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Abstract Benthic (seafloor) remineralization of organic material determines the fate of carbon in the ocean and its sequestration. Bottom water temperature and labile carbon supply to the seafloor are expected to increase in a warming Arctic and correspondingly, benthic remineralization rates. We provide some of the first experimental data on the response of sediment oxygen demand (SOD), an established proxy for benthic remineralization, to increased temperature and/or food supply across a range of Arctic conditions and regimes. Each factor significantly increased SOD rates (with different degrees of variability); however the largest increases were seen with both factors combined (50% to ten-fold increases), consistently across the four seasons and the spatial gradient covering shelf to deep basin included in our study. This ability of the Arctic benthos to process increased pulses of carbon suggests that increased sedimented carbon under warming conditions is likely to be utilized and processed, not accumulated, impacting carbon storage and decreasing the Arctic’s role as a global carbon sink.

Abstract Spread of multidrug-resistant Pseudomonas aeruginosa strains threatens to render currently available antibiotics obsolete, with limited prospects for the development of new antibiotics. Lytic bacteriophages, the viruses of bacteria, represent a path to combat this threat. In vitro-directed evolution is traditionally applied to expand the bacteriophage host range or increase bacterial suppression in planktonic cultures. However, while up to 80% of human microbial infections are biofilm-associated, research towards targeted improvement of bacteriophages’ ability to combat biofilms remains scarce. This study aims at an in vitro biofilm evolution assay to improve multiple bacteriophage parameters in parallel and the optimisation of bacteriophage cocktail design by exploiting a bacterial bacteriophage resistance trade-off. The evolved bacteriophages show an expanded host spectrum, improved antimicrobial efficacy and enhanced antibiofilm performance, as assessed by isothermal microcalorimetry and quantitative polymerase chain reaction, respectively. Our two-phage cocktail reveals further improved antimicrobial efficacy without incurring dual-bacteriophage-resistance in treated bacteria. We anticipate this assay will allow a better understanding of phenotypic-genomic relationships in bacteriophages and enable the training of bacteriophages against other desired pathogens. This, in turn, will strengthen bacteriophage therapy as a treatment adjunct to improve clinical outcomes of multidrug-resistant bacterial infections.

Abstract Background Arbuscular mycorrhizas (AM) are the most widespread terrestrial symbiosis and are both a key determinant of plant health and a major contributor to ecosystem processes through their role in biogeochemical cycling. Until recently, it was assumed that the fungi which form AM comprise the subphylum Glomeromycotina (G-AMF), and our understanding of the diversity and ecosystem roles of AM is based almost exclusively on this group. However recent evidence shows that fungi which form the distinctive 'fine root endophyte’ (FRE) AM morphotype are members of the subphylum Mucoromycotina (M-AMF), so that AM symbioses are actually formed by two distinct groups of fungi. Results We investigated the influence of nitrogen (N) addition and wheat variety on the assembly of AM communities under field conditions. Visual assessment of roots showed co-occurrence of G-AMF and M-AMF, providing an opportunity to compare the responses of these two groups. Existing ‘AM’ 18S rRNA primers which co-amplify G-AMF and M-AMF were modified to reduce bias against Mucoromycotina, and compared against a new ‘FRE’ primer set which selectively amplifies Mucoromycotina. Using the AM-primers, no significant effect of either N-addition or wheat variety on G-AMF or M-AMF diversity or community composition was detected. In contrast, using the FRE-primers, N-addition was shown to reduce M-AMF diversity and altered community composition. The ASV which responded to N-addition were closely related, demonstrating a clear phylogenetic signal which was identified only by the new FRE-primers. The most abundant Mucoromycotina sequences we detected belonged to the same Endogonales clades as dominant sequences associated with FRE morphology in Australia, indicating that closely related M-AMF may be globally distributed. Conclusions The results demonstrate the need to consider both G-AMF and M-AMF when investigating AM communities, and highlight the importance of primer choice when investigating AMF community dynamics.

Abstract Cryptococcal meningitis is a high-mortality infection. Adding 5-fluorocytosine (5-FC) to its treatment improves outcomes, but resistance to 5-FC presents a significant challenge. We conducted whole-genome sequencing on seven C. neoformans isolates with varying 5-FC susceptibility, along with proteomic and in silico analyses. Our findings indicate that mutations in genes of the pyrimidine salvage pathway are responsible for 5-FC resistance. Specifically, we identified an E64G missense mutation in the FUR1 gene, a large deletion in the FCY1 gene, and a point mutation in FCY1 leading to a truncated protein. The proteomic data indicated that these mutations resulted in the absence or reduction of crucial enzymes in resistant isolates. Genetic transformations confirmed the association between these mutations and 5-FC resistance. Resistance to 5-FC can develop during treatment and is closely tied to mutations in key metabolic enzymes. Understanding in vivo resistance development is crucial for combating resistance and enhancing patient outcomes.

Abstract Background Veterans with substance use disorder (SUD) are at high risk for cognitive problems due to neurotoxic effects of chronic drug and alcohol use coupled in many cases with histories of traumatic brain injury (TBI). These problems may in turn result in proneness to SUD relapse and reduced adherence to medical self-care regimens and therefore reliance on health care systems. However, the direct relationship between cognitive function and utilization of Veterans Health Administration (VHA) SUD and other VHA health care services has not been evaluated. We sought initial evidence as to whether neurocognitive performance relates to repeated health care engagement in Veterans as indexed by estimated VHA care costs. Methods Neurocognitive performance in 76 Veterans being treated for SUD was assessed using CNS-Vital Signs, a commercial computerized cognitive testing battery, and related to histories of outpatient and inpatient/residential care costs as estimated by the VHA Health Economics Resource Center. Results After controlling for age, an aggregate metric of overall neurocognitive performance (Neurocognition Index) correlated negatively with total VHA health care costs, particularly with SUD-related outpatient care costs but also with non-mental health-related care costs. Barratt Impulsiveness Scale scores also correlated positively with total VHA care costs. Conclusions In Veterans receiving SUD care, higher impulsivity and lower cognitive performance were associated with greater health care utilization within the VHA system. This suggests that veterans with SUD who show lower neurocognitive performance are at greater risk for continued health problems that require healthcare engagement. Cognitive rehabilitation programs developed for brain injury and other neurological conditions could be tried in Veterans with SUD to improve their health outcomes.

Abstract Background Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. Methods Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. Discussion This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. Trial registration ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1

Subterranean arthropods are important components of soils and contribute essential food-web functions and other ecosystem services, however, their diversity and community composition has scarcely been assessed. Subterranean pitfall traps are a commonly used method for sampling soil habitats in Europe but have never been widely implemented in the Americas. We used subterranean pitfall traps to sample previously unsurveyed arthropod communities in southwestern Virginia, U.S. Traps were placed in shallow subterranean habitats (SSHs), underground habitats close to the surface where light does not penetrate, and more specifically at the interface between the soil and underlying “milieu souterrain superficiel”—a microhabitat consisting of the air-filled interstitial spaces between rocks (abbreviated MSS). In total, 2,260 arthropod specimens were collected constituting 345 morphospecies from 8 classes, 33 orders, and 94 families. A region of the mitochondrial cytochrome c oxidase subunit I (COI) gene was amplified and sequenced, and objective sequence clustering of 3% was used to establish molecular operational taxonomic units (mOTUs) to infer observed species richness. In all, 272 COI barcodes representing 256 mOTUs were documented for rare soil-dwelling arthropod taxa and are published to build a molecular library for future research in this system. This work is the first taxonomically extensive survey of North American soil-dwelling arthropods greater than 10 cm below the soil surface.

A list of Scoliidae species recorded in Panama is presented. Considering the recent taxonomic updates made on this tribe of wasps, as well as the lack of a formal study on its geographical distribution, richness, and species diversity in Panama, this study aimed to document the existing species in the country. Based on literature records and an examination of 383 specimens, we found a total of 13 species and 7 genera. The following two species and one subspecies are recorded for the first time in Panama: Dielis tolteca (Saussure, 1857), Pygodasis hyalina (Saussure, 1864), and Pygodasis ephippium wagneriana (Saussure, 1864).

Abstract Post-harvest loss significantly affects food security in sub-Saharan Africa (SSA) and elsewhere across developing countries. Weak institutional factors like ineffective agricultural extension services in rural communities can exacerbate such problems among smallholder farmers in SSA and other developing countries. Therefore, international development policies have prioritized strengthening rural extension systems to enhance access to effective extension services and thereby enhance food security outcomes like ineffective agriculturalpost-harvest loss reduction among rural households. As such, the US-Agency for International Development supported the Strengthening Agricultural and Nutrition Extension program in Malawi from 2015 to 2021 to improve access to rural extension services by promoting Agricultural Stakeholder Panels (ASPs)—platforms designed to enhance farmer interaction with local extension agents in rural communities and thereby enhance improved access to quality extension services in rural areas. The ASP approach can reduce post-harvest losses for major crops, such as maize. However, rigorous analyses of the effects of ASPs on post-harvest loss reduction remain limited. To address this knowledge gap, we apply recursive bivariate probit regression to primary survey data from 2134 households in Malawi to estimate the effects of the ASP approach on post-harvest loss reduction in 2018. The results show that ASPs reduced post-harvest losses among households by 53%, and a crucial outcome that can improve household food security. The result demonstrates that policies that strengthen rural extension systems can contribute to the achievement of the Sustainable Development Goals on hunger and food security in rural Malawi and similar contexts.

Abstract TLR4 and TNFR1 signalling promotes potent proinflammatory signal transduction events, thus, are often hijacked by pathogenic microorganisms. We recently reported that myeloid cells retaliate Yersinia blockade of TAK1/IKK signalling by triggering RIPK1-dependent caspase-8 activation that promotes downstream GSDMD and GSDME-mediated pyroptosis in macrophages and neutrophils respectively. However, the upstream signalling events for RIPK1 activation in these cells are not well defined. Here, we demonstrate that unlike in macrophages, RIPK1-driven pyroptosis and cytokine priming in neutrophils are driven through TNFR1 signalling, while TLR4-TRIF signalling is dispensable. Furthermore, we demonstrate that activation of RIPK1-dependent pyroptosis in neutrophils during Yersinia infection requires IFN-γ priming, which serves to induce surface TNFR1 expression and amplify soluble TNF secretion. In contrast, macrophages utilise both TNFR1 and TLR4-TRIF signalling to trigger cell death, but only require TRIF but not autocrine TNFR1 for cytokine production. Together, these data highlight the emerging theme of cell type-specific regulation in cell death and immune signalling in myeloid cells.

Abstract The human oral microbiome may alter oral and systemic disease risk. Consuming high sugar content beverages (HSB) can lead to caries development by altering the microbial composition in dental plaque, but little is known regarding HSB-specific oral microbial alterations. Therefore, we conducted a large, population-based study to examine associations of HSB intake with oral microbiome diversity and composition. Using mouthwash samples of 989 individuals in two nationwide U.S. cohorts, bacterial 16S rRNA genes were amplified, sequenced, and assigned to bacterial taxa. HSB intake was quantified from food frequency questionnaires as low ( 3 servings/week). We assessed overall bacterial diversity and presence of specific taxa with respect to HSB intake in each cohort separately and combined in a meta-analysis. Consistently in the two cohorts, we found lower species richness in high HSB consumers (> 3 cans/week) (p = 0.027), and that overall bacterial community profiles differed from those of non-consumers (PERMANOVA p = 0.040). Specifically, presence of a network of commensal bacteria (Lachnospiraceae, Peptostreptococcaceae, and Alloprevotella rava) was less common in high compared to non-consumers, as were other species including Campylobacter showae, Prevotella oulorum, and Mycoplasma faucium. Presence of acidogenic bacteria Bifodobacteriaceae and Lactobacillus rhamnosus was more common in high consumers. Abundance of Fusobacteriales and its genus Leptotrichia, Lachnoanaerobaculum sp., and Campylobacter were lower with higher HSB consumption, and their abundances were correlated. No significant interaction was found for these associations with diabetic status or with microbial markers for caries (S. mutans) and periodontitis (P. gingivalis). Our results suggest that soft drink intake may alter the salivary microbiota, with consistent results across two independent cohorts. The observed perturbations of overrepresented acidogenic bacteria and underrepresented commensal bacteria in high HSB consumers may have implications for oral and systemic disease risk.

Abstract Background Creatinine‐based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C‐based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFRCRE and eGFRCYS in adult patients with cancer. Methods This study is a cross‐sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFRCRE and eGFRCYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross‐sectional areas were measured at the level of the third lumbar vertebral body using a validated deep‐learning pipeline. CT‐defined sarcopenia was defined using independent sex‐specific cut‐offs for skeletal muscle index ( 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFRCYS and eGFRCRE. Results Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non‐Hispanic white), 320 (58.7%) met the criteria for CT‐defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT‐defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12–3.24; aOR 2.01, 95% CI 1.15–3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21–4.51; aOR 2.23, 95% CI 1.19–4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFRCRE and eGFRCYS widens considerably. Conclusions CT‐defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates.

Caregivers for spouses with Alzheimer's disease and related dementias (ADRD) experience drastic changes in the marital relationship that may put them at risk for worsening well-being. Perceived partner responsiveness, or feeling cared for, understood, and appreciated by one's spouse, may help mitigate these effects. In this study, we investigated the associations between marital distress, perceived partner responsiveness, and psychological and physiological well-being indicators among ADRD spousal caregivers. Method: A sample of 161 caregivers provided blood samples and completed self-report measures of marital distress, perceived partner responsiveness, and depressive symptoms. We tested hypotheses in our sample cross-sectionally based on two theoretical frameworks. Results: Testing the marital discord model of depression, caregivers who reported greater marital distress also reported more depressive symptoms, and this association was stronger as participants reported lower perceived partner responsiveness. Caregivers who reported greater marital distress exhibited elevated proinflammatory cytokine production by in vitro lipopolysaccharide (LPS)-stimulated peripheral blood leukocytes at low levels of perceived partner responsiveness, but not mean or high levels. Testing the vulnerability-stress-adaptation model, caregivers who reported more depressive symptoms also reported greater marital distress. Further, caregivers who exhibited elevated LPS-stimulated proinflammatory cytokine production reported greater marital distress at mean and high levels of perceived partner responsiveness, but not low levels. These patterns of results held even when accounting for the dementia stage and reported hours of caregiving per day. Discussion: This study's findings contribute to the body of research examining interpersonal factors that shape health and well-being among the caregiver population.

Introduction/Objectives: We aimed to investigate the effect of family structure on depression program outcomes for adolescents enrolled in a depression-focused, primary care-based collaborative care program. Methods: This was a retrospective study of primary care patients ages 12 to 18 years seen at a Midwestern academic center with data obtained by medical record review. We used logistic regression models to assess the effect of family structure on program graduation and achievement of a single Patient Health Questionnaire 9–Modified for Adolescents (PHQ-9M) score

Abstract Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient‐specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health‐system‐wide, mixed‐methods study. Clinicians representing multiple practices and care settings (N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient‐specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0–100 points) of each alert, the perceived impact of each alert on stress and decision‐making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision‐making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician‐guided design of PGx alerts in the era of digital medicine.

Abstract Objective The objective of this study is to assess disparities in adherence to swallowing therapy for clinically diagnosed oropharyngeal dysphagia (OD) patients. Methods Analysis was conducted on data from 600 patients with OD and confirmed impairments in swallowing safety and/or efficiency on a videofluoroscopic swallow study. Patients were classified based on their adherence to treatment sessions, defined as the number of swallow treatment sessions attended. The outcome of treatment adherence was categorized into two groups: those who attended fewer than 50% of the prescribed treatment sessions and those who attended 50% or more of the sessions. Continuous variables were presented as mean ± standard deviation or median ± interquartile range. Categorical variables were compared using Pearson chi‐square tests and Fisher's exact test when appropriate. Univariable and multivariable binary logistic regression models were employed to identify factors associated with successful adherence. Results Approximately 79% adhered to swallowing treatment. We found no significant relationship between adherence and age, sex, race, ethnicity, primary language, marital status, insurance status, occupation, median income, distance, education, OD severity, and diagnosis year (p > 0.05). We found no covariables to be significant predictors to swallowing treatment nonadherence in both univariable and multivariable binary regression models (p > 0.05). Conclusion The variables analyzed in this study were not significantly associated with nonadherence to swallow therapy. Nevertheless, our study still addressed an important knowledge gap and future studies would benefit from exploring other relevant socioeconomic and disease‐related factors. Level of evidence Level 4.

DNA metabarcoding and morphological taxonomic (microscopic) analysis of the gut contents was used to examine diet diversity of seven species of fishes collected from mesopelagic depths (200-1000 m) in the NW Atlantic Ocean Slope Water during Summer 2018 and 2019. Metabarcoding used two gene regions: V9 hypervariable region of nuclear 18S rRNA and mitochondrial cytochrome oxidase I (COI). V9 sequences were classified into 14 invertebrate prey groups, excluding fish due to predator swamping. Ecological network analysis was used to evaluate relative strengths of predator-prey linkages. Multivariate statistical analysis revealed consistently distinct diets of four fish species in 2018 and/or 2019: Argyropelecus aculeatus, Chauliodus sloani, Hygophum hygomii, and Sigmops elongatus. Three other species analyzed (Malacosteus niger, Nemichthys scolopaceus, and Scopelogadus beanii) showed more variability between sampling years. COI sequences were classified into eight invertebrate prey groups, within which prey species were detected and identified. Considering all predator species together, a total of 77 prey species were detected with a minimum of 1,000 COI sequences, including 22 copepods, 18 euphausiids, and 7 amphipods. Morphological prey counts were classified into seven taxonomic groups, including a gelatinous group comprised of soft-bodied organisms. The ocean twilight zone or is home to exceptional diversity and biomass of marine fish, which are key players in deep sea food webs. This study used integrative morphological-molecular analysis to provide new insights into trophic relationships and sources of productivity for mesopelagic fishes, including identification of key prey species, recognition of the importance of gelatinous prey, and characterization of differences in diet among fish predators in the NW Atlantic Slope Water.

Environmental pollution is increasingly becoming a major global problem. Surface water pollution impacts human life and the ecosystem, emphasizing the need for water quality assessment and monitoring. In this study, water Samples were collected in Ogun River for two years (twice a year) and analyzed for the physicochemical parameters using standard methods. The results show that there was spatial and seasonal variation in the water quality of the river. The physical parameters Turbidity, EC, and TDS had significant positive correlations with each other but correlated negatively with DO and pH. A significant positive correlation also existed between pH and DO (0.918). Cluster analysis grouped the parameters into three clusters, while the PCA yielded 2-components, which explained 85.61 % of the total variance in the data set. Component 1 accounts for 69.26 % of the total variance and has strong positive loadings for Turbidity, EC, and TDS and strong negative loadings for pH and DO. Component 2 accounts for 16.35 % of the total variance, with strong positive loading for BOD. The results indicate that factors that increase the Turbidity, EC, and TDS levels will decrease the levels of pH and DO while exerting a less significant effect on BOD. This study provides valuable insight into the changes and interactions of parameters that affect the water quality, which is crucial for the sustainability and quality management of the water system.

A “rhythmic agent” is simulated based on the foundation of a previously published behavioral sensorimotor synchronization (SMS) model. The model is adjustable to control the auditory and tactile modalities of the tap's feedback. In addition to the conventional mechanisms of phase and period error correction, as well as their activation conditions, the period is estimated by modeling a central timekeeper impacted by a novel short-term memory. Inspired by The ADaptation and Anticipation Model (ADAM), a mechanism for linearly extrapolating anticipation is also tested. To better match the perceptual and motor cognitive functions, the model's parameters have been tuned to observations from experimental neurosensory literature with an emphasis on transduction delays. The agent is programmed to synchronize with various external rhythmic input signals while accounting for both adaptive and predictive mechanisms. The definition of the agent is based on a minimal set of rules yet has successfully replicated results of real-world observations: against a metronome; it produces the well-known negative mean asynchrony. In a rhythmic joint action, the simulation of joint delayed coordination shows a behavior previously observed in human subjects: in a rhythmic collaboration, a moderate amount of delay is necessary to keep the tempo steady, and below that threshold, the rhythm tends to speed up. It is also shown that giving more weight to the tactile afferent feedback than the auditory intensifies this effect. Moreover, it is observed that including anticipation in addition to the reactive mechanism will decrease the effect. The proposed model as a rhythmic engine, combined with other standard modules such as a beat detection algorithm, can be used to implement musical co-performers that could improvise with a human rhythmically or perform a given score in a way that feels human-like.

IntroductionThe COVID-19 pandemic brought unprecedented challenges to healthcare systems worldwide, particularly the often challenging physical recovery from critical illness. Among the myriad complications faced by these patients, ICU-acquired weakness (ICU-AW) stands out due to its significant impact on patient outcomes. ICU-AW, characterized by skeletal muscle atrophy and weakness, is linked to critical illness polyneuropathy (CIN), myopathy (CIM), and muscle atrophy. Notably, fasciculations, or involuntary muscle twitches, have been observed in patients with ICU-AW, suggesting altered muscle fiber excitability. This study aimed to describe the pattern of fasciculations in critically ill mechanically ventilated COVID-19 patients, assess clinical features associated with fasciculations, and evaluate their prognostic significance.MethodsThe study enrolled patients admitted to the Intensive Care Unit (ICU) with COVID-19 infection requiring intubation and mechanical ventilation. Quadriceps muscles were assessed using muscle skeletal (MSK) ultrasound and Phase Angle (PhA) through multifrequency segmental bioelectrical impedance analysis (MFBIA) every 72 h. PhA is considered a marker of cell membrane integrity and function, with lower PhA values indicating reduced skeletal muscle quality and increased risk of sarcopenia. Fasciculations were classified based on their appearance and frequency.ResultsA total of 35 intubated patients were studied, with 15 patients (43%) displaying scattered fasciculations exclusively in the vastus intermedius muscles. Upon admission, the study found no significant difference in PhA between the fasciculation and non-fasciculation groups. However, PhA decreased significantly from admission to discharge ICU only in the fasciculation group. Patients with fasciculations exhibited higher mortality rates, though not statistically significant, and this correlated with prolonged ICU and hospital lengths of stay.DiscussionThis study is the first to report scattered fasciculations in the vastus intermedius muscles of multiple patients with SARS-CoV-2 infection identified with MSK ultrasound. The findings suggest that the combination of impaired muscle cellular function (PhA) and the onset of fasciculations could serve as a potential biomarker of adverse outcomes and ICU-related muscle dysfunction and muscle loss.

This paper presents a comprehensive study on Herschel–Bulkley flow, where the flow parameters are dependent on the density. The Herschel–Bulkley model is a generalized power-law model used to simulate viscoplastic fluids defined by a plasticity threshold. We consider the case where the plasticity threshold and the viscosity depend on the shear rate and fluid density. To analyze this model, we use a Huber regularization of the stress and propose an H(div)-conforming and discontinuous Galerkin (DG) numerical approximation for the coupled equations governing the flow. We discuss the stability and existence of discrete solutions and propose a semismooth Newton linearization for the numerical solution of the discretized system. Our numerical scheme is validated through several experiments that explore the behavior of Herschel–Bulkley flow under different conditions. The results demonstrate the robustness of our numerical method.

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are popular methods for inducing neuroplastic changes to alter cognition and behaviour. One challenge for the field is to optimise stimulation protocols to maximise benefits. For this to happen, we need a better understanding of how stimulation modulates cortical functioning/behaviour. To date, there is increasing evidence for a dose-response relationship between tDCS and brain excitability, however how this relates to behaviour is not well understood. Even less is known about the neurochemical mechanisms which may drive the dose-response relationship between stimulation intensities and behaviour. Here, we examine the effect of three different tDCS stimulation intensities (1 mA, 2 mA, 4 mA anodal motor cortex tDCS) administered during the explicit learning of motor sequences. Further, to assess the role of dopamine in the dose-response relationship between tDCS intensities and behaviour, we examined how pharmacologically increasing dopamine availability, via 100 mg of levodopa, modulated the effect of stimulation on learning. In the absence of levodopa, we found that 4 mA tDCS improved and 1 mA tDCS impaired acquisition of motor sequences relative to sham stimulation. Conversely, levodopa reversed the beneficial effect of 4 mA tDCS. This effect of levodopa was no longer evident at the 48-h follow-up, consistent with previous work characterising the persistence of neuroplastic changes in the motor cortex resulting from combining levodopa with tDCS. These results provide the first direct evidence for a role of dopamine in the intensity-dependent effects of tDCS on behaviour.

Abstract Background On 20 September 2022, Uganda declared its fifth Sudan virus disease (SVD) outbreak, culminating in 142 confirmed and 22 probable cases. The reproductive rate (R) of this outbreak was 1.25. We described persons who were exposed to the virus, became infected, and they led to the infection of an unusually high number of cases during the outbreak. Methods In this descriptive cross-sectional study, we defined a super-spreader person (SSP) as any person with real-time polymerase chain reaction (RT-PCR) confirmed SVD linked to the infection of ≥ 13 other persons (10-fold the outbreak R). We reviewed illness narratives for SSPs collected through interviews. Whole-genome sequencing was used to support epidemiologic linkages between cases. Results Two SSPs (Patient A, a 33-year-old male, and Patient B, a 26-year-old male) were identified, and linked to the infection of one probable and 50 confirmed secondary cases. Both SSPs lived in the same parish and were likely infected by a single ill healthcare worker in early October while receiving healthcare. Both sought treatment at multiple health facilities, but neither was ever isolated at an Ebola Treatment Unit (ETU). In total, 18 secondary cases (17 confirmed, one probable), including three deaths (17%), were linked to Patient A; 33 secondary cases (all confirmed), including 14 (42%) deaths, were linked to Patient B. Secondary cases linked to Patient A included family members, neighbours, and contacts at health facilities, including healthcare workers. Those linked to Patient B included healthcare workers, friends, and family members who interacted with him throughout his illness, prayed over him while he was nearing death, or exhumed his body. Intensive community engagement and awareness-building were initiated based on narratives collected about patients A and B; 49 (96%) of the secondary cases were isolated in an ETU, a median of three days after onset. Only nine tertiary cases were linked to the 51 secondary cases. Sequencing suggested plausible direct transmission from the SSPs to 37 of 39 secondary cases with sequence data. Conclusion Extended time in the community while ill, social interactions, cross-district travel for treatment, and religious practices contributed to SVD super-spreading. Intensive community engagement and awareness may have reduced the number of tertiary infections. Intensive follow-up of contacts of case-patients may help reduce the impact of super-spreading events.

Abstract A pilot implementation of the rapid diagnostic test program was performed to collect evidence of the feasibility, acceptability, and uptake of the COVID-19 AgRDT in Tanzania. We conducted a prospective cross-sectional study in the community to provide quantitative details of the pilot implementation of the antigen rapid diagnostic test (AgRDT) in Tanzania. This study was undertaken between March 2022 and September 2022. The pilot was implemented by distributing and offering test kits to people suspected of having COVID-19 in Dar es Salaam through community health workers. A total of 1039 participants consented to participate in the survey. All the participants reported having heard about the disease. The radio was the main source (93.2%) of information on COVID-19. With regard to prevention measures, approximately 930 (89.5%) of the respondents thought that COVID-19 could be prevented. Approximately 1035 (99.6%) participants reported that they were willing to have a COVID-19 AgRDT test and wait for 20 min for the results. With regard to the participants’ opinions on the AgRDT device, the majority 907 (87.3%) felt comfortable with the test, and 1,029 (99.0%) were very likely to recommend the AgRDT test to their friends. The majority of participants 848 (83.1%) mentioned that they would be willing to pay for the test if it was not available for free. The results suggest overall good acceptance of the COVID-19 AgRDT test. It is evident that the use of trained community healthcare workers allows easy screening of all possible suspects and helps them receive early treatment.

Abstract Marine organisms are simultaneously exposed to anthropogenic stressors associated with ocean acidification and ocean warming, with expected interactive effects. Species from different trophic levels with dissimilar characteristics and evolutionary histories are likely to respond differently. Here, we perform a meta-analysis of controlled experiments including both ocean acidification and ocean warming factors to investigate single and interactive effects of these stressors on marine species. Contrary to expectations, we find that synergistic interactions are less common (16%) than additive (40%) and antagonistic (44%) interactions overall and their proportion decreases with increasing trophic level. Predators are the most tolerant trophic level to both individual and combined effects. For interactive effects, calcifying and non-calcifying species show similar patterns. We also identify climate region-specific patterns, with interactive effects ranging from synergistic in temperate regions to compensatory in subtropical regions, to positive in tropical regions. Our findings improve understanding of how ocean warming, and acidification affect marine trophic levels and highlight the need for deeper consideration of multiple stressors in conservation efforts.

Abstract Background Alzheimer’s Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer’s Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas. Method To better understand how AD-related data elements in these resources are interoperable with each other, we leverage different representation models to map data elements from different resources: NACC to ADNI, NACC to NIH CDE, and ADNI to NIH CDE. We explore bag-of-words based and word embeddings based models (Word2Vec and BioWordVec) to perform the data element mappings in these resources. Results The data dictionaries downloaded on November 23, 2021 contain 1,195 data elements in NACC, 13,918 in ADNI, and 27,213 in NIH CDE Repository. Data element preprocessing reduced the numbers of NACC and ADNI data elements for mapping to 1,099 and 7,584 respectively. Manual evaluation of the mapping results showed that the bag-of-words based approach achieved the best precision, while the BioWordVec based approach attained the best recall. In total, the three approaches mapped 175 out of 1,099 (15.92%) NACC data elements to ADNI; 107 out of 1,099 (9.74%) NACC data elements to NIH CDE; and 171 out of 7,584 (2.25%) ADNI data elements to NIH CDE. Conclusions The bag-of-words based and word embeddings based approaches showed promise in mapping AD-related data elements between different resources. Although the mapping approaches need further improvement, our result indicates that there is a critical need to standardize CDEs across these valuable AD research resources in order to maximize the discoveries regarding AD pathophysiology, diagnosis, and treatment that can be gleaned from them.

Abstract Bacteriophage therapy is a promising approach to address antimicrobial infections though questions remain regarding the impact of the immune response on clinical effectiveness. Here, we develop a mouse model to assess phage treatment using a cocktail of five phages from the Myoviridae and Siphoviridae families that target Vancomycin-Resistant Enterococcus gut colonization. Phage treatment significantly reduces fecal bacterial loads of Vancomycin-Resistant Enterococcus. We also characterize immune responses elicited following administration of the phage cocktail. While minimal innate responses are observed after phage administration, two rounds of treatment induces phage-specific neutralizing antibodies and accelerate phage clearance from tissues. Interestingly, the myophages in our cocktail induce a more robust neutralizing antibody response than the siphophages. This anti-phage immunity reduces the effectiveness of the phage cocktail in our murine model. Collectively, this study shows phage-specific immune responses may be an important consideration in the development of phage cocktails for therapeutic use.

Abstract Background Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases. Methods For this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. Results The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and − 16.3% for SUVmax, and 21.2% and − 17.5% for SULpeak. 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak. Conclusion In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Abstract Background and aim Studies suggest prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may influence wheezing or asthma in preschool-aged children. However, the impact of prenatal PAH exposure on asthma and wheeze in middle childhood remain unclear. We investigated these associations in socio-demographically diverse participants from the ECHO PATHWAYS multi-cohort consortium. Methods We included 1,081 birth parent–child dyads across five U.S. cities. Maternal urinary mono-hydroxylated PAH metabolite concentrations (OH-PAH) were measured during mid-pregnancy. Asthma at age 8–9 years and wheezing trajectory across childhood were characterized by caregiver reported asthma diagnosis and asthma/wheeze symptoms. We used logistic and multinomial regression to estimate odds ratios of asthma and childhood wheezing trajectories associated with five individual OH-PAHs, adjusting for urine specific gravity, various maternal and child characteristics, study site, prenatal and postnatal smoke exposure, and birth year and season in single metabolite and mutually adjusted models. We used multiplicative interaction terms to evaluate effect modification by child sex and explored OH-PAH mixture effects through Weighted Quantile Sum regression. Results The prevalence of asthma in the study population was 10%. We found limited evidence of adverse associations between pregnancy OH-PAH concentrations and asthma or wheezing trajectories. We observed adverse associations between 1/9-hydroxyphenanthrene and asthma and persistent wheeze among girls, and evidence of inverse associations with asthma for 1-hydroxynathpthalene, which was stronger among boys, though tests for effect modification by child sex were not statistically significant. Conclusions In a large, multi-site cohort, we did not find strong evidence of an association between prenatal exposure to PAHs and child asthma at age 8–9 years, though some adverse associations were observed among girls.

The number of peer-reviewed publications that feature biosensor data increases every year. A search of PubMed using common technique terminology, including bio-layer interferometry (BLI), surface plasmon resonance (SPR) and grating-coupled interferometry (GCI) generated more than 2500 scientific papers from 2022. Compared to 2009, when David Myszka and Rebecca Rich presented their most recent review of biosensor literature (Rich and Myszka, 2011), this number has nearly doubled. With this increasing number of publications comes an increasing need for standardization of the way biosensor data is reported in journals to allow for replication of the experiments that were performed. Biosensor data is often poorly described in papers which makes it difficult, if not impossible, to replicate the experiment. Critical information typically missing includes sample preparation, method settings, and data evaluation details. We have also found published work in which the authors have failed to report the type of sensor that was used, or which biosensor instrumentation was used. To come to terms with this growing problem, we propose a standardization of the way biosensor data is reported in scientific journals. We call this standard STROBE, standards for reporting optical biosensor experiments.

Rationale & Objective: Cilastatin is an inhibitor of drug metabolism in the proximal tubule that demonstrates nephroprotective effects in animals. It has been used in humans in combination with the antibiotic imipenem to block imipenem’s renal metabolism. This systematic review and meta-analysis evaluated the nephroprotective effects of cilastatin in humans. Study Design: Systematic review and meta-analysis of observational (comparative effectiveness) studies or randomized clinical trials (RCTs). Setting & Study Populations: People of any age at risk of acute kidney injury (AKI). Selection Criteria for Studies: We systematically searched MEDLINE, Embase, Web of Science, and the Cochrane Controlled Trials registry from database inception to November 2023 for observational studies or RCTs that compared kidney outcomes among groups treated with cilastatin, either alone or as combination imipenem-cilastatin, versus an inactive or active control group not treated with cilastatin. Data Extraction: Two reviewers independently evaluated studies for inclusion and risk of bias. Analytical Approach: Treatment effects were estimated using random-effects models, and heterogeneity was quantified using the I2 statistic. Results: We identified 10 studies (5 RCTs, n = 531 patients; 5 observational studies, n = 6,321 participants) that met the inclusion criteria, including 4 studies with comparisons to inactive controls and 6 studies with comparisons to alternate antibiotics. Based on pooled results from 7 studies, the risk of AKI was lower with imipenem-cilastatin (risk ratio [RR], 0.52; 95% confidence intervals [CI], 0.40-0.67; I2 = 26.5%), with consistent results observed in RCTs (3 RCTs, RR, 0.26; 95% CI, 0.09-0.77; I2 = 44.4%) and observational studies (4 studies, RR, 0.54; 95% CI, 0.41-0.72; I2 = 44.4%). Based on results from 6 studies, serum creatinine concentration was lower following treatment with imipenem-cilastatin than comparators (weighted mean difference in serum creatinine −0.14 mg/dL (95% CI, −0.21 to −0.07; I2 = 0%). The overall certainty of the evidence was low due to heterogeneity of the results, high risk of bias, and indirectness among the identified studies. Limitations: Clinical and statistical heterogeneity could not be fully explained due to a limited number of studies. Conclusions: Patients treated with imipenem-cilastatin developed AKI less frequently and had lower serum creatinine concentration following treatment than control groups or those who had received comparator antibiotics. Larger clinical trials with less risk of detection bias due to lack of allocation concealment and blinding are needed to establish the efficacy of cilastatin for AKI prevention. Plain-Language Summary: Cilastatin, used with the antibiotic imipenem, has shown kidney-protective effects in animals and preclinical studies of acute kidney injury (AKI). This systematic review and meta-analysis identified 10 studies (5 randomized controlled trials and 5 observational studies) of imipenem-cilastatin involving people at risk of AKI. Pooled estimates of treatment effects indicated that patients who received imipenem-cilastatin had a lower incidence of AKI and lower serum creatinine concentrations following treatment compared to comparator groups. Despite these promising findings, the overall certainty of the evidence was low due to heterogeneity among studies, high risk of bias, and indirectness of the data. Although cilastatin appears to be a promising medication for preventing AKI, larger, well-designed trials are needed to establish its effectiveness.

Background Ambient fine particulate matter (PM2.5) exposure adversely impacts child airway health; however, research on prenatal PM2.5 exposure, and child lung function is limited. We investigated these associations in the ECHO-PATHWAYS Consortium, focusing on the role of exposure timing during different phases of fetal lung development.Methods We included 675 children in the CANDLE cohort born between 2007 and 2011 in Memphis, TN, USA. Prenatal exposure to ambient PM2.5 was estimated using a spatiotemporal model based on maternal residential history and averaged over established prenatal periods of lung development. Forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) were measured by spirometry at age 8–9 years. We used linear regression and Bayesian Distributed Lag Interaction Models (BDLIM) to estimate associations between exposure and lung function z-scores, adjusting for maternal/child characteristics, prenatal/postnatal tobacco exposure, and birth year/season, and evaluating effect modification by child sex and allergic sensitization.Results The average ambient concentration of PM2.5 during pregnancy was 11.1 µg/m3 (standard deviation:1.0 µg/m3). In the adjusted linear regression and BDLIM models, adverse, but not statistically significant, associations were observed between exposure during the pseudoglandular (5–16 weeks of gestation) and saccular (24–36 weeks) phases of lung development and FEV1 and FVC. The strongest association was between a 2 μg/m3 higher concentration of PM2.5 during the saccular phase and FEV1 z-score (−0.176, 95% Confidence Interval [CI]: −0.361, 0.010). The FEV1/FVC ratio was not associated with PM2.5 in any exposure window. No effect modification by child sex or allergic sensitization was observed.Conclusions We did not find strong evidence of associations between prenatal ambient PM2.5 exposure and child lung function in a large, well-characterized study sample. However, there was a suggested adverse association between FEV1 and exposure during late pregnancy. The saccular phase of lung development might be an important window for exposure to PM2.5.

The increased use of plastics and the associated environmental impact has catalyzed research on the development of bio-derived polymers. Bio-based polyesters have gained increased attention due to the abundance of their starting materials and ease of processing. Lignin is naturally occurring in biomass with rich carbon content, whose functionality and rigidity make it an ideal bio-derived candidate for bio-based polyesters. Herein, a lignin-based polyester with good thermal stability and self-repairability was synthesized from carboxylated lignin and epoxidized soybean oil. The synthesized lignin/epoxidized soybean oil (ESO) vitrimer was brittle such that its mechanical performance could not be recorded. However, when polyethylene glycol (PEG) was incorporated as a plasticizer, polymer samples exhibited acceptable ductility. From thermomechanical analysis of the synthesized polyesters, the plasticizer did not impair thermal stability of polymers, but greatly enhanced mechanical properties. Notably, all samples exhibited stability at high temperatures, and good glass transition temperatures (51.0 ± 0.9–78.0 ± 1.2 °C). The highest tensile strength (3.983 ± 0.1 MPa) and storage modulus (1463.67 ± 12.6 MPa) were recorded for the polyester containing 6 % w/w PEG. Moreover, the polymer samples exhibited self-healing capability at 180 °C. This work expands on valorization of lignin through the synthesis of bio-derived materials.

Background: The cardiopulmonary exercise test (CPET) is considered a gold standard in assessing cardiorespiratory fitness (CRF) but has limited accessibility due to competency requirements and cost. Incorporating portable sensor devices into a simple bedside test of CRF could improve diagnostic and prognostic value. Objectives: The authors sought to evaluate the association of an augmented 6-minute incremental step test (6MIST) with standard CPET. Methods: We enrolled patients undergoing clinically indicated supine cycle ergometry CPET with invasive hemodynamics (iCPET) for the same-day 6MIST. CRF-related variables were simultaneously recorded using a signal morphology-based impedance cardiograph (PhysioFlow Enduro) and a portable metabolic analyzer (VO2 Master Pro) during incremental pace stationary stepping. The correlation between CPET and hemodynamic parameters from both tests was assessed using the intraclass correlation coefficient (ICC). Results: Fifteen patients (mean age 60 ± 14 years, 40% female, 27% Black) were included. All patients who agreed to undergo 6MIST completed the study without any test-related adverse events. We observed good to excellent correlation between iCPET- and 6MIST-measured CPET parameters: peak heart rate (ICC = 0.60; 95% CI: 0.15-0.85), absolute peak O2 consumption (VO2) (ICC = 0.77; 95% CI: 0.44-0.92), relative peak VO2 (ICC = 0.64; 95% CI: 0.20-0.86), maximum ventilation (ICC = 0.59; 95% CI: 0.13-0.84), O2 pulse (ICC = 0.71; 95% CI: 0.33-0.89), and cardiorespiratory optimal point (ICC = 0.82; 95% CI: 0.52-0.94). No significant correlation was determined between iCPET and 6MIST in measuring cardiac index at rest (ICC = 0.19; 95% CI: −0.34 to 0.63) or at peak exercise (ICC = 0.36; 95% CI: −0.17 to 0.73). Conclusions: We demonstrate the feasibility of a novel augmented 6MIST with wearable devices for simultaneous CPET and hemodynamic assessment. 6MIST-measured CPET parameters were strongly correlated with the iCPET-derived measurements. Additional studies are needed to confirm the validity of the 6MIST compared to standard upright CPET.

Background: Severe asthma pathology encompasses a wide range of pulmonary and extrapulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health-related quality-of-life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. Objective: We sought to examine the impact of pulmonary and extrapulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centers. Methods: Patients’ characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. Results: Patients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extrapulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms, and requirement for maintenance oral corticosteroids were observed. Conclusions: Both pulmonary and extrapulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasizing the importance of early identification and management of severe asthma before comorbidities develop.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Quantum emitters, such as the negatively charged nitrogen-vacancy center in diamond, are attractive for quantum technologies, such as nano-sensing, quantum information processing, and as a non-classical light source. However, it is still challenging to position individual emitters in photonic structures while preserving the spin coherence properties of the defect. In this paper, we investigate single and ensemble waveguide-integrated nitrogen-vacancy centers in diamond fabricated by femtosecond laser writing followed by thermal annealing. Their spin coherence properties are systematically investigated and are shown to be comparable to native nitrogen-vacancy centers in diamond. This method paves the way for the fabrication of coherent spins integrated within photonic devices.

Wastewater-based epidemiology (WBE) is an environmental approach to monitor community health through the analysis of sewage. The COVID-19 pandemic catalyzed scientists and public health professionals to revisit WBE as a tool to optimize resource allocation to mitigate disease spread and prevent outbreaks. Some studies have highlighted the value of WBE programs that coordinate with public health professionals; however, the details necessary for implementation are not well-characterized. To respond to this knowledge gap, this article documents the framework of a successful WBE program in Arizona, titled Wastewater Analysis for Tactical Epidemiological Response Systems (WATERS), detailing the developed structure and methods of communication that enabled public health preparedness and response actions. This communication illustrates how program operations were employed to reduce outbreak severity. The structure outlined here is customizable and may guide other programs in the implementation of WBE as a public health tool.

Background Intracranial aneurysms (IAs) are more common in women than in men; however, there is still limited knowledge on sex‐dependent differences regarding aneurysm location, multiplicity, rupture risk, risk factors, and histopathology. Methods This cross‐sectional, consecutive cohort study examined whether IAs differ in multiplicity, location, geometry, rupture risk, risk factors, and histology between sexes. Results We included 982 patients (714 women, 268 men) totaling 1484 IAs (1056 unruptured, 397 ruptured). A total of 363 patients (36.97%) had multiple IAs, the proportion of which was significantly higher in women. In women, the internal carotid artery (40.79%) was the most frequent location for IAs, whereas in men most were found along the anterior carotid artery territory (32.86%). Men were significantly more often diagnosed with ruptured aneurysms. Aneurysm geometry did not differ between sexes; however, ruptured aneurysms in men presented with a significantly larger neck diameter than unruptured ones. Regarding risk factors for aneurysm rupture, blood pressure control was more effective in women, whereas the effect of smoking status did not show clear sex‐dependent differences. Histologically, wall‐type classification analysis showed significantly more severe aneurysm wall types in men. Conclusion IA prevalence in women is significantly higher than in men. Women more often present with multiple IAs, whereas men were more often diagnosed with ruptured IAs. Sex‐specific differences in IA location were identified, whereas geometry of IAs did not differ between sexes. IAs in men showed a more severe histological wall type. Further research is needed to unravel the molecular mechanisms underlying these important sex‐dependent manifestations in IAs.

The paper argues that part of C. S. Lewis’s perennial success owes to his persona as a Public Intellectual. It is therefore useful and instructive to trace the steps in the evolution that led him from literary historian and Oxford professor to Public Intellectual, a process that took place between 1938 and 1944 during the dire days of World War II.

Summary: Thymocyte development requires precise control of PI3K-Akt signaling to promote proliferation and prevent leukemia and autoimmune disorders. Here, we show that ablating individual clusters of the miR-17∼92 family has a negligible effect on thymocyte development, while deleting the entire family severely impairs thymocyte proliferation and reduces thymic cellularity, phenocopying genetic deletion of Dicer. Mechanistically, miR-17∼92 expression is induced by Myc-mediated pre-T cell receptor (TCR) signaling, and miR-17∼92 promotes thymocyte proliferation by suppressing the translation of Pten. Retroviral expression of miR-17∼92 restores the proliferation and differentiation of Myc-deficient thymocytes. Conversely, partial deletion of the miR-17∼92 family significantly delays Myc-driven leukemogenesis. Intriguingly, thymocyte-specific transgenic miR-17∼92 expression does not cause leukemia or lymphoma but instead aggravates skin inflammation, while ablation of the miR-17∼92 family ameliorates skin inflammation. This study reveals intricate roles of the miR-17∼92 family in balancing thymocyte development, leukemogenesis, and autoimmunity and identifies those microRNAs (miRNAs) as potential therapeutic targets for leukemia and autoimmune diseases.

Abstract. Purpose:. To identify factors associated with delays in administration and pharmacy and nursing preparation of antibiotics for patients with open fractures. Design:. Retrospective review. Setting:. Level I trauma center. Patients:. Nine hundred sixty-three adults with open fractures administered antibiotics. Main Outcome Measurements:. Delay in antibiotic administration greater than 66 minutes from arrival and significant pharmacy-related and nursing-related delay. Results:. Isolated injury, Charlson Comorbidity Index, and transfer from another facility were associated with delay in antibiotic administration greater than 66 minutes. Injury Severity Score, transfer, and trauma team activation were associated with pharmacy-related or nursing-related delay. Conclusion:. Interventions to reduce antibiotic administration time for open fractures should focus on early identification of open fractures and standardization of antibiotic protocols to ensure timely administration even in complex or resource-scarce care situations. Level of Evidence:. Prognostic level III.

Abstract Background When job demand exceeds job resources, burnout occurs. Burnout in healthcare workers extends beyond negatively affecting their functioning and physical and mental health; it also has been associated with poor medical outcomes for patients. Data-driven technology holds promise for the prediction of occupational burnout before it occurs. Early warning signs of burnout would facilitate preemptive institutional responses for preventing individual, organizational, and public health consequences of occupational burnout. This protocol describes the design and methodology for the decentralized Burnout PRedictiOn Using Wearable aNd ArtIficial IntelligEnce (BROWNIE) Study. This study aims to develop predictive models of occupational burnout and estimate burnout-associated costs using consumer-grade wearable smartwatches and systems-level data. Methods A total of 360 registered nurses (RNs) will be recruited in 3 cohorts. These cohorts will serve as training, testing, and validation datasets for developing predictive models. Subjects will consent to one year of participation, including the daily use of a commodity smartwatch that collects heart rate, step count, and sleep data. Subjects will also complete online baseline and quarterly surveys assessing psychological, workplace, and sociodemographic factors. Routine administrative systems-level data on nursing care outcomes will be abstracted weekly. Discussion The BROWNIE study was designed to be decentralized and asynchronous to minimize any additional burden on RNs and to ensure that night shift RNs would have equal accessibility to study resources and procedures. The protocol employs novel engagement strategies with participants to maintain compliance and reduce attrition to address the historical challenges of research using wearable devices. Trial Registration NCT05481138.

Abstract Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.

Abstract Muscle function is compromised by gravitational unloading in space affecting overall musculoskeletal health. Astronauts perform daily exercise programmes to mitigate these effects but knowing which muscles to target would optimise effectiveness. Accurate inflight assessment to inform exercise programmes is critical due to lack of technologies suitable for spaceflight. Changes in mechanical properties indicate muscle health status and can be measured rapidly and non-invasively using novel technology. A hand-held MyotonPRO device enabled monitoring of muscle health for the first time in spaceflight (> 180 days). Greater/maintained stiffness indicated countermeasures were effective. Tissue stiffness was preserved in the majority of muscles (neck, shoulder, back, thigh) but Tibialis Anterior (foot lever muscle) stiffness decreased inflight vs. preflight (p