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A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/ mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms were detected both in the proband and in his cousin. Treatment with topical testosterone started in August 2010. Over the next 8 years, testosterone dosage was varied and switched from topical gel to injections and maintained on depo-injections of testosterone at about 60 mg once per week. Re-examination in March 2012 included a brain MRI to exclude pituitary lesions; hyperparathyroidism was ruled out (normal serum parathyroid hormone, calcium, and calcium to phosphorous ratio) and celiac disease was excluded (negative transglutaminase antibodies). Follow-up in October 2018 showed improved bone mineral density of the lumbar spine by 29% and of the left femoral hip by 15% compared to baseline measurements. This reveals the importance of measuring serum E2 for making the correct diagnosis, as well as for monitoring a therapeutic effect. Herein, we propose treatment of male osteoporosis where serum E2 levels are below about 20 pg/mL with testosterone to reverse osteoporosis.

Abstract Compared to microbiomes on other skin sites, the bacterial microbiome of the human hand has been found to have greater variability across time. To increase understanding regarding the longitudinal transfer of the hand microbiome to objects in the built environment, and vice versa, 22 participants provided skin microbiome samples from their dominant hands, as well as from frequently and infrequently touched objects in their office environments. Additional longitudinal samples from home environments were obtained from a subset of 11 participants. We observed stability of the microbiomes of both the hand and built environments within the office and home settings; however, differences in the microbial communities were detected across the two built environments. Occupants’ frequency of touching an object correlated to that object having a higher relative abundance of human microbes, yet the percent of shared microbes was variable by participants. Finally, objects that were horizontal surfaces in the built environment had higher microbial diversity as compared to objects and the occupants’ hands. This study adds to the existing knowledge of microbiomes of the built environment, enables more detailed studies of indoor microbial transfer, and contributes to future models and building interventions to reduce negative outcomes and improve health and well-being.

Abstract Detecting and mitigating off-target activity is critical to the practical application of CRISPR-mediated genome and epigenome editing. While numerous methods have been developed to map Cas9 binding specificity genome-wide, they are generally time-consuming and/or expensive, and not applicable to catalytically dead CRISPR enzymes. We have developed CasKAS, a rapid, inexpensive, and facile assay for identifying off-target CRISPR enzyme binding and cleavage by chemically mapping the unwound single-stranded DNA structures formed upon binding of a sgRNA-loaded Cas9 protein. We demonstrate this method in both in vitro and in vivo contexts.

Abstract Background Understanding human genetic influences on the gut microbiota helps elucidate the mechanisms by which genetics may influence health outcomes. Typical microbiome genome-wide association studies (GWAS) marginally assess the association between individual genetic variants and individual microbial taxa. We propose a novel approach, the covariate-adjusted kernel RV (KRV) framework, to map genetic variants associated with microbiome beta-diversity, which focuses on overall shifts in the microbiota. The KRV framework evaluates the association between genetics and microbes by comparing similarity in genetic profiles, based on groups of variants at the gene level, to similarity in microbiome profiles, based on the overall microbiome composition, across all pairs of individuals. By reducing the multiple-testing burden and capturing intrinsic structure within the genetic and microbiome data, the KRV framework has the potential of improving statistical power in microbiome GWAS. Results We apply the covariate-adjusted KRV to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) in a two-stage (first gene-level, then variant-level) genome-wide association analysis for gut microbiome beta-diversity. We have identified an immunity-related gene, IL23R, reported in a previous microbiome genetic association study and discovered 3 other novel genes, 2 of which are involved in immune functions or autoimmune disorders. In addition, simulation studies show that the covariate-adjusted KRV has a greater power than other microbiome GWAS methods that rely on univariate microbiome phenotypes across a range of scenarios. Conclusions Our findings highlight the value of the covariate-adjusted KRV as a powerful microbiome GWAS approach and support an important role of immunity-related genes in shaping the gut microbiome composition. Video Abstract

Abstract Whole-body hyperthermia (WBH) shows promise for the treatment of major depressive disorder (MDD). Because MDD is associated with increased inflammation, and anti-inflammatory agents show some promise as antidepressants, the current study sought to identify the acute and longer-term immune effects of WBH in participants with MDD and to explore whether these effects associate with the procedure’s antidepressant properties. Thirty participants who met DSM-IV-TR criteria for MDD were randomized to receive a single session of WBH (n = 16) or sham treatment (n = 14). Hamilton Depression Rating Scale (HDRS) scores were assessed at baseline and 1, 2, 4, and 6 weeks post-treatment (WBH vs. sham), and plasma cytokine concentrations were assessed at baseline, immediately post-treatment, and 1 and 4 weeks post-treatment. As previously reported, WBH produced a rapid and sustained antidepressant effect. When compared to sham, WBH increased plasma interleukin (IL)-6 immediately post-treatment (time by treatment: χ 2 (3, N=108) = 47.33, p

Abstract Spectral CT has been increasingly implemented clinically for its better characterization and quantification of materials through its multi-energy results. It also facilitates calculation of physical density, allowing for non-invasive mass measurements and temperature evaluations by manipulating the definition of physical density and thermal volumetric expansion, respectively. To develop spectral physical density quantifications, original and parametrized Alvarez–Macovski model and electron density-physical density model were validated with a phantom. The best physical density model was then implemented on clinical spectral CT scans of ex vivo bovine muscle to determine the accuracy and effect of acquisition parameters on mass measurements. In addition, the relationship between physical density and changes in temperature was evaluated by scanning and subjecting the tissue to a range of temperatures. The parametrized Alvarez–Macovski model performed best in both model development and validation with errors within ± 0.02 g/mL. No effect from acquisition parameters was observed in mass measurements, which demonstrated accuracy with a maximum percent error of 0.34%. Furthermore, physical density was strongly correlated (R of 0.9781) to temperature changes through thermal volumetric expansion. Accurate and precise spectral physical density quantifications enable non-invasive mass measurements for pathological detection and temperature evaluation for thermal therapy monitoring in interventional oncology.

Abstract Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels. We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.

Abstract Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Background: We examined how breast cancer-related lymphedema (BCRL) affects health-related quality of life (HRQOL), productivity, and compliance with therapeutic interventions to guide structuring BCRL screening programs. Methods: We prospectively followed consecutive breast cancer patients who underwent axillary lymph node dissection (ALND) with arm volume screening and measures assessing patient-reported health-related quality of life (HRQOL) and perceptions of BCRL care. Comparisons by BCRL status were made with Mann-Whitney U, Chi-square, Fisher's exact, or t tests. Trends over time from ALND were assessed with linear mixed-effects models. Results: With a median follow-up of 8 months in 247 patients, 46% self-reported ever having BCRL, a proportion that increased over time. About 73% reported fear of BCRL, which was stable over time. Further in time from ALND, patients were more likely to report that BCRL screening reduced fear. Patient-reported BCRL was associated with higher soft tissue sensation intensity, biobehavioral, and resource concerns, absenteeism, and work/activity impairment. Objectively measured BCRL had fewer associations with outcomes. Most patients reported performing prevention exercises, but compliance decreased over time; patient-reported BCRL was not associated with exercise frequency. Fear of BCRL was positively associated with performing prevention exercises and using compressive garments. Conclusions: Both incidence and fear of BCRL were high after ALND for breast cancer. Fear was associated with improved therapeutic compliance, but compliance decreased over time. Patient-reported BCRL was more strongly associated with worse HRQOL and productivity than was objective BCRL. Screening programs must support patients’ psychological needs and aim to sustain long-term compliance with recommended interventions.

A diagnostic investigation into an outbreak of fatal respiratory disease among young goats in Iowa, USA revealed bronchitis lesions of unknown etiology and secondary bacterial bronchopneumonia. Hypothesis-free metagenomics identified a previously unreported picornavirus (USA/IA26017/2023), and further phylogenetic analysis classified USA/IA26017/2023 as an aphthovirus related to bovine rhinitis B virus. Viral nucleic acid was localized to lesions of bronchitis using in situ hybridization. This marks the first report of a picornavirus putatively causing respiratory disease in goats and highlights the potential for cross-species transmission of aphthoviruses.

Addressing complex social-ecological issues requires all relevant sources of knowledge and data, especially those held by communities who remain close to the land. Centuries of oppression, extractive research practices, and misrepresentation have hindered balanced knowledge exchange with Indigenous communities and inhibited innovation and problem-solving capacity in all scientific fields. A recent shift in the research landscape reflects a growing interest in engaging across diverse communities and ways of knowing. Scientific discussions increasingly highlight the inherent value of Indigenous environmental ethics frameworks and processes as the original roadmaps for sustainable development planning, including their potential in addressing the climate crisis and related social and environmental concerns. Momentum in this shift is also propelled by an increasing body of research evidencing the role of Indigenous land stewardship for maintaining ecological health and biodiversity. However, a key challenge straining this movement lies rooted in colonial residue and ongoing actions that suppress and co-opt Indigenous knowledge systems. Scientists working with incomplete datasets privilege a handful of narratives, conceptual understandings, languages, and historical contexts, while failing to engage thousands of collective bodies of intergenerational, place-based knowledge systems. The current dominant colonial paradigm in scientific research risks continued harmful impacts to Indigenous communities that sustain diverse knowledge systems. Here, we outline how ethical standards in researcher practice can be raised in order to reconcile colonial legacies and ongoing settler colonial practices. We synthesize across Indigenous and community-based research protocols and frameworks, transferring knowledge across disciplines, and ground truthing methods and processes in our own practice, to present a relational science working model for supporting Indigenous rights and reconciliation in research. We maintain that core Indigenous values of integrity, respect, humility, and reciprocity should shape researcher responsibilities and methods applied in order to raise ethical standards and long-term relational accountability regarding Indigenous lands, rights, communities, and our shared futures.

Background: Extracellular volume fraction (ECV), measured with contrast-enhanced magnetic resonance imaging (CE-MRI), has been utilized to study myocardial fibrosis, but its role in peripheral artery disease (PAD) remains unknown. We hypothesized that T1 mapping and ECV differ between PAD patients and matched controls. Methods and Results: A total of 37 individuals (18 PAD patients and 19 matched controls) underwent 3.0T CE-MRI. Skeletal calf muscle T1 mapping was performed before and after gadolinium contrast with a motion-corrected modified look–locker inversion recovery (MOLLI) pulse sequence. T1 values were calculated with a three-parameter Levenberg–Marquardt curve fitting algorithm. ECV and T1 maps were quantified in five calf muscle compartments (anterior [AM], lateral [LM], and deep posterior [DM] muscle groups; soleus [SM] and gastrocnemius [GM] muscles). Averaged peak blood pool T1 values were obtained from the posterior and anterior tibialis and peroneal arteries. T1 values and ECV are heterogeneous across calf muscle compartments. Native peak T1 values of the AM, LM, and DM were significantly higher in PAD patients compared to controls (all p < 0.028). ECVs of the AM and SM were significantly higher in PAD patients compared to controls (AM: 26.4% (21.2, 31.6) vs. 17.3% (10.2, 25.1), p = 0.046; SM: 22.7% (19.5, 27.8) vs. 13.8% (10.2, 19.1), p = 0.020). Conclusions: Native peak T1 values across all five calf muscle compartments, and ECV fractions of the anterior muscle group and the soleus muscle were significantly elevated in PAD patients compared with matched controls. Non-invasive T1 mapping and ECV quantification may be of interest for the study of PAD.

The expansive utility of polymeric 3D-printing technologies and demand for high- performance lightweight structures has prompted the emergence of various carbon-reinforced polymer composite filaments. However, detailed characterization of the processing–microstructure–property relationships of these materials is still required to realize their full potential. In this study, acrylonitrile butadiene styrene (ABS) and two carbon-reinforced ABS variants, with either carbon nanotubes (CNT) or 5 wt.% chopped carbon fiber (CF), were designed in a bio-inspired honeycomb geometry. These structures were manufactured by fused filament fabrication (FFF) and investigated across a range of layer thicknesses and hexagonal (hex) sizes. Microscopy of material cross-sections was conducted to evaluate the relationship between print parameters and porosity. Analyses determined a trend of reduced porosity with lower print-layer heights and hex sizes compared to larger print-layer heights and hex sizes. Mechanical properties were evaluated through compression testing, with ABS specimens achieving higher compressive yield strength, while CNT-ABS achieved higher ultimate compressive strength due to the reduction in porosity and subsequent strengthening. A trend of decreasing strength with increasing hex size across all materials was supported by the negative correlation between porosity and increasing print-layer height and hex size. We elucidated the potential of honeycomb ABS, CNT-ABS, and ABS-5wt.% CF polymer composites for novel 3D-printed structures. These studies were supported by the development of a predictive classification and regression supervised machine learning model with 0.92 accuracy and a 0.96 coefficient of determination to help inform and guide design for targeted performance.

Users of escalators and moving walkways with sufficient space to accommodate two lanes of users often follow an implied etiquette for the two lanes: one for walking and one for standing (in the US, China, and many countries, the convention is “walk left, stand right”). When there is high volume, e.g., when exiting a subway or train station or at the conclusion of an athletic event, the escalators often experience bottleneck congestion that constitutes the primary source of delay. It has been suggested that during such high-congestion periods, it would be more efficient if everyone just stood in both lanes, with empirical evidence used to support this counterintuitive finding. Simple deterministic queueing models are used to show under what conditions such results hold and also to provide further insights regarding tradeoffs between performance metrics as a function of the distribution of walkers and standers, which could inform practical implementation policies to increase efficiency.

Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood–brain barrier (BBB). Nanoparticles can be an attractive solution for the treatment of GBM as they can transport drugs across the BBB into the tumor. In this study, normal and GBM organoids comprising six brain cell types were developed and applied to study the uptake, BBB penetration, distribution, and efficacy of fluorescent, ultrasmall gold nanoparticles (AuTio-Dox-AF647s) conjugated with doxorubicin (Dox) and AlexaFluor-647-cadaverine (AF647) by confocal laser scanning microscopy (CLSM), using a mixture of dissolved doxorubicin and fluorescent AF647 molecules as a control. It was shown that the nanoparticles could easily penetrate the BBB and were found in normal and GBM organoids, while the dissolved Dox and AF647 molecules alone were unable to penetrate the BBB. Flow cytometry showed a reduction in glioblastoma cells after treatment with AuTio-Dox nanoparticles, as well as a higher uptake of these nanoparticles by GBM cells in the GBM model compared to astrocytes in the normal cell organoids. In summary, our results show that ultrasmall gold nanoparticles can serve as suitable carriers for the delivery of drugs into organoids to study BBB function.

Fentanyl (FTN) and synthetic analogs of FTN continue to ravage populations across the globe, including in the United States where opioids are increasingly being used and abused and are causing a staggering and growing number of overdose deaths each year. This growing pandemic is worsened by the ease with which FTN can be derivatized into numerous derivatives. Understanding the chemical properties/behaviors of the FTN class of compounds is critical for developing effective chemical detection schemes using nanoparticles (NPs) to optimize important chemical interactions. Halogen bonding (XB) is an intermolecular interaction between a polarized halogen atom on a molecule and e−-rich sites on another molecule, the latter of which is present at two or more sites on most fentanyl-type structures. Density functional theory (DFT) is used to identify these XB acceptor sites on different FTN derivatives. The high toxicity of these compounds necessitated a “fragmentation” strategy where smaller, non-toxic molecules resembling parts of the opioids acted as mimics of XB acceptor sites present on intact FTN and its derivatives. DFT of the fragments’ interactions informed solution measurements of XB using 19F NMR titrations as well as electrochemical measurements of XB at self-assembled monolayer (SAM)-modified electrodes featuring XB donor ligands. Gold NPs, known as monolayer-protected clusters (MPCs), were also functionalized with strong XB donor ligands and assembled into films, and their interactions with FTN “fragments” were studied using voltammetry. Ultimately, spectroscopy and TEM analysis were combined to study whole-molecule FTN interactions with the functionalized MPCs in solution. The results suggested that the strongest XB interaction site on FTN, while common to most of the drug’s derivatives, is not strong enough to induce NP-aggregation detection but may be better exploited in sensing schemes involving films.

Many clinical studies have shown wide performance variation in tests to identify coronary artery disease (CAD). Coronary computed tomography angiography (CCTA) has been identified as an effective rule-out test but is not widely available in the USA, particularly so in rural areas. Patients in rural areas are underserved in the healthcare system as compared to urban areas, rendering it a priority population to target with highly accessible diagnostics. We previously developed a machine-learned algorithm to identify the presence of CAD (defined by functional significance) in patients with symptoms without the use of radiation or stress. The algorithm requires 215 s temporally synchronized photoplethysmographic and orthogonal voltage gradient signals acquired at rest. The purpose of the present work is to validate the performance of the algorithm in a frozen state (i.e., no retraining) in a large, blinded dataset from the IDENTIFY trial. IDENTIFY is a multicenter, selectively blinded, non-randomized, prospective, repository study to acquire signals with paired metadata from subjects with symptoms indicative of CAD within seven days prior to either left heart catheterization or CCTA. The algorithm’s sensitivity and specificity were validated using a set of unseen patient signals (n = 1816). Pre-specified endpoints were chosen to demonstrate a rule-out performance comparable to CCTA. The ROC-AUC in the validation set was 0.80 (95% CI: 0.78–0.82). This performance was maintained in both male and female subgroups. At the pre-specified cut point, the sensitivity was 0.85 (95% CI: 0.82–0.88), and the specificity was 0.58 (95% CI: 0.54–0.62), passing the pre-specified endpoints. Assuming a 4% disease prevalence, the NPV was 0.99. Algorithm performance is comparable to tertiary center testing using CCTA. Selection of a suitable cut-point results in the same sensitivity and specificity performance in females as in males. Therefore, a medical device embedding this algorithm may address an unmet need for a non-invasive, front-line point-of-care test for CAD (without any radiation or stress), thus offering significant benefits to the patient, physician, and healthcare system.

This study investigates the association among management fees, ESG scores, and investment performance of ESG funds in China. It explores the significance of comprehending the cost–benefit analysis and long-term yields associated with sustainable investing. The investigation specifically concentrates on China’s open-end equity funds and uncovers some noteworthy discoveries. Initially, funds with higher management fees tend to yield greater returns, suggesting a potential validation for these fees. Nevertheless, when taking risk-adjusted metrics into account, these funds do not exhibit superior performance, indicating that the elevated fees may not necessarily result in enhanced performance after factoring in risk. Furthermore, the analysis discloses an adverse influence of ESG factors on fund performance. In general, the findings indicate that ESG funds in China do not impose higher management fees and do not ensure better returns but often produce superior risk-adjusted investment performance if their ESG scores are moderately higher. Exceptionally high ESG scores can end up with the worst risk-adjusted investment performance.

This study focuses on understanding the association of rare earth elements (REE; lanthanides + yttrium + scandium) with organic matter from the Middle Devonian black shales of the Appalachian Basin. Developing a better understanding of the role of organic matter (OM) and thermal maturity in REE partitioning may help improve current geochemical models of REE enrichment in a wide range of black shales. We studied relationships between whole rock REE content and total organic carbon (TOC) and compared the correlations with a suite of global oil shales that contain TOC as high as 60 wt.%. The sequential leaching of the Appalachian shale samples was conducted to evaluate the REE content associated with carbonates, Fe–Mn oxyhydroxides, sulfides, and organics. Finally, the residue from the leaching experiment was analyzed to assess the mineralogical changes and REE extraction efficiency. Our results show that heavier REE (HREE) have a positive correlation with TOC in our Appalachian core samples. However, data from the global oil shales display an opposite trend. We propose that although TOC controls REE enrichment, thermal maturation likely plays a critical role in HREE partitioning into refractory organic phases, such as pyrobitumen. The REE inventory from a core in the Appalachian Basin shows that (1) the total REE ranges between 180 and 270 ppm and the OM-rich samples tend to contain more REE than the calcareous shales; (2) there is a relatively higher abundance of middle REE (MREE) to HREE than lighter REE (LREE); (3) there is a disproportionate increase in Y and Tb with TOC likely due to the rocks being over-mature; and (4) the REE extraction demonstrates that although the OM has higher HREE concentration, the organic leachates contain more LREE, suggesting it is more challenging to extract HREE from OM than using traditional leaching techniques.

Blood–brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia–ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention.

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient’s treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.

The American burying beetle, Nicrophorus americanus Olivier (Coleoptera: Siliphidae), is a federally threatened species in the United States, occurring in less than 10% of its historic range. The continued monitoring of extant populations found in South Dakota, the northernmost edge of its confirmed range, is imperative to future conservation efforts, especially with the predicted loss of the species in southern regions because of climate change. Proposed strategies to preserve the species include the reintroduction or translocation of individuals from habitats that have become unsuitable. Beyond adequate habitat and carrion resource requirements, community-level silphid interactions may challenge these efforts because of competition. From 2018 to 2020, we used 80 carrion-baited pitfall traps per year to conduct two 5-day surveys in June and August. A total of 25,923 Silphidae belonging to 15 species were collected in 1200 trap nights. Cumulatively, 1150 N. americanus were captured and marked with 263 recaptures. Like past findings, N. americanus was concentrated in western Tripp County with limited occurrence in Gregory and Todd Counties, suggesting no expansion of their known range in the past decade. Generalized linear mixed-effects models indicated N. americanus abundance was significantly predicted by the co-occurrence of the carrion beetles Oieceoptoma inaequale F. and Oiceoptoma noveboracense Forster, whereas pitfall trap catches dominated by the burying beetle Nicrophorus marginatus F. had predictively less N. americanus. Collectively, these data provide insights into the existing, northernmost N. americanus population dynamics and silphid beetle communities. Concurrent with monitoring extant populations, the characterization of silphid communities that co-occur with N. americanus may provide much-needed information for managed relocation opportunities.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Key Clinical Message Persistent pneumatoceles in neonates increase mortality, and little literature regarding emergent treatment in a decompensating patient exists. We present the emergent management of a pneumatocele in a decompensating neonate by isolation with a Fogarty catheter.

Abstract Impact of climate change is expected to be especially noticeable at the edges of a species' distribution, where they meet suboptimal habitat conditions. In Mauritania and Iberia, two genetically differentiated populations of harbor porpoises (Phocoena phocoena) form an ecotype adapted to local upwelling conditions and distinct from other ecotypes further north on the NE Atlantic continental shelf and in the Black Sea. By analyzing the evolution of mitochondrial genetic variation in the Iberian population between two temporal cohorts (1990–2002 vs. 2012–2015), we report a substantial decrease in genetic diversity. Phylogenetic analyses including neighboring populations identified two porpoises in southern Iberia carrying a divergent haplotype closely related to those from the Mauritanian population, yet forming a distinct lineage. This suggests that Iberian porpoises may not be as isolated as previously thought, indicating possible dispersion from Mauritania or an unknown population in between, but none from the northern ecotype. Demo‐genetic scenario testing by approximate Bayesian computation showed that the rapid decline in the Iberian mitochondrial diversity was not simply due to the genetic drift of a small population, but models support instead a substantial decline in effective population size, possibly resulting from environmental stochasticity, prey depletion, or acute fishery bycatches. These results illustrate the value of genetics time series to inform demographic trends and emphasize the urgent need for conservation measures to ensure the viability of this small harbor porpoise population in Iberian waters.

Abstract Understanding where, when, and why agroecosystems are changing requires quality information about ecosystems that span land tenure, ecological processes, and spatial scales. Over the past two decades, land management agencies and research groups have adopted a suite of standardized methods for monitoring rangelands, which have been implemented at over 85,000 monitoring locations globally. However, the ability to use these data to understand agroecosystem dynamics and change across scales and across land ownership has been limited because, until now, these data have not been available in a harmonized, accessible format for analyses, modeling, and decision‐support tools. We present the Landscape Data Commons, a cyberinfrastructure platform that harmonizes and aggregates standardized agroecosystem data, enables linkages to models, and facilitates analysis and interpretation of data within decision‐support tools. The Landscape Data Commons provides a community platform for users to contribute data and develop next‐generation tools to support agroecosystem management through the 21st century.

Dissection occurring after percutaneous transluminal angioplasty (PTA) is associated with decreased vessel patency and an increased incidence of target lesion revascularization. Management of post-PTA dissection with the Tack Endovascular System (Philips, N.V., Amsterdam, Netherlands) has created an effective and durable treatment strategy for infrainguinal dissections. In this report, we discuss the indications and optimal methods for using Tack devices in post-PTA dissections.

Osteonecrosis (ON) is a common disabling complication of treatment for patients with acute lymphoblastic leukaemia (ALL). Reported incidence rates range from 1% to 61% and multiple possible risk factors have been identified. This review explored existing evidence to provide new perspectives and recommendations for future interdisciplinary research. PEDro, CINAHL, AMED, EMBSAE, OVID, EMCARE databases were systematically searched from their inception to March 2022. Published original research reporting the incidence rates of osteonecrosis in patients aged 10–25 with ALL were included. Study reporting quality was assessed against appropriate reporting guidelines (STROBE, CONSORT and CROSS). All relevant data reporting incidence rates and risk factors were extracted for narrative synthesis. 3146 report titles were screened, with 34 studies included (n = 12,056) (30 observational cohort studies, three randomised trials, and one questionnaire study). The median study quality reporting score was 68% (IQR 64–82%). Median overall incidence rate of ON was 51.8% (IQR 41.4–58.9%) and 15.65% (IQR 9.2–24.2%) for asymptomatic and symptomatic patient screening respectively. Five possible risk factor categories were identified: sex assigned at birth, age, ethnicity, steroid regimen, and genotype. The female sex and white ethnicity were consistently reported as risk factors independently associated with an increased risk of osteonecrosis in all studies. A heterogenous body of literature with moderate reporting quality identified a high incidence rate of osteonecrosis in patients with ALL. Future research investigating the efficacy of stratified treatments that focus on reducing the risk of osteonecrosis through modification of steroid regimen particularly in females of white ethnicity is needed. Obtaining multidisciplinary consensus with regards to screening methodologies and intervention outcomes may also help to improve evidence synthesis in this area. This may in turn facilitate early diagnosis and improve long term patient outcomes through treatment regimen modification and possible prevention of ON progression.

ABSTRACTEnteroviruses (EVs)—positive-sense single-strand RNA viruses of Picornaviridae—are among the most common human viral pathogens. Unlike other cytoplasmic viral RNAs (vRNAs), which are detected by RIG-I, sensing of EV RNAs is mediated primarily by MDA5. EVs evolved with rapid, cytotoxic life cycles as a means of host cell interference, ostensibly to suppress MDA5-orchestrated antiviral type-I interferon (IFN) responses. At the core of this strategy are viral 2A protease (2Apro)-directed cleavage of the eukaryotic initiation factor (eIF)4G—the central translation initiation scaffold and ribosome adaptor—and degradation of nuclear pores. EV MDA5 agonism has an intriguing innate footprint, characterized by polar TBK1-IFN regulatory factor 3 (IRF3) signaling, which fuels sustained type-I IFN release to provide context for antitumor CD8+ T-cell priming after in situ cancer vaccination. Here we compared EV-host interactions between wild-type EVs and the highly attenuated recombinant polio:rhinovirus chimera and cancer immunotherapy agent (PVSRIPO) to test how targeted inhibition of discrete steps in the viral life cycle affects the innate antiviral response. Our investigations demonstrate that sustained MDA5-TBK1-IRF3 signaling elicited by PVSRIPO is the result of inefficient immediate 2Apro-directed eIF4G degradation, while wild-type EVs counter host innate type-I IFN defenses via rapid eIF4G cleavage. The MDA5-directed innate signature of profoundly attenuated EVs may provide efficient innate immune-stimulatory assets, for example, in in situ cancer vaccination strategies.IMPORTANCEMultiple pattern recognition receptors sense vRNAs and initiate downstream innate signaling: endosomal Toll-like receptors (TLRs) 3, 7, and 8 and cytoplasmic RIG-I-like receptors (RLRs) RIG-I, and MDA5. They engage distinct signaling scaffolds: mitochondrial antiviral signaling protein (RLR), MyD88, and TLR-adaptor interacting with SLC15A4 on the lysosome (TLR7 and TLR8) and toll/IL-1R domain-containing adaptor inducing IFN (TLR3). By virtue of their unusual vRNA structure and direct host cell entry path, the innate response to EVs uniquely is orchestrated by MDA5. We reported that PVSRIPO’s profound attenuation and loss of cytopathogenicity triggers MDA5-directed polar TBK1-IRF3 signaling that generates priming of polyfunctional antitumor CD8+ T-cell responses and durable antitumor surveillance in vivo. Here we unraveled EV-host relations that control suppression of host type-I IFN responses and show that PVSRIPO’s deficient immediate host eIF4G cleavage generates unopposed MDA5-directed downstream signaling cascades resulting in sustained type-I IFN release.

Children born to women who sell sex for money or commodities may face economic and social insecurity because of their mother’s work, particularly in settings where sex work is illegal. From October 2020 to May 2021, we conducted a study with 60 children aged 12–24 years, born to sex workers in Kampala, Uganda. The children took part in 60 semi-structured interviews, 20 life history interviews, and 4 focus group discussions, which were used to explore their social, economic, and mental health experiences and investigate their vulnerabilities and resilience. Quantitative data were collected using REDcap, and descriptive analysis was done using Stata 14. Qualitative data were collected using semi-structured topic guides, and data analysed thematically. We explored findings in relation to a wellbeing framework. The findings showed that children experienced contextual and structural hardships, including incomplete and irregular schooling, a lack of privacy at home, food insecurity, and physical and psychological violence from relatives and sometimes from their mothers. Some children reported mental wellbeing struggles with hopelessness, nervousness, and sadness. Alcohol and drug use were common in most families. Community social network support systems, including neighbours and grandparents, were important; most children had absentee fathers. Some children suspected or knew how their mother earned her income. Resilience for most children was tagged to support from close networks and financial support from the government and civil society. Children of sex workers in Kampala experience structural, contextual, and mental health challenges but have a positive attitude towards the future. It is important to strengthen community support systems for these children and those living in similar circumstances in low- and middle-income countries.

The atomic structure of FLiNaK and its evolution with temperature are examined with x-ray scattering and molecular dynamics (MD) simulations in the temperature range 460–636 °C. In accord with previous studies, it’s observed that the average nearest-neighbor (NN) cation-anion coordination number increases with increasing cation size, going from ∼4 for Li-F to ∼6.4 for K-F. In addition, we find that there is a coupled change in local coordination geometry – going from tetrahedral for Li-F to octahedral for Na to very disordered quasi-cuboidal for K. The varying geometry and coordination distances for the cation-anion pairs cause a relatively constant F-F next-nearest neighbor (NNN) distance of approximately 3.1 Å. This relatively fixed distance allows the F anions to assume an overall correlated structure very similar to that of a hard-sphere liquid with an extended radius which is beyond the normal F ion size but reflects the cation-anion coordination requirements. Careful consideration of the evolution of the experimental atomic distribution functions with increasing temperature shows that the changes in correlation at each distance can be understood within the context of broadening asymmetric neighbor distributions. Within the temperature range studied, the evolution of F-F correlations with increasing temperature is consistent with changes expected in a hard-sphere liquid simply due to decreasing density.

Hemispherectomy is a surgical procedure in which an entire hemisphere of a patient’s brain is resected or functionally disconnected to manage seizures in individuals with drug-resistant epilepsy. Despite the extensive loss of both ventral and dorsal visual pathways in one hemisphere, pediatric patients who have undergone hemispherectomy show a remarkably high degree of perceptual function across many domains. In the current study, we sought to understand the extent to which functions of the ventral and dorsal visual pathways reorganize to the contralateral hemisphere following childhood hemispherectomy. To this end, we collected fMRI data from an equal number of left and right hemispherectomy patients who completed tasks that typically elicit lateralized responses from the ventral or the dorsal pathway, namely, word (left ventral), face (right ventral), tool (left dorsal), and global form (right dorsal) perception. Overall, there was greater evidence of functional reorganization in the ventral pathway than in the dorsal pathway. Importantly, because ventral and dorsal reorganization was tested within the very same patients, these results cannot be explained by idiosyncratic factors such as disease etiology, age at the time of surgery, or age at testing. These findings suggest that because the dorsal pathway may mature earlier, it may have a shorter developmental window of plasticity than the ventral pathway and, hence, be less malleable after perturbation.

Background: Histological grade has been regarded as the most important prognostic factor in conventional central chondrosarcoma. To evaluate whether the presence of an extraosseous tumour component is associated with a decreased metastasis-free survival or disease-specific survival and alternatively to develop a simple prognostic and clinical decision-making tool. Material and methods: We searched two prospectively maintained international sarcoma centre databases for primary non metastatic central conventional chondrosarcomas of all grades in pelvis, scapula or long bone location, undergoing curative treatment, diagnosed between 2000 and 2020. Pre-treatment MRI scans were reviewed for the presence of an extraosseous mass. The metastasis-free survival (MFS) and disease-specific survival (DSS) were estimated by the Kaplan-Meier method from surgery to event, death or last follow-up. Results: 336 patients were identified between 2000 and 2020, undergoing surgical treatment for conventional central chondrosarcoma. 111 patients (33 %) had grade 1 tumours, 149 patients (44 %) had grade 2, and 76 patient (23 %) had grade 3 chondrosarcomas determined as the highest grade in the final resected specimen. An extraosseous soft tissue component was more frequent in higher grade tumours (p

The executive function (EF) domains of working memory (WM), response inhibition (RI), and set shifting (SS) show maturational gains and are linked to neuroimaging-measured brain changes. This study explored ways in which maturation-linked differences in EF abilities are systematically associated with white matter microstructural differences from adolescence into young adulthood. Diffusion tensor imaging (DTI) and nine neurocognitive tests were collected from 120 healthy subjects ages 12–24. Analyses across the white matter skeleton were performed, focusing on fractional anisotropy (FA). Data were ‘fused’ using a multivariate technique (CCA+jICA), producing four independent components (ICs) depicting white matter FA values that covaried with test performance. Correlations between age and IC loading coefficients identified three EF-DTI profiles that may change developmentally. In one, SS performance was linked to greater reliance on the FA of ventral brain tracts, and less on dorsal tracts with age. In another, white matter microstructure was related to a pattern of strong WM and weak SS that became more pronounced with age. A final IC revealed that younger individuals with low RI and high WM/SS skills typically matured out of this cognitive imbalance, underscored by white matter changes with age. These novel multivariate results begin to emphasize the complexity of brain structure-cognition relationships in adolescents and young adults.

AbstractFocused Ultrasound (FUS)-triggered nano-sized drug delivery, as a smart stimuli-responsive system for treating solid tumors, is computationally investigated to enhance localized delivery of drug and treatment efficacy. Integration of thermosensitive liposome (TSL), as a doxorubicin (DOX)-loaded nanocarrier, and FUS, provides a promising drug delivery system. A fully coupled partial differential system of equations, including the Helmholtz equation for FUS propagation, bio-heat transfer, interstitial fluid flow, drug transport in tissue and cellular spaces, and a pharmacodynamic model is first presented for this treatment approach. Equations are then solved by finite element methods to calculate intracellular drug concentration and treatment efficacy. The main objective of this study is to present a multi-physics and multi-scale model to simulate drug release, transport, and delivery to solid tumors, followed by an analysis of how FUS exposure time and drug release rate affect these processes. Our findings not only show the capability of model to replicate this therapeutic approach, but also confirm the benefits of this treatment with an improvement of drug aggregation in tumor and reduction of drug delivery in healthy tissue. For instance, the survival fraction of tumor cells after this treatment dropped to 62.4%, because of a large amount of delivered drugs to cancer cells. Next, a combination of three release rates (ultrafast, fast, and slow) and FUS exposure times (10, 30, and 60 min) was examined. Area under curve (AUC) results show that the combination of 30 min FUS exposure and rapid drug release leads to a practical and effective therapeutic response.

Purpose: To investigate the relationship between complement pathway activities and progression of geographic atrophy (GA) secondary to age-related macular degeneration in samples collected from patients enrolled in the Chroma and Spectri trials. Design: Chroma and Spectri were phase III, double-masked, and sham-controlled, 96-week trials. Participants: Aqueous humor (AH) samples collected at baseline and week 24 visits from 81 patients with bilateral GA across all 3 treatment groups (intravitreal lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested, along with patient-matched plasma samples collected at baseline. Methods: Antibody capture assays using the Simoa platform were used to measure the levels of complement factor B, the Bb fragment of complement factor B, intact complement component 3 (C3), processed C3, intact complement C4, and processed C4. Complement factor D levels were measured using enzyme-linked immunosorbent assay. Main Outcome Measures: Correlations of complement levels and activities (i.e., processed:intact ratio of complement component) in AH and plasma with baseline GA lesion size and growth rate. Results: In baseline AH, there were strong correlations (Spearman’s rho ≥ 0.80) between intact complement proteins, between processed complement proteins, and between linked processed and intact complement proteins; weak correlations (rho ≤ 0.24) were found between complement pathway activities. There were no strong correlations between complement protein levels and activities measured in AH and plasma at baseline (rho ≤ 0.37). Baseline complement levels and activities in AH and plasma did not correlate with baseline GA lesion size or change from baseline in GA lesion area at week 48 (i.e., annualized growth rate). There were no strong correlations between changes in complement levels/activities in the AH from baseline to week 24 and annualized GA lesion growth rate. Genotype analysis did not reveal a meaningful correlation between complement-related, age-related macular degeneration risk single-nucleotide polymorphisms and complement levels and activities. Conclusions: Complement levels or activities in AH and plasma did not correlate with GA lesion size or growth rate. This suggests that local complement activation as measured in AH does not appear to be related to GA lesion progression. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Surgical access and visualization for excision of large pathologic lesions of the orbitozygomaticomaxillary complex (OZMC) and caudal oral cavity can be a challenge in veterinary oromaxillofacial surgery and may limit one’s ability to perform such procedures. Combined intra- and extra-oral approaches as well as commissurotomy have been advocated in the past. However, each of these approaches present unique limitations specific to each approach. A transfacial approach that ameliorated these limitations could be advantageous. In this descriptive cohort study, we investigate the application and outcomes of a maxillary transfacial approach to the OZMC and caudal oral cavity in six client-owned dogs. The approach is based on the Weber–Ferguson approach for human applications and provided excellent exposure of the intended region in all six patients. We contend the maxillary transfacial approach provides some advantages to the more conventional combined intra-oral/extra-oral approach or commissurotomy for excision of large pathologic lesions of the OZMC and caudal oral cavity.

This study investigated the potential of employing plantain leaves as a natural bio-based sorbent for crude oil spill polluted seawater remediation. Type L9(34) Taguchi orthogonal array technique was used to evaluate the effect of four independent bio-sorption factors at three different levels (crude oil initial concentration (X1 7.8, 11.5 and 15.6 g/L), seawater-crude oil temperature (X2 25, 35 and 45 °C), bio-sorbent dosage (X3 1, 2 and 3 g) and bio-sorbent particle size (X4 1.18, 2.36 and 4.72 mm) on two response indices (bio-sorption efficiency (%) and bio-sorption capacity (g/g)). Taguchi optimization technique, numerical-desirability index function optimization technique and a proposed optimization method were utilized to determine the optimum bio-sorption factors needed for the optimum bio-sorption efficiency and bio-sorption capacity. The results demonstrated that the crude oil bio-sorption efficiency of the plantain leaves was significantly influenced by X1, X3 and X4 and the bio-sorption capacity was mainly influenced by X1 and X3. The optimum bio-sorption efficiency and the optimum bio-sorption capacity were 99.05 % and 12.82 g/g, respectively, obtained at optimum combination of factors and levels of X11 (7.8 g/L), X33 (3 g) and X41 (1.18 mm) for bio-sorption efficiency and X13 (15.6 g/L) X31 (1 g) for bio-sorption capacity. The Freundlich and Dubinin-Rudeshkevich isotherm models best explain the equilibrium bio-sorption data, while the pseudo-second order kinetic model best describes the bio-sorption kinetics. The bio-sorptive remediation mechanism followed dual mechanism of physical and chemical bio-sorption and the mass transfer controlled by film diffusion. The maximum bio-sorption capacity (Kf) was 14.0 gg-1.

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate of 80%, complete response rate of 60%, and a median progression-free survival of 17.9 months in patients with relapsed/refractory (r/r) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for r/r FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with r/r FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching-adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. Overall response rates (73%, 95% CI:65-80%) and complete response rates (53%, 95% CI:45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI:70-88%; CR=60%, 95% CI:49-70% respectively). Progression-free survival at 12 months was similar in the weighted LEO CReWE (60%, 95% CI:51-69%) and the mosunetuzumab trial (PFS 58%, 95% CI:47-68%). Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria, provide context for best practices in this setting.

Controlled, localized, and timely activation of nanosized drug delivery systems (NSDDSs), using an external stimulus such as therapeutic ultrasound (TUS), can improve the efficacy of cancer treatments compared to either conventional chemotherapy methods or passive NSDDSs alone. Specifically, TUS induces thermal and mechanical effects that trigger drug release from NSDDSs and overcomes drug delivery barriers in tumor microenvironments to allow nanoparticle drug carriers to penetrate more deeply into tumor tissue while minimizing side effects. This review highlights recent advancements, contemplates future prospects, and addresses challenges in using TUS-mediated NSDDSs for cancer treatment, encompassing preclinical and clinical applications.

Rationale There is conflicting evidence whether aerobic exercise training (AET) reduces pulse wave velocity (PWV) in adults with and without long-term conditions (LTCs).Objective To explore whether PWV improves with AET in adults with and without LTC, to quantify the magnitude of any effect and understand the influence of the exercise prescription.Data sources CENTRAL, MEDLINE and EMBASE were among the databases searched.Eligibility criteria We included studies with a PWV measurement before and after supervised AET of at least 3 weeks duration. Exclusion criteria included resistance exercise and alternative measures of arterial stiffness.Design Controlled trials were included in a random effects meta-analysis to explore the effect of AET on PWV. Uncontrolled studies were included in a secondary meta-analysis and meta-regression exploring the effect of patient and programme factors on change in PWV. The relevant risk of bias tool was used for each study design.Results 79 studies (n=3729) were included: 35 controlled studies (21 randomised control trials (RCT) (n=1240) and 12 non-RCT (n=463)) and 44 uncontrolled (n=2026). In the controlled meta- analysis, PWV was significantly reduced following AET (mean (SD) 11 (7) weeks) in adults with and without LTC (mean difference −0.63; 95% CI −0.82 to −0.44; p

Abstract This paper summarizes the open community conventions developed by the Ecological Forecasting Initiative (EFI) for the common formatting and archiving of ecological forecasts and the metadata associated with these forecasts. Such open standards are intended to promote interoperability and facilitate forecast communication, distribution, validation, and synthesis. For output files, we first describe the convention conceptually in terms of global attributes, forecast dimensions, forecasted variables, and ancillary indicator variables. We then illustrate the application of this convention to the two file formats that are currently preferred by the EFI, netCDF (network common data form), and comma‐separated values (CSV), but note that the convention is extensible to future formats. For metadata, EFI's convention identifies a subset of conventional metadata variables that are required (e.g., temporal resolution and output variables) but focuses on developing a framework for storing information about forecast uncertainty propagation, data assimilation, and model complexity, which aims to facilitate cross‐forecast synthesis. The initial application of this convention expands upon the Ecological Metadata Language (EML), a commonly used metadata standard in ecology. To facilitate community adoption, we also provide a Github repository containing a metadata validator tool and several vignettes in R and Python on how to both write and read in the EFI standard. Lastly, we provide guidance on forecast archiving, making an important distinction between short‐term dissemination and long‐term forecast archiving, while also touching on the archiving of code and workflows. Overall, the EFI convention is a living document that can continue to evolve over time through an open community process.

Cumulative scientific progress requires empirical results that are robust enough to support theory construction and extension. Yet in psychology, some prominent findings have failed to replicate, and large-scale studies suggest replicability issues are widespread. The identification of predictors of replication success is limited by the difficulty of conducting large samples of independent replication experiments, however: most investigations reanalyse the same set of [Formula: see text]. We introduce a new dataset of 176 replications from students in a graduate-level methods course. Replication results were judged to be successful in 49% of replications; of the 136 where effect sizes could be numerically compared, 46% had point estimates within the prediction interval of the original outcome (versus the expected 95%). Larger original effect sizes and within-participants designs were especially related to replication success. Our results indicate that, consistent with prior reports, the robustness of the psychology literature is low enough to limit cumulative progress by student investigators.

O26 is the commonest non-O157 Shiga toxin (stx)-producing Escherichia coli serogroup reported in human infections worldwide. Ruminants, particularly cattle, are the primary reservoir source for human infection. In this study, we compared the whole genomes and virulence profiles of O26:H11 strains (n = 99) isolated from Scottish cattle with strains from human infections (n = 96) held by the Scottish Escherichia coli O157/STEC Reference Laboratory, isolated between 2002 and 2020. Bovine strains were from two national cross-sectional cattle surveys conducted between 2002–2004 and 2014–2015. A maximum likelihood phylogeny was constructed from a core-genome alignment with the O26:H11 strain 11368 reference genome. Genomes were screened against a panel of 2,710 virulence genes using the Virulence Finder Database. All stx-positive bovine O26:H11 strains belonged to the ST21 lineage and were grouped into three main clades. Bovine and human source strains were interspersed, and the stx subtype was relatively clade-specific. Highly pathogenic stx2a-only ST21 strains were identified in two herds sampled in the second cattle survey and in human clinical infections from 2010 onwards. The closest pairwise distance was 9 single-nucleotide polymorphisms (SNPs) between Scottish bovine and human strains and 69 SNPs between the two cattle surveys. Bovine O26:H11 was compared to public EnteroBase ST29 complex genomes and found to have the greatest commonality with O26:H11 strains from the rest of the UK, followed by France, Italy, and Belgium. Virulence profiles of stx-positive bovine and human strains were similar but more conserved for the stx2a subtype. O26:H11 stx-negative ST29 (n = 17) and ST396 strains (n = 5) were isolated from 19 cattle herds; all were eae-positive, and 10 of these herds yielded strains positive for ehxA, espK, and Z2098, gene markers suggestive of enterohaemorrhagic potential. There was a significant association (p

BackgroundUnderstanding of the epidemiology and biology of pediatric CNS tumors has advanced dramatically over the last decade; however there remains a discrepancy in the understanding of epidemiologic data and clinical capacity between high- and lower-income countries.ObjectiveWe collected and analyzed hospital-level burden and capacity-oriented data from pediatric neurosurgical oncology units at 7 referral hospitals in Sub-Saharan Africa (SSA).MethodsA cross sectional epidemiological survey was conducted using REDCap at the 7 SSA sites, capturing 3-month aggregate data for patients managed over a total of 9 months. Descriptive statistical analyses for the aggregate data were performed.ResultsAcross the neurosurgical spectrum, 15% of neurosurgery outpatient and 16% of neurosurgery operative volume was represented by pediatric neuro-oncology across the 7 study sites. Eighty-six percent and 87% of patients who received surgery underwent preoperative CT scan and/or MRI respectively. Among 312 patients evaluated with a CNS tumor, 211 (68%) underwent surgery. Mean surgery wait time was 26.6 ± 36.3 days after initial presentation at the clinic. The most common tumor location was posterior fossa (n=94, 30%), followed by sellar/suprasellar region (n=56, 18%). Histopathologic analysis was performed for 189 patients (89%). The most common pathologic diagnosis was low grade glioma (n=43, 23%), followed by medulloblastoma (n=37, 20%), and craniopharyngioma (n=31, 17%). Among patients for whom adjuvant therapy was indicated, only 26% received chemotherapy and 15% received radiotherapy.ConclusionThe histopathologic variety of pediatric brain and spinal tumors managed across 7 SSA referral hospitals was similar to published accounts from other parts of the world. About two-thirds of patients received a tumor-directed surgery with significant inter-institutional variability. Less than a third of patients received adjuvant therapy when indicated. Multi-dimensional capacity building efforts in neuro-oncology are necessary to approach parity in the management of children with brain and spinal tumors in SSA.