Geriatric Oncology: A 5-Year Strategic Plan.

The increasing rate of the older adult population across the world over the next 20 years along with significant developments in the treatment of oncology will require a more granular understanding of the older adult population with cancer. The ASCO Geriatric Oncology Community of Practice (COP) herein provides an outline for the field along three fundamental pillars: education, research, and implementation, inspired by ASCO's 5-Year Strategic Plan. Fundamental to improving the understanding of geriatric oncology is research that intentionally includes older adults with clinically meaningful data supported by grants across all career stages. The increased knowledge base that is developed should be conveyed among health care providers through core competencies for trainees and continuing education for practicing oncologists. ASCO's infrastructure can serve as a resource for fellowship programs interested in acquiring geriatric oncology content and provide recommendations on developing training pathways for fellows interested in pursuing formalized training in geriatrics. Incorporating geriatric oncology into everyday practice is challenging as each clinical setting has unique operational workflows with barriers that limit implementation of valuable geriatric tools such as Geriatric Assessment. Partnerships among experts in quality improvement from the ASCO Geriatric Oncology COP, the Cancer and Aging Research Group, and ASCO's Quality Training Program can provide one such venue for implementation of geriatric oncology through a structured support mechanism. The field of geriatric oncology must continue to find innovative strategies using existing resources and partnerships to address the pressing needs of the older adult population with cancer to improve patient outcomes.

Understanding health outcome preferences of older adults diagnosed with multiple myeloma.

INTRODUCTION: Health outcome preferences of older adults with cancer vary based on burden/intensity of treatment and its impact on health outcomes such as survival, quality of life, and functional and cognitive well-being. We studied the association between age and health outcome preferences of adults with multiple myeloma (MM). MATERIALS AND METHODS: Using a single center prospective cohort study, we identified adults ≥50y with MM who underwent geriatric assessment (GA) within 30 days of initiating a new line of therapy. We assessed health outcome preferences using a nine-item health outcome preference scale where patients were asked to prioritize varying treatment outcomes in a Likert scale. We compared the response patterns for each item by age group (50-69y vs ≥70y) using Mantel-Haenszel chi-squared test. For items significant in bi-variable analysis, we built proportional odds models to study the association between age and health outcome preferences adjusting for sex, race, frailty, and high risk cytogenetics. RESULTS: We included 119 patients with a median age of 65y. Of these, 58% were male, 56% were non-Hispanic White, and 28% were frail. Older adults (≥70y) versus younger adults (50-69y) were more likely to prioritize health outcomes such as quality of life (53% vs. 34%), functional independence (74% vs. 33%), maintaining cognitive ability (79% vs. 54%), and living free from pain (50% vs 18%) over longer survival (all p values <0.05). In multivariable models, each one interquartile range (IQR) increase in age was associated with increased odds of prioritization of functional independence [adjusted odds ratio (aOR) 2.55, 95% confidence interval (CI) (1.44-4.53)], maintaining cognitive ability [aOR 1.75, 95% CI (1.01-3.02)], and willingness to take milder/ fewer treatments [aOR 2.40, 95% CI (1.36-4.26)] over longer survival. Similarly, each IQR increase in age was associated with decreased odds of prioritization of survival over quality of life [aOR 0.45, 95% CI (0.26-0.78)] and survival over being free from pain [aOR 0.39, 95% CI (0.22-0.69)]. DISCUSSION: Three out of four older adults (age ≥ 70y) with MM rated other outcomes, particularly functional and cognitive well-being, above survival. Determining the most significant treatment outcomes for older adults with MM can aid in establishing treatment goals and enhance shared decision-making.

Physical Fitness Surveillance and Monitoring Systems Inventory for Children and Adolescents: A Scoping Review with a Global Perspective.

Surveillance of health-related physical fitness can improve decision-making and intervention strategies promoting health for children and adolescents. However, no study has comprehensively analyzed surveillance/monitoring systems for physical fitness globally. This review sought to address this gap by identifying: (1) national-level surveillance/monitoring systems for physical fitness among children and adolescents globally, (2) the main barriers and challenges to implementing surveillance/monitoring systems, and (3) governmental actions related to existing surveillance/monitoring systems. We used a scoping review to search, obtain, group, summarize, and analyze available evidence. Our review involved three stages: (1) identification of surveillance systems through a systematic literature review, with complementary search of the grey literature (e.g., reference lists, Google Scholar, webpages, recommendations), (2) systematic consultation with relevant experts using a Delphi method to confirm/add systems and to gather and analyze information on the barriers and challenges to implementing systems, and (3) Web searches for public documents on government sites and surveillance/monitoring system pages, and direct internet searches to identify relevant governmental actions related to surveillance systems. A total of 15 fitness surveillance/monitoring systems met our inclusion criteria. Experts identified a lack of government support and funding, and the low priority of fitness on the public health agenda as the main barriers/challenges to implementation. Several governmental actions related to surveillance systems were identified, including policies, strategies, programs, and guidelines. We propose a Global Observatory of Physical Fitness to help address these issues.

Weakness Thresholds Are Differentially Linked to Cognitive Function by Obesity Status in Older Americans.

Background: Weakness can be operationalized with several thresholds, which in turn, could impact associations with cognitive impairment when considering obesity status. Objective: We examined the associations of absolute, normalized, and collective weakness thresholds on future cognitive impairment by obesity status in older adults. Methods: We performed a secondary data analysis on the 2006-2018 waves of the Health and Retirement Study. A spring-type dynamometer collected handgrip strength (HGS). Males were categorized weak if their HGS was <35.5-kg (absolute), <0.45-kg/kg (body mass normalized), or <1.05-kg/kg/m2 (body mass index (BMI) normalized), while females were defined as weak if their HGS was <20.0-kg, <0.337-kg/kg, or <0.79-kg/kg/m2. The modified Telephone Interview of Cognitive Status examined cognitive function. Persons scoring ≤10 had a cognitive impairment. Obesity was categorized as BMI ≥30 kg/m2. Results: We included 7,532 and 3,584 persons aged ≥65-years living without and with obesity, respectively. Those without obesity but beneath the absolute weakness threshold had 1.54 (95% confidence interval (CI): 1.24-1.91) greater odds for future cognitive impairment. Persons with obesity and beneath each threshold also had greater odds for future cognitive impairment: 1.89 (95% CI: 1.28-2.78) for absolute, 2.17 (95% CI: 1.02-4.62) for body mass normalized, and 1.75 (95% CI: 1.10-2.80) for BMI normalized. Older Americans without obesity but underneath all the weakness thresholds had 1.32 (95% CI: 1.00-1.74) greater odds for impairment in cognitive function, while persons with obesity had 2.76 (95% CI: 1.29-5.93) greater odds. Conclusions: There should be consideration for how body size and different weakness thresholds may influence future cognitive outcomes.

Body composition and late-occurring chronic health conditions after autologous stem cell transplantation for lymphoma.

BACKGROUND: Autologous peripheral blood stem cell transplantation (aPBSCT) is the standard of care for adults with relapsed lymphoma, yet recipients remain at risk of developing chronic health conditions (CHCs). It was hypothesized that body composition measurements of skeletal muscle and fat are associated with late-onset CHCs and nonrelapse mortality after aPBSCT. METHODS: Leveraging the Blood or Marrow Transplant Survivor Study, we examined association between pre-aPBSCT body composition and new-onset grade 3-5 CHCs among 187 adults with lymphoma treated with aPBSCT (2011-2014) surviving ≥2 years after aPBSCT. Using computed tomography scans at the L3 level, skeletal muscle mass (skeletal muscle area and skeletal muscle density [SMD]) and body fat (subcutaneous adipose tissue and visceral adipose tissue) were measured and quantified as sex-specific z-scores. Competing risk models were built to study the impact of body composition on incident grade 3 through 5 CHCs and nonrelapse mortality (NRM) adjusting for confounders. RESULTS: The study cohort had a median age at aPBSCT of 57 years with 63% males, 77% non-Hispanic Whites and 81% with non-Hodgkin lymphoma. The 5-year cumulative incidence of grade 3 through 5 CHCs was 47% (95% Confidence Interval, CI, 38%-56%). Each SD increase in SMD was associated with 30% reduced risk of grade 3 through 5 CHCs (95% CI, 0.50-0.96). The 10-year cumulative incidence of NRM was 16% (95% CI, 10-22). No body composition measure was associated with NRM. CONCLUSIONS: The association between SMD and grade 3 through 5 CHCs following aPBSCT could inform development of prognostic models to identify adults with lymphoma at greatest risk of morbidity following aPBSCT.

Sex-specific associations between AD genotype and the microbiome of human amyloid beta knock-in (hAß-KI) mice.

INTRODUCTION: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome. METHODS: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAß-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD). RESULTS: Eighteen-month female (but not male) hAß-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAß-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups. DISCUSSION: These findings highlight a sex-dependent variation in the microbiomes of hAß-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD. HIGHLIGHTS: Microbial diversity and the abundance of several species differed in human amyloid beta knock-in (hAß-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAß-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

Low skeletal muscle mass and treatment outcomes among adults with haematologic malignancies: A systematic review and meta-analysis.

BACKGROUND: Low skeletal muscle mass (LSMM) and/or, function associated with an increased risk of treatment-related toxicities and inferior overall survival (OS) among adults with solid malignancies. However, the association between LSMM and treatment-related toxicities among adults with haematologic malignancies remains unclear. METHODS: Using a pre-published protocol (CRD42020197814), we searched seven bibliographic databases from inception to 08/2021 for studies reporting the impact of LSMM among adults ≥18 years with a known haematologic malignancy. The primary outcome of interest was OS, and secondary outcomes included progression free survival (PFS) and non-relapse mortality (NRM). These effect sizes were quantified in terms of hazards ratio (HR) along with 95% confidence interval (CI) and pooled across studies using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the Cochran's Q and the I2 statistic. All hypothesis testing was two-sided with an alpha of 0.05. RESULTS: Of 3791 studies screened, we identified 20 studies involving 3468 patients with a mean age of 60 years; 44% were female and the most common malignancy was diffuse large B-cell lymphoma (42%). Most studies measured muscle mass using single slice computed tomography imaging at the L3 level. The presence of LSMM was associated with worse OS (pooled HR = 1.81, 95% CI = 1.48-2.22, P < 0.001) with moderate heterogeneity (Cochran's Q, I2 = 60.4%), PFS (pooled HR = 1.61, 95% CI = 1.28-2.02, P < 0.001) with moderate heterogeneity (Cochran's Q, I2 = 66.0%). Similarly, LSMM was associated with worse NRM (HR = 1.72, 95% CI = 1.34-2.22, P < 0.001) with little evidence of heterogeneity (Cochran's Q, I2 = 0.0%). CONCLUSIONS: LSMM is associated with worse survival outcomes among adults with haematologic malignancies. Further research into understanding the underlying mechanism of this association and mitigating the negative effects of LSMM among adults with haematologic malignancies is needed.

Tracking of serum lipid levels from childhood to adulthood: Systematic review and meta-analysis.

BACKGROUND AND AIMS: The utility of lipid screening in pediatric settings for preventing adult atherosclerotic cardiovascular diseases partly depends on the lifelong tracking of lipid levels. This systematic review aimed to quantify the tracking of lipid levels from childhood and adolescence to adulthood. METHODS: We systematically searched MEDLINE, Embase, Web of Science, and Google Scholar in March 2022. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; ID: CRD42020208859). We included cohort studies that measured tracking of lipids from childhood or adolescence (<18 years) to adulthood (≥18) with correlation or tracking coefficients. We estimated pooled correlation and tracking coefficients using random-effects meta-analysis. Risk of bias was assessed with a review-specific tool. RESULTS: Thirty-three studies of 19 cohorts (11,020 participants) were included. The degree of tracking from childhood and adolescence to adulthood differed among lipids. Tracking was observed for low-density lipoprotein cholesterol (pooled r = 0.55-0.65), total cholesterol (pooled r = 0.51-0.65), high-density lipoprotein cholesterol (pooled r = 0.46-0.57), and triglycerides (pooled r = 0.32-0.40). Only one study included tracking of non-high-density lipoprotein cholesterol (r = 0.42-0.59). Substantial heterogeneity was observed. Study risk of bias was moderate, mostly due to insufficient reporting and singular measurements at baseline and follow-up. CONCLUSIONS: Early-life lipid measurements are important for predicting adult levels. However, further research is needed to understand the tracking of non-high-density lipoprotein cholesterol and the stability of risk classification over time, which may further inform pediatric lipid screening and assessment strategies.

Collective Weakness Is Associated With Time to Mortality in Americans.

ABSTRACT: McGrath, R, McGrath, BM, Jurivich, D, Knutson, P, Mastrud, M, Singh, B, and Tomkinson, GR. Collective weakness is associated with time to mortality in Americans. J Strength Cond Res XX(X): 000-000, 2024-Using new weakness cutpoints individually may help estimate time to mortality, but their collective use could improve value. We sought to determine the associations of (a) each absolute and body size normalized cut point and (b) collective weakness on time to mortality in Americans. The analytic sample included 14,178 subjects aged ≥50 years from the 2006-2018 waves of the Health and Retirement Study. Date of death was confirmed from the National Death Index. Handgrip dynamometry measured handgrip strength (HGS). Men were categorized as weak if their HGS was <35.5 kg (absolute), <0.45 kg·kg-1 (body mass normalized), or <1.05 kg·kg-1·m-2 (body mass index [BMI] normalized). Women were classified as weak if their HGS was <20.0 kg, <0.337 kg·kg-1, or <0.79 kg·kg-1·m-2. Collective weakness categorized persons as below 1, 2, or all 3 cutpoints. Cox proportional hazard regression models were used for analyses. Subject values below each absolute and normalized cutpoint for the 3 weakness parameters had a higher hazard ratio for early all-cause mortality: 1.45 (95% confidence interval [CI]: 1.36-1.55) for absolute weakness, 1.39 (CI: 1.30-1.49) for BMI normalized weakness, and 1.33 (CI: 1.24-1.43) for body mass normalized weakness. Those below 1, 2, or all 3 weakness cut points had a 1.37 (CI: 1.26-1.50), 1.47 (CI: 1.35-1.61), and 1.69 (CI: 1.55-1.84) higher hazard for mortality, respectively. Weakness determined by a composite measure of absolute and body size adjusted strength capacity provides robust prediction of time to mortality, thus potentially informing sports medicine and health practitioner discussions about the importance of muscle strength during aging.

Cardiorespiratory fitness is a strong and consistent predictor of morbidity and mortality among adults: an overview of meta-analyses representing over 20.9 million observations from 199 unique cohort studies.

OBJECTIVE: To examine and summarise evidence from meta-analyses of cohort studies that evaluated the predictive associations between baseline cardiorespiratory fitness (CRF) and health outcomes among adults. DESIGN: Overview of systematic reviews. DATA SOURCE: Five bibliographic databases were searched from January 2002 to March 2024. RESULTS: From the 9062 papers identified, we included 26 systematic reviews. We found eight meta-analyses that described five unique mortality outcomes among general populations. CRF had the largest risk reduction for all-cause mortality when comparing high versus low CRF (HR=0.47; 95% CI 0.39 to 0.56). A dose-response relationship for every 1-metabolic equivalent of task (MET) higher level of CRF was associated with a 11%-17% reduction in all-cause mortality (HR=0.89; 95% CI 0.86 to 0.92, and HR=0.83; 95% CI 0.78 to 0.88). For incident outcomes, nine meta-analyses described 12 unique outcomes. CRF was associated with the largest risk reduction in incident heart failure when comparing high versus low CRF (HR=0.31; 95% CI 0.19 to 0.49). A dose-response relationship for every 1-MET higher level of CRF was associated with a 18% reduction in heart failure (HR=0.82; 95% CI 0.79 to 0.84). Among those living with chronic conditions, nine meta-analyses described four unique outcomes in nine patient groups. CRF was associated with the largest risk reduction for cardiovascular mortality among those living with cardiovascular disease when comparing high versus low CRF (HR=0.27; 95% CI 0.16 to 0.48). The certainty of the evidence across all studies ranged from very low-to-moderate according to Grading of Recommendations, Assessment, Development and Evaluations. CONCLUSION: We found consistent evidence that high CRF is strongly associated with lower risk for a variety of mortality and incident chronic conditions in general and clinical populations.

Geriatric assessment-identified impairments and frailty in adults with cancer younger than 65: An opportunity to optimize oncology care.

INTRODUCTION: Frailty, a state of increased vulnerability to stressors due to aging or treatment-related accelerated aging, is associated with declines in physical, cognitive and/or social functioning, and quality of life for cancer survivors. For survivors aged <65 years, little is known about frailty status and associated impairments to inform intervention. We aimed to evaluate the prevalence of frailty and contributing geriatric assessment (GA)-identified impairments in adults aged <65 versus ≥65 years with cancer. MATERIALS AND METHODS: This study is a secondary analysis of clinical trial data (NCT04852575). Participants were starting a new line of systemic therapy at a community-based oncology private practice. Before starting treatment, participants completed an online patient-reported GA and the Physical Activity (PA) Vital Sign questionnaire. Frailty score and category were derived from GA using a validated deficit accumulation model: frail (>0.35), pre-frail (0.2-0.35), or robust (0-0.2). PA mins/week were calculated, and participants were coded as either meeting/not-meeting guidelines (≥90 min/week). We used Spearman (ρ) correlation to examine the association between age and frailty score and chi-squared/Fisher's-exact or ANOVA/Kruskal-Wallis statistic to compare frailty and PA outcomes between age groups. RESULTS: Participants (n = 96) were predominantly female (62%), Caucasian (68%), beginning first-line systemic therapy (69%), and 1.75 months post-diagnosis (median). Most had stage III to IV disease (66%). Common cancer types included breast (34%), gastrointestinal (23%), and hematologic (15%). Among participants <65, 46.8% were frail or pre-frail compared to 38.7% of those ≥65. There was no association between age and frailty score (ρ = 0.01, p = 0.91). Between age groups, there was no significant difference in frailty score (p = 0.95), the prevalence of frailty (p = 0.68), number of GA impairments (p = 0.33), or the proportion meeting PA guidelines (p = 0.72). However, older adults had more comorbid conditions (p = 0.03) and younger adults had non-significant but clinically relevant differences in functional ability, falls, and PA level. DISCUSSION: In our cohort, the prevalence of frailty was similar among adults with cancer <65 when compared to those older than 65, however, types of GA impairments differed. These results suggest GA and the associated frailty index could be useful to identify needs for intervention and inform clinical decisions during cancer treatment regardless of age. Additional research is needed to confirm our findings.

How smart was T. rex? Testing claims of exceptional cognition in dinosaurs and the application of neuron count estimates in palaeontological research.

Recent years have seen increasing scientific interest in whether neuron counts can act as correlates of diverse biological phenomena. Lately, Herculano-Houzel (2023) argued that fossil endocasts and comparative neurological data from extant sauropsids allow to reconstruct telencephalic neuron counts in Mesozoic dinosaurs and pterosaurs, which might act as proxies for behaviors and life history traits in these animals. According to this analysis, large theropods such as Tyrannosaurus rex were long-lived, exceptionally intelligent animals equipped with "macaque- or baboon-like cognition", whereas sauropods and most ornithischian dinosaurs would have displayed significantly smaller brains and an ectothermic physiology. Besides challenging established views on Mesozoic dinosaur biology, these claims raise questions on whether neuron count estimates could benefit research on fossil animals in general. Here, we address these findings by revisiting Herculano-Houzel's (2023) work, identifying several crucial shortcomings regarding analysis and interpretation. We present revised estimates of encephalization and telencephalic neuron counts in dinosaurs, which we derive from phylogenetically informed modeling and an amended dataset of endocranial measurements. For large-bodied theropods in particular, we recover significantly lower neuron counts than previously proposed. Furthermore, we review the suitability of neurological variables such as neuron numbers and relative brain size to predict cognitive complexity, metabolic rate and life history traits in dinosaurs, coming to the conclusion that they are flawed proxies for these biological phenomena. Instead of relying on such neurological estimates when reconstructing Mesozoic dinosaur biology, we argue that integrative studies are needed to approach this complex subject.

Obesity-Preventive Behaviors and Improvements in Depression among Diverse Utah Women Receiving Coaching from Community Health Workers.

OBJECTIVES: This study evaluated how high versus low-intensity community wellness coaching and health behaviors were associated with changes in depression screen results over one year. METHODS: This was an analysis of secondary data collected in a 12-month obesity-related community health worker (CHW) program for 485 Utah women of color. Depression screen (Patient Health Questionnaire-2 score ³3) and self-reported fruit/vegetable consumption and physical activity (FV/PA) were recorded quarterly. Associations between FV/PA and changes in depression screen over time were evaluated in multivariable models. RESULTS: Positive depression screen prevalence declined over 12 months (21.7% to 9.5%) with no difference between study arms. Overall, FV ³5 times/day (AOR=1.5; 95% CI 1.0-2.2), any PA (AOR=3.1; 95% CI 1.5-6.4), and muscle strengthening activities (AOR=1.13; 95% CI 1.01-1.26) were associated with improved depression screen results over time. CONCLUSION: These results indicate value in addressing and evaluating depression in obesity-related interventions in underserved communities.

A Timeline of Biosynthetic Gene Cluster Discovery in Aspergillus fumigatus: From Characterization to Future Perspectives.

In 1999, the first biosynthetic gene cluster (BGC), synthesizing the virulence factor DHN melanin, was characterized in Aspergillus fumigatus. Since then, 19 additional BGCs have been linked to specific secondary metabolites (SMs) in this species. Here, we provide a comprehensive timeline of A. fumigatus BGC discovery and find that initial advances centered around the commonly expressed SMs where chemical structure informed rationale identification of the producing BGC (e.g., gliotoxin, fumigaclavine, fumitremorgin, pseurotin A, helvolic acid, fumiquinazoline). Further advances followed the transcriptional profiling of a ΔlaeA mutant, which aided in the identification of endocrocin, fumagillin, hexadehydroastechrome, trypacidin, and fumisoquin BGCs. These SMs and their precursors are the commonly produced metabolites in most A. fumigatus studies. Characterization of other BGC/SM pairs required additional efforts, such as induction treatments, including co-culture with bacteria (fumicycline/neosartoricin, fumigermin) or growth under copper starvation (fumivaline, fumicicolin). Finally, four BGC/SM pairs were discovered via overexpression technologies, including the use of heterologous hosts (fumicycline/neosartoricin, fumihopaside, sphingofungin, and sartorypyrone). Initial analysis of the two most studied A. fumigatus isolates, Af293 and A1160, suggested that both harbored ca. 34-36 BGCs. However, an examination of 264 available genomes of A. fumigatus shows up to 20 additional BGCs, with some strains showing considerable variations in BGC number and composition. These new BGCs present a new frontier in the future of secondary metabolism characterization in this important species.

Cardiorespiratory fitness has declined among French children since 1999, although the decline appears to be getting smaller.

BACKGROUND: Cardiorespiratory fitness (CRF) is a strong marker of current and future health. The aim of this study was to assess the national temporal trends in CRF for French children and adolescents between 1999 and 2022. METHODS: CRF data were obtained from several cross-sectional studies on 15 420 (51.1% boys) French children and adolescents aged 9-16 years between 1999 and 2022. The 20-m shuttle run test (20mSRT) estimated CRF. Body mass index (BMI) was calculated from measured height and body mass, with BMI z-scores (BMIz) calculated using WHO growth curves. The 20mSRT results were corrected for protocol and converted to z-scores (20mSRTz) using international sex- and age-specific norms. With additional adjustment for BMIz, temporal trends in mean 20mSRT performance (20mSRTz) were estimated using linear regression, with the distance max (Dmax) method used to locate a breakpoint and linear segments fitted to points below and above the breakpoint. Trends in distributional characteristics were assessed visually and described as the ratio of the coefficients of variation (CVs). RESULTS: After adjustment for protocol, age, sex, and BMIz, a large decline in mean 20mSRT performance (trend per decade (95% CI): -1.42 SDs (-1.45, -1.39) or -18.4% (95% CI: -18.8, -18.0)) between 1999 and 2022 was found. Dmax located a breakpoint for the two-linear-segment model in year 2010. There was a large decline in mean 20mSRT performance pre-2010 (trend per decade (95% CI): -2.31 SDs (-2.39, -2.24)), which reduced 0.06-fold to a negligible decline post-2010 (trend per decade (95% CI): -0.15 SD (-0.20, -0.10)). We also found that the trend in mean 20mSRT performance was not uniform across the population distribution. Between 1999 and 2022, there was a small trend in distributional asymmetry, with slightly smaller declines experienced by the high performers (above the 75th percentile). CONCLUSIONS: Our data suggest a large decline in the 20mSRT performance of French children and adolescents since 1999. This declining trend seems to have diminished considerably since 2010. Such declines in CRF could translate into declines in health status. Although a slowing in the declining trend in CRF in recent years is encouraging, more data are needed to confirm these findings.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Racial differences in body composition and survival among older adults with gastrointestinal malignancies.

INTRODUCTION: Muscle and adipose tissue measures can be quantified from routinely obtained computed tomography (CT) images and are predictors of chemotherapy-related toxicities and survival among patients with gastrointestinal (GI) malignancies. Most studies to date have consisted of predominantly White patients, and the role of body composition among minoritized racial groups is unknown. We examined racial differences in body composition and survival among patients with GI malignancies. MATERIALS AND METHODS: This was a prospective cohort study of patients with GI malignancies. Single slices of axial CT images from L3 segments were analyzed using Slice-O-Matic software. The skeletal muscle area (cm2) was divided by height to obtain the skeletal muscle index (SMI, cm2/m2). Skeletal muscle radiodensity (SMD) in Hounsfield units (HU) was used for muscle composition. We compared body composition parameters between non-Hispanic (NH)-White and NH-Black participants. Cox models were used to examine the impact of body composition on survival. We proposed new race-specific cutoffs for body composition using optimal stratification. RESULTS: Five hundred forty patients were included, of which 24% were NH-Black. In Cox models stratified by race, each 5 cm2/m2 decrease in SMI was associated with increase in risk of all-cause mortality in NH-Black patients (hazard ratio [HR] 1.25; 95% confidence interval [CI] 1.04-1.49 p = 0.02). With the existing cut points, neither sarcopenia nor myosteatosis was associated with worse survival. Using a new cutoff for sarcopenia in NH-Black patients, NH-Black patients with sarcopenia (HR 2.31 95%CI 1.10-4.88 p = 0.03) and myosteatosis (HR 2.63 95% CI 1.25-5.53 p = 0.01) had worse survival. DISCUSSION: NH-Black older patients with GI cancers and sarcopenia or myosteatosis have worse overall survival.

Predicting consequences of COVID-19 control measure de-escalation on nosocomial transmission and mortality: a modelling study in a French rehabilitation hospital.

INTRODUCTION: Infection control measures are effective for nosocomial COVID-19 prevention but bear substantial health-economic costs, motivating their "de-escalation" in settings at low risk of SARS-CoV-2 transmission. Yet consequences of de-escalation are difficult to predict, particularly in light of novel variants and heterogeneous population immunity. AIM: To estimate how infection control measure de-escalation influences nosocomial COVID-19 risk. METHODS: An individual-based transmission model was used to simulate SARS-CoV-2 outbreaks and control measure de-escalation in a French long-term care hospital with multi-modal control measures in place (testing and isolation, universal masking, single-occupant rooms). Estimates of COVID-19 case fatality rates (CFRs) from reported outbreaks were used to quantify excess COVID-19 mortality due to de-escalation. RESULTS: In a population fully susceptible to infection, de-escalating both universal masking and single rooms resulted in hospital-wide outbreaks of 114 (95% CI: 103-125) excess infections, compared with five (three to seven) excess infections when de-escalating only universal masking or 15 (11-18) when de-escalating only single rooms. When de-escalating both measures and applying CFRs from the first wave of COVID-19, excess patient mortality ranged from 1.57 (1.41-1.71) to 9.66 (8.73-10.57) excess deaths/1000 patient-days. By contrast, when applying CFRs from subsequent pandemic waves and assuming susceptibility to infection among 40-60% of individuals, excess mortality ranged from 0 (0-0) to 0.92 (0.77-1.07) excess deaths/1000 patient-days. CONCLUSIONS: The de-escalation of bundled COVID-19 control measures may facilitate widespread nosocomial SARS-CoV-2 transmission. However, excess mortality is probably limited in populations at least moderately immune to infection and given CFRs resembling those estimated during the 'post-vaccine' era.

Genetic diversity promotes resilience in a mouse model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention. METHODS: We crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages. RESULTS: Genetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD. DISCUSSION: Increasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD. HIGHLIGHTS: Genetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.