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Background: Postural orthostatic tachycardia syndrome (POTS) is a chronic form of orthostatic intolerance that primarily affects female patients. Despite the severity of POTS, there are no approved medications for use in patients with this disorder. Compression garments are a commonly prescribed nonpharmacological treatment, but little is known about the patient experience with compression. In this study we aimed to evaluate the patient experience with compression garments using a structured survey and semistructured telephone interviews. Methods: A focused survey was designed as a component of a larger clinical trial on compression garment use in patients diagnosed with POTS. Building on the survey, semistructured telephone interviews were conducted with POTS patients. Recorded interviews were transcribed and coded in a thematic analysis using a descriptive-interpretive approach. Results: A total of 27 participants completed the survey, and 20 participants completed the telephone interview. Patient experiences with compression were variable, with some participants experiencing significant benefits, and others reporting minimal to no benefits. Six themes that influenced garment use were identified: the potential benefit of the garment to improve symptoms, specific activities patients will be undertaking, environmental conditions, garment attributes, psychological and cognitive aspects, and financial considerations. Conclusions: Participants engage in a daily cost-benefit analysis when making decisions to use a compression garment. Clinicians should be aware of the benefits of and factors that limit use of compression garments as a treatment for POTS. Résumé: Contexte: Le syndrome de tachycardie orthostatique posturale (STOP) est une forme chronique d’intolérance orthostatique qui touche principalement les femmes. Malgré la gravité de ce syndrome, il n’existe aucun médicament approuvé pour traiter les patients qui en sont atteints. Les vêtements de compression constituent souvent le seul traitement non pharmacologique prescrit, mais il existe peu d’information sur l’expérience des patients avec ces vêtements. Dans cette étude, nous avons cherché à évaluer l’expérience des patients utilisant des vêtements de compression par le biais d’un sondage structuré et d’entrevues téléphoniques semi-structurées. Méthodologie: Un sondage ciblé constituait une composante d’une étude clinique plus vaste sur l’utilisation de vêtements de compression par des patients atteints du STOP. À partir du sondage, des entrevues téléphoniques semi-structurées des patients ont été réalisées. Ces entrevues ont été enregistrées, retranscrites et codées au moyen d’une analyse thématique utilisant une approche descriptive et interprétative. Résultats: Au total, 27 participants ont répondu au sondage et 20, à l’entrevue téléphonique. L’expérience des patients avec les vêtements de compression était variable, certains y trouvant des avantages significatifs tandis que d’autres en tiraient peu d’avantages, voire aucun. Six thèmes influant sur l’emploi de vêtements de compression ont été relevés : effet positif potentiel des vêtements de compression sur les symptômes, activités spécifiques projetées par les patients, conditions environnementales, attributs des vêtements, aspects psychologiques et cognitifs et considérations financières. Conclusions: Les participants devaient effectuer chaque jour une analyse du coût et des avantages avant de décider s’ils allaient utiliser un vêtement de compression. Les cliniciens doivent être conscients des bénéfices et des contraintes associés à l’utilisation des vêtements de compression dans le traitement du STOP.

Abstract Background Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. Methods We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. Results We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Conclusions Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.

Abstract Maternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function. In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the “Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function” (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers. Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health.

Abstract Background The 13-valent pneumococcal conjugate vaccine (PCV-13) was introduced in Malawi in 2011 with an expected impact of reducing pneumococcal pneumonia in children. We aimed to describe clinical characteristics and nasopharyngeal (NP) carriage of pneumococcus by serotype in children hospitalized with primary end-point pneumonia (PEP) between 2013 and 19 after the introduction of PCV-13. Methods We conducted a secondary analysis of children aged under-5-years hospitalized with acute respiratory illness (ARI) in Malawi. Chest radiographs conducted at admission were read by two independent clinicians according to WHO criteria for PEP, and a third reviewer resolved discordant diagnoses. NP swab specimens were processed and Streptococcus pneumoniae growth was serotyped. Multivariable regression analysis was conducted to assess the association between clinical characteristics, NP serotypes, and PEP. Results We had complete radiographic and NP serotype data for 500 children, of which 54 isolates were vaccine-type (VT) (10.8%), 165 were non-VT (NVT; 33.0%), and 281 had no pneumococcal growth (56.2%). Among these, 176 (35.2%) had PEP on chest x-ray. Among those with PEP, pneumococcal carriage was documented in 43.8% of cases, and VT serotypes accounted for 10.8%. For children with PEP, we found no association between clinical characteristics and carrying either VT, NVT, or no pneumococcus. Conclusion Carriage of S. pneumoniae remains high among children hospitalized with ARI in Malawi, but children with VT carriage were no more likely to have PEP than children carrying no pneumococcus or those with NVT carriage. There were no differences in clinical characteristics between those carrying VT, NVT, or no pneumococcus.

Abstract Altering posture relative to the direction of gravity, or exposure to microgravity has been shown to affect many aspects of perception, including size perception. Our aims in this study were to investigate whether changes in posture and long-term exposure to microgravity bias the visual perception of object height and to test whether any such biases are accompanied by changes in precision. We also explored the possibility of sex/gender differences. Two cohorts of participants (12 astronauts and 20 controls, 50% women) varied the size of a virtual square in a simulated corridor until it was perceived to match a reference stick held in their hands. Astronauts performed the task before, twice during, and twice after an extended stay onboard the International Space Station. On Earth, they performed the task of sitting upright and lying supine. Earth-bound controls also completed the task five times with test sessions spaced similarly to the astronauts; to simulate the microgravity sessions on the ISS they lay supine. In contrast to earlier studies, we found no immediate effect of microgravity exposure on perceived object height. However, astronauts robustly underestimated the height of the square relative to the haptic reference and these estimates were significantly smaller 60 days or more after their return to Earth. No differences were found in the precision of the astronauts’ judgments. Controls underestimated the height of the square when supine relative to sitting in their first test session (simulating Pre-Flight) but not in later sessions. While these results are largely inconsistent with previous results in the literature, a posture-dependent effect of simulated eye height might provide a unifying explanation. We were unable to make any firm statements related to sex/gender differences. We conclude that no countermeasures are required to mitigate the acute effects of microgravity exposure on object height perception. However, space travelers should be warned about late-emerging and potentially long-lasting changes in this perceptual skill.

Cartograms serve as representations of geographical and abstract data, employing a value-by-area mapping technique. As a variant of the Dorling cartogram, the Demers cartogram utilizes squares instead of circles to represent regions. This alternative approach allows for a more intuitive comparison of regions, utilizing screen space more efficiently. However, a drawback of the Dorling cartogram and its variants lies in the potential displacement of regions from their original positions, ultimately compromising legibility, readability, and accuracy. To tackle this limitation, we propose a novel hybrid cartogram layout algorithm that incorporates topological elements, such as rivers, into Demers cartograms. The presence of rivers significantly impacts both the layout and visual appearance of the cartograms. Through a user study conducted on an Electronic Health Records (EHR) dataset, we evaluate the efficacy of the proposed hybrid layout algorithm. The obtained results illustrate that this approach successfully retains key aspects of the original cartogram while enhancing legibility, readability, and overall accuracy.

Abstract Adaptive deep brain stimulation (aDBS) is an emerging advancement in DBS technology; however, local field potential (LFP) signal rate detection sufficient for aDBS algorithms and the methods to set-up aDBS have yet to be defined. Here we summarize sensing data and aDBS programming steps associated with the ongoing Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease (ADAPT-PD) pivotal trial (NCT04547712). Sixty-eight patients were enrolled with either subthalamic nucleus or globus pallidus internus DBS leads connected to a Medtronic PerceptTM PC neurostimulator. During the enrollment and screening procedures, a LFP (8–30 Hz, ≥1.2 µVp) control signal was identified by clinicians in 84.8% of patients on medication (65% bilateral signal), and in 92% of patients off medication (78% bilateral signal). The ADAPT-PD trial sensing data indicate a high LFP signal presence in both on and off medication states of these patients, with bilateral signal in the majority, regardless of PD phenotype.

Barley net form net blotch (NFNB) is a destructive foliar disease caused by Pyrenophora teres f. teres. Barley line CIho5791, which harbors the broadly effective chromosome 6H resistance gene Rpt5, displays dominant resistance to P. teres f. teres. To genetically characterize P. teres f. teres avirulence/virulence on the barley line CIho5791, we generated a P. teres f. teres mapping population using a cross between the Moroccan CIho5791-virulent isolate MorSM40-3 and the avirulent reference isolate 0-1. Full genome sequences were generated for 103 progenies. Saturated chromosome-level genetic maps were generated, and quantitative trait locus (QTL) mapping identified two major QTL associated with P. teres f. teres avirulence/virulence on CIho5791. The most significant QTL mapped to chromosome (Ch) 1, where the virulent allele was contributed by MorSM40-3. A second QTL mapped to Ch8; however, this virulent allele was contributed by the avirulent parent 0-1. The Ch1 and Ch8 loci accounted for 27 and 15% of the disease variation, respectively, and the avirulent allele at the Ch1 locus was epistatic over the virulent allele at the Ch8 locus. As a validation, we used a natural P. teres f. teres population in a genome-wide association study that identified the same Ch1 and Ch8 loci. We then generated a new reference quality genome assembly of parental isolate MorSM40-3 with annotation supported by deep transcriptome sequencing of infection time points. The annotation identified candidate genes predicted to encode small, secreted proteins, one or more of which are likely responsible for overcoming the CIho5791 resistance. [Figure: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2024.

Abstract Background Previous research has shown that repeated COVID-19 mRNA vaccination leads to a marked increase of SARS-CoV-2 spike-specific serum antibodies of the IgG4 subclass, indicating far-reaching immunoglobulin class switching after booster immunization. Considering that repeated vaccination has been recommended especially for older adults, the aim of this study was to investigate IgG subclass responses in the ageing population and assess their relation with Fc-mediated antibody effector functionality. Results Spike S1-specific IgG subclass concentrations (expressed in arbitrary units per mL), antibody-dependent NK cell activation, complement deposition and monocyte phagocytosis were quantified in serum from older adults (n = 38–50, 65–83 years) at one month post-second, -third and -fifth vaccination. Subclass distribution in serum was compared to that in younger adults (n = 64, 18–47 years) at one month post-second and -third vaccination. Compared to younger individuals, older adults showed increased levels of IgG2 and IgG4 at one month post-third vaccination (possibly related to factors other than age) and a further increase following a fifth dose. The capacity of specific serum antibodies to mediate NK cell activation and complement deposition relative to S1-specific total IgG concentrations decreased upon repeated vaccination. This decrease associated with an increased IgG4/IgG1 ratio. Conclusions In conclusion, these findings show that, like younger individuals, older adults produce antibodies with reduced functional capacity upon repeated COVID-19 mRNA vaccination. Additional research is needed to better understand the mechanisms underlying these responses and their potential implications for vaccine effectiveness. Such knowledge is vital for the future design of optimal vaccination strategies in the ageing population.

Abstract Streptococcus mitis is a leading cause of infective endocarditis (IE). However, our understanding of the genomic epidemiology and pathogenicity of IE-associated S. mitis is hampered by low IE incidence. Here we use whole genome sequencing of 129 S. mitis bloodstream infection (BSI) isolates collected between 2001–2016 from clinically diagnosed IE cases in the UK to investigate genetic diversity, antimicrobial resistance, and pathogenicity. We show high genetic diversity of IE-associated S. mitis with virtually all isolates belonging to distinct lineages indicating no predominance of specific lineages. Additionally, we find a highly variable distribution of known pneumococcal virulence genes among the isolates, some of which are overrepresented in disease when compared to carriage strains. Our findings suggest that S. mitis in patients with clinically diagnosed IE is not primarily caused by specific hypervirulent or antimicrobial resistant lineages, highlighting the accidental pathogenic nature of S. mitis in patients with clinically diagnosed IE.

Silver nanoparticles are among the most widely researched and used for nanotechnology-derived structures due to their extraordinary inherent optical properties, chemical stability, catalytic activity, and high conductivity. These idiosyncratic properties can be attributed to their unique physico-chemical characteristics, such as ultrafine sizes, high surface area, diverse shapes, and strong localized surface plasmon resonance. These distinctive features can be tailored using various physical, chemical, and biological synthesis methods. Various physical techniques are viable for producing silver nanoparticles on a large scale, but they suffer from drawbacks such as high-power consumption, expensive set-up, and limited control over nanoparticle size distribution. Chemical methods provide benefits like high yield, consistent shape and size distribution, and cost efficiency, but the residual toxicity of the chemicals involved hinders their biological applications. Biological synthesis approaches effectively overcome the limitations of both physical and chemical methods by eliminating the need for hazardous chemicals, requiring less energy, enabling diverse nanoparticle morphologies, and offering eco-friendliness and exceptional biocompatibility. The novel and promising properties of nanosilver-based biomaterials have been demonstrated to be suitable for a wide range of pharmacological and therapeutic biomedical applications. Their extensive application in wound healing, dentistry, cardiovascular disease treatment, nerve tissue engineering, cancer treatment, and biosensing can be attributed to their inherent antimicrobial and antibiofilm activity, antithrombotic properties, potential for nerve regeneration, photothermal conversion efficiency and sensitivity, respectively. This review discusses the different methods employed for synthesising silver nanoparticles and focuses on using nanosilver-based biomaterials for various biomedical applications.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rarely described in the pregnant population, and knowledge of their impact on the mother/fetus is limited. Objective: To describe SJS/TEN in pregnant women and to investigate the risk factors for developing SJS/TEN in pregnancy. Methods: We utilized hospitalization data from the 2009–2020 National Inpatient Sample. Pregnancy hospitalizations and SJS/TEN involvement were identified by ICD-9/10 codes and analyzed by chi-square and logistic regression. Results: We identified 650 pregnancies complicated by SJS/TEN requiring hospitalization. The median age was 28 years, and most were non-Hispanic White (55.2%). There were ≤10 cases associated with mortality. Most SJS/TEN cases (73.9%) occurred during the third trimester. HIV infection (OR = 9.49; P = .030), herpes simplex virus infection (OR = 2.49; P = .021), genitourinary tract infections (OR = 3.80; 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.

Abstract Background Whole blood host transcript signatures show great potential for diagnosis of infectious and inflammatory illness, with most published signatures performing binary classification tasks. Barriers to clinical implementation include validation studies, and development of strategies that enable simultaneous, multiclass diagnosis of febrile illness based on gene expression. Methods We validated five distinct diagnostic signatures for paediatric infectious diseases in parallel using a single NanoString nCounter® experiment. We included a novel 3-transcript signature for childhood tuberculosis, and four published signatures which differentiate bacterial infection, viral infection, or Kawasaki disease from other febrile illnesses. Signature performance was assessed using receiver operating characteristic curve statistics. We also explored conceptual frameworks for multiclass diagnostic signatures, including additional transcripts found to be significantly differentially expressed in previous studies. Relaxed, regularised logistic regression models were used to derive two novel multiclass signatures: a mixed One-vs-All model (MOVA), running multiple binomial models in parallel, and a full-multiclass model. In-sample performance of these models was compared using radar-plots and confusion matrix statistics. Results Samples from 91 children were included in the study: 23 bacterial infections (DB), 20 viral infections (DV), 14 Kawasaki disease (KD), 18 tuberculosis disease (TB), and 16 healthy controls. The five signatures tested demonstrated cross-platform performance similar to their primary discovery-validation cohorts. The signatures could differentiate: KD from other diseases with area under ROC curve (AUC) of 0.897 [95% confidence interval: 0.822–0.972]; DB from DV with AUC of 0.825 [0.691–0.959] (signature-1) and 0.867 [0.753–0.982] (signature-2); TB from other diseases with AUC of 0.882 [0.787–0.977] (novel signature); TB from healthy children with AUC of 0.910 [0.808–1.000]. Application of signatures outside of their designed context reduced performance. In-sample error rates for the multiclass models were 13.3% for the MOVA model and 0.0% for the full-multiclass model. The MOVA model misclassified DB cases most frequently (18.7%) and TB cases least (2.7%). Conclusions Our study demonstrates the feasibility of NanoString technology for cross-platform validation of multiple transcriptomic signatures in parallel. This external cohort validated performance of all five signatures, including a novel sparse TB signature. Two exploratory multi-class models showed high potential accuracy across four distinct diagnostic groups.

Abstract Background The United States has lost many lives to COVID-19. The role of social capital and collective action has been previously explored in the context of COVID-19. The current study specifically investigates the role of social trust at the county level and COVID-19 mortality in the US, hypothesizing that counties with higher social trust will have lower COVID-19 mortality rates. Methods We used cross-sectional data from the General Social Survey (GSS). We collected COVID-19 mortality data from the COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University until October 31, 2021. We obtained county characteristics from the 2019 American Community Survey and supplemented this data source with additional publicly available county-level data, such as measures of income inequality and political leanings. We measured social trust as a single item from the GSS and calculated mean social trust in a county by pooling responses from 2002 to 2018. We then modeled the relationship between mean social trust and COVID-19 mortality. Results Results indicate that counties with higher social trust have lower COVID-19 mortality rates. Higher values of mean social trust at the county level are associated with a decrease in COVID-19 mortality (b= -0.25, p-value

Abstract Oscillatory activity within the beta frequency range (13–30 Hz) serves as a Parkinson’s disease biomarker for tailoring deep brain stimulation (DBS) treatments. Currently, identifying clinically relevant beta signals, specifically frequencies of peak amplitudes within the beta spectral band, is a subjective process. To inform potential strategies for objective clinical decision making, we assessed algorithms for identifying beta peaks and devised a standardized approach for both research and clinical applications. Employing a novel monopolar referencing strategy, we utilized a brain sensing device to measure beta peak power across distinct contacts along each DBS electrode implanted in the subthalamic nucleus. We then evaluated the accuracy of ten beta peak detection algorithms against a benchmark established by expert consensus. The most accurate algorithms, all sharing similar underlying algebraic dynamic peak amplitude thresholding approaches, matched the expert consensus in performance and reliably predicted the clinical stimulation parameters during follow-up visits. These findings highlight the potential of algorithmic solutions to overcome the subjective bias in beta peak identification, presenting viable options for standardizing this process. Such advancements could lead to significant improvements in the efficiency and accuracy of patient-specific DBS therapy parameterization.

Abstract Omics-based biomarker technologies, including metabolic profiling (metabolomics/metabonomics) and lipidomics, are making a significant impact on disease understanding, drug development, and translational research. A wide range of patho-physiological processes involve lipids and monitoring changes in lipid abundance can give valuable insights into mechanisms of drug action, off target pharmacology and toxicity. Here we report changes, detected by untargeted LC–MS, in the plasma lipid profiles of male C57Bl/6JRj mice following the PO and IV administration of the epidermal growth factor receptor (EGFR) inhibitor gefitinib. Statistical analysis of the data obtained for both the IV and PO samples showed time-related changes in the amounts of lipids from several different classes. The largest effects were associated with a rapid onset of these changes following gefitinib administration followed by a gradual return by 24 h post dose to the type of lipid profile seen in predose samples. Investigation of the lipids responsible for the variance observed in the data showed that the PI, PC, LPC, PE and TG were subject to the largest disruption with both transient increases and decreases in relative amounts seen in response to administration of the drug. The pattern of the changes in the relative abundances of those lipids subject to variation appeared to be correlated to the pharmacokinetics of gefitinib (and its major metabolites). These observations support the concept of a distinct pharmacolipidodynamic relationship between drug exposure and plasma lipid abundance.

Abstract Salmonella Typhi is a human-restricted pathogen that is transmitted by the faecal–oral route and causative organism of typhoid fever. Using health facility data from 2016 to 2020, this study focuses on modelling the spatial variation in typhoid risk in Ndirande township in Blantyre. To pursue this objective, we developed a marked inhomogeneous Poisson process model that allows us to incorporate both individual-level and environmental risk factors. The results from our analysis indicate that typhoid cases are spatially clustered, with the incidence decreasing by 54% for a unit increase in the water, sanitation, and hygiene (WASH) score. Typhoid intensity was also higher in children aged below 18 years than in adults. However, our results did not show evidence of a strong temporal variation in typhoid incidence. We also discuss the inferential benefits of using point pattern models to characterise the spatial variation in typhoid risk and outline possible extensions of the proposed modelling framework.

Abstract Background Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer. Methods In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m2) men with localized prostate cancer, aged 43–72 years, were randomized (1:1) with permuted blocks to 4–6 weeks of customized isocaloric PR diets (0.8 g protein/kg lean body mass) or their usual diet. Biomarkers influencing cancer biology, including serum IGF-1 and its binding proteins were measured longitudinally. Results Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration. Conclusion These findings demonstrate that protein restriction without calorie restriction does not reduce serum IGF-1 concentration or increase IGFBP-1 and IGFBP-3 in men with localized prostate cancer. Further research is needed to identify dietary interventions for safely and effectively reducing IGF-1 in this patient group.

Abstract Background High flow nasal cannula (HFNC) has been increasingly adopted in the past 2 decades as a mode of respiratory support for children hospitalized with bronchiolitis. The growing use of HFNC despite a paucity of high-quality data regarding the therapy’s efficacy has led to concerns about overutilization. We developed an electronic health record (EHR) embedded, quality improvement (QI) oriented clinical trial to determine whether standardized management of HFNC weaning guided by clinical decision support (CDS) results in a reduction in the duration of HFNC compared to usual care for children with bronchiolitis. Methods The design and summary of the statistical analysis plan for the REspiratory SupporT for Efficient and cost-Effective Care (REST EEC; “rest easy”) trial are presented. The investigators hypothesize that CDS-coupled, standardized HFNC weaning will reduce the duration of HFNC, the trial’s primary endpoint, for children with bronchiolitis compared to usual care. Data supporting trial design and eventual analyses are collected from the EHR and other real world data sources using existing informatics infrastructure and QI data sources. The trial workflow, including randomization and deployment of the intervention, is embedded within the EHR of a large children’s hospital using existing vendor features. Trial simulations indicate that by assuming a true hazard ratio effect size of 1.27, equivalent to a 6-h reduction in the median duration of HFNC, and enrolling a maximum of 350 children, there will be a > 0.75 probability of declaring superiority (interim analysis posterior probability of intervention effect > 0.99 or final analysis posterior probability of intervention effect > 0.9) and a > 0.85 probability of declaring superiority or the CDS intervention showing promise (final analysis posterior probability of intervention effect > 0.8). Iterative plan-do-study-act cycles are used to monitor the trial and provide targeted education to the workforce. Discussion Through incorporation of the trial into usual care workflows, relying on QI tools and resources to support trial conduct, and relying on Bayesian inference to determine whether the intervention is superior to usual care, REST EEC is a learning health system intervention that blends health system operations with active evidence generation to optimize the use of HFNC and associated patient outcomes. Trial registration ClinicalTrials.gov NCT05909566. Registered on June 18, 2023.

Abstract Tackling inequities in cancer outcomes is a global health priority. One avenue for improving early diagnosis of cancer is to ensure people know when and how to seek help for cancer symptoms and that this knowledge (and behaviour) is equitably distributed across the population. In this perspective piece we highlight the challenges in understanding sociodemographic differences in help-seeking behaviour (for example, how help-seeking is defined / conceptualised and subsequently assessed), as well as challenges with using existing datasets that are now more readily accessible than ever. Addressing these will strengthen methodological approaches to understand inequities in help-seeking and ways to tackle them.

Abstract Hybrid genotypes can provide significant yield gains over conventional inbred varieties due to heterosis or hybrid vigor. However, hybrids can also display unintended negative attributes or phenotypes such as extreme pathogen susceptibility. The necrotrophic pathogen Pyrenophora teres f. maculata (Ptm) causes spot form net blotch, which has caused significant yield losses to barley worldwide. Here, we report on a non-transgressive hybrid susceptibility locus in barley identified between the three parental lines CI5791, Tifang and Golden Promise that are resistant to Ptm isolate 13IM.3. However, F2 progeny from CI5791 × Tifang and CI5791 × Golden Promise crosses exhibited extreme susceptibility. The susceptible phenotype segregated in a ratio of 1 resistant:1 susceptible representing a genetic segregation ratio of 1 parental (res):2 heterozygous (sus):1 parental (res) suggesting a single hybrid susceptibility locus. Genetic mapping using a total of 715 CI5791 × Tifang F2 individuals (1430 recombinant gametes) and 149 targeted SNPs delimited the hybrid susceptibility locus designated Susceptibility to Pyrenophora teres 2 (Spt2) to an ~ 198 kb region on chromosome 5H of the Morex V3 reference assembly. This single locus was independently mapped with 83 CI5791 × Golden Promise F2 individuals (166 recombinant gametes) and 180 genome wide SNPs that colocalized to the same Spt2 locus. The CI5791 genome was sequenced using PacBio Continuous Long Read technology and comparative analysis between CI5791 and the publicly available Golden Promise genome assembly determined that the delimited region contained a single high confidence Spt2 candidate gene predicted to encode a pentatricopeptide repeat-containing protein.

The weevil Exophthalmus albofasciatus Champion, previously known from Honduras and Belize, is recorded for the first time in Mexico. In addition, the species Coccoloba barbadensis (Polygonaceae) is recorded for the first time as a new adult host plant of this species. Photographs of adults are provided to facilitate identification.

Abstract Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1–40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5–40 mg zavegepant or placebo for 1–14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia‐corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T‐wave morphology, and U‐wave presence) were analyzed pre‐ and post‐zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time‐matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed‐effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration‐dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration‐QTcF model was −0.053 ms per ng/mL with a 90% confidence interval of −0.0955 to −0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Abstract Bulk-rock sulfur isotope data from pyrite in the ~2.1 billion-year sedimentary rocks of the Francevillian Basin, Gabon, have underpinned ideas about initial oxygenation of Earth’s surface environments and eukaryote evolution. Here, we show, using micro-scale analytical methods, that the bulk sulfur isotope record represents progressive diagenetic modification. Our findings indicate no significant change in microbial sulfur cycling processes and seawater sulfate composition throughout that initial phase of atmosphere-ocean oxygenation of Paleoproterozoic time. This offers an alternative view of Earth system evolution during the transition from an anoxic to an oxic state and highlights the need for a judicious reappraisal of conceptual models using sulfur isotope data as primary depositional signals linked to global-scale biogeochemical processes.

Abstract Background Two propensity score (PS) based balancing covariate methods, the overlap weighting method (OW) and the fine stratification method (FS), produce superb covariate balance. OW has been compared with various weighting methods while FS has been compared with the traditional stratification method and various matching methods. However, no study has yet compared OW and FS. In addition, OW has not yet been evaluated in large claims data with low prevalence exposure and with low frequency outcomes, a context in which optimal use of balancing methods is critical. In the study, we aimed to compare OW and FS using real-world data and simulations with low prevalence exposure and with low frequency outcomes. Methods We used the Texas State Medicaid claims data on adult beneficiaries with diabetes in 2012 as an empirical example (N = 42,628). Based on its real-world research question, we estimated an average treatment effect of health center vs. non-health center attendance in the total population. We also performed simulations to evaluate their relative performance. To preserve associations between covariates, we used the plasmode approach to simulate outcomes and/or exposures with N = 4,000. We simulated both homogeneous and heterogeneous treatment effects with various outcome risks (1-30% or observed: 27.75%) and/or exposure prevalence (2.5-30% or observed:10.55%). We used a weighted generalized linear model to estimate the exposure effect and the cluster-robust standard error (SE) method to estimate its SE. Results In the empirical example, we found that OW had smaller standardized mean differences in all covariates (range: OW: 0.0–0.02 vs. FS: 0.22–3.26) and Mahalanobis balance distance (MB) ( 0.049) than FS. In simulations, OW also achieved smaller MB (homogeneity: 0.04; heterogeneity: 0.0-0.11 vs. 0.07–0.29), relative bias (homogeneity: 4.04–56.20 vs. 20–61.63; heterogeneity: 7.85–57.6 vs. 15.0-60.4), square root of mean squared error (homogeneity: 0.332–1.308 vs. 0.385–1.365; heterogeneity: 0.263-0.526 vs 0.313-0.620), and coverage probability (homogeneity: 0.0–80.4% vs. 0.0-69.8%; heterogeneity: 0.0-97.6% vs. 0.0-92.8%), than FS, in most cases. Conclusions These findings suggest that OW can yield nearly perfect covariate balance and therefore enhance the accuracy of average treatment effect estimation in the total population.

Abstract Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

Background: Neighborhood disadvantage, a social driver of health (SDOH), has been associated with adverse perinatal outcomes; yet little is known about its association with anesthetic choice. Objective: The purpose of this study is to assess the association of neighborhood disadvantage and anesthetic choice for cesarean deliveries. We hypothesize that people from the most disadvantaged neighborhoods are more likely to receive general anesthesia for cesarean deliveries compared to those from the most advantaged neighborhoods. Study design: This single-center retrospective cohort study identified index cesarean deliveries performed between 2008 and 2017. People were categorized into no, low, moderate, and high disadvantage neighborhood using the area deprivation index. The odds of receiving general anesthesia versus neuraxial anesthesia (epidural, spinal, or combined spinal-epidural) were compared using logistic regression models. Results: Of the 16,351 people with cesarean deliveries, 96.0% received neuraxial versus 4.0% general anesthesia. The rates of general anesthesia were 6.3%, 4.2%, 3.1%, and 2.4% for the high, moderate, low, and no disadvantage groups (P

Background: Systemic mastocytosis (SM), a rare condition affecting about 32,000 individuals in the United States, is often misdiagnosed or underdiagnosed owing to its nonspecific symptoms and the need for invasive biopsies. Objective: Our aim was to identify, classify, and characterize the natural history of patients with SM. Methods: In a retrospective cohort study, administrative data from a large managed care organization was used to identify patients with confirmed SM, based on World Health Organization criteria. Demographic data, delay to diagnosis, disease progression, and health care resource utilization were examined. Results: Of 116 patients with confirmed SM, 77% had indolent SM, 2% had smoldering SM, 12% had SM with associated hematologic neoplasm, 9% had aggressive SM, and none had mast cell leukemia. In all, 5 patients were misclassified as having a less advanced SM subtype initially and 3 were completely undiagnosed (missed diagnosis). The average delay to diagnosis of SM was 58.3 plus or minus 73.1 months. In all, 18% of patients progressed from a nonadvanced form of SM (indolent or smoldering SM) to an advanced form of SM (aggressive SM, SM with associated hematologic neoplasm, or mast cell leukemia) over an average of 88.3 plus or minus 82.7 months. Patients with SM had increased health care utilization, including increases in their numbers of hospital admissions, emergency room visits, urgent care visits, and specialty provider visits, after diagnosis versus before. Conclusions: Rare diseases such as SM would benefit from increased understanding and awareness to improve diagnostic accuracy. Prospective studies are needed to better characterize this patient population and determine the type of follow-up needed to recognize advanced forms of SM so that appropriate treatment can be implemented.

ABSTRACT We assessed changes in fundamental climate‐niche space for lizard and snake species in western North America under modeled climate scenarios to inform natural resource managers of possible shifts in species distributions. We generated eight distribution models for each of 130 snake and lizard species in western North America under six time‐by‐climate scenarios. We combined the highest‐performing models per species into a single ensemble model for each scenario. Maps were generated from the ensemble models to depict climate‐niche space for each species and scenario. Patterns of species richness based on climate suitability and niche shifts were calculated from the projections at the scale of the entire study area and individual states and provinces, from Canada to Mexico. Squamate species' climate‐niche space for the recent‐time climate scenario and published known ranges were highly correlated (r = 0.81). Overall, reptile climate‐niche space was projected to move northward in the future. Sixty‐eight percent of species were projected to expand their current climate‐niche space rather than to shift, contract, or remain stable. Only 8.5% of species were projected to lose climate‐niche space in the future, and these species primarily occurred in Mexico and the southwestern U.S. We found few species were projected to lose all suitable climate‐niche space at the state or province level, although species were often predicted to occupy novel areas, such as at higher elevations. Most squamate species were projected to increase their climate‐niche space in future climate scenarios. As climate niches move northward, species are predicted to cross administrative borders, resulting in novel conservation issues for local landowners and natural resource agencies. However, information on species dispersal abilities, landscape connectivity, biophysical tolerances, and habitat suitability is needed to contextualize predictions relative to realized future niche expansions.

Abstract We develop a novel approach to detect cloud‐subcloud coupling during the cloud life cycle and analyze a large eddy simulation of marine shallow cumulus based on the Barbados oceanographic and meteorological experiment campaign. Our results demonstrate how the activity of sub‐cloud coherent updrafts (SCUs) affect the evolution of shallow cloud properties during their life cycles, from triggering to development, and through to dissipation. Most clouds (∼80%) are related to SCUs during their lifetime but not every SCU (∼20% for short‐lived ones) leads to cloud formation. The fastest growing SCUs in a relatively moist region are most likely to initiate clouds. The evolution of cloud base mass‐flux depends on cloud lifetime. Compared with short‐lived clouds, longer lived clouds have longer periods of development, even normalized by the full lifetime, and tend to increase their cloud base mass‐flux to a stronger maximum. This is consistent with the evolution of mass flux near the top of SCU, indicating that the development of clouds is closely related to the sub‐cloud activity. When the SCUs decay and detach from the lifting condensation level, the corresponding cloud base starts to rise, signifying the start of cloud dissipation, during which the cloud top lowers to approach the rising cloud base. Previous studies have described similar conceptual pieces of this relationship but here we provide a continuous framework to cover all the stages of cloud‐subcloud coupling. Our findings provide quantitative evidence to supplement the conceptual model of shallow cloud life cycle and is critical to improve the steady‐state assumption in parameterization.

Cereal rust diseases, including leaf, stem, and stripe rust, are some of the most devastating and economically important diseases of barley. However, host–pathogen genetic interaction research for each pathosystem is typically conducted independently and in isolation. Examples of host resistance/susceptibility genes functioning sympathetically to multiple pathogens or antagonistically to additional pathogens have been reported. Therefore, consolidation of loci that have been reported in multiple studies and across pathosystems is useful for variety development to maximize resistance to multiple pathogens and avoid inadvertent incorporation of susceptibility loci that act antagonistically to other pathogens. This review summarizes loci reported in three key biotrophic pathosystems of barley, including leaf, stem, and stripe rust. In conjunction with previously consolidated net blotch loci, this review lays the foundation for a wider barley rust resistance/susceptibility atlas. This review aims to inform breeders and researchers in rapidly identifying accessions and loci that need further characterization and which loci would be most useful to introgress into elite varieties.

Abstract Feedstock variability represents a challenge in lignocellulosic biorefineries, as it can influence both lignocellulose deconstruction and microbial conversion processes for biofuels and biochemicals production. The impact of feedstock variability on microbial performance remains underexplored, and predictive tools for microbial behaviour are needed to mitigate risks in biorefinery scale‐up. Here, twelve batches of corn stover were deconstructed via deacetylation, mechanical refining, and enzymatic hydrolysis to generate lignin‐rich and sugar streams. These batches and their derived streams were characterised to identify their chemical components, and the streams were used as substrates for producing muconate and butyrate by engineered Pseudomonas putida and wildtype Clostridium tyrobutyricum, respectively. Bacterial performance (growth, product titers, yields, and productivities) differed among the batches, but no strong correlations were identified between feedstock composition and performance. To provide metabolic insights into the origin of these differences, we evaluated the effect of twenty‐three isolated chemical components on these microbes, including three components in relevant bioprocess settings in bioreactors, and we found that growth‐inhibitory concentrations were outside the ranges observed in the streams. Overall, this study generates a foundational dataset on P. putida and C. tyrobutyricum performance to enable future predictive models and underscores their resilience in effectively converting fluctuating lignocellulose‐derived streams into bioproducts.

Food insecurity is a complex societal problem that disproportionately impacts households with children and those led by minoritized populations, with negative impacts on health across the life course. System to Achieve Food Equity adapted the learning systems model, used to address similarly complex problems, to tackle food insecurity at a neighborhood level. SAFE, born out of the COVID-19 pandemic, leverages a family-centered, community-based, cross-sector network fundamentally aimed at changing the food system so that all children in Cincinnati have the food they need to thrive. Through the following principles, Community-Led Network, Co-Production with Community, Equitable Sustainability, Learning to Learn Together, Distributing Leadership and Power, and Shared Data and Governance, SAFE has grown to over 300 individuals and 100 organizations, funded 9 novel interventions, distributed over 270,000 meals, and created a collaborative of motivated like-minded stakeholders. Future work includes improved data collection and sharing, support for increased stakeholder engagement and greater distribution of leadership and power, advocacy for policy change, refining measurement tools of network maturity for community settings, and collaboration with other efforts that contribute to food security indirectly.

The intermixed mandibular lesion of cemento-ossifying fibroma (COF) and aneurysmal bone cyst (ABC) is a rare occurrence with dramatic ramifications if left untreated. COF is a benign fibro-osseous neoplasm that predominantly affects the tooth bearing regions of the jaws. It is most commonly observed in women during their third and fourth decades of life. ABC, alternatively, is a vascular lesion characterized by blood-filled spaces within the bone. The coexistence of these two distinct pathologies in the mandible presents diagnostic challenges due to their overlapping radiographic features. Once a diagnosis is obtained, smaller lesions can be enucleated and curettaged, although for larger and mixed lesions, en bloc resection is advised to reduce risk of recurrence. We present a case of a 17-year-old female with an intermixed lesion of the left mandible, undiagnosed for over 1 year, which led to severe facial asymmetry and mass effect on surrounding tissues. Treatment was completed with a left hemimandibulectomy and reconstruction with a custom plate, condylar head and free fibular flap transfer.

The Revised Cardiac Risk Index (RCRI) and the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) preoperative risk assessment tools are the most widely used methods for quantifying the risk of major negative perioperative cardiac outcomes that a patient may face during and after noncardiac surgery. However, these tools were created to include as wide a range of surgical factors as possible; thus, some predictive accuracy is sacrificed when it comes to certain surgical subpopulations. In this review, we explore the various surgical oncology patient populations for whom these assessment tools can be reliably applied and for whom they demonstrate poor reliability.

Abstract The COVID-19 pandemic led to 231,841 deaths and 940,243 hospitalisations in England, by the end of March 2023. This paper calculates the real-time infection hospitalisation risk (IHR) and infection fatality risk (IFR) using the Office for National Statistics Coronavirus Infection Survey (ONS CIS) and the Real-time Assessment of Community Transmission Survey between November 2020 to March 2023. The IHR and the IFR in England peaked in January 2021 at 3.39% (95% Credible Intervals (CrI): 2.79, 3.97) and 0.97% (95% CrI: 0.62, 1.36), respectively. After this time, there was a rapid decline in the severity from infection, with the lowest estimated IHR of 0.32% (95% CrI: 0.27, 0.39) in December 2022 and IFR of 0.06% (95% CrI: 0.04, 0.08) in April 2022. We found infection severity to vary more markedly between regions early in the pandemic however, the absolute heterogeneity has since reduced. The risk from infection of SARS-CoV-2 has changed substantially throughout the COVID-19 pandemic with a decline of 86.03% (80.86, 89.35) and 89.67% (80.18, 93.93) in the IHR and IFR, respectively, since early 2021. From April 2022 until March 2023, the end of the ONS CIS study, we found fluctuating patterns in the severity of infection with the resumption of more normative mixing, resurgent epidemic waves, patterns of waning immunity, and emerging variants that have shown signs of convergent evolution.

Abstract Introduction Coronavirus disease 2019 (COVID-19)-associated tracheal stenosis (COATS) may occur as a result of prolonged intubation during COVID-19 infection. We aimed to investigate patterns of gene expression in the tracheal granulation tissue of patients with COATS, leverage gene expression data to identify dysregulated cellular pathways and processes, and discuss potential therapeutic options based on the identified gene expression profiles. Methods Adult patients (age ≥ 18 years) presenting to clinics for management of severe, recalcitrant COATS were included in this study. RNA sequencing and differential gene expression analysis was performed with transcriptomic data for normal tracheal tissue being used as a control. The top ten most highly upregulated and downregulated genes were identified. For each of these pathologically dysregulated genes, we identified key cellular pathways and processes they are involved in using Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) applied via Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results Two women, aged 36 years and 37 years, were included. The profile of dysregulated genes indicated a cellular response consistent with viral infection (CXCL11, PI15, CCL8, DEFB103A, IFI6, ACOD1, and DEFB4A) and hyperproliferation/hypergranulation (MMP3, CASP14 and HAS1), while downregulated pathways included retinol metabolism (ALDH1A2, RBP1, RBP4, CRABP1 and CRABP2). Conclusion Gene expression changes consistent with persistent viral infection and dysregulated retinol metabolism may promote tracheal hypergranulation and hyperproliferation leading to COATS. Given the presence of existing literature highlighting retinoic acid’s ability to favorably regulate these genes, improve cell-cell adhesion, and decrease overall disease severity in COVID-19, future studies must evaluate its utility for adjunctive management of COATS in animal models and clinical settings.

Abstract Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners — representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner–Curtius–Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.

Abstract Enhancers are fast-evolving genomic sequences that control spatiotemporal gene expression patterns. By examining enhancer turnover across mammalian species and in multiple tissue types, we uncover a relationship between the emergence of enhancers and genome organization as a function of germline DNA replication time. While enhancers are most abundant in euchromatic regions, enhancers emerge almost twice as often in late compared to early germline replicating regions, independent of transposable elements. Using a deep learning sequence model, we demonstrate that new enhancers are enriched for mutations that alter transcription factor (TF) binding. Recently evolved enhancers appear to be mostly neutrally evolving and enriched in eQTLs. They also show more tissue specificity than conserved enhancers, and the TFs that bind to these elements, as inferred by binding sequences, also show increased tissue-specific gene expression. We find a similar relationship with DNA replication time in cancer, suggesting that these observations may be time-invariant principles of genome evolution. Our work underscores that genome organization has a profound impact in shaping mammalian gene regulation.

The research career of Justin O. Schmidt (1947–2023) is reviewed and assessed. The pioneering nature of his research lay in treating the defensive means and tactics of aculeate hymenoptera and some arachnids as features of their overall anti-predator strategies. He devised methods for comparing the effects of hymenopteran venoms and stings that challenged the assumed correlation between venom potency and the pain that it induces.

Abstract Background Understanding the dynamics of gametocyte production in polyclonal Plasmodium falciparum infections requires a genotyping method that detects distinct gametocyte clones and estimates their relative frequencies. Here, a marker was identified and evaluated to genotype P. falciparum mature gametocytes using amplicon deep sequencing. Methods A data set of polymorphic regions of the P. falciparum genome was mined to identify a gametocyte genotyping marker. To assess marker resolution, the number of unique haplotypes in the marker region was estimated from 95 Malawian P. falciparum whole genome sequences. Specificity of the marker for detection of mature gametocytes was evaluated using reverse transcription-polymerase chain reaction of RNA extracted from NF54 mature gametocytes and rings from a non-gametocyte-producing strain of P. falciparum. Amplicon deep sequencing was performed on experimental mixtures of mature gametocytes from two distinct parasite clones, as well as gametocyte-positive P. falciparum field isolates to evaluate the quantitative ability and determine the limit of detection of the genotyping approach. Results A 400 bp region of the pfs230 gene was identified as a gametocyte genotyping marker. A larger number of unique haplotypes was observed at the pfs230 marker (34) compared to the sera-2 (18) and ama-1 (14) markers in field isolates from Malawi. RNA and DNA genotyping accurately estimated gametocyte and total parasite clone frequencies when evaluating agreement between expected and observed haplotype frequencies in gametocyte mixtures, with concordance correlation coefficients of 0.97 [95% CI: 0.92–0.99] and 0.92 [95% CI: 0.83–0.97], respectively. The detection limit of the genotyping method for male gametocytes was 0.41 pfmget transcripts/µl [95% CI: 0.28–0.72] and for female gametocytes was 1.98 ccp4 transcripts/µl [95% CI: 1.35–3.68]. Conclusions A region of the pfs230 gene was identified as a marker to genotype P. falciparum gametocytes. Amplicon deep sequencing of this marker can be used to estimate the number and relative frequency of parasite clones among mature gametocytes within P. falciparum infections. This gametocyte genotyping marker will be an important tool for studies aimed at understanding dynamics of gametocyte production in polyclonal P. falciparum infections.

Abstract Background Hepatitis C virus (HCV) is a major health threat in Canada. In British Columbia (BC) province, 1.6% of the population had been exposed to HCV by 2012. Prevalence and incidence of HCV are very high in populations of people who use drugs (PWUD) and sex workers (SW), who may experience unique barriers to healthcare. Consequently, they are less likely to be treated for HCV. Overcoming these barriers is critical for HCV elimination. This research sought to explore the healthcare experiences of PWUD and SW and how these experiences impact their willingness to engage in healthcare in the future, including HCV care. Methods Interpretive Description guided this qualitative study of healthcare experiences in BC, underpinned by the Health Stigma and Discrimination framework. The study team included people with living/lived experience of drug use, sex work, and HCV. Twenty-five participants completed in-depth semi-structured interviews on their previous healthcare and HCV-related experiences. Thematic analysis was used to identify common themes. Results Three major themes were identified in our analysis. First, participants reported common experiences of delay and refusal of care by healthcare providers, with many negative healthcare encounters perceived as rooted in institutional culture reflecting societal stigma. Second, participants discussed their choice to engage in or avoid healthcare. Many avoided all but emergency care following negative experiences in any kind of healthcare. Third, participants described the roles of respect, stigma, dignity, fear, and trust in communication in healthcare relationships. Conclusions Healthcare experiences shared by participants pointed to ways that better understanding and communication by healthcare providers could support positive change in healthcare encounters of PWUD and SW, who are at high risk of HCV infection. More positive healthcare encounters could lead to increased healthcare engagement which is essential for HCV elimination.

Abstract Despite the significant burden, cost, and worse prognosis of Alzheimer’s disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.

Abstract Background Despite significant success in the fight against malaria over the past two decades, malaria control programmes rely on only two insecticidal methods: indoor residual spraying and insecticidal-treated nets. House improvement (HI) can complement these interventions by reducing human-mosquito contact, thereby reinforcing the gains in disease reduction. This study assessed the implementation fidelity, which is the assessment of how closely an intervention aligns with its intended design, feasibility, and sustainability of community-led HI in southern Malawi. Methods The study, conducted in 22 villages (2730 households), employed a mixed-methods approach. Implementation fidelity was assessed using a modified framework, with longitudinal surveys collecting data on HI coverage indicators. Quantitative analysis, employing descriptive statistics, evaluated the adherence to HI implementation. Qualitative data came from in-depth interviews, key informant interviews, and focus groups involving project beneficiaries and implementers. Qualitative data were analysed using content analysis guided by the implementation fidelity model to explore facilitators, challenges, and factors affecting intervention feasibility. Results The results show that HI was implemented as planned. There was good adherence to the intended community-led HI design; however, the adherence could have been higher but gradually declined over time. In terms of intervention implementation, 74% of houses had attempted to have eaves closed in 2016-17 and 2017-18, compared to 70% in 2018–19. In 2016–17, 42% of houses had all four sides of the eaves closed, compared to 33% in 2018–19. Approximately 72% of houses were screened with gauze wire in 2016-17, compared to 57% in 2018-19. High costs, supply shortages, labour demands, volunteers’ poor living conditions and adverse weather were reported to hinder the ideal HI implementation. Overall, the community described community-led HI as feasible and could be sustained by addressing these socioeconomic and contextual challenges. Conclusion Our study found that although HI was initially implemented as planned, its fidelity declined over time. Using trained volunteers facilitated the fidelity and feasibility of implementing the intervention. A combination of rigorous community education, consistent training, information, education and communication, and intervention modifications may be necessary to address the challenges and enhance the intervention’s fidelity, feasibility, and sustainability.

Abstract This case report describes an 80-year-old man who presented with a growing erythematous nodule with erosion, measuring 0.6 cm × 0.6 cm, on his right temple. This lesion was later diagnosed as atypical fibroxanthoma (AFX). Instead of undergoing Mohs surgery, the gold standard treatment, the patient opted to pursue a topical treatment regimen because of financial costs associated with surgical removal and repair. This topical regimen consisted of tazarotene cream, imiquimod cream, and 5-fluorouracil solution, applied for 30 days. The patient was directed to use this combination 5 days per week for 6 weeks. The specified dosage for each medication was a fifth of a packet of imiquimod 5% cream, an equivalent amount of tazarotene 0.1% cream, and a single drop of 5-fluorouracil 2% solution. These were combined on a bandage and placed on the lesion overnight. Following the treatment, a 3-week post-application examination revealed an erosion, 1.0 cm × 0.9 cm, amidst erythema. A subsequent incisional biopsy with histopathology and stains for CD10 and CD99, 3 weeks after treatment, and three punch biopsies with histopathology and stains for CD10 and CD99, 1-year post-treatment, confirmed the absence of AFX. AFX is a superficial variant of pleomorphic dermal sarcoma (PDS), which shares histologic similarities, yet the exact relationship between AFX/PDS and undifferentiated pleomorphic sarcoma is still not well understood. Previous studies have indicated a genomic similarity between AFX/PDS and cutaneous squamous cell carcinoma (cSCC), which suggests the potential efficacy of cSCC-targeted treatments for AFX/PDS. This case marks the first recorded instance of successful topical medical treatment of AFX, offering an alternative for patients who may opt out of surgical intervention. Continued research to assess the broader efficacy of this approach is encouraged.

Abstract The accumulation of microplastics in various ecosystems has now been well documented and recent evidence suggests detrimental effects on various biological processes due to this pollution. Accumulation of microplastics in the natural environment is ultimately due to the chemical nature of widely used petroleum-based plastic polymers, which typically are inaccessible to biological processing. One way to mitigate this crisis is adoption of plastics that biodegrade if released into natural environments. In this work, we generated microplastic particles from a bio-based, biodegradable thermoplastic polyurethane (TPU-FC1) and demonstrated their rapid biodegradation via direct visualization and respirometry. Furthermore, we isolated multiple bacterial strains capable of using TPU-FC1 as a sole carbon source and characterized their depolymerization products. To visualize biodegradation of TPU materials as real-world products, we generated TPU-coated cotton fabric and an injection molded phone case and documented biodegradation by direct visualization and scanning electron microscopy (SEM), both of which indicated clear structural degradation of these materials and significant biofilm formation.

Abstract In May 2022, individuals infected with the monkeypox virus were detected in the UK without clear travel links to endemic areas. Understanding the clinical characteristics and infection severity of mpox is necessary for effective public health policy. The study period of this paper, from the 1st June 2022 to 30th September 2022, included 3,375 individuals that tested positive for the monkeypox virus. The posterior mean times from infection to hospital admission and length of hospital stay were 14.89 days (95% Credible Intervals (CrI): 13.60, 16.32) and 7.07 days (95% CrI: 6.07, 8.23), respectively. We estimated the modelled Infection Hospitalisation Risk to be 4.13% (95% CrI: 3.04, 5.02), compared to the overall sample Case Hospitalisation Risk (CHR) of 5.10% (95% CrI: 4.38, 5.86). The overall sample CHR was estimated to be 17.86% (95% CrI: 6.06, 33.11) for females and 4.99% (95% CrI: 4.27, 5.75) for males. A notable difference was observed between the CHRs that were estimated for each sex, which may be indicative of increased infection severity in females or a considerably lower infection ascertainment rate. It was estimated that 74.65% (95% CrI: 55.78, 86.85) of infections with the monkeypox virus in the UK were captured over the outbreak.

Abstract Self-motion perception is a multi-sensory process that involves visual, vestibular, and other cues. When perception of self-motion is induced using only visual motion, vestibular cues indicate that the body remains stationary, which may bias an observer’s perception. When lowering the precision of the vestibular cue by for example, lying down or by adapting to microgravity, these biases may decrease, accompanied by a decrease in precision. To test this hypothesis, we used a move-to-target task in virtual reality. Astronauts and Earth-based controls were shown a target at a range of simulated distances. After the target disappeared, forward self-motion was induced by optic flow. Participants indicated when they thought they had arrived at the target’s previously seen location. Astronauts completed the task on Earth (supine and sitting upright) prior to space travel, early and late in space, and early and late after landing. Controls completed the experiment on Earth using a similar regime with a supine posture used to simulate being in space. While variability was similar across all conditions, the supine posture led to significantly higher gains (target distance/perceived travel distance) than the sitting posture for the astronauts pre-flight and early post-flight but not late post-flight. No difference was detected between the astronauts’ performance on Earth and onboard the ISS, indicating that judgments of traveled distance were largely unaffected by long-term exposure to microgravity. Overall, this constitutes mixed evidence as to whether non-visual cues to travel distance are integrated with relevant visual cues when self-motion is simulated using optic flow alone.

Abstract Objectives Arterial catheters (ACs) are critical for haemodynamic monitoring and blood sampling but are prone to complications. We investigated the incidence and risk factors of AC failure. Methods Secondary analysis of a multi-centre randomised controlled trial (ACTRN 12610000505000). Analysis included a subset of adult intensive care unit patients with an AC. The primary outcome was all-cause device failure. Secondary outcomes were catheter associated bloodstream infection (CABSI), suspected CABSI, occlusion, thrombosis, accidental removal, pain, and line fracture. Risk factors associated with AC failure were investigated using Cox proportional hazards and competing-risk models. Results Of 664 patients, 173 (26%) experienced AC failure (incidence rate [IR] 37/1000 catheter days). Suspected CABSI was the most common failure type (11%; IR 15.3/1000 catheter days), followed by occlusion (8%; IR 11.9/1,000 catheter days), and accidental removal (4%; IR 5.5/1000 catheter days). CABSI occurred in 16 (2%) patients. All-cause failure and occlusion were reduced with ultrasound-assisted insertion (failure: adjusted hazard ratio [HR] 0.43, 95% CI 0.25, 0.76; occlusion: sub-HR 0.11, 95% CI 0.03, 0.43). Increased age was associated with less AC failure (60–74 years HR 0.63, 95% CI 0.44 to 0.89; 75 + years HR 0.36, 95% CI 0.20, 0.64; referent 15–59 years). Females experienced more occlusion (adjusted sub-HR 2.53, 95% CI 1.49, 4.29), while patients with diabetes had less (SHR 0.15, 95% CI 0.04, 0.63). Suspected CABSI was associated with an abnormal insertion site appearance (SHR 2.71, 95% CI 1.48, 4.99). Conclusions AC failure is common with ultrasound-guided insertion associated with lower failure rates. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN 12610000505000); date registered: 18 June 2010.