEA). The sensitivity and specificity of the RWMA on the TTE for detecting CAD in the adults were 49.5% and 78.8%, respectively. The positive and negative likelihood ratios were 2.33 and 0.641, respectively. The use of UEA made no significant difference in the sensitivity or specificity. Discussion: Our results show that the presence of the RWMA on the TTE has a high ability to rule in CAD, but the absence of the RWMA displays a much lower ability to rule out CAD than previously reported. Our results also show UEA did not enhance or detract from the sensitivity or specificity of TTE on CAD. The clinicians should be aware that the presence of the RWMA on the resting TTE has a high association with obstructive CAD, but the absence of the RWMA does not sufficiently exclude CAD.

Abstract Introduction Cancer multi-disciplinary team meetings (MDTM) assemble clinical experts to make diagnostic and treatment recommendations. MDTMs can take place in person, virtually, or in a hybrid format. Virtual and hybrid MDTMs have been in use for over two decades. This systematic scoping review aims to map the evidence on virtual and hybrid MDTM formats over time, providing insights into their quality, and the facilitators and barriers to their effective delivery. Methods The PRISMA scoping review checklist has been followed. A systematic search of PubMed, PsychINFO, and Embase between 1990–2023 identified 9399 records. These were independently screened by two researchers to identify primary research of any design that assessed quality or effectiveness of cancer VMDTMs. Results were narratively synthesised. Results Eight quantitative, two qualitative and three mixed-methods studies were included. All were observational and most were retrospective (n = 8). Varied outcome measures were used to evaluate meeting quality, including treatment recommendations, survival, time from diagnosis, and overall attendance. VMDTMs were superior (N = 6) or sometimes equivalent (N = 4) to face-to-face meetings. Studies identified implementation factors critical to their effective delivery, including internet-stability and chairing. Conclusion The heterogeneous literature suggests VMDTMs offer some benefits over face-to-face meetings. Training and infrastructure are key to prevent risks to patient safety. A definitive comparative evaluation is needed to inform best practice.

Abstract Non-homologous chromosomal contacts (NHCCs) between different chromosomes participate considerably in gene and genome regulation. Due to analytical challenges, NHCCs are currently considered as singular, stochastic events, and their extent and fundamental principles across cell types remain controversial. We develop a supervised and unsupervised learning algorithm, termed Signature, to call NHCCs in Hi-C datasets to advance our understanding of genome topology. Signature reveals 40,282 NHCCs and their properties across 62 Hi-C datasets of 53 diploid human cell types. Genomic regions of NHCCs are gene-dense, highly expressed, and harbor genes for cell-specific and sex-specific functions. Extensive inter-telomeric and inter-centromeric clustering occurs across cell types [Rabl’s configuration] and 61 NHCCs are consistently found at the nuclear speckles. These constitutive ‘anchor loci’ facilitate an axis of genome activity whilst cell-type-specific NHCCs act in discrete hubs. Our results suggest that non-random chromosome positioning is supported by constitutive NHCCs that shape genome topology along an off-centered spatial gradient of genome activity.

Abstract Background Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. Methods Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. Results Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4–20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. Clinical trial registration number NCT02348320.

Abstract Volcanic heating is predicted by theory to affect the velocity of nearby glaciers. However, conclusive studies on a large scale are lacking. Here, we conduct a global comparison of the velocities of glaciers near active volcanoes (i.e. within 5 km) and those located elsewhere ( > 5 km from an active volcano). Our findings show that, when considered over an annual scale (e.g. 2017-2018) and controlling for other factors, glaciers near volcanoes flow 46% faster than those located elsewhere (based on median values). This finding strongly suggests that volcanic heating impacts glacier velocity at a global scale, and supports the idea that glacier velocity monitoring could be a valuable indirect tool to help volcano monitoring and eruption prediction, particularly where volcanic heating (and therefore subglacial melt) intensifies months or years prior to eruptions.

Abstract Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant‐producing cells and lower surfactant‐protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12 mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term = 150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45 min before tissue collection. Lung function and structure were similar in control lambs (n = 16, 11 ewes) and lambs from asthma ewes (n = 14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n = 12, 8 ewes) compared to those from controls (P = 0.003) or asthma ewes (P = 0.008). Lung expression of surfactant protein genes SFTPA (P = 0.048) and SFTPB (P

Abstract SARS-CoV-2 initiates infection in the conducting airways, where mucociliary clearance inhibits pathogen penetration. However, it is unclear how mucociliary clearance impacts SARS-CoV-2 spread after infection is established. To investigate viral spread at this site, we perform live imaging of SARS-CoV-2 infected differentiated primary human bronchial epithelium cultures for up to 12 days. Using a fluorescent reporter virus and markers for cilia and mucus, we longitudinally monitor mucus motion, ciliary motion, and infection. Infected cell numbers peak at 4 days post infection, forming characteristic foci that tracked mucus movement. Inhibition of MCC using physical and genetic perturbations limits foci. Later in infection, mucociliary clearance deteriorates. Increased mucus secretion accompanies ciliary motion defects, but mucociliary clearance and vectorial infection spread resume after mucus removal, suggesting that mucus secretion may mediate MCC deterioration. Our work shows that while MCC can facilitate SARS-CoV-2 spread after initial infection, subsequent MCC decreases inhibit spread, revealing a complex interplay between SARS-CoV-2 and MCC.

Abstract Urban green space and urban compactness are each important principles for designing healthy, climate-resilient cities. The principles can co-exist, but greening may come at density’s expense if not considered deliberately. Existing studies estimating health impacts of greening scenarios have not considered what level of greenness is attainable for different population densities. Here, using the square kilometer as the unit of analysis, we estimate non-accidental mortality that could be prevented among adults older than 30 by greening that small area to a level of greenness assumed to be attainable based on its broader urban area (N = 15,917 globally), population density, and ecological zone. Results suggest a large potential for urban greening even in the most population-dense parts of cities such that on average 54 deaths per 100,000 could be prevented per year in those areas. That estimate may be about 25% higher or lower due to uncertainty in the underlying model.

Abstract We examined how resistance exercise (RE), cycling exercise and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation. The 1boutRE study involved younger men (n = 8; 5 ± 2 years of RE experience) performing a lower body RE bout with vastus lateralis (VL) biopsies being obtained prior to and acutely following exercise. With the 10weekRT study, VL biopsies were obtained in 36 younger adults before and 24 h after their first/naïve RE bout. Participants also engaged in 10 weeks of resistance training and donated VL biopsies before and 24 h after their last RE bout. VL biopsies were also examined in an acute cycling study (n = 7) and a study involving 2 weeks of leg immobilization (n = 20). In the 1boutRE study, fragmentation of all MyHC isoforms (MyHCTotal) increased 3 h post‐RE (∼200%, P = 0.018) and returned to pre‐exercise levels by 6 h post‐RE. Interestingly, a greater magnitude increase in MyHC type IIa versus I isoform fragmentation occurred 3 h post‐RE (8.6 ± 6.3‐fold vs. 2.1 ± 0.7‐fold, P = 0.018). In 10weekRT participants, the first/naïve and last RE bouts increased MyHCTotal fragmentation 24 h post‐RE (+65% and +36%, P

Abstract Task functional magnetic resonance imaging research has generally shielded away from studying individuals due to the low reproducibility. Here, we propose that heterogeneous brain activations across individuals localize to a common network. To test this hypothesis, we use working memory (WM) as our example. First, we showed that discrete-brain-based reproducibility of brain activation during WM across individuals was low. Then, we used activation network mapping (ANM) technique to identify each individual’s brain network of WM and found that network-based reproducibility was rather high. Prediction analyses using machine learning algorithms indicated that individual WM networks identified via ANM can predict WM behavioral performance. This predictive ability even outperformed that of brain activations. Our study provides a new explanation on the low reproducibility of brain activations across individuals. The results suggest that ANM can be used to identify individual brain networks of cognitive processes, thus promising broad potential applications.

Abstract Physical inactivity poses a significant risk to morbidity and mortality. Chinese American women, as part of the larger group of Asian American women, exhibit low adherence to recommended physical activity guidelines. To date, few physical activity interventions have been tailored to address specific sociocultural considerations in this population, and the heterogeneity among Asian Americans is often not considered. The purpose of this qualitative descriptive study was to understand facilitators, motivations, and barriers to physical activity perceived by Chinese American women to help inform tailored physical activity interventions for this population. Virtual, semi-structured individual interviews with 21 Chinese American women were completed. Data were analyzed using Clarke and Braun’s thematic analysis approach. Six main themes emerged: (1) desires to stay healthy; (2) achievement and satisfaction; (3) facilitators and motivations from social networks; (4) COVID-19 pandemic; (5) prioritizing family needs; and (6) weight status satisfaction. Participants expressed motivations rooted in their desire for improved health, personal experience of improvement and accomplishment gained from physical activity, and the influence of social networks, both online and in-person. The COVID-19 pandemic acted as both a facilitator and a barrier to physical activity. Identified barriers include prioritizing family needs over personal engagement in physical activity and lacking motivation due to perceiving a normal weight that does not necessitate participation in physical activity. The findings facilitate the development of culturally appropriate interventions to improve physical activity and enhance overall well-being in this population.

Abstract The coordinated biomechanical performance of maternal tissues facilitates healthy pregnancy. Quantifying uterine and cervical biomechanical function has been challenging due to minimal data on the anatomy’s shape, size, and material properties across gestation. Addressing this challenge, this study quantifies structural features of human pregnancy by assessing maternal reproductive tissues and estimated fetal weight in 47 low-risk pregnancies at four gestation times. Uterocervical size and estimated fetal weight were measured via ultrasound, and cervical stiffness was measured via mechanical aspiration. Patient-specific uterocervical solid models were built for each time point, and uterocervical dimensions and cervical stiffness rate changes were assessed between time points. We found that uterine growth rates are time- and direction-dependent, with cervical softening occurring fastest in early gestation and cervical shortening fastest in late gestation. In conclusion, this work enables computational modeling platforms (i.e., digital twins) to explore the structural performance of the uterus and cervix in pregnancy.

Abstract Wrist function is a top priority for transradial amputees. However, the combined functional, biomechanical, and cognitive impact of using a powered prosthetic wrist is unclear. Here, we quantify task performance, compensatory movements, and cognitive load while three transradial amputees performed a modified Clothespin Relocation Task using two myoelectric prostheses with and without the wrists. The two myoelectric prostheses include a commercial prosthesis with a built-in powered wrist, and a newly developed inexpensive prosthetic wrist for research purposes, called the “Utah wrist”, that can be adapted to work with various sockets and prostheses. For these three participants, task failure rate decreased significantly from 66% ± 12% without the wrist to 39% ± 9% with the Utah wrist. Compensatory forward leaning movements also decreased significantly, from 24.2° ± 2.5 without the wrist to 12.6° ± 1.0 with the Utah wrist, and from 23.6° ± 7.6 to 15.3° ± 7.2 with the commercial prosthesis with an integrated wrist. Compensatory leftward bending movements also significantly decreased, from 20.8° ± 8.6 to 12.3° ± 5.3, for the commercial with an integrated wrist. Importantly, simultaneous myoelectric control of either prosthetic wrist had no significant impact on cognitive load, as assessed by the NASA Task Load Index survey and a secondary detection response task. This work suggests that functional prosthetic wrists can improve dexterity and reduce compensation without significantly increasing cognitive effort. These results, and the introduction of a new inexpensive prosthetic wrist for research purposes, can aid future research and development and guide the prescription of upper-limb prostheses.

Abstract This paper explores the mapping from specific digitalization practices to specific resilient performance against a great shock. Based on an adapted structure–conduct–performance framework, this paper hypothesizes by theoretically analyzing how the pre-shock establishment of digital retailing practices could trigger physical retailers’ bounce-back and bounce-forward performance against the COVID-19 crisis. Using a difference-in-differences strategy, the hypotheses are examined with a sample including 549 observations of 50 Chinese listed retailers from the first quarter of 2018 to the third quarter of 2020. The empirical results mainly indicate the following binary findings. First, regardless of the differences in triggering bounce-back performance, different digital retailing practices are found to be effective in triggering physical retailers’ bounce-forward performance against the COVID-19 crisis. This somewhat addresses the concern about the temporality of digitalization-enabled resilience by revealing the generality across digital retailing practices in the sense of triggering resilient performance. Second, it is shown that physical retailers’ bounce-back performance at a specific stage of the COVID-19 crisis could only be triggered by digital retailing practices that coincidentally apply to the shock-induced market structure changes at the stage. The results emphasize each digitalization practice’s individuality in triggering resilient performance. This justifies the non-negligibility of the direct mapping from specific digitalization practices to specific resilient performance in digitalization-enabled resilience evaluation.

Abstract With the National Institutes of Health’s mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.