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Abstract Background Hypertension is the most common cardiovascular disease in Peru despite the availability of cost-effective, evidence-based treatment. Here we describe the rationale and study design for a hybrid type 2 randomized controlled trial to test the implementation and effectiveness of a community health worker (CHW)-led hypertension control program within the national primary care system in Puno, Peru. Methods We will recruit 1068 adult participants with hypertension aged ≥ 18 years in Puno, Peru, via facility-based enrollment and community health fairs. Participants will be individually randomized (1:1) to either continue with usual care or participate in a 12-month CHW-led home-based hypertension control program consisting of blood pressure monitoring, medication adherence support, and healthy lifestyle counseling. Outcome development and reporting are guided by the Consolidated Framework for Implementation Research (CFIR), the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, and the Proctor et al. framework. Clinical effectiveness outcomes include mean change in systolic blood pressure (primary outcome), diastolic blood pressure, and HbA1C. Implementation outcomes include fidelity (i.e., CHW protocol adherence and dose), reach, adoption, sustainability, acceptability, and cost-effectiveness. Discussion The ANDES trial is testing the first CHW-led multicomponent strategy for hypertension and type 2 diabetes management in Peru. This type 2 hybrid trial will provide critical insights into the individual, community, and system-level factors necessary for successful implementation and effectiveness. These data can inform the future adaptation and scaling of the ANDES strategy in Peru and other LMICs, as well as influence policies at the system level to support this transition. Furthermore, by addressing both hypertension and diabetes, the ANDES strategy supports integrated care approaches advocated by the WHO HEARTS technical package, ultimately enhancing health outcomes and reducing morbidity and mortality in the region. Trial registration ClinicalTrials.gov, ID: NCT05524987 , Addressing Hypertension and Diabetes through Community-Engaged Systems in Puno, Peru (ANDES study), prospectively registered on September 1, 2021.

Abstract The gut microbiota of infants in low- to middle-income countries is underrepresented in microbiome research. This study explored the faecal microbiota composition and faecal cytokine profiles in a cohort of infants in a rural province of Cambodia and investigated the impact of sample storage conditions and infant environment on microbiota composition. Faecal samples collected at three time points from 32 infants were analysed for microbiota composition using 16S rRNA amplicon sequencing and concentrations of faecal cytokines. Faecal bacterial isolates were subjected to whole genome sequencing and genomic analysis. We compared the effects of two sample collection methods due to the challenges of faecal sample collection in a rural location. Storage of faecal samples in a DNA preservation solution preserved Bacteroides abundance. Microbiota analysis of preserved samples showed that Bifidobacterium was the most abundant genus with Bifidobacterium longum the most abundant species, with higher abundance in breast-fed infants. Most infants had detectable pathogenic taxa, with Shigella and Klebsiella more abundant in infants with recent diarrhoeal illness. Neither antibiotics nor infant growth were associated with gut microbiota composition. Genomic analysis of isolates showed gene clusters encoding the ability to digest human milk oligosaccharides in B. longum and B. breve isolates. Antibiotic-resistant genes were present in both potentially pathogenic species and in Bifidobacterium. Faecal concentrations of Interlukin-1alpha and vascular endothelial growth factor were higher in breast-fed infants. This study provides insights into an underrepresented population of rural Cambodian infants, showing pathogen exposure and breastfeeding impact gut microbiota composition and faecal immune profiles.

Background: A grading system was developed for computerized tomography (CT) scans evaluating patients with suspected small bowel obstruction (SBO). We hypothesized that patients with a higher grade of suspected SBO on CT scan would be more likely to require surgical intervention. Methods: Retrospective chart review of patients who presented to the Emergency Room (ER) who had a CT of the abdomen and pelvis for suspected SBO. Patients were divided into 5 groups: Grade 1 (SBO unlikely), Grade 2 (probable partial or early SBO), Grade 3 (probable high grade SBO), Grade 4 (SBO with changes concerning for ischemia) and Not Graded. Results: The CT scans of 655 patients were graded. Of the 22 patients with a grade 1 SBO, only 1 went for surgery (4.5 %). For grade 2 patients, 23 out of 299 had an operation (7.7 %), for grade 3 it was 84 out of 299 (28.1 %) and for grade 4 SBO, 25 out of 35 patients (71.4 %) had surgery. The p value is

Abstract Introduction Our understanding of particular gut microbiota members such as Bifidobacterium and Enterococcus in low-middle-income countries remains very limited, particularly early life strain-level beneficial traits. This study addresses this gap by exploring a collection of bacterial strains isolated from the gut of Zimbabwean infants; comparing their genomic characteristics with strains isolated from infants across North America, Europe, and other regions of Africa. Materials and method From 110 infant stool samples collected in Harare, Zimbabwe, 20 randomly selected samples were used to isolate dominant early-life gut microbiota members Bifidobacterium and Enterococcus. Isolated strains were subjected to whole genome sequencing and bioinformatics analysis including functional annotation of carbohydrates, human milk oligosaccharide (HMO) and protein degradation genes and clusters, and the presence of antibiotic resistance genes (ARGs). Results The study observed some location-based clustering within the main five identified taxonomic groups. Furthermore, there were varying and overall species-specific numbers of genes belonging to different GH families encoded within the analysed dataset. Additionally, distinct strain- and species-specific variances were identified in the potential of Bifidobacterium for metabolizing HMOs. Analysis of putative protease activity indicated a consistent presence of gamma-glutamyl hydrolases in Bifidobacterium, while Enterococcus genomes exhibited a high abundance of aspartyl peptidases. Both genera harboured resistance genes against multiple classes of antimicrobial drugs, with Enterococcus genomes containing a higher number of ARGs compared to Bifidobacterium, on average. Conclusion This study identified promising probiotic strains within Zimbabwean isolates, offering the potential for early-life diet and microbial therapies. However, the presence of antibiotic resistance genes in infant-associated microbes raises concerns for infection risk and next-stage probiotic development. Further investigation in larger cohorts, particularly in regions with limited existing data on antibiotic and probiotic use, is crucial to validate these initial insights. Impact statement This research represents the first investigation of its kind in the Zimbabwean context, focusing on potential probiotic strains within the early-life gut microbiota. By identifying local probiotic strains, this research can contribute to the development of probiotic interventions that are tailored to the Zimbabwean population, which can help address local health challenges and promote better health outcomes for infants. Another essential aspect of the study is the investigation of antimicrobial resistance genes present in Zimbabwean bacterial strains. Antimicrobial resistance is a significant global health concern, and understanding the prevalence and distribution of resistance genes in different regions can help inform public health policies and interventions.

Abstract Polymicrobial infection of the airways is a hallmark of obstructive lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary disease. Pulmonary exacerbations (PEx) in these conditions are associated with accelerated lung function decline and higher mortality rates. Understanding PEx ecology is challenged by high inter-patient variability in airway microbial community profiles. We analyze bacterial communities in 880 CF sputum samples collected during an observational prospective cohort study and develop microbiome descriptors to model community reorganization prior to and during 18 PEx. We identify two microbial dysbiosis regimes with opposing ecology and dynamics. Pathogen-governed PEx show hierarchical community reorganization and reduced diversity, whereas anaerobic bloom PEx display stochasticity and increased diversity. A simulation of antimicrobial treatment predicts better efficacy for hierarchically organized communities. This link between PEx, microbiome organization, and treatment success advances the development of personalized clinical management in CF and, potentially, other obstructive lung diseases.

Background: Patient-reported outcome measures (PROMs) correlate with heart failure (HF) severity among adults and are adjunct tools in clinical care. Limited data exist regarding the validity of PROMs in pediatric HF. Hypothesis: Patient-Reported Outcome Measurement Information System (PROMIS) Pediatric Fatigue correlates with HF severity, measured by the New York University Pediatric Heart Failure Index (NYU PHFI). Methods: Children ≥8 and

ABSTRACT Background Approximately one‐third of US adults have a tattoo, and the prevalence is increasing. Tattooing can result in long‐term exposure to carcinogens and inflammatory and immune responses. Methods We examined tattooing and risk of hematologic cancers in a population‐based case–control study with 820 cases diagnosed 2019–2021 and 8200 frequency‐matched controls, ages 18–79 years. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable‐adjusted logistic regression models. Results The prevalence of tattooing was 22% among Hodgkin lymphoma (HL) cases, 11% among non‐Hodgkin lymphoma (NHL) cases, 16% among myeloid neoplasm cases, and 15% among controls. Though there were no clear patterns of associations between ever receiving a tattoo and risk of HL, NHL, or myeloid neoplasms overall, in analyses restricted to ages 20–60 years, ever receiving a tattoo (OR 2.06 [95% CI 1.01, 4.20]) and receiving a tattoo 10+ years prior (OR 2.64 [95% CI 1.23, 5.68]) were associated with an aggregated group of rarer mature B‐cell NHLs. We also observed elevated risks for a 10+ year latency for myelodysplastic syndromes and chronic myeloid leukemia (OR 1.48 [95% CI 0.40, 5.41], and OR 1.24 [95% CI 0.45, 3.43], respectively). Conclusions Though estimates were imprecise, we found some suggestive evidence that tattooing may be associated with an increased risk of certain hematologic cancer subtypes. With an estimated 46% prevalence of tattooing in US individuals ages 30–49, additional studies are needed to understand the degree to which these exposures may be associated with hematologic cancer risk.

For few taxonomic groups do conservation efforts have such a disproportionate impact on biodiversity and human well-being as they do with bats. Bats face significant conservation challenges that affect their long-term viability, inhibit their ecosystem functions and services, and increase zoonotic spillover risks. Protecting bat populations and their habitats ultimately reduces these conservation threats, helps prevent pandemics, and supports essential ecosystem services. MENTOR-Bat is a fellowship program focused on strengthening technical research, and leadership capacity in the Global South to promote healthy environments where bats and humans can coexist with reduced risks of pathogen transmission. Co-designed by the United States Fish and Wildlife Service (USFWS) and Bat Conservation International (BCI), MENTOR-Bat mirrors the One Health framework by featuring a transdisciplinary team of three mentors and nine fellows from Cameroon, Colombia, and Indonesia. Fellows and mentors receive academic and field-based training on bat ecology and conservation, One Health, human dimensions of conservation, behavior change, strategic communications, international policy, adaptive management, project planning, conservation leadership, and public health. Fellows will then design and implement team pilot projects to advance One Health and bat conservation in their respective countries. Program evaluation of MENTOR-Bat is based on Kirkpatrick’s Hierarchy and focuses on measuring the development of established One Health core competences. By incorporating One Health and conservation within its activities, MENTOR-Bat can become a valuable programmatic template for transdisciplinary programming advancing evidence-based strategies for improving the well-being of bats, humans, and the environment.

Background: Recent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored. Objective: This study investigates the impact of Bifidobacterium breve UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy. Methods: Germ-free pregnant mice were colonized with or without B. breve UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways. Results: Maternal colonization with B. breve resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-β-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function. Conclusions: The presence of maternal B. breve during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that Bifidobacterium could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions.

Among performers and pedagogues of string instruments, “tone” is a term summoned often and valued deeply, yet seldom defined. While many traditional teaching approaches regard a young musician's tone as something that develops naturally with guidance, Japanese violinist Shinichi Suzuki (1898–1998) established a teaching method that challenged these traditional understandings. Insisting that neither tone nor talent were an “accident of birth,” Suzuki contended that every child can become musically fluent through an immersive approach that mirrors language acquisition. Focusing on string-playing communities in the U.S., this article examines the tensions surrounding Suzuki's philosophy—encapsulated by his oft-quoted aphorism, “beautiful tone, beautiful heart.” I argue that although Suzuki's approach disrupted certain hegemonic beliefs about tone, it has afforded the reification of others. Drawing upon archival footage and historical discourses, the first part of the article contextualizes Suzuki's pedagogical and philosophical interventions. The latter sections turn to outcomes that have fallen short of the method's promise. In particular, I consider a disturbing episode in the Suzuki community, in which celebrated Suzuki violinist William Preucil, Jr. was found guilty of sexual misconduct against multiple women in 2018, leading many to question the method's fundamental claims about the relationship between tone and character. Together, the article's sections emphasize tone's function as a floating signifier that relies on definitional looseness to obscure and perpetuate systems of power, within and beyond Suzuki communities. Despite Suzuki's many pedagogical successes, the method's disparate outcomes across lines of race and class offer a poignant reminder that even the wisest and most skillful teaching cannot fully counteract hegemonic forces that enable material advantages to masquerade as personal merit.

Abstract Background The ability to perform transvenous temporary cardiac pacing (TV‐TP) is critical to stabilize horses with symptomatic bradyarrhythmias. Reports of successful TV‐TP in horses are limited, and only briefly describe short‐term pacing. Objective To describe temporary, medium‐term (24 h) transvenous right ventricular pacing in awake horses using a bipolar torque‐directed pacing catheter. Animals Six healthy adult institutional teaching horses. Methods Prospective experimental study with 2 immediately successive TV‐TP lead placements in each horse with a target location of the RV apex. One placement was performed primarily with echocardiographic guidance and 1 primarily with fluoroscopic guidance. In all placements, corresponding images were obtained with both imaging modalities. Horses were then paced for 24 h, unrestricted in a stall with continuous telemetric ECG monitoring. Echocardiographically determined lead position, episodes of pacing failure in the preceding 6 h, and pacing thresholds were recorded every 6 h. Pacing failure was defined as a period of loss of capture longer than 20 s. Results Pacing leads were placed with both guidance methods and maintained for 24 h with no complications. Two horses with leads angled caudally in the right ventricular apex had no pacing failure, the remaining 4 horses had varying degrees of loss of capture. Leads located in the right ventricular apex had longer time to pacing failure and lower capture thresholds P

Abstract Objective Study of the human infant gut microbiome requires the use of surrogate mammalian species such as mice. We sought to investigate the usefulness of the greater wax moth larva, Galleria mellonella, as an alternative. Results We have analysed the native gut microbiome of Galleria and developed methods for clearing the native microbiome and introducing species from human infant faecal samples. We find that some species, e.g. enterococci, are more successful at recolonisation, but that others, e.g. Bifidobacterium, are less so. The work paves the way for using Galleria rather than mice in this and similar work.

Abstract Introduction Patients with hormone receptor positive breast cancer are recommended at least five years of adjuvant endocrine therapy, but adherence to this treatment is often suboptimal. We investigated longitudinal trends in adjuvant endocrine therapy (AET) adherence among premenopausal breast cancer patients and identified clinical characteristics, including baseline comorbidities and non-cancer chronic medication use, associated with AET adherence. Methods We included stage I–III premenopausal breast cancer patients diagnosed during 2002–2011 and registered in the Danish Breast Cancer Group clinical database who initiated AET. We used group-based trajectory modeling to describe AET adherence patterns. We also linked patients to Danish population-based registries and fit multinomial logistic models to compute odds ratios (ORs) and 95% confidence intervals (95% CIs) associating clinical characteristics with AET adherence patterns. Results We identified three adherence patterns among 4,353 women—high adherers (57%), slow decliners (36%), and rapid decliners (6.9%). Women with stage I disease (vs. stage II; OR: 1.9, 95% CI 1.5, 2.5), without chemotherapy (vs. chemotherapy; OR: 4.3, 95% CI 3.0, 6.1), with prevalent comorbid disease (Charlson Comorbidity Index score ≥ 1 vs. 0; OR: 1.6, 95% CI 1.1, 2.3), and with a history of chronic non-cancer medication use (vs. none; OR: 1.3, 95% CI 1.0, 1.8) were more likely to be rapid decliners compared with high adherers. Conclusions Women with stage I cancer, no chemotherapy, higher comorbidity burden, and history of chronic non-cancer medication use were less likely to adhere to AET. Taking steps to promote adherence in these groups of women may reduce their risk of recurrence.

Abstract Background Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. Methods The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. Results Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. Conclusions Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.

Severe brain damage is common among premature infants, and the gut microbiota has been implicated in its pathology. Although the order of colonizing bacteria is well described, the mechanisms underlying aberrant assembly of the gut microbiota remain elusive. Here, we employed long-read nanopore sequencing to assess abundances of microbial species and their functional genomic potential in stool samples from a cohort of 30 extremely premature infants. We identify several key microbial traits significantly associated with severe brain damage, such as the genomic potential for nitrate respiration and iron scavenging. Members of the Enterobacteriaceae were prevalent across the cohort and displayed a versatile metabolic potential, including pathogenic and nonpathogenic traits. Predominance of Enterobacter hormaechei and Klebsiella pneumoniae were associated with an overall loss of genomic functional redundancy as well as poor neurophysiological outcome. These findings reveal microbial traits that may be involved in exacerbating brain injury in extremely premature infants and provide suitable targets for therapeutic interventions.

This study develops a method to use deep learning models to predict the mineral assemblages and their relative abundances in paleolake cores using high-resolution XRF core scan elemental data and X-ray diffraction (XRD) mineralogical results from the same core taken at coarser resolution. It uses the XRF core scan data along with published mineralogical information from the Olduvai Gorge Coring Project (OGCP) 2014 sediment cores 1A, 2A, and 3A from Paleolake Olduvai, Tanzania. Both regression and classification models were developed using a Keras deep learning framework to assess the predictability of mineral assemblages with their relative abundances (in regression models) or at least the mineral assemblages (in classification models) using XRF core scan data. Models were created using the Sequential class and Functional API with different model architectures. The correlation matrix of element ratios calculated from XRF element intensity records from the cores and XRD-derived mineralogical information was used to select the most useful features to train the models. 1057 training data records were used for the models. Lithological classes were also used for some models using Wide & Deep neural networks since those combine the benefits of memorization and generalization for mineral prediction. The results were validated using 265 validation data records unseen by the model and discuss the accuracy of models using six test records. The optimized Deep Neural Network (DNN) classification model achieved over 86% binary accuracy while the regression models were also able to predict the relative mineral abundances of samples with high accuracies. Overall, the study shows the efficacy of a carefully crafted Deep Learning (DL) model for predicting mineral assemblages and abundances using high-resolution XRF core scan data.

ABSTRACTClostridium perfringens causes multiple diseases in humans and animals. Its pathogenic effect is supported by a broad and heterogeneous arsenal of toxins and other virulence factors associated with a specific host tropism. Molecular approaches have indicated that most C. perfringens toxins produce membrane pores, leading to osmotic cell disruption and apoptosis. However, identifying mechanisms involved in cell tropism and selective toxicity effects should be studied more. The differential presence and polymorphisms of toxin-encoding genes and genes encoding other virulence factors suggest that molecular mechanisms might exist associated with host preference, receptor binding, and impact on the host; however, this information has not been reviewed in detail. Therefore, this review aims to clarify the current state of knowledge on the structural features and mechanisms of action of the major toxins and virulence factors of C. perfringens and discuss the impact of genetic diversity of toxinotypes in tropism for several hosts.

Abstract Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype‐guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6‐months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient‐Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ‐8) measure of depression severity, remission rates defined by PROMIS score

How social media influences users depends largely on motivations for its use and how the user interprets social media-facilitated interactions. Contingent self-esteem, a construct rooted in self-determination theory (Deci & Ryan, 2000), can account for differential effects, including addictive use. Three preregistered studies (ntotal = 822) derived social media contingent self-esteem (SMCSE) and examined the factor structure and associations with social media use, addiction, and disorder criteria. Study 1 (N = 412) analyzed exploratory and confirmatory factors. Study 2 (N = 230) examined associations with other domains of contingent self-esteem, basic psychological needs satisfaction and frustration, and measures of social media use and addiction. Study 3 (N = 192) examined associations between SMCSE, identity bubble reinforcement (echo chambers), and social media outcomes. SMCSE was associated with greater social media use and intensity, identity bubble reinforcement, social media addiction, and disorder criteria. Exploratory support was found for mediation models in which identity bubble reinforcement predicted greater SMCSE, which in turn predicted a greater likelihood of social media addiction and disorder.

Although anthropogenic climate change has resulted in significant alterations of ocean environments, the degree to which marine organisms can respond behaviorally to climate effects remains poorly understood, especially for species with increased extinction risk. We monitored marine space use and movement of the threatened marbled murrelet (Brachyramphus marmoratus) along the central coast of Oregon, USA during the 2017–2019 breeding seasons to quantify marine habitat selection patterns across a range of ocean conditions. We hypothesized that marine locations characterized by upwelling, nearshore areas adjacent to old-growth forest nesting habitat, and protected marine areas would be preferentially selected by tagged birds. Using >4800 locations collected from >180 individuals, we found that murrelets selected areas near small estuaries and with localized upwelling (as characterized by decreased sea-surface temperatures and high salinity), both of which are expected to lead to greater food availability during periods when sea-surface temperatures are elevated and coastal upwelling is reduced (i.e., poor ocean conditions). In addition, we found that individuals did not preferentially select marine areas adjacent to potential old-growth nesting habitat, and that murrelets exhibited limited overlap with protected marine areas regardless of ocean conditions. Unexpectedly, the majority (62%) of tagged individuals moved beyond the boundaries of our 135-km long study area in the year with the poorest ocean conditions (2017), with 15% of birds moving >500 km from their capture location. Our results confirm that marine habitat selection in murrelets becomes decoupled from terrestrial nesting habitat during periods of poor ocean conditions, and that such conditions are associated with low breeding propensity and long-distance movements during the breeding season. In addition to demonstrating murrelets undertake fine- and coarse-scale movements to buffer against poor ocean conditions, our study also emphasizes the importance of considering broad spatial scales in the marine environment when undertaking measures to conserve murrelet populations.

Abstract Coherent microwave-to-optical conversion is crucial for transferring quantum information generated in the microwave domain to optical frequencies, where propagation losses can be minimized. Coherent, atom-based transducers have shown rapid progress in recent years. This paper reports an experimental demonstration of coherent microwave-to-optical conversion that maps a microwave signal to a large, tunable 550(30) MHz range of optical frequencies using room-temperature 87Rb atoms. The inhomogeneous Doppler broadening of the atomic vapor advantageously supports the tunability of an input microwave channel to any optical frequency channel within the Doppler width, along with the simultaneous conversion of a multi-channel input microwave field to corresponding optical channels. In addition, we demonstrate phase-correlated amplitude control of select channels, providing an analog to a frequency domain beam splitter across five orders of magnitude in frequency. With these capabilities, neutral atomic systems may also be effective quantum processors for quantum information encoded in frequency-bin qubits.

Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post‐translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S‐phase kinase‐associated protein 2) catalyzes K6‐ and K29‐linked polyubiquitination of FOXA1 for lysosomal‐dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I–III, together with a strong inverse correlation (r = −0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2–FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2–Foxa1–Pcna signaling and colocalization, whereas disruption of the Skp2–Foxa1 interplay in Pten/Trp53/Skp2 triple‐null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1‐41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2–FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

Abstract Background Little is known regarding the association between insurance status and treatment delays in women with breast cancer and whether this association varies by neighborhood socioeconomic deprivation status. Methods In this cohort study, we used medical record data of women diagnosed with breast cancer between 2004 and 2022 at two Georgia‐based healthcare systems. Treatment delay was defined as >90 days to surgery or >120 days to systemic treatment. Insurance coverage was categorized as private, Medicaid, Medicare, other public, or uninsured. Area deprivation index (ADI) was used as a proxy for neighborhood‐level socioeconomic status. Associations between delayed treatment and insurance status were analyzed using logistic regression, with an interaction term assessing effect modification by ADI. Results Of the 14,195 women with breast cancer, 54% were non‐Hispanic Black and 52% were privately insured. Compared with privately insured patients, those who were uninsured, Medicaid enrollees, and Medicare enrollees had 79%, 75%, and 27% higher odds of delayed treatment, respectively (odds ratio [OR]: 1.79, 95% confidence interval [CI]: 1.32–2.43; OR: 1.75, 95% CI: 1.43–2.13; OR: 1.27, 95% CI: 1.06–1.51). Among patients living in low–deprivation areas, those who were uninsured, Medicaid enrollees, and Medicare enrollees had 100%, 84%, and 26% higher odds of delayed treatment than privately insured patients (OR: 2.00, 95% CI: 1.44–2.78; OR: 1.84, 95% CI: 1.48–2.30; OR: 1.26, 95% CI: 1.05–1.53). No differences in the odds of delayed treatment by insurance status were observed in patients living in high‐deprivation areas. Discussion/Conclusion Insurance status was associated with treatment delays for women living in low‐deprivation neighborhoods. However, for women living in neighborhoods with high deprivation, treatment delays were observed regardless of insurance status.

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-driven connective tissue disorder that results in fibrosis of the skin and internal organs such as the lung. Fibroblasts are known as the main effector cells involved in the progression of SSc through the induction of extracellular matrix (ECM) proteins and myofibroblast differentiation. Here, we demonstrate that 4'-(cyclopropylmethyl)-N2-4-pyridinyl-[4,5'-bipyrimidine]-2,2'-diamine (PIK-III), known as class III phosphatidylinositol 3-kinase (PIK3C3/VPS34) inhibitor, exerts potent antifibrotic effects in human dermal fibroblasts (HDFs) by attenuating transforming growth factor-beta 1 (TGF-β1)-induced ECM expression, cell contraction and myofibroblast differentiation. Unexpectedly, neither genetic silencing of PIK3C3 nor other PIK3C3 inhibitors (e.g., SAR405 and Autophinib) were able to mimic PIK-III-mediated antifibrotic effect in dermal fibroblasts, suggesting that PIK-III inhibits fibroblast activation through another signaling pathway. We identified that PIK-III effectively inhibits p38 activation in TGF-β1-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.

Traditional patient- and provider-level hypertension interventions have proven insufficient to halt hypertension as the leading cause of morbidity and mortality globally. Systems-level interventions are required to address factors challenging hypertension control across a social ecological framework, an under-studied topic particularly salient in low- and middle-income countries (LMICs) such as Peru. To inform such interventions, we sought to identify key health systems barriers to hypertension care in Puno, Peru. A participatory stakeholder workshop (October 2021) and 21 in-depth interviews (October 2021-March 2022) were conducted with 55 healthcare professionals (i.e., doctors, nurses, midwives, dentists, nutritionists), followed by a deductive qualitative analysis of transcripts and notes. Participating healthcare providers indicated that low prioritization and lack of national policies for hypertension care have resulted in limited funding and lack of societal-level prevention efforts. Additionally, limited cultural consideration, both in national guidelines as well as by some providers in Puno, results in inadequate care that may not align with local traditions. Providers highlighted that patient care is also hampered by inadequate distribution and occasional shortages of medications and equipment, as well as a lack of personnel and limited opportunities for training in hypertension. Multiple incompatible health information systems, complicated referral systems, and geographic barriers additionally hinder continuity of care and care seeking. Insights gained from health providers on the healthcare system in Puno provide essential contextual information to inform development of organizational-level strategies necessary to improve provider and patient behaviors to achieve better hypertension care outcomes.

Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.

Creating and developing new drugs can take decades, costs millions of dollars, requires untold human effort and usually, takes thousands of animal lives. Despite regulators professing confidence in non-animal approaches and guidance documents that permit submission of non-animal data, toxicity testing is routinely carried out in animals, employing rodents (invariably mice) and non-rodents. However, extensive preclinical testing in animals is still no guarantee that drugs will be safe and/or effective. In fact, more than nine out of every ten drugs that appear safe from animal trials will fail when tested in people, often due to unexplained toxicity or a lack of efficacy. This paper will describe recent advances in drug development where non-animal approaches have been used, to explore how and where these could be applied more widely to revolutionize the drug development pipeline and accelerate the creation of safe and effective medicines. As one case study, we look at the small molecule channel modifiers developed to address the consequences of the mutated chloride channel in the fatal genetic condition, cystic fibrosis. We then take a closer look at where drug development could be accelerated by focusing on innovative, human biology-based testing methods. Finally, we put forward recommendations, targeting all stakeholders, including the public, that will be needed to put this into practice and enable drug development to become more efficient - focusing on human-biology based testing and cutting out the middle-mouse.

ABSTRACTThe development of infant gut microbiome is a pivotal process affecting the ecology and function of the microbiome, as well as host health. While the establishment of the infant microbiome has been of interest for decades, the focus on gut microbial metabolism and the resulting small molecules (metabolites) has been rather limited. However, technological and computational advances are now enabling researchers to profile the plethora of metabolites in the infant gut, allowing for improved understanding of how gut microbial-derived metabolites drive microbiome community structuring and host-microbial interactions. Here, we review the current knowledge on development of the infant gut microbiota and metabolism within the first year of life, and discuss how these microbial metabolites are key for enhancing our basic understanding of interactions during the early life developmental window.

Life-threatening vascular tumors can be associated with uncontrolled activity of the guanine nucleotide-binding protein subunit alpha (Gαq). Here, the authors develop a murine model for these tumors and show that MEK inhibition prevents formation of vascular lesions and improves survival.

Here, the authors comparatively analyze the impact of three successful clinical preventive interventions against NEC in preterm, VLBW infants and demonstrate a major impact of especially probiotic-based strategies on the development and maturation of the gut microbiome.

Abstract The evolution of the climate and hydrochemistry of Mars is still a mystery but it must have been at least occasionally warm and wet to have formed the ancient fluvial and lacustrine landforms observed today. Terrestrial examples and geochemical modeling under proposed early Mars conditions show that zeolite minerals are likely to have formed under alkaline (pH > 8) conditions with low water/rock ratio and surface temperatures below 150°C. The identification and spatial association of zeolites on the surface of Mars could thus be used to reconstruct the paleoclimate, paleohydrochemistry, and geological evolution of some locations on Mars. Previous studies identified the zeolite analcime and discuss the difficulties of identifying other zeolite species on the surface of Mars using orbital spectroscopy. We used published global mineralogical, geological, geomorphological, hydrological, physical, and elemental abundance maps and the locations of hydrous minerals detected and mapped using orbital data to create a map that delineates favorable areas to look for zeolites on Mars. We used the data‐driven fuzzy‐based Weights‐of‐Evidence method to identify and map favorable areas for zeolites on the surface of Mars up to ±40° latitude toward the poles. The final map shows that the eastern and western Arabia deposits, some sites in the Medusae Fossae formation, and some areas within and near Valles Marineris, Mawrth Vallis, highlands north of Hellas, and the Terra Cimmeria and Terra Sirenum regions would be favorable areas to look for zeolites using targeted orbital spectral analysis or future in situ observations.

Background: Reducing household air pollution (HAP) to levels associated with health benefits requires nearly exclusive use of clean cooking fuels and abandonment of traditional biomass fuels. Methods: The Household Air Pollution Intervention Network (HAPIN) trial randomized 3,195 pregnant women in Guatemala, India, Peru, and Rwanda to receive a liquefied petroleum gas (LPG) stove intervention (n = 1,590), with controls expected to continue cooking with biomass fuels (n = 1,605). We assessed fidelity to intervention implementation and participant adherence to the intervention starting in pregnancy through the infant’s first birthday using fuel delivery and repair records, surveys, observations, and temperature-logging stove use monitors (SUMs). Results: Fidelity and adherence to the HAPIN intervention were high. Median time required to refill LPG cylinders was 1 day (interquartile range 0–2). Although 26% (n = 410) of intervention participants reported running out of LPG at some point, the number of times was low (median: 1 day [Q1, Q3: 1, 2]) and mostly limited to the first four months of the COVID-19 pandemic. Most repairs were completed on the same day as problems were reported. Traditional stove use was observed in only 3% of observation visits, and 89% of these observations were followed up with behavioral reinforcement. According to SUMs data, intervention households used their traditional stove a median of 0.4% of all monitored days, and 81% used the traditional stove

ABSTRACT: Background: Motor function in patients with spinal metastatic disease (SMD) directly impacts a patient's ability to receive systemic therapy and overall survival. Spine surgeons may be in the challenging position to advise a patient on expected motor function outcomes and determine a patient's suitability as a surgical candidate. We present this study to provide this critical information on anticipated motor function change to spine surgeons. Methods: Consecutive patients undergoing spinal surgery for SMD at a National Cancer Institute-designated cancer institute were prospectively enrolled. Patient motor function status before and after surgery was assessed using the standard 0 to 5 five-point muscle strength grading scale. The difference in presurgical and postsurgical motor function (proximal and distal) was used to assess motor function changes following surgery. Results: A total of 171 patients were included. The mean age was 62.7±10.46 years and 40.9% (70) were female. Common primary malignancy types were lung (49), kidney (28), breast (25), and prostate (23). The average proximal and distal motor function difference was 0.38 (standard deviation=1.02, p

Background and Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bell’s staging is routinely used to guide diagnosis, but early diagnostic signs are nonspecific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed. We investigated fecal cytokine levels, coupled with gut microbiota profiles, as a noninvasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers. Methods: Premature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Mary’s or Queen Charlotte’s & Chelsea) between January 2011 and December 2012. During the NICU stay, expert neonatologists grouped individuals by modified Bell’s staging (healthy, NEC1, NEC2/3) and fecal samples from diapers were collected consecutively. Microbiota profiles were assessed by 16S rRNA gene amplicon sequencing and cytokine concentrations were measured by V-Plex multiplex assays. Results: Early evaluation of microbiota profiles revealed only minor differences. However, at later time points, significant changes in microbiota composition were observed for Bacillota (adj. P = .0396), with Enterococcus being the least abundant in Bell stage 2/3 NEC. Evaluation of fecal cytokine levels revealed significantly higher concentrations of IL-1α (P = .045), IL-5 (P = .0074), and IL-10 (P = .032) in Bell stage 1 NEC compared to healthy individuals. Conclusion: Differences in certain fecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles contribute to improving knowledge about NEC pathogenesis.

Abstract Marine infectious diseases are a leading cause of population declines globally due, in large part, to challenges in diagnosis and limited treatment options. Mitigating disease spread is particularly important for species targeted for conservation. In some systems, strategic arrangement of organisms in space can constrain disease outbreaks, however, this approach has not been used in marine restoration. Reef building corals have been particularly devastated by disease and continue to experience catastrophic population declines. We show that mixtures of genotypes (i.e., diversity) increased disease resistance in the critically endangered Acropora cervicornis, a species that is frequently targeted for restoration of degraded reefs in the broader Caribbean region. This finding suggests a more generalized relationship between diversity and disease and offers a viable strategy for mitigating the spread of infectious diseases in corals that likely applies to other foundation species targeted for restoration.

Abstract Perturbations in the gut microbiome have been associated with colorectal cancer (CRC), with the colonic overabundance of Fusobacterium nucleatum shown as the most consistent marker. Despite its significance in the promotion of CRC, genomic studies of Fusobacterium is limited. We enrolled 43 Vietnamese CRC patients and 25 participants with non-cancerous colorectal polyps to study the colonic microbiomes and genomic diversity of Fusobacterium in this population, using a combination of 16S rRNA gene profiling, anaerobic microbiology, and whole genome analysis. Oral bacteria, including F. nucleatum and Leptotrichia, were significantly more abundant in the tumour microbiomes. We obtained 53 Fusobacterium genomes, representing 26 strains, from the saliva, tumour and non-tumour tissues of six CRC patients. Isolates from the gut belonged to diverse F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and a potential new subspecies of Fusobacterium periodonticum. The Fusobacterium population within each individual was distinct and in some cases diverse, with minimal intra-clonal variation. Phylogenetic analyses showed that within four individuals, tumour-associated Fusobacterium were clonal to those isolated from non-tumour tissues. Genes encoding major virulence factors (Fap2 and RadD) showed evidence of horizontal gene transfer. Our work provides a framework to understand the genomic diversity of Fusobacterium within the CRC patients, which can be exploited for the development of CRC diagnostic and therapeutic options targeting this oncobacterium.

PurposePlace-based measures of structural racism have been associated with breast cancer mortality, which may be driven, in part, by epigenetic perturbations. We examined the association between contemporary redlining, a measure of structural racism at the neighborhood level, and DNA methylation in breast tumor tissue.MethodsWe identified 80 Black and White women diagnosed and treated for a first-primary breast cancer at Emory University Hospitals (2008–2017). Contemporary redlining was derived for census tracts using the Home Mortgage Disclosure Act database. Linear regression models were used to calculate the association between contemporary redlining and methylation in breast tumor tissue. We also examined epigenetic age acceleration for two different metrics, regressing β values for each cytosine-phosphate-guanine dinucleotide (CpG) site on redlining while adjusting for covariates. We employed multivariable Cox-proportional hazards models and 95% confidence intervals (CI) to estimate the association between aberrant methylation and mortality.ResultsContemporary redlining was associated with 5 CpG sites after adjustment for multiple comparisons (FDR

Studying unexpected, ephemeral, or transient events in ocean ecosystems, such as gelatinous zooplankton blooms, is important because it provides us with valuable data on how our oceans may be changing in response to climate change and other anthropogenic activities. However, planning for such events is nearly impossible and making use of opportunistically acquired data allows the marine science community to be adaptive and efficient given the logistical and financial constraints of time at sea and in the field. Because such sampling events are often responsive rather than planned, they are typically not accompanied by outreach and education efforts. This commentary considers if opportunistically acquired data sets can be applied to generate opportunistic outreach and education activities. A case study is provided with successes and caveats outlined.

Background Coral diseases are one of the leading causes of declines in coral populations. In the Caribbean, white band disease (WBD) has led to a substantial loss of Acropora corals. Although the etiologies of this disease have not been well described, characterizing the coral microbiome during the transition from a healthy to diseased state is critical for understanding disease progression. Coral nurseries provide unique opportunities to further understand the microbial changes associated with diseased and healthy corals, because corals are monitored over time. We characterized the microbiomes before and during an outbreak of WBD in Acropora cervicornis reared in an ocean nursery in Little Cayman, CI. We asked (1) do healthy corals show the same microbiome over time (before and during a disease outbreak) and (2) are there disease signatures on both lesioned and apparently healthy tissues on diseased coral colonies? Methods Microbial mucus-tissue slurries were collected from healthy coral colonies in 2017 (before the disease) and 2019 (during the disease onset). Diseased colonies were sampled at two separate locations on an individual coral colony: at the interface of Disease and ∼10 cm away on Apparently Healthy coral tissue. We sequenced the V4 region of the 16S rRNA gene to characterize bacterial and archaeal community composition in nursery-reared A. cervicornis. We assessed alpha diversity, beta diversity, and compositional differences to determine differences in microbial assemblages across health states (2019) and healthy corals between years (2017 and 2019). Results Microbial communities from healthy A. cervicornis from 2017 (before disease) and 2019 (after disease) did not differ significantly. Additionally, microbial communities from Apparently Healthy samples on an otherwise diseased coral colony were more similar to Healthy colonies than to the diseased portion on the same colony for both alpha diversity and community composition. Microbial communities from Diseased tissues had significantly higher alpha diversity than both Healthy and Apparently Healthy tissues but showed no significant difference in beta-diversity dispersion. Our results show that at the population scale, Healthy and Apparently Healthy coral tissues are distinct from microbial communities associated with Diseased tissues. Furthermore, our results suggest stability in Little Cayman nursery coral microbiomes over time. We show healthy Caymanian nursery corals had a stable microbiome over a two-year period, an important benchmark for evaluating coral health via their microbiome.

Background: With an aging population and growing number of patients with chronic kidney disease (CKD), integrating the latest risk factors when deciding on a treatment plan can result in better patient care. Frailty remains a prevalent syndrome in CKD resulting in adverse health outcomes. However, measures of frailty and functional status remain excluded from clinical decision making. Objective: To examine the degree to which different measures of frailty and functional status are associated with mortality, hospitalization, and other clinical outcomes in patients with advanced CKD. Design: Systematic review. Setting: Observation studies including cohort study, case-control study, or cross-sectional study examining frailty and functional status on clinical outcomes. There were no restrictions on type of setting or country of origin. Patients: Adults with advanced CKD, including both types of dialysis patients. Measurements: Data including demographic information (e.g., sample size, follow-up time, age, country), assessments of frailty or functional status and their domains, and outcomes including mortality, hospitalization, cardiovascular events, kidney function, and composite outcomes were extracted. Methods: A search was conducted using databases Medline, Embase, and Cochrane Central Register for Controlled Trials. Studies were included from inception to March 17, 2021. The eligibility of studies was screened by 2 independent reviewers. Data were presented by instrument and clinical outcome. Point estimates and 95% confidence intervals from the fully adjusted statistical model were reported or calculated from the raw data. Results: A total of 117 unique instruments were found among 140 studies. The median sample size of studies was 319 (interquartile range, 161-893). Most studies focused on incident and chronic dialysis patient populations, with only 15% of studies examining non-dialysis CKD patients. Frailty and lower functional status were associated with an increased risk for adverse clinical outcomes such as mortality and hospitalization. The 5 individual domains of frailty were also found to be associated with poor health outcomes. Limitations: Meta-analysis could not be performed due to significant heterogeneity between studies and methods used to measure frailty and functional status. Many studies had issues with methodological rigor. Selection bias and the validity of data collection could not be ascertained for some studies. Conclusion: Frailty and functional status measures should be integrated to help guide clinical care decision making for a comprehensive assessment of risk for adverse outcomes among patients with advanced CKD. Registration (PROSPERO): CRD42016045251

Holonomic quantum computing functions by transporting an adiabatically degenerate manifold of computational states around a closed loop in a control-parameter space; this cyclic evolution results in a non-Abelian geometric phase which may couple states within the manifold. Realizing the required degeneracy is challenging and typically requires auxiliary levels or intermediate-level couplings. One potential way to circumvent this is through Floquet engineering, where the periodic driving of a nondegenerate Hamiltonian leads to degenerate Floquet bands, and subsequently non-Abelian gauge structures may emerge. Here we present an experiment in ultracold ^{87}Rb atoms where atomic spin states are dressed by modulated RF fields to induce periodic driving of a family of Hamiltonians linked through a fully tuneable parameter space. The adiabatic motion through this parameter space leads to the holonomic evolution of the degenerate spin states in SU(2), characterized by a non-Abelian connection. We study the holonomic transformations of spin eigenstates in the presence of a background magnetic field, characterizing the fidelity of these single-qubit gate operations. Results indicate that while the Floquet engineering technique removes the need for explicit degeneracies, it inherits many of the same limitations present in degenerate systems.

Abstract Scarless genome editing of induced pluripotent stem cells (iPSCs) is crucial for the precise modeling of genetic disease. Here we present CRISPR Del/Rei, a two-step deletion-reinsertion strategy with high editing efficiency and simple PCR-based screening that generates isogenic clones in ~ 2 months. We apply our strategy to edit iPSCs at 3 loci with only rare off target editing.

BackgroundThe treatment landscape for ovarian cancer has changed in recent years with the introduction of targeted therapies to treat patients with advanced disease. We investigated patient demographic and clinical factors associated with use of targeted therapies as a part of the first-line treatment for ovarian cancer.MethodsThis study included patients diagnosed with stage I–IV ovarian cancer between 2012 and 2019 from the National Cancer Database. Information on demographic and clinical characteristics were collected and described using frequency and percent across receipt of targeted therapy. Logistic regression was used to compute the odds ratios (ORs) and 95% confidence intervals (CI) associating patient demographic and clinical factors with receipt of targeted therapy.ResultsAmong 99,286 ovarian cancer patients (mean age 62 years), 4.1% received targeted therapy. The rate of targeted therapy receipt across racial and ethnic groups over the study period was fairly similar; however, non-Hispanic Black women were less likely to receive targeted therapy than their non-Hispanic White counterparts (OR=0.87, 95% CI: 0.76–1.00). Patients who received neoadjuvant chemotherapy were more likely to receive targeted therapy than those who received adjuvant chemotherapy (OR=1.26; 95% CI: 1.15–1.38). Moreover, among patients who received targeted therapy, 28% received neoadjuvant targeted therapy, with non-Hispanic Black women being most likely to receive neoadjuvant targeted therapy (34%) compared with other racial and ethnic groups.ConclusionsWe observed differences in receipt of targeted therapy by factors such as age at diagnosis, stage, and comorbidities present at diagnosis, as well as factors related to healthcare access—including neighborhood education level and health insurance status. Approximately 28% of patients received targeted therapy in the neoadjuvant setting, which could negatively impact treatment outcomes and survival due to the increased risk of complications associated with targeted therapies that may delay or prevent surgery. These results warrant further evaluation in a cohort of patients with more comprehensive treatment information.

Background This study assesses outcomes in revision shoulder replacements where the glenoid bone loss was managed using a structural allograft (donated femoral head) in combination with a trabecular titanium (TT) implant. Methods We contacted patients who had undergone revision shoulder arthroplasty using the Lima Axioma TT metal-backed glenoid with an allologous bone graft as a composite who were over 2 years since surgery. Patients underwent computerd tomography evaluation, clinical review, and scoring preoperatively, at 6 months and the latest follow-up. Results Fifteen patients were included with a mean age of 59 (33-76). The average follow-up period was 40.5 months (24-51). 80% showed satisfactory bone graft incorporation and peg integration at the latest follow-up. Three had signs of significant bone graft resorption, although in 2 patients the pegs were still soundly fixed in the host bone. Clinically all patients showed a statistically significant improvement in pain relief, movement, and function. No unusual complications were reported. Conclusion Results show femoral head structural allograft in combination with TT metal-backed glenoid baseplate is a viable option for revision total shoulder replacement in the context of massive glenoid bone loss. We do, however, acknowledge that this resorption rate is higher than in other reported series where autograft is used.

Abstract Background Malnutrition amongst under-fives remains common in resource-poor countries and is resistant to current interventions. New opportunities have emerged to target “environmental enteric dysfunction” (EED) that refers to the abnormal gut structure and function that results from colonisation of the gut with pathogenic microbes and compromises nutrition and growth in early life. Although the gut microbiome may provide a defence against ingested gut pathogens through colonisation resistance, its development is adversely affected by multiple environmental factors. Dietary supplements of pro- or synbiotics may build the resilience of the gut microbiome against these environmental factors and boost colonisation resistance. We aim to assess whether dietary supplementation of newborns in rural Kenya with pro/synbiotics prevents or ameliorates EED and improves growth. Methods Six hundred newborns less than 4 days old will be recruited from Homa Bay County Teaching and Referral Hospital, western Kenya. Newborns will be randomly allocated, stratified by HIV exposure, in a 1:1:1:1 ratio to one of 4 study arms to receive either of two synbiotics, a probiotic or no supplement. Supplements will be given daily for 10 days and then weekly until 6 months of age. Participants will be followed until the age of 2 years. The primary outcome is systemic inflammation at 6 months assessed by plasma alpha-1-acid glycoprotein. Secondary outcomes include biomarkers of gut health and growth, anthropometric indices, morbidity and mortality. Discussion As dietary supplements with pro- or synbiotics may improve gut health and can be administered in early life, our findings may inform the package of interventions to prevent malnutrition and improve growth in Africa and similar low-resource settings. Trial registration Pan African Clinical Trials Registry, Trial number: PACTR202003893276712. Date: 02/03/2020 https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9798

Single Nucleotide Polymorphisms (SNPs) affect cellular regulatory networks, and SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Here the authors introduce iSNP, a precision medicine pipeline that combines genomics and network biology approaches to uncover patient specific pathways affected in complex diseases.

Here, Forster et al. compare 1354 cultured commensal strains (540 species) to 45,403 pathogen strains (12 species), identifying 64,188 MGE-mediated antibiotic resistance gene transfer events between the two groups, and show that 15 broad host range MGEs are able to transfer between phyla.

Abstract Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.

While non-analcime zeolites are plausible mineral constituents of the Martian surface, their lack of prominent spectral characteristics in the visible to shortwave infrared wavelength region makes them difficult to identify using orbital data. This lack of detection has led to the assumption that they are limited or absent. Here we assess the capability of mapping non-analcime zeolites using different mapping techniques and present the possible reasons that could lead to limited detection of zeolites using an analog study from Paleolake Tecopa, California. We used spaceborne hyperspectral Hyperion and multispectral ASTER data to identify zeolites following X-ray Diffraction (XRD) and visible-near infrared and shortwave infrared (VNIR-SWIR) spectral analysis of collected samples containing zeolites and other associated minerals. We used four of the most common spectral mapping methods: (1) band ratios, (2) minimum noise fraction (MNF), (3) spectral angle mapper (SAM), and (4) linear spectral unmixing (LSU). We were able to map zeolite-rich tuff beds using carefully selected band indices, MNF band combinations, and the pixel spectra corresponding to a zeolite-rich abandoned quarry area. Hyperion results show less overall accuracy than the ASTER image products mostly due to the low signal-to-noise ratio of the Hyperion data. The spectral characteristics of zeolites in zeolite-rich pixels are masked by phyllosilicates (e.g., smectite) present in the ground resolution cell (GRC), making it difficult to identify zeolites in phyllosilicate-bearing deposits solely based on zeolite spectra. Therefore, the SAM product derived using the pixel spectrum of the well-exposed zeolite-rich quarry shows the highest accuracy in Hyperion image products. ASTER band ratio Band 2/Band 1, representing the ferric ion, was able to identify the zeolite-rich beds with the highest accuracies. However, most of the zeolite-rich paleolake beds were difficult to identify since they are buried by other beds, mixed with other beds due to physical weathering, or the areas of exposed beds are smaller than the GRC of the satellite. The results imply that the paucity of detected zeolites on Mars, as we see at Lake Tecopa, does not preclude their wider presence, either beneath other materials, obscured by surface dust, or mixed with more spectrally dominant phases.

Patellofemoral pain (PFP) is a chronic condition that presents with patellar pain during various daily and recreational activities. Individuals with PFP have a wide range of impairments that result in long-term disability and reduced quality of life. Current interventions target hip muscle weakness with strength-based exercises, but recurrence rates are as high as 90%. A single feasibility study demonstrated success with power-based exercises; however, there is limited evidence evaluating pain or self-reported function in larger cohorts, and no study has assessed recurrence rates. This protocol details a study evaluating a strength-based rehabilitation programme compared with a strength-based programme incorporating power-based exercises in individuals with PFP. This single-blinded randomised controlled trial will evaluate 88 participants with PFP, aged 18–40 years old. Participants will be recruited from three universities, the surrounding community and sports medicine clinics. Participants will receive three telemedicine rehabilitation sessions a week for 6 weeks. The rehabilitation programme will consist of either strength-based exercises or a combination of power and strength-based exercises. Pain, subjective function and recurrence rates will be assessed at baseline, immediately after the intervention and at four follow-up time points: 6-month, 12-month, 18-month and 24-month postintervention. We will also assess neuromuscular function of the hips and global rating of change at each postintervention time point. Trial registration number NCT05403944.