How Do Plastic Surgery Program's Websites Feature Diversity and Inclusion Elements? An Analysis of 89 Integrated Plastic Surgery Programs' Websites.

INTRODUCTION: Plastic surgery residency programs leverage their websites as platforms for promoting their commitment to diversity and inclusion to potential candidates. Medical students who are seeking residency positions, including individuals from underrepresented backgrounds, place significant importance on the alignment of program culture and diversity. The authors assessed how these programs showcased diversity and inclusion efforts on their websites. METHODS: The authors analyzed 89 plastic surgery integrated residency program websites for the presence of 12 elements, (1) nondiscrimination, (2) diversity and inclusion statement, (3) community resources, (4) extended resident biographies, (5) faculty biographies, (6) faculty photos, (7) resident photos, (8) additional financial resources for trainees, (9) wellness, (10) mental health resources, (11) health disparities/community engagement, and (12) presence of a diversity council. Additionally, we examined the presence of these 12 elements by geographic region (West, Midwest, South, and Northeast). Our analyzed use chi-squared, t-tests, and Mann-Whitney U; significance level was p = 0.005. The independent plastic surgery programs were excluded, considering their websites were combined with the integrated-residency programs. RESULTS: We reviewed 89 websites from February 9, 2024 until February 24, 2024 and on average had 6.32 ± 1.1 diversity and inclusion elements. Resident photos (n = 84, 94.4%), community resources (n = 55, 61.8%), faculty photos (n = 63, 70.8%), and additional financial resources for trainees (n = 56, 62.9%) were the most common. The least common diversity and inclusion elements were diversity councils (n = 12, 13.5%), wellness resources (n = 36, 40.4%), and diversity and inclusion statements (n = 42, 47.2%). The primary analysis revealed that programs with higher number of incoming positions (3 or more) (5.2 ± 1.8) had a significantly higher diversity and inclusion scores when compared to programs with lower number of incoming positions (3.6 ± 2.1) (p = 0.002). Furthermore, based on the geographic regions from the U.S. Census, there was no significant difference between geographic regions. CONCLUSIONS: Characterizing the number of program websites and quantifying the number of diversity elements on each site provide an opportunity for more residency programs to further commit to diversity and inclusion. Displaying different diversity and inclusive initiatives on program websites may attract more diverse applicants, particularly individuals from underrepresented populations in medicine.

Impact of Cardiovascular Imaging Results on Medication Use and Adherence: A Systematic Review and Meta-Analysis.

INTRODUCTION: Cardiovascular imaging results offer valuable information that can guide health decisions, but their impact on medication use and adherence is unclear. This systematic review and meta-analysis aimed to determine the downstream impact of cardiovascular imaging results on medication use and adherence. METHODS: Searches were conducted across databases, including MEDLINE, PsychINFO, EMBASE, and relevant references up to 2024. Data were extracted from studies comparing outcomes for individuals with diseased versus normal arteries and trials comparing outcomes for individuals who were provided imaging results versus those with no access to imaging results and analysed in 2023 and 2024. Pooled odds ratios (ORs) for outcomes were calculated. RESULTS: The analysis included 29 studies with 24 contributing data points. Initiation (OR:2.77;95% CI:1.82-4.20) and continuation (OR:2.06;95% CI:1.28-3.30) of lipid-lowering medications (LLMs), antihypertensives (OR:2.02;95% CI:1.76-2.33), and antiplatelets (OR:2.47;95% CI:1.68-3.64) were significantly higher in individuals with diseased arteries. The proportion of individuals on LLM increased by 2.7-fold in those with diseased arteries and 1.5-fold in those with normal arteries post-screening. The proportion on LLM increased by 4.2 times in the imaging group and 2.2 times in the "no imaging group" post-screening. There was a significant increase in LLM initiation (OR:2.37;95% CI: 1.17-4.79) in the imaging group, but medication continuation did not significantly differ between the imaging and "no imaging group". DISCUSSION: Cardiovascular imaging results can prompt initiation of medications, particularly lipid-lowering medications, reflecting a proactive response to identified risk factors. However, evidence regarding medication continuation is mixed, and further research is required.

Exercise and diet support in breast and prostate cancer survivors: findings from focus groups.

PURPOSE: Cancer survival is improving, making optimal management of long-term treatment-related adverse effects increasingly important. Exercise and a healthy diet are beneficial and regularly recommended in cancer survivorship guidelines; however, few cancer survivors meet these recommendations so there is a need to explore why. This study aimed to understand experiences receiving exercise and diet support among Australian breast and prostate cancer survivors during and following treatment, and to explore what support they would like to receive. METHODS: Adults who completed active treatment for breast or prostate cancer were recruited via a private cancer care centre. Using a qualitative descriptive study design, participants attended in-person focus groups that were recorded, transcribed, then analysed using reflexive thematic analysis. RESULTS: In total, 26 cancer survivors (15 breast, 11 prostate) participated in one of seven focus groups (4 breast, 3 prostate). Two themes were developed: 1) It was just brushed over, and 2) Wanting more. Theme 1 reports that exercise, and especially diet, were rarely discussed. If they were, it was often limited to general recommendations. Theme 2 shows that participants wanted more specific and personalised support, and information about how exercise and/or diet could benefit their cancer treatment. CONCLUSION: Despite strong interest in receiving personalised exercise and diet support, neither are routinely provided to Western Australian breast and prostate cancer survivors. If support was provided, there was inconsistency in the level and type of support provided. These findings identify important gaps in exercise and diet support provision to cancer survivors and will inform future strategies aiming to improve cancer survivorship care.

Simultaneous automated ascertainment of prevalent vertebral fracture and abdominal aortic calcification in clinical practice: role in fracture risk assessment.

Whether simultaneous automated ascertainments of prevalent vertebral fracture (auto-PVFx) and abdominal aortic calcification (auto-AAC) on vertebral fracture assessment (VFA) lateral spine bone density (BMD) images jointly predict incident fractures in routine clinical practice is unclear. We estimated the independent associations of auto-PVFx and auto-AAC primarily with incident major osteoporotic and secondarily with incident hip and any clinical fractures in 11 013 individuals (mean [SD] age 75.8 [6.8] years, 93.3% female) who had a BMD test combined with VFA between March 2010 and December 2017. Auto-PVFx and auto-AAC were ascertained using convolutional neural networks (CNNs). Proportional hazards models were used to estimate the associations of auto-PVFx and auto-AAC with incident fractures over a mean (SD) follow-up of 3.7 (2.2) years, adjusted for each other and other risk factors. At baseline, 17% (n = 1881) had auto-PVFx and 27% (n = 2974) had a high level of auto-AAC (≥ 6 on scale of 0 to 24). Multivariable-adjusted hazard ratios (HR) for incident major osteoporotic fracture (95% C.I.) were 1.85 (1.59, 2.15) for those with compared to those without auto-PVFx, and 1.36 (1.14, 1.62) for those with high compared to low auto-AAC. The multivariable-adjusted HRs for incident hip fracture were 1.62 (95% C.I. 1.26 to 2.07) for those with compared to those without auto-PVFx, and 1.55 (95% C.I. 1.15 to 2.09) for those high auto-AAC compared to low auto-AAC. The 5-year cumulative incidence of major osteoporotic fracture was 7.1% in those with no auto-PVFx and low auto-AAC, 10.1% in those with no auto-PVFx and high auto-AAC, 13.4% in those with auto-PVFx and low auto-AAC, and 18.0% in those with auto-PVFx and high auto-AAC. While physician manual review of images in clinical practice will still be needed to confirm image quality and provide clinical context for interpretation, simultaneous automated ascertainment of auto-PVFx and auto-AAC can aid fracture risk assessment.

Individuals with calcification of their abdominal aorta (AAC) and vertebral fractures seen on lateral spine bone density images (easily obtained as part of a bone density test) are much more likely to have subsequent fractures. Prior studies have not shown if both AAC and prior vertebral fracture both contribute to fracture prediction in routine clinical practice. Additionally, a barrier to using these images to aid fracture risk assessment at the time of bone density testing has been the need for expert readers to be able to accurately detect both AAC and vertebral fractures. We have developed automated computer methods (using artificial intelligence) to accurately detect vertebral fracture (auto-PVFx) and auto-AAC on lateral spine bone density images for 11 013 older individuals having a bone density test in routine clinical practice. Over a 5-year follow-up period, 7.1% of those with no auto-PVFx and low auto-AAC, 10.1% of those with no auto-PVFx and high auto-AAC, 13.4% of those with auto-PVFx and low auto-AAC, and 18.0% of those with auto-PVFx and high auto-AAC had a major osteoporotic fracture. Auto-PVFx and auto-AAC, ascertained simultaneously on lateral spine bone density images, both contribute to the risk of subsequent major osteoporotic fractures in routine clinical practice settings.

Associations of vegetable and potato intakes with markers of type 2 diabetes risk in the AusDiab cohort.

CONTEXT: The associations of vegetable and potato intakes with type 2 diabetes (T2D) appear to be nuanced, depending on vegetable types and preparation method, respectively. OBJECTIVE: We investigated the associations of total vegetable, vegetable subgroup, and potato intakes with 1) markers of T2D at baseline and 2) incident T2D cumulative over a 12-year follow-up period in Australian adults. METHODS: Using data from the Australian Diabetes, Obesity and Lifestyle Study, intakes of vegetables and potatoes were assessed via a food frequency questionnaire at baseline. Associations between vegetable intake and 1) fasting plasma glucose (FPG), 2-hour post load plasma glucose (PLG), updated homeostasis model assessment of ß-cell function (HOMA2-%ß), HOMA2 of insulin sensitivity (HOMA2-%S), and fasting insulin levels at baseline and 2) cumulative incident T2D at the end of 12-year follow-up were examined using generalized linear and Cox proportional hazards models, respectively. RESULTS: In total, 8,009 participants were included having median age of 52 years, and vegetable intake of 132 g/day. Higher intake of total vegetable, green leafy, yellow/orange/red, and moderate intakes of cruciferous vegetables was associated with lower PLG. Additionally, higher green leafy vegetable intake was associated with lower HOMA2-%ß and serum insulin. Conversely, higher potato fries/chips intakes were associated with higher FPG, HOMA2-%ß, serum insulin, and lower HOMA2-%S. Participants with moderate cruciferous vegetables intake had a 25% lower risk of T2D at the end of 12 years follow-up. CONCLUSIONS: A higher intake of vegetables, particularly green leafy vegetables, may improve while consuming potato fries/chips, but not potatoes prepared in a healthy way, may worsen glucose tolerance and insulin sensitivity. Our findings suggest a nuanced relationship between vegetable subgroups and their impact on glucose tolerance.

Artificial Intelligence and Healthcare: A Journey through History, Present Innovations, and Future Possibilities.

Artificial intelligence (AI) has emerged as a powerful tool in healthcare significantly impacting practices from diagnostics to treatment delivery and patient management. This article examines the progress of AI in healthcare, starting from the field's inception in the 1960s to present-day innovative applications in areas such as precision medicine, robotic surgery, and drug development. In addition, the impact of the COVID-19 pandemic on the acceleration of the use of AI in technologies such as telemedicine and chatbots to enhance accessibility and improve medical education is also explored. Looking forward, the paper speculates on the promising future of AI in healthcare while critically addressing the ethical and societal considerations that accompany the integration of AI technologies. Furthermore, the potential to mitigate health disparities and the ethical implications surrounding data usage and patient privacy are discussed, emphasizing the need for evolving guidelines to govern AI's application in healthcare.

S-Methyl Cysteine Sulfoxide Does Not Ameliorate Weight Gain or Hyperlipidemia in Mice Fed a High-Fat Diet.

SCOPE: Higher intake of cruciferous and allium vegetables is associated with lower cardiometabolic risk. Little research has investigated the cardiometabolic effects of S-methyl cysteine sulfoxide (SMCSO), found abundant in these vegetables. This study hypothesizes that SMCSO will blunt development of metabolic syndrome features in mice fed high-fat feed. METHODS AND RESULTS: Fifty C57BL/6 male mice are randomly assigned to standard-chow, high-fat, or high-fat supplemented with low-SMCSO (43 mg kg-1 body weight [BW] day-1), medium-SMCSO (153 mg kg-1 BW day-1), or high-SMCSO (256 mg kg-1 BW day-1) for 12-weeks. High-fat with SMCSO did not prevent diet-induced obesity, glucose intolerance, or hypercholesterolemia. Mice fed high-fat with SMCSO has higher hepatic lipids than mice fed standard-chow or high-fat alone. Urinary SMCSO increases at 6- and 12-weeks in the low-SMCSO group, before reducing 46% and 28% in the medium- and high-SMCSO groups, respectively, at 12-weeks, suggesting possible tissue saturation. Interestingly, two SMCSO-fed groups consume significantly more feed, without significant weight gain. Due to limitations in measuring consumed feed, caution should be taken interpreting these results. CONCLUSION: SMCSO (43-256 mg kg-1 BW day-1) does not ameliorate metabolic syndrome features in high-fat fed mice. Substantial knowledge gaps remain. Further studies should administer SMCSO separately (i.e., gavage), with metabolic studies exploring tissue levels to better understand its physiological action.

Higher plant-derived nitrate intake is associated with lower odds of frailty in a cross-sectional study of community-dwelling older women.

PURPOSE: Dietary nitrate intake is inversely related to numerous contributors towards frailty, including cardiovascular disease and poor physical function. Whether these findings extend to frailty remain unknown. We investigated if habitual nitrate intake, derived from plants or animal-based foods, was cross-sectionally associated with frailty in women. METHODS: Community-dwelling older Australian women (n = 1390, mean age 75.1 ± 2.7 years) completed a validated semi-quantitative food frequency questionnaire (FFQ). Nitrate concentrations in food were obtained from international nitrate databases. We adopted the Rockwood frailty index (FI) of cumulative deficits comprising 33 variables across multiple health domains (scored 0 to 1), which predicts increased hospitalisation and mortality risk. A FI ≥ 0.25 indicated frailty. Cross-sectional associations between nitrate intake (total plant and animal nitrate, separately) and frailty were analysed using multivariable-adjusted logistic regression models (including lifestyle factors), as part of restricted cubic splines. RESULTS: A non-linear inverse relationship was observed between total plant nitrate intake and frailty. Compared to women with the lowest plant nitrate intake (Quartile [Q]1), women with greater intakes in Q2 (OR 0.69 95%CI 0.56-0.84), Q3 (OR 0.67 95%CI 0.50-0.90) and Q4 (OR 0.66 95%CI 0.45-0.98) had lower odds for frailty. A nadir in the inverse association was observed once intakes reached ~ 64 mg/d (median Q2). No relationship was observed between total animal nitrate and frailty. CONCLUSION: Community-dwelling older women consuming low amounts of plant-derived nitrate were more likely to present with frailty. Consuming at least one daily serving (~ 75 g) of nitrate-rich green leafy vegetables may be beneficial in preventing frailty.

Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Apolipoprotein ɛ4 Is Associated With Increased Risk of Fall- and Fracture-Related Hospitalization: The Perth Longitudinal Study of Ageing Women.

Apolipoprotein ɛ4 (APOE ɛ4) may be a genetic risk factor for reduced bone mineral density (BMD) and muscle function, which could have implications for fall and fracture risk. We examined the association between APOE ɛ4 status and long-term fall- and fracture-related hospitalization risk in older women. A total of 1 276 community-dwelling women from the Perth Longitudinal Study of Aging Women (mean age ±â€…SD = 75.2 ±â€…2.7 years) were included. At baseline, women underwent APOE genotyping and detailed phenotyping for covariates including prevalent falls and fractures, as well as health and lifestyle factors. The association between APOE ɛ4 and fall-, any fracture-, and hip fracture-related hospitalizations, obtained over 14.5 years from linked health records, was examined using multivariable-adjusted Cox-proportional hazard models. Over 14.5 years, 507 (39.7%) women experienced a fall-related hospitalization and 360 (28.2%) women experienced a fracture-related hospitalization, including 143 (11.2%) attributed to a hip fracture. In multivariable-adjusted models, compared to noncarriers, APOE ɛ4 carriers (n = 297, 23.3%) had greater risk for a fall- (hazard ratio [HR] 1.48, 95% CI: 1.22-1.81), fracture- (HR 1.28, 95% CI: 1.01-1.63), or hip fracture-related hospitalization (HR 1.83, 95% CI: 1.29-2.61). The estimates remained similar when specific fall and fracture risk factors (fear of falling, plasma 25-hydroxyvitamin D, grip strength, timed up-and-go, hip BMD, vitamin K status, prevalent diabetes, HbA1c, cholesterol, and abbreviated mental test score) were added to the multivariable model. In conclusion, APOE ɛ4 is a potential risk factor for fall- and fracture-related hospitalization in community-dwelling older women. Screening for APOE ɛ4 could provide clinicians an opportunity to direct higher-risk individuals to appropriate intervention strategies.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Decline in muscle strength and physical function after fracture in men - the prospective STRAMBO study.

Studies on muscle strength and physical function after fracture are focused on short follow-ups and adjacent anatomical region. We compared loss of muscle strength and physical function in men after fracture with normal ageing-related decline. In 823 men aged 60-87, measurements of grip strength and clinical tests (chair stands, balance) were performed every 4 years for 12 years. In 155 men with incident fracture, we compared the status after vs. before the fracture. In men without fracture (controls), we compared the status on the first follow-up (4 years) vs. baseline. In men with fracture, grip strength decreased more than in the controls (41%, 0.28SD, P < .01). Men with fracture had higher risk of incident deterioration on the five chair-stand test vs. the controls (OR = 2.45, P < .001). They had higher risk of incident inability to stand for 10s with closed eyes vs. the controls (OR = 4.80, P < .01). They also had higher risk of deterioration on the tandem walk than the controls: forwards (OR = 2.04, P < .01), backwards (OR = 2.25, P < .005). The rapid physical decline was not limited to the region of the fracture site. In men who had incident non-upper limb fractures, grip strength decreased more (32%, P < .05) vs. the controls. In men who had incident non-lower limb fractures, the risk of decline in the tests of the lower limbs was higher vs. controls (chair stands, OR = 2.73, P < .001). The risk of decline was higher in men with clinical fractures which occurred >1 year before the next visit vs. controls (tandem walk forwards, OR = 2.98, P < .005). Overall, in older men, fractures were associated with greater loss of muscle strength and physical function vs. normal ageing. This accelerated decline was also found in the anatomical regions remote from the fracture site. Thus, programs to decrease or reverse the post-fracture decline could have beneficial effects on subsequent fracture risk.

Studies on muscle strength and physical function after fracture are focused on short follow-ups and adjacent anatomical region. We compared loss of muscle strength and physical function in men after fracture with normal ageing. In 823 older men, we assessed physical function every 4 years for 12 years. In men with incident fracture, we compared the status after vs. before the fracture. In men without fracture (controls), we compared the status at 4 years vs. baseline. Men with fracture had significantly greater loss of muscle strength (grip, thighs) as well as greater decline in static balance (standing with closed eyes) and dynamic balance (tandem walk) than the controls. The rapid physical decline was not limited to the region of the fracture site. In men who had non-upper limb fractures, grip strength decreased more than in the controls. In men who had non-lower limb fractures, lower limb physical function decreased more than in the controls. Thus, in older men, fractures were associated with greater loss of muscle strength and physical function vs. normal ageing. This rapid decline was also found in the anatomical regions remote from the fracture site. Therefore, programs to decrease the post-fracture decline could have beneficial effects.

Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

Frailty increases the long-term risk for fall and fracture-related hospitalizations and all-cause mortality in community-dwelling older women.

Frailty is associated with declines in physiological capacity across sensory, neurological, and musculoskeletal systems. An underlying assumption is that the frailer an individual, the more likely they are to experience falls and fractures. We examined whether grades of frailty can assess the long-term risk of hospitalized falls, fractures, and all-cause mortality in 1261 community-dwelling older women (mean age [SD] of 75.1 [2.7] yr) over 14.5 yr. Frailty was operationalized using a frailty index (FI) of cumulative deficits from 33 variables across multiple health domains (physical, mental, comorbidities) at baseline. The total score across these variables was summed and divided by 33 to obtain the FI. Participants were graded as fit (FI ≤ 0.12), mildly frail (FI > 0.12-0.24), moderately frail (FI > 0.24-0.36), or severely frail (FI > 0.36). Fall-related (n = 498), any fracture-related (n = 347), and hip fracture-related hospitalizations (n = 137) and deaths (n = 482) were obtained from linked health records. Associations between FI grades and clinical outcomes were analyzed using multivariable-adjusted Cox-proportional hazard models including age, treatment (calcium/placebo), BMI, smoking history, socioeconomic status, plasma vitamin D (25OHD) status plus season obtained, physical activity, self-reported prevalent falls in the last 3 mo, and self-reported fractures since the age of 50 yr. At baseline, 713 (56.5%), 350 (27.8%), 163 (12.9%), and 35 (2.8%) of women were classified as fit, mildly frail, moderately frail, and severely frail, respectively. Women with mild, moderate, and severe frailty had significantly higher hazards (all P < .05) for a fall-related (46%, 104%, 168%), any fracture-related (88% for moderate, 193% for severe frailty), hip fracture-related hospitalizations (93%, 127%, 129%), and all-cause mortality (47%, 126%, 242%). The FI identified community-dwelling older women at risk for the most serious falls and fractures and may be incorporated into risk assessment tools to identify individuals with poorer clinical prognosis.

Frailty is often linked to decline in the sensory, neurological, and musculoskeletal systems. Frailty can be identified and graded using a frailty index (FI). In a cohort of 1261 community-dwelling older women with an average age of 75 yr, this study found that increasing grades of frailty fit, (mildly, moderately and severely frail) were associated with higher long-term risk for a fall and/or fracture (including hip fractures) that required hospitalization. Increasing grades of frailty were also linked with greater risk of death, especially due to cardiovascular causes. In conclusion, the FI may be used to identify community-dwelling older women with a high long-term risk for the most serious falls and fractures, as well as individuals with a poorer prognosis.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Vitamin K1 intake is associated with lower risk for all-cause and cardiovascular disease mortality in community-dwelling older Australian women.

BACKGROUND AND AIMS: Assessing the relationship between vitamin K1 intakes, using region-specific food databases, with both all-cause, and cardiovascular disease (CVD) mortality warrants further investigation to inform future preventative strategies. Consequently, we examined the aforementioned associations in the Perth Longitudinal Study of Ageing Women (PLSAW). METHODS AND RESULTS: 1436 community-dwelling older Australian women (mean ± SD age 75.2 ± 2.7 years) completed a validated food frequency questionnaire at baseline (1998). Vitamin K1 intake was calculated based on an Australian vitamin K food database, supplemented with published data. All-cause and CVD mortality data was obtained from linked health records. Associations were examined using restricted cubic splines within Cox-proportional hazard models, adjusted for a range of cardiovascular and lifestyle related risk factors. Over 15 years of follow-up, 601 (41.9%) women died, with 236 deaths (16.4%) due to CVD. Compared to women with the lowest vitamin K1 intakes (Quartile 1, median 49.1 µg/day), those with the highest intakes (Quartile 4, median 119.3 µg/day) had lower relative hazards for all-cause mortality (HR 0.66 95%CI 0.51-0.86) and CVD mortality (HR 0.61 95%CI 0.41-0.92). A plateau in the inverse association was observed from vitamin K1 intakes of approximately ≥80 µg/day. CONCLUSION: Higher vitamin K1 intakes were associated with lower risk for both all-cause and CVD mortality in community-dwelling older women, independent of CVD related risk factors. A higher intake of vitamin K1 rich foods, such as leafy green vegetables, may support cardiovascular health.

Extent of Abdominal Aortic Calcification Is Associated With Incident Rapid Weight Loss Over 5 Years: The Perth Longitudinal Study of Ageing Women.

BACKGROUND: Abdominal aortic calcification (AAC), a marker of vascular disease, is associated with disease in other vascular beds including gastrointestinal arteries. We investigated whether AAC is related to rapid weight loss over 5 years and whether rapid weight loss is associated with 9.5-year all-cause mortality in community-dwelling older women. METHODS: Lateral spine images from dual-energy x-ray absorptiometry (1998/1999) were used to assess AAC (24-point AAC scoring method) in 929 older women. Over 5 years, body weight was assessed at 12-month intervals. Rapid weight loss was defined as >5% decrease in body weight within any 12-month interval. Multivariable-adjusted logistic regression was used to assess AAC and rapid weight loss and Cox regression to assess the relationship between rapid weight loss and 9.5-year all-cause mortality. RESULTS: Mean±SD age of women was 75.0±2.6 years. During the initial 5 years, 366 (39%) women presented with rapid weight loss. Compared with women with low AAC (24-point AAC score 0-1), those with moderate (24-point AAC score 2-5: odds ratio, 1.36 [95% CI, 1.00-1.85]) and extensive (24-point AAC score 6+: odds ratio, 1.59 [95% CI, 1.10-2.31]) AAC had higher odds for presenting with rapid weight loss. Results remained similar after further adjustment for dietary factors (alcohol, protein, fat, and carbohydrates), diet quality, blood pressure, and cholesterol measures. The estimates were similar in subgroups of women who met protein intake (n=599) and physical activity (n=735) recommendations (extensive AAC: odds ratios, 1.81 [95% CI, 1.12-2.92] and 1.58 [95% CI, 1.02-2.44], respectively). Rapid weight loss was associated with all-cause mortality over the next 9.5 years (hazard ratio, 1.49 [95% CI, 1.17-1.89]; P=0.001). CONCLUSIONS: AAC extent was associated with greater risk for rapid weight loss over 5 years in older women, a risk for all-cause mortality. Since the association was unchanged after taking nutritional intakes into account, these data support the possibility that vascular disease may play a role in the maintenance of body weight.

Automated Deep Learning-Based Diagnosis and Molecular Characterization of Acute Myeloid Leukemia Using Flow Cytometry.

The current flow cytometric analysis of blood and bone marrow samples for diagnosis of acute myeloid leukemia (AML) relies heavily on manual intervention in the processing and analysis steps, introducing significant subjectivity into resulting diagnoses and necessitating highly trained personnel. Furthermore, concurrent molecular characterization via cytogenetics and targeted sequencing can take multiple days, delaying patient diagnosis and treatment. Attention-based multi-instance learning models (ABMILMs) are deep learning models that make accurate predictions and generate interpretable insights regarding the classification of a sample from individual events/cells; nonetheless, these models have yet to be applied to flow cytometry data. In this study, we developed a computational pipeline using ABMILMs for the automated diagnosis of AML cases based exclusively on flow cytometric data. Analysis of 1820 flow cytometry samples shows that this pipeline provides accurate diagnoses of acute leukemia (area under the receiver operating characteristic curve [AUROC] 0.961) and accurately differentiates AML vs B- and T-lymphoblastic leukemia (AUROC 0.965). Models for prediction of 9 cytogenetic aberrancies and 32 pathogenic variants in AML provide accurate predictions, particularly for t(15;17)(PML::RARA) [AUROC 0.929], t(8;21)(RUNX1::RUNX1T1) (AUROC 0.814), and NPM1 variants (AUROC 0.807). Finally, we demonstrate how these models generate interpretable insights into which individual flow cytometric events and markers deliver optimal diagnostic utility, providing hematopathologists with a data visualization tool for improved data interpretation, as well as novel biological associations between flow cytometric marker expression and cytogenetic/molecular variants in AML. Our study is the first to illustrate the feasibility of using deep learning-based analysis of flow cytometric data for automated AML diagnosis and molecular characterization.

Study Protocol for a Stepped-Wedge Cluster (Nested) Randomized Controlled Trial of Antenatal Colostrum Expression (ACE) Instruction in First-Time Mothers: The ACE Study.

BACKGROUND: Although many mothers initiate breastfeeding, supplementation with human-milk substitutes (formula) during the birth hospitalization is common and has been associated with early breastfeeding cessation. Colostrum hand expressed in the last few weeks before birth, known as antenatal colostrum expression (ACE), can be used instead of human-milk substitutes. However, evidence is lacking on the efficacy of ACE on breastfeeding outcomes and in non-diabetic mothers. METHODS AND PLANNED ANALYSIS: This multicenter stepped-wedge cluster (nested) randomized controlled trial aims to recruit 945 nulliparous pregnant individuals. The trial is conducted in two phases. During Phase 1, control group participants are under standard care. During Phase 2, participants are randomized to ACE instruction via a pre-recorded online video or a one-on-one session with a midwife. Adjusted logistic regression analysis will be used to examine the relationship between ACE instruction and breastfeeding outcomes. RESEARCH AIMS AND QUESTIONS: Primary aim: (1) Does advising pregnant individuals to practice ACE and providing instruction improve exclusive breastfeeding rates at 4 months postpartum? Secondary research questions: (2) Do individuals who practice ACE have higher rates of exclusive breastfeeding during the initial hospital stay after birth? (3) Is teaching ACE via an online video non-inferior to one-on-one instruction from a midwife? (4) Does expressing colostrum in pregnancy influence time to secretory activation, or (5) result in any differences in the composition of postnatal colostrum? DISCUSSION: Trial findings have important implications for maternity practice, with the online video providing an easily accessible opportunity for ACE education as part of standard antenatal care.