Twenty Years of Get With The Guidelines-Stroke: Celebrating Past Successes, Lessons Learned, and Future Challenges.

The Get With The Guidelines-Stroke program which, began 20 years ago, is one of the largest and most important nationally representative disease registries in the United States. Its importance to the stroke community can be gauged by its sustained growth and widespread dissemination of findings that demonstrate sustained increases in both the quality of care and patient outcomes over time. The objectives of this narrative review are to provide a brief history of Get With The Guidelines-Stroke, summarize its major successes and impact, and highlight lessons learned. Looking to the next 20 years, we discuss potential challenges and opportunities for the program.

Sex Differences in Trends in Stroke Recurrence and Postrecurrence Mortality 2000-2020: Population-Based Brain Attack Surveillance in Corpus Christi Project.

OBJECTIVE: This study was undertaken to delineate 21-year sex-specific trends in recurrence and postrecurrence mortality. METHODS: Between 2000 and 2020, first-ever ischemic stroke (IS) patients, ascertained from the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in South Texas, were followed for recurrent stroke and all-cause mortality until December 31, 2020. Multivariable regression models with an interaction between calendar year and sex were used to estimate sex-specific trends and sex differences in recurrence and postrecurrence mortality. RESULTS: Of the 6,057 IS patients (median age = 69 years, 49.8% women), 654 (10.8%) had a recurrence and 399 (47.7%) had postrecurrence mortality during 5 years of follow-up. In 2000, women had 2.5% higher albeit non-statistically significant 5-year risk of recurrence than men in absolute scale. With the trend declining in women by 7.6% (95% confidence interval [CI] = -10.8 to -4.5%) and in men by 3.6% (95% CI = -6.5% to -0.7%), the risk at the end of the study period was 1.5% (95% CI = -0.3% to 3.6%) lower among women than men. For postrecurrence mortality, the risk was 10.2% lower among women in 2000, but the sex difference was 3.3% by the end of the period, which was due to a larger overall increase in the risk among women than men over the entire time period. INTERPRETATION: The declines in recurrent stroke suggest successful secondary stroke prevention, especially in women. However, the continued high postrecurrence mortality among both sexes at the end of study period emphasizes the need for ongoing interventions to improve prognosis in those who have had recurrent cerebrovascular events. ANN NEUROL 2024.

Symptoms, concerns, and experiences of women living with and beyond breast cancer in Africa: A mixed-methods systematic review.

OBJECTIVE: A mixed-methods systematic review to determine reported symptoms, concerns, and experiences of women living with and beyond breast cancer in Africa. METHODS: Literature searches were conducted in Medline, Embase, PsycINFO, Global Health, Web of Science, CINAHL, and the Cochrane Library. Quantitative and qualitative studies that comprised study populations of women with breast cancer from countries in Africa, detailing symptoms, concerns, and experiences of living with and beyond breast cancer were included. Inductive framework analysis was applied to organise existing literature with the Adversity, Restoration, and Compatibility framework and quality was assessed using the Mixed Methods Appraisal Tool. RESULTS: In total, 48 studies were included, comprising quantitative (n = 24), qualitative (n = 23) and mixed method (n = 1) studies. Women reported multiple complex and burdensome symptoms at all stages of the breast cancer disease trajectory. Multiple pervasive factors influencing participants' experiences included a lack of cancer knowledge, being removed from decision-making, religion, and the presence and use of traditional medicines. Literature relating to benefit finding, understanding identity for the future, and broader perspectives of well-being was absent. CONCLUSIONS: This review contributes insights and mapping of symptoms, concerns, and experiences of women with breast cancer in Africa. There is a great necessity to increase an understanding of the needs and experiences of women with breast cancer in Africa following cancer treatment, stages of remission, and longer-term monitoring and follow-up. This is required to ensure access to prompt and timely clinical and individualized supportive care for women with breast cancer in Africa.

Single nucleus and spatial transcriptomic profiling of healthy human hamstring tendon.

The molecular and cellular basis of health in human tendons remains poorly understood. Among human tendons, hamstring tendon has markedly low pathology and can provide a prototypic healthy tendon reference. The aim of this study was to determine the transcriptomes and location of all cell types in healthy hamstring tendon. Using single nucleus RNA sequencing, we profiled the transcriptomes of 10 533 nuclei from four healthy donors and identified 12 distinct cell types. We confirmed the presence of two fibroblast cell types, endothelial cells, mural cells, and immune cells, and identified cell types previously unreported in tendons, including different skeletal muscle cell types, satellite cells, adipocytes, and undefined nervous system cells. The location of these cell types within tendon was defined using spatial transcriptomics and imaging, and potential transcriptional networks and cell-cell interactions were analyzed. We demonstrate that fibroblasts have the highest number of potential cell-cell interactions in our dataset, are present throughout the tendon, and play an important role in the production and organization of extracellular matrix, thus confirming their role as key regulators of hamstring tendon homeostasis. Overall, our findings underscore the complexity of the cellular networks that underpin healthy human tendon function and the central role of fibroblasts as key regulators of hamstring tendon tissue homeostasis.

Tibial and femoral articular cartilage exhibit opposite outcomes for T1ρ and T2* relaxation times in response to acute compressive loading in healthy knees.

Abnormal loading is thought to play a key role in the disease progression of cartilage, but our understanding of how cartilage compositional measurements respond to acute compressive loading in-vivo is limited. Ten healthy subjects were scanned at two timepoints (7 ± 3 days apart) with a 3 T magnetic resonance imaging (MRI) scanner. Scanning sessions included T1ρ and T2* acquisitions of each knee in two conditions: unloaded (traditional MRI setup) and loaded in compression at 40 % bodyweight as applied by an MRI-compatible loading device. T1ρ and T2* parameters were quantified for contacting cartilage (tibial and femoral) and non-contacting cartilage (posterior femoral condyle) regions. Significant effects of load were found in contacting regions for both T1ρ and T2*. The effect of load (loaded minus unloaded) in femoral contacting regions ranged from 4.1 to 6.9 ms for T1ρ, and 3.5 to 13.7 ms for T2*, whereas tibial contacting regions ranged from -5.6 to -1.7 ms for T1ρ, and -2.1 to 0.7 ms for T2*. Notably, the responses to load in the femoral and tibial cartilage revealed opposite effects. No significant differences were found in response to load between the two visits. This is the first study that analyzed the effects of acute loading on T1ρ and T2* measurements in human femoral and tibial cartilage separately. The results suggest the effect of acute compressive loading on T1ρ and T2* was: 1) opposite in the femoral and tibial cartilage; 2) larger in contacting regions than in non-contacting regions of the femoral cartilage; and 3) not different visit-to-visit.

Who is the majority group? Signaling majority group membership with name-based treatments in multilingual contexts: The case of Catalonia.

An increasing body of work has shown how the selection of names shapes patterns of ethnic and racial discrimination in hiring observed in correspondence audit studies. A clear limitation of the existing research on name perceptions and ethnic discrimination in employment is that is predominantly based in the US, which limits its applicability to contexts with high linguistic diversity among the majority population. These territories confront a reality where language preferences and uses, social class, and ancestry are associated with specific names among the native majority group. The result is notable diversity in the labor market (dis)advantages conferred by different names within the majority population. To fill this gap, this article focuses on Catalonia, a diverse multilingual region and Spain's second most populated area. Using two complementary studies, this work identifies the direct influence of names in the hiring process (Study 1) and evaluates the associations between names and perceptions of geographic origin, social class, and linguistic competence (Study 2). The results show that having a Catalan name confers an advantage in the labour market via three mechanisms. First, names inform a perception of language proficiency, which is tied to an expectation of productivity. Second, names signal social class and certain names in the majority group (applicants with two Catalan surnames, a minority within the region), indicate higher social class, which affords an advantage. Third, some advantage could be linked to tastes that favor an ingroup for reasons of assumed cultural, historical, or political compatibility. The approach adopted in this article holds significant relevance to other research on ethnic discrimination conducted in multilingual contexts with comparable autochthonous diversity.

Deficiency of the paternally-expressed imprinted Peg3 gene in mice has sexually dimorphic consequences for offspring communication and social behaviour.

Introduction: Imprinted genes are expressed from one parental allele as a consequence of epigenetic processes initiated in the germline. Consequently, their ability to influence phenotype depends on their parent-of-origin. Recent research suggests that the sex of the individual expressing the imprinted gene is also important. We have previously reported that genetically wildtype (WT) dams carrying and caring for pups mutant for PEG3 exhibit anxiety-like behaviours and their mutant pups show a reduction in ultrasonic vocalisation when separated from their mothers. Sex-specificity was not examined. Methods: WT female mice were mated with WT, heterozygous Peg3-/+ or homozygous Peg3-/- studs to generate all WT (control), 50:50 mixed or 100% mutant litters, respectively, followed by behavioural assessment of both dams and their pups. Results: We reproduced our original finding that WT dams carrying and caring for 100% mutant litters exhibit postpartum anxiety-like symptoms and delayed pup retrieval. Additionally, these WT dams were found to allocate less time to pup-directed care behaviours relative to controls. Male Peg3-deficient pups demonstrated significantly reduced vocalisation with a more subtle communication deficit in females. Postweaning, male mutants exhibited deficits across a number of key social behaviours as did WT males sharing their environment with mutants. Only modest variations in social behaviour were detected in experimental females. Discussion: We have experimentally demonstrated that Peg3 deficiency confined to the offspring causes anxiety in mouse mothers and atypical behaviour including deficits in communication in their male offspring. A male-specific reduction in expression PEG3 in the fetally-derived placenta has previously been associated with maternal depression in human pregnancy. Maternal mood disorders such as depression and anxiety are associated with delays in language development and neuroatypical behaviour more common in sons. Peg3 deficiency could drive the association of maternal and offspring behavioural disorders reported in humans.

Factors Associated With Premature Termination of Hyperacute Stroke Trials: A Review.

BACKGROUND: We performed a review of acute stroke trials to determine features associated with premature termination of trial enrollment, defined by the authors as not meeting preplanned sample size. METHODS AND RESULTS: MEDLINE was searched for randomized clinical stroke trials published in 9 major clinical journals between 2013 and 2022. We included randomized clinical trials that were phase 2 or 3 with a preplanned sample size ≥100 and a time-to-treatment within 24 hours of onset for transient ischemic attack, ischemic stroke, or intracerebral hemorrhage. Data were abstracted on trial features including trial design, inclusion criteria, imaging, location and number of sites, masking, treatment complexity, control group (standard therapy, placebo), industry involvement, and preplanned stopping rules (futility and efficacy). Least absolute shrinkage and selection operator regression was used to select the most important factors associated with premature termination; then, a multivariable logistic regression was fit including only the least absolute shrinkage and selection operator selected variables. Of 1475 studies assessed, 98 trials met eligibility criteria. Forty-five (46%) trials were prematurely terminated, of which 27% were stopped for benefit/efficacy, 20% for lack of money/slow enrollment, 18% for futility, 16% for newly available evidence, 17% for other reasons, and 4% due to harm. Complex trials (adjusted odds ratio [aOR], 2.76 [95% CI, 1.13-7.49]), presence of a futility rule (aOR, 4.43 [95% CI, 1.62-17.91]), and exclusion of prestroke dependency (none/slight disability only; aOR, 2.19 [95% CI, 0.84-6.72] versus dependency allowed) were identified as the strongest predictors. CONCLUSIONS: Nearly half of acute stroke trials were terminated prematurely. Broadening inclusion criteria and simplifying trial design may decrease the likelihood of unplanned termination, whereas planned futility analyses may appropriately terminate trials early, saving money and resources.

Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair (MMR) alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.

Active and Transfer Learning of High-Dimensional Neural Network Potentials for Transition Metals.

Classical molecular dynamics (MD) simulations represent a very popular and powerful tool for materials modeling and design. The predictive power of MD hinges on the ability of the interatomic potential to capture the underlying physics and chemistry. There have been decades of seminal work on developing interatomic potentials, albeit with a focus predominantly on capturing the properties of bulk materials. Such physics-based models, while extensively deployed for predicting the dynamics and properties of nanoscale systems over the past two decades, tend to perform poorly in predicting nanoscale potential energy surfaces (PESs) when compared to high-fidelity first-principles calculations. These limitations stem from the lack of flexibility in such models, which rely on a predefined functional form. Machine learning (ML) models and approaches have emerged as a viable alternative to capture the diverse size-dependent cluster geometries, nanoscale dynamics, and the complex nanoscale PESs, without sacrificing the bulk properties. Here, we introduce an ML workflow that combines transfer and active learning strategies to develop high-dimensional neural networks (NNs) for capturing the cluster and bulk properties for several different transition metals with applications in catalysis, microelectronics, and energy storage, to name a few. Our NN first learns the bulk PES from the high-quality physics-based models in literature and subsequently augments this learning via retraining with a higher-fidelity first-principles training data set to concurrently capture both the nanoscale and bulk PES. Our workflow departs from status-quo in its ability to learn from a sparsely sampled data set that nonetheless covers a diverse range of cluster configurations from near-equilibrium to highly nonequilibrium as well as learning strategies that iteratively improve the fingerprinting depending on model fidelity. All the developed models are rigorously tested against an extensive first-principles data set of energies and forces of cluster configurations as well as several properties of bulk configurations for 10 different transition metals. Our approach is material agnostic and provides a methodology to transfer and build upon the learnings from decades of seminal work in molecular simulations on to a new generation of ML-trained potentials to accelerate materials discovery and design.

Overcoming barriers to single-cell RNA sequencing adoption in low- and middle-income countries.

The advent of single-cell resolution sequencing and spatial transcriptomics has enabled the delivery of cellular and molecular atlases of tissues and organs, providing new insights into tissue health and disease. However, if the full potential of these technologies is to be equitably realised, ancestrally inclusivity is paramount. Such a goal requires greater inclusion of both researchers and donors in low- and middle-income countries (LMICs). In this perspective, we describe the current landscape of ancestral inclusivity in genomic and single-cell transcriptomic studies. We discuss the collaborative efforts needed to scale the barriers to establishing, expanding, and adopting single-cell sequencing research in LMICs and to enable globally impactful outcomes of these technologies.

Antibody-mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium.

BACKGROUND: Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. There is a paucity of large-scale pediatric-specific data regarding AMR treatment outcomes. METHODS: Data were obtained from 14 centers within the Pediatric Nephrology Research Consortium. Kidney transplant recipients aged 1-18 years at transplant with biopsy-proven AMR between 2009 and 2019 and at least 12 months of follow-up were included. The primary outcome was graft failure or an eGFR <20 mL/min/1.73 m2 at 12 months following AMR treatment. AMR treatment choice, histopathology, and DSA class were also examined. RESULTS: We reviewed 123 AMR episodes. Median age at diagnosis was 15 years at a median 22 months post-transplant. The primary outcome developed in 27.6%. eGFR <30 m/min/1.73 m2 at AMR diagnosis was associated with a 5.6-fold higher risk of reaching the composite outcome. There were no significant differences in outcome by treatment modality. Histopathology scores and DSA class at time of AMR diagnosis were not significantly associated with the primary outcome. CONCLUSIONS: In this large cohort of pediatric kidney transplant recipients with AMR, nearly one-third of patients experienced graft failure or significant graft dysfunction within 12 months of diagnosis. Poor graft function at time of diagnosis was associated with higher odds of graft failure.

Road vehicle collision suicide in Australia: Trends, collision types, and individual characteristics.

BACKGROUND: Suicide by road vehicle collision in Australia is under-explored with mixed findings. We aimed to address this research gap by examining time trends, different types of vehicle collision, and individual characteristics related to vehicle-collision suicide. METHOD: We retrospectively analyzed deaths by suicide between 1st January 2001 and 31st December 2017 in Australia, using coronial records from the National Coronial Information System. The travel mode used and collision counterpart were retrieved from records of death by vehicle-collision suicide using all available information. We conducted negative binomial regression analysis to examine annual changes in suicide rate by vehicle collision on a public road (N = 640) and other methods of suicide (N = 41,890), and logistic regression analysis to examine individual characteristics associated with the likelihood of dying by suicide via road vehicle collision. RESULTS: Overall, the national suicide rate involving road vehicle collision significantly increased, while the rate by other methods significantly decreased. Drivers accounted for 61% of suicide events by vehicle collision, of which 72% were single-vehicle collisions (commonly involving a tree). For multiple-vehicle collision suicide events, 82% involved collision with a truck. Pedestrians accounted for more than one-third of suicide events, of which 58% involved collision with a truck and 23% involved collision with a car/van. Individuals who were male (odds ratio 1.15; 95% CI 0.88-1.50), aged <25 years old (odds ratio 5.27; 95% CI 3.05-9.10), non-Indigenous (odds ratio 3.36; 95% CI 1.71-6.62), and born overseas (odds ratio 1.40; 95% CI 1.10-1.79) were more likely to die by vehicle-collision suicide than by other methods of suicide. CONCLUSIONS: This study provides a better understanding of road vehicle collision suicide in Australia and informs future research directions on topic. Our findings can be used to inform suicide prevention initiatives to reduce vehicle-collision suicide deaths.

Study protocol for a pilot clinical trial to understand neural mechanisms of response to a psychological treatment for pain and anxiety in pediatric functional abdominal pain disorders (FAPD).

BACKGROUND: Functional abdominal pain disorders (FAPD) are the most common chronic pain conditions of childhood and are made worse by co-occurring anxiety. Our research team found that the Aim to Decrease Pain and Anxiety Treatment (ADAPT), a six-session coping skills program using cognitive behavioral therapy strategies, was effective in improving pain-related symptoms and anxiety symptoms compared to standard care. In follow-up, this current randomized clinical trial (RCT) aims to test potential neural mechanisms underlying the effect of ADAPT. Specifically, this two-arm RCT will explore changes in amygdalar functional connectivity (primary outcome) following the ADAPT protocol during the water loading symptom provocation task (WL-SPT). Secondary (e.g., changes in regional cerebral blood flow via pulsed arterial spin labeling MRI) and exploratory (e.g., the association between the changes in functional connectivity and clinical symptoms) outcomes will also be investigated. METHODS: We will include patients ages 11 to 16 years presenting to outpatient pediatric gastroenterology care at a midwestern children's hospital with a diagnosis of FAPD plus evidence of clinical anxiety based on a validated screening tool (the Generalized Anxiety Disorder-7 [GAD-7] measure). Eligible participants will undergo baseline neuroimaging involving the WL-SPT, and assessment of self-reported pain, anxiety, and additional symptoms, prior to being randomized to a six-week remotely delivered ADAPT program plus standard medical care or standard medical care alone (waitlist). Thereafter, subjects will complete a post assessment neuroimaging visit similar in nature to their first visit. CONCLUSIONS: This small scale RCT aims to increase understanding of potential neural mechanisms of response to ADAPT. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT03518216.

On-Demand Bioactivation of Inert Materials With Plasma-Polymerized Nanoparticles.

Conventional gas plasma treatments are crucial for functionalizing materials in biomedical applications, but have limitations hindering their broader use. These methods require exposure to reactive media under vacuum conditions, rendering them unsuitable for substrates that demand aqueous environments, such as proteins and hydrogels. In addition, complex geometries are difficult to treat, necessitating extensive customization for each material and shape. To address these constraints, an innovative approach employing plasma polymer nanoparticles (PPN) as a versatile functionalization tool is proposed. PPN share similarities with traditional plasma polymer coatings (PPC) but offer unique advantages: compatibility with aqueous systems, the ability to modify complex geometries, and availability as off-the-shelf products. Robust immobilization of PPN on various substrates, including synthetic polymers, proteins, and complex hydrogel structures is demonstrated in this study. This results in substantial improvements in surface hydrophilicity. Materials functionalization with arginylglycylaspartic acid (RGD)-loaded PPN significantly enhances cell attachment, spreading, and substrate coverage on inert scaffolds compared to passive RGD coatings. Improved adhesion to complex geometries and subsequent differentiation following growth factor exposure is also demonstrated. This research introduces a novel substrate functionalization approach that mimics the outcomes of plasma coating technology but vastly expands its applicability, promising advancements in biomedical materials and devices.

Impacts of updated reaction kinetics on the global GEOS-Chem simulation of atmospheric chemistry.

We updated the chemical mechanism of the GEOS-Chem global 3-D model of atmospheric chemistry to include new recommendations from the NASA Jet Propulsion Laboratory (JPL) chemical kinetics Data Evaluation 19-5 and from the International Union of Pure and Applied Chemistry (IUPAC) and to balance carbon and nitrogen. We examined the impact of these updates on the GEOS-Chem version 14.0.1 simulation. Notable changes include 11 updates to reactions of reactive nitrogen species, resulting in a 7% net increase in the stratospheric NOx (NO + NO2) burden; an updated CO + OH rate formula leading to a 2.7% reduction in total tropospheric CO; adjustments to the rate coefficient and branching ratios of propane + OH, leading to reduced tropospheric propane (-17%) and increased acetone (+3.5%) burdens; a 41% increase in the tropospheric burden of peroxyacetic acid due to a decrease in the rate coefficient for its reaction with OH, further contributing to reductions in peroxyacetyl nitrate (PAN; -3.8%) and acetic acid (-3.4%); and a number of minor adjustments to halogen radical cycling. Changes to the global tropospheric burdens of other species include -0.7% for ozone, +0.3% for OH (-0.4% for methane lifetime against oxidation by tropospheric OH), +0.8% for formaldehyde, and -1.7% for NOx. The updated mechanism reflects the current state of the science, including complex chemical dependencies of key atmospheric species on temperature, pressure, and concentrations of other compounds. The improved conservation of carbon and nitrogen will facilitate future studies of their overall atmospheric budgets.

Utilization and Reporting of Patient-Reported Outcome Measures in Randomized Clinical Trials of Acute Stroke (2010-2020).

BACKGROUND: Patient-reported outcome measures (PROMs) describe health status from the perspective of the patient. There is growing interest in incorporating PROMs into clinical trials, but the extent that such measures are used in contemporary stroke trials is uncertain. We sought to determine how often acute stroke trials included PROMs as outcome measures and assessed the completeness of methodological reporting. METHODS: We searched MEDLINE for randomized controlled trials published in 9 high-impact journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials that tested therapeutic interventions within 1 month of stroke onset. Using the trial's primary publication and protocol, we abstracted key study characteristics including all primary and secondary outcome measures. We defined PROMs as self-reported measures of quality of life, symptoms, or function collected without interpretation of an external party. RESULTS: Of 116 trials that met eligibility, 57 (49%) included at least 1 PROM. Of these, 41 trials (35%) included a PROM in its primary publication, while 16 (14%) identified a PROM in its protocol. Only 1 trial used a PROM as a primary outcome. Among the 57 total trials, the most commonly used measures were Euro-QOL (n=41, 72%), Stroke Impact Scale (n=10, 18%), and Short-Form 36 (n=6, 11%). Trials were more likely to include a PROM if they were published after 2016, were phase 3, or included only hemorrhagic stroke. Of the 41 trials that included a PROM in the primary publication, 40 (97%) provided PROM results, but only 9 (22%) found statistically significant differences between treatment groups. Quality of methodological reporting was generally poor. CONCLUSIONS: Half of contemporary acute stroke trials published in high-impact journals listed at least 1 PROM as a secondary outcome, but they played a minor role in the presentation of the final trial results. Inclusion of PROMs in acute stroke trials requires greater attention during both the design and reporting phases of the trial. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019128727.

Durability of the moderate-to-heavy-intensity transition is related to the effects of prolonged exercise on severe-intensity performance.

PURPOSE: Power output at the moderate-to-heavy-intensity transition decreases during prolonged exercise, and resilience to this has been termed 'durability'. The purpose of this study was to assess the relationship between durability and the effect of prolonged exercise on severe-intensity performance, and explore intramuscular correlates of durability. METHODS: On separate days, 13 well-trained cyclists and triathletes (V̇O2peak, 57.3 ± 4.8 mL kg-1 min-1; training volume, 12 ± 2.1 h week-1) undertook an incremental test and 5-min time trial (TT) to determine power output at the first ventilatory threshold (VT1) and severe-intensity performance, with and without 150-min of prior moderate-intensity cycling. A single resting vastus lateralis microbiopsy was obtained. RESULTS: Prolonged exercise reduced power output at VT1 (211 ± 40 vs. 198 ± 39 W, ∆ -13 ± 16 W, ∆ -6 ± 7%, P = 0.013) and 5-min TT performance (333 ± 75 vs. 302 ± 63 W, ∆ -31 ± 41 W, ∆ -9 ± 10%, P = 0.017). The reduction in 5-min TT performance was significantly associated with durability of VT1 (rs = 0.719, P = 0.007). Durability of VT1 was not related to vastus lateralis carnosine content, citrate synthase activity, or complex I activity (P > 0.05). CONCLUSION: These data provide the first direct support that durability of the moderate-to-heavy-intensity transition is an important performance parameter, as more durable athletes exhibited smaller reductions in 5-min TT performance following prolonged exercise. We did not find relationships between durability and vastus lateralis carnosine content, citrate synthase activity, or complex I activity.

Covert Cerebrovascular Changes in People With Heart Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: To determine the prevalence of silent brain infarction (SBI) and cerebral small vessel disease (CSVD) in adults with atrial fibrillation (AF), coronary artery disease, heart failure or cardiomyopathy, heart valve disease, and patent foramen ovale (PFO), with comparisons between those with and without recent stroke and an exploration of associations between heart disease and SBI/CSVD. METHODS: Medline, Embase, and Cochrane Library were systematically searched for hospital-based or community-based studies reporting SBI/CSVD in people with heart disease. Data were extracted from eligible studies. Outcomes were SBI (primary) and individual CSVD subtypes. Summary prevalence (95% confidence intervals [CIs]) were obtained using random-effects meta-analysis. Pooled prevalence ratios (PRs) (95% CI) were calculated to compare those with heart disease with available control participants without heart disease from studies. RESULTS: A total of 221 observational studies were included. In those with AF, the prevalence was 36% (31%-41%) for SBI (70 studies, N = 13,589), 25% (19%-31%) for lacune (26 studies, N = 7,172), 62% (49%-74%) for white matter hyperintensity/hypoattenuation (WMH) (34 studies, N = 7,229), and 27% (24%-30%) for microbleed (44 studies, N = 13,654). Stratification by studies where participants with recent stroke were recruited identified no differences in the prevalence of SBI across subgroups (phomogeneity = 0.495). Results were comparable across participants with different heart diseases except for those with PFO, in whom there was a lower prevalence of SBI [21% (13%-30%), 11 studies, N = 1,053] and CSVD. Meta-regressions after pooling those with any heart disease identified associations of increased (study level) age and hypertensives with more SBIs and WMH (pregression <0.05). There was no evidence of a difference in the prevalence of microbleed between those with and without heart disease (PR [95% CI] 1.1 [0.7-1.7]), but a difference was seen in the prevalence of SBI and WMH (PR [95% CI] 2.3 [1.6-3.1] and 1.7 [1.1-2.6], respectively). DISCUSSION: People with heart disease have a high prevalence of SBI (and CSVD), which is similar in those with vs without recent stroke. More research is required to assess causal links and implications for management. TRIAL REGISTRATION INFORMATION: PROSPERO CRD42022378272 (crd.york.ac.uk/PROSPERO/).

Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.