Neighborhood Disadvantage and Prostate Tumor RNA Expression of Stress-Related Genes.

Importance: African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations. Objective: To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes. Design, Setting, and Participants: This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024. Exposures: Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants' addresses. Self-reported race was determined using electronic medical records. Main Outcomes and Measures: A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included. Results: A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (ß = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6, were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, ß = 0.008; SE, 0.003; P = .01; q value = .21). Conclusions and Relevance: In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.

Data Interoperability for Ambulatory Monitoring of Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Wearable devices are increasingly used by a growing portion of the population to track health and illnesses. The data emerging from these devices can potentially transform health care. This requires an interoperability framework that enables the deployment of platforms, sensors, devices, and software applications within diverse health systems, aiming to facilitate innovation in preventing and treating cardiovascular disease. However, the current data ecosystem includes several noninteroperable systems that inhibit such objectives. The design of clinically meaningful systems for accessing and incorporating these data into clinical workflows requires strategies to ensure the quality of data and clinical content and patient and caregiver accessibility. This scientific statement aims to address the best practices, gaps, and challenges pertaining to data interoperability in this area, with considerations for (1) data integration and the scope of measures, (2) application of these data into clinical approaches/strategies, and (3) regulatory/ethical/legal issues.

Serotype distribution, virulence and antibiotic resistance of Streptococcus agalactiae isolated from cultured tilapia Oreochromis niloticus in Lake Volta, Ghana.

Streptococcus agalactiae infection is one of the major factors limiting the expansion of tilapia farming globally. In this study, we investigated the serotype distribution, virulence and antimicrobial resistance of S. agalactiae isolates from tilapia farmed in Lake Volta, Ghana. Isolates from 300 moribund fish were characterised by Gram staining, MALDI-TOF/MS and 16S rRNA sequencing. Serotype identification was based on multiplex polymerase chain reaction (PCR) amplification of the capsular polysaccharide genes. Detection of virulence genes (cfb, fbsA and cspA) and histopathology were used to infer the pathogenicity of the isolates. The susceptibility of isolates to antibiotics was tested using the Kirby-Bauer disk diffusion assay. All 32 isolates identified as S. agalactiae were of serotype Ia. This was notably different from isolates previously collected from the farms in 2017, which belonged to serotype Ib, suggesting a possible serotype replacement. The prevalence of the pathogen was related to the scale of farm operation, with large-scale farms showing higher S. agalactiae positivity. Data from histopathological analysis and PCR amplification of targeted virulence genes confirmed the virulence potential and ability of the isolates to cause systemic infection in tilapia. Except for gentamicin, the majority of the isolates were less resistant to the tested antibiotics. All isolates were fully sensitive to oxytetracycline, erythromycin, florfenicol, enrofloxacin, ampicillin and amoxicillin. This study has improved our understanding of the specific S. agalactiae serotypes circulating in Lake Volta and demonstrates the need for continuous monitoring to guide the use of antimicrobials and vaccines against streptococcal infections in Ghanaian aquaculture systems.

Correlates and consequences of atrial fibrillation in a prospective study of 25 000 participants in the China Kadoorie Biobank.

Aims: The prevalence of atrial fibrillation (AF) is positively correlated with prior cardiovascular diseases (CVD) and CVD risk factors but is lower in Chinese than Europeans despite their higher burden of CVD. We examined the prevalence and prognosis of AF and other electrocardiogram (ECG) abnormalities in the China Kadoorie Biobank. Methods and results: A random sample of 25 239 adults (mean age 59.5 years, 62% women) had a 12-lead ECG recorded and interpreted using a Mortara VERITAS™ algorithm in 2013-14. Participants were followed up for 5 years for incident stroke, ischaemic heart disease, heart failure (HF), and all CVD, overall and by CHA2DS2-VASc scores, age, sex, and area. Overall, 1.2% had AF, 13.6% had left ventricular hypertrophy (LVH), and 28.1% had ischaemia (two-thirds of AF cases also had ischaemia or LVH). The prevalence of AF increased with age, prior CVD, and levels of CHA2DS2-VASc scores (0.5%, 1.3%, 2.1%, 2.9%, and 4.4% for scores <2, 2, 3, 4, and ≥5, respectively). Atrial fibrillation was associated with two-fold higher hazard ratios (HR) for CVD (2.15; 95% CI, 1.71-2.69) and stroke (1.88; 1.44-2.47) and a four-fold higher HR for HF (3.79; 2.21-6.49). The 5-year cumulative incidence of CVD was comparable for AF, prior CVD, and CHA2DS2-VASc scores ≥ 2 (36.7% vs. 36.2% vs. 37.7%, respectively) but was two-fold greater than for ischaemia (19.4%), LVH (18.0%), or normal ECG (14.1%), respectively. Conclusion: The findings highlight the importance of screening for AF together with estimation of CHA2DS2-VASc scores for prevention of CVD in Chinese adults.

Iron Status and Risk of Heart Disease, Stroke, and Diabetes: A Mendelian Randomization Study in European Adults.

BACKGROUND: The relevance of iron status biomarkers for coronary artery disease (CAD), heart failure (HF), ischemic stroke (IS), and type 2 diabetes (T2D) is uncertain. We compared the observational and Mendelian randomization (MR) analyses of iron status biomarkers and hemoglobin with these diseases. METHODS AND RESULTS: Observational analyses of hemoglobin were compared with genetically predicted hemoglobin with cardiovascular diseases and diabetes in the UK Biobank. Iron biomarkers included transferrin saturation, serum iron, ferritin, and total iron binding capacity. MR analyses assessed associations with CAD (CARDIOGRAMplusC4D [Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus The Coronary Artery Disease Genetics], n=181 522 cases), HF (HERMES [Heart Failure Molecular Epidemiology for Therapeutic Targets), n=115 150 cases), IS (GIGASTROKE, n=62 100 cases), and T2D (DIAMANTE [Diabetes Meta-Analysis of Trans-Ethnic Association Studies], n=80 154 cases) genome-wide consortia. Observational analyses demonstrated J-shaped associations of hemoglobin with CAD, HF, IS, and T2D. In contrast, MR analyses demonstrated linear positive associations of higher genetically predicted hemoglobin levels with 8% higher risk per 1 SD higher hemoglobin for CAD, 10% to 13% for diabetes, but not with IS or HF in UK Biobank. Bidirectional MR analyses confirmed the causal relevance of iron biomarkers for hemoglobin. Further MR analyses in global consortia demonstrated modest protective effects of iron biomarkers for CAD (7%-14% lower risk for 1 SD higher levels of iron biomarkers), adverse effects for T2D, but no associations with IS or HF. CONCLUSIONS: Higher levels of iron biomarkers were protective for CAD, had adverse effects on T2D, but had no effects on IS or HF. Randomized trials are now required to assess effects of iron supplements on risk of CAD in high-risk older people.

Self-Assembly of Rod-Coil Bottlebrush Copolymers into Degradable Nanodiscs with a UV-Triggered Self-Immolation Process.

Polymer nanodiscs, especially with stimuli-responsive features, represent an unexplored frontier in the nanomaterial landscape. Such 2D nanomaterials are considered highly promising for advanced biomedicine applications. Herein, we designed a rod-coil copolymer architecture based on an amphiphilic, tadpole-like bottlebrush copolymer, which can directly self-assemble into core-shell nanodiscs in an aqueous environment. As the bottlebrush side chains are made of amorphous, UV-responsive poly(ethyl glyoxylate) (PEtG) chains, they can undergo rapid end-to-end self-immolation upon light irradiation. This triggered nanodisc disassembly can be used to boost small molecule release from the nanodisc core, which is further aided by a morphological change from discs to spheres.

Use of Artificial Intelligence in Improving Outcomes in Heart Disease: A Scientific Statement From the American Heart Association.

A major focus of academia, industry, and global governmental agencies is to develop and apply artificial intelligence and other advanced analytical tools to transform health care delivery. The American Heart Association supports the creation of tools and services that would further the science and practice of precision medicine by enabling more precise approaches to cardiovascular and stroke research, prevention, and care of individuals and populations. Nevertheless, several challenges exist, and few artificial intelligence tools have been shown to improve cardiovascular and stroke care sufficiently to be widely adopted. This scientific statement outlines the current state of the art on the use of artificial intelligence algorithms and data science in the diagnosis, classification, and treatment of cardiovascular disease. It also sets out to advance this mission, focusing on how digital tools and, in particular, artificial intelligence may provide clinical and mechanistic insights, address bias in clinical studies, and facilitate education and implementation science to improve cardiovascular and stroke outcomes. Last, a key objective of this scientific statement is to further the field by identifying best practices, gaps, and challenges for interested stakeholders.

Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review.

Background: Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. Methods: We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children <15 years were excluded. Using an ecological study design, we examined the associations of folic acid fortification types with NTD prevalence (n = 108 studies) and stroke mortality rates (n = 3 countries). Findings: Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification (accounting for 32%, 53% and 15% of worldwide population, respectively). Mean plasma folate levels were 36, 21 and 17 nmol/L in populations with mandatory, voluntary and no fortification, respectively (and proportions with mean folate levels >25 nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11-4.28), 7.61 (7.47-7.75) and 9.66 (9.52-9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. Interpretation: There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50-100% higher population mean plasma folate levels and 25-50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Funding: Medical Research Council (UK) and British Heart Foundation.

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

AIMS: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition. METHODS AND RESULTS: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI. CONCLUSION: The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections. LAY SUMMARY: Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.

Plasma Proteomics to Identify Drug Targets for Ischemic Heart Disease.

BACKGROUND: Integrated analyses of plasma proteomic and genetic markers in prospective studies can clarify the causal relevance of proteins and discover novel targets for ischemic heart disease (IHD) and other diseases. OBJECTIVES: The purpose of this study was to examine associations of proteomics and genetics data with IHD in population studies to discover novel preventive treatments. METHODS: We conducted a nested case-cohort study in the China Kadoorie Biobank (CKB) involving 1,971 incident IHD cases and 2,001 subcohort participants who were genotyped and free of prior cardiovascular disease. We measured 1,463 proteins in the stored baseline samples using the OLINK EXPLORE panel. Cox regression yielded adjusted HRs for IHD associated with individual proteins after accounting for multiple testing. Moreover, cis-protein quantitative loci (pQTLs) identified for proteins in genome-wide association studies of CKB and of UK Biobank were used as instrumental variables in separate 2-sample Mendelian randomization (MR) studies involving global CARDIOGRAM+C4D consortium (210,842 IHD cases and 1,378,170 controls). RESULTS: Overall 361 proteins were significantly associated at false discovery rate <0.05 with risk of IHD (349 positively, 12 inversely) in CKB, including N-terminal prohormone of brain natriuretic peptide and proprotein convertase subtilisin/kexin type 9. Of these 361 proteins, 212 had cis-pQTLs in CKB, and MR analyses of 198 variants in CARDIOGRAM+C4D identified 13 proteins that showed potentially causal associations with IHD. Independent MR analyses of 307 cis-pQTLs identified in Europeans replicated associations for 4 proteins (FURIN, proteinase-activated receptor-1, Asialoglycoprotein receptor-1, and matrix metalloproteinase-3). Further downstream analyses showed that FURIN, which is highly expressed in endothelial cells, is a potential novel target and matrix metalloproteinase-3 a potential repurposing target for IHD. CONCLUSIONS: Integrated analyses of proteomic and genetic data in Chinese and European adults provided causal support for FURIN and multiple other proteins as potential novel drug targets for treatment of IHD.

MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults.

BACKGROUND: The relevance of folic acid for stroke prevention in low-folate populations such as in China is uncertain. Genetic studies of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which increases plasma homocysteine (tHcy) levels, could clarify the causal relevance of elevated tHcy levels for stroke, ischaemic heart disease (IHD) and other diseases in populations without folic acid fortification. METHODS: In the prospective China Kadoorie Biobank, 156 253 participants were genotyped for MTHFR and 12 240 developed a stroke during the 12-year follow-up. Logistic regression was used to estimate region-specific odds ratios (ORs) for total stroke and stroke types, IHD and other diseases comparing TT genotype for MTHFR C677T (two thymine alleles at position 677 of MTHFR C677T polymorphism) vs CC (two cytosine alleles) after adjustment for age and sex, and these were combined using inverse-variance weighting. RESULTS: Overall, 21% of participants had TT genotypes, but this varied from 5% to 41% across the 10 study regions. Individuals with TT genotypes had 13% (adjusted OR 1.13, 95% CI 1.09-1.17) higher risks of any stroke [with a 2-fold stronger association with intracerebral haemorrhage (1.24, 1.17-1.32) than for ischaemic stroke (1.11, 1.07-1.15)] than the reference CC genotype. In contrast, MTHFR C677T was unrelated to risk of IHD or any other non-vascular diseases, including cancer, diabetes and chronic obstructive lung disease. CONCLUSIONS: In Chinese adults, the MTHFR C677T polymorphism was associated with higher risks of stroke. The findings warrant corroboration by further trials of folic acid and implementation of mandatory folic acid fortification programmes for stroke prevention in low-folate populations.

First genome-wide association study for lymphatic filariasis in a West African population points to a human leukocyte antigen-mediated disease pathophysiology.

OBJECTIVES: Lymphatic filariasis (LF) represents a parasitic disease caused by filarial nematodes. Although some infected individuals present an asymptomatic course, others suffer severe chronic lymphatic pathology, including lymphedema, hydrocele, and elephantiasis. Several studies have shown that host genetic factors influence LF susceptibility and chronic pathology. The current study aimed to conduct the first genome-wide association study to systematically determine LF susceptibility. METHODS: We analyzed genome-wide single-nucleotide polymorphism data from 1459 LF cases and 1492 asymptomatic controls of West African (Ghanaian) descent. RESULTS: We identified two independent genome-wide significant associated genetic variants near the genes HLA-DQB2 (rs7742085) and HLA-DQA1 (rs4959107) contributing to LF and/or lymphedema susceptibility (P <5.0 × 10-8, odds ratios [ORs] >1.30). We also observed suggestive evidence of LF associations (P <1.0 × 10-6) at two non-HLA loci, near the genes ZFHX4-AS1 (rs79562145) and CHP2 (rs12933387). In contrast, we could not replicate any previously reported LF associations drawn from candidate gene association studies. On the polygenic level, we show that our genome-wide association study data explain 24-42% of LF heritability, depending on an assumed population prevalence of 0.5-5.0%. CONCLUSION: Our findings point to an involvement of HLA-mediated immune mechanisms in LF pathophysiology.

Genetically Predicted Differences in Systolic Blood Pressure and Risk of Cardiovascular and Noncardiovascular Diseases: A Mendelian Randomization Study in Chinese Adults.

BACKGROUND: Mendelian randomization studies of systolic blood pressure (SBP) can assess the shape and strength of the associations of genetically predicted differences in SBP with major disease outcomes and are less constrained by biases in observational analyses. This study aimed to compare the associations of usual and genetically predicted SBP with major cardiovascular disease (CVD) outcomes, overall and by levels of SBP, age, and sex. METHODS: The China Kadoorie Biobank involved a 12-year follow-up of a prospective study of 489 495 adults aged 40 to 79 years with no prior CVD and 86 060 with genetic data. Outcomes included major vascular events (59 490/23 151 in observational/genetic analyses), and its components (ischemic stroke [n=39 513/12 043], intracerebral hemorrhage [7336/5243], and major coronary events [7871/4187]). Genetically predicted SBP used 460 variants obtained from European ancestry genome-wide studies. Cox regression estimated adjusted hazard ratios for incident CVD outcomes down to usual SBP levels of 120 mm Hg. RESULTS: Both observational and genetic analyses demonstrated log-linear positive associations of SBP with major vascular event and other major CVD types in the range of 120 to 170 mm Hg. Consistent with the observational analyses, the hazard ratios per 10 mm Hg higher genetically predicted SBP were 2-fold greater for intracerebral hemorrhage (1.71 [95% CI, 1.58-1.87]) than for ischemic stroke (1.37 [1.30-1.45]) or major coronary event (1.29 [1.18-1.42]). Genetic analyses also demonstrated 2-fold greater hazard ratios for major vascular event in younger (1.69 [95% CI, 1.54-1.86]) than in older people (1.28 [1.18-1.38]). CONCLUSIONS: The findings provide support for initiation of blood pressure-lowering treatment at younger ages and below the conventional cut-offs for hypertension to maximize CVD prevention, albeit the absolute risks of CVD are far greater in older people.

Personalized knowledge to reduce the risk of stroke (PERKS-International): Protocol for a randomized controlled trial.

RATIONALE: Theoretically, most strokes could be prevented through the management of modifiable risk factors. The Stroke Riskometer™ mobile phone application (hereon "The App") uses an individual's data to provide personalized information and advice to reduce their risk of stroke. AIMS: To determine the effect of The App on a combined cardiovascular risk score (Life's Simple 7®, LS7) of modifiable risk factors at 6 months post-randomization. METHODS AND DESIGN: PERKS-International is a Phase III, multicentre, prospective, pragmatic, open-label, single-blinded endpoint, two-arm randomized controlled trial (RCT). Inclusion criteria are as follows: age ⩾ 35 and ⩽75 years; ⩾2 LS7 risk factors; smartphone ownership; no history of stroke/myocardial infarction/cognitive impairment/terminal illness. The intervention group (IG) will be provided with The App, and the usual care group (UCG) is provided with generic online information about risk factors, but not be informed about The App. Face-to-face assessments will be conducted at baseline and 6 months, and online at 3 and 12 months. The RCT includes a process and economic evaluation. STUDY OUTCOMES AND SAMPLE SIZE: The primary outcome is a difference in the mean change in LS7 (seven individual items: blood pressure, cholesterol, glucose, body mass index (BMI), smoking, physical activity, and diet) from baseline to 6 months post-randomization with intention-to-treat analysis. Secondary outcomes include: change in individual LS7 items, quality of life; stroke awareness, adverse events; health service use; and costs. Based on pilot data, 790 participants (395 IG, 395 UCG) will be required to provide 80% power (two-sided α = 0.05) to detect a mean difference in the LS7 of ⩾0.40 (SD 1.61) in IG compared to 0.01 (SD 1.44) in the UCG at 6 months post-randomization. DISCUSSION: Stroke is largely preventable. This study will provide evidence of the effectiveness of a mobile app to reduce stroke risk. TRIAL REGISTRATION: ACTRN12621000211864.

Systematic review of the utility of the frailty index and frailty phenotype to predict all-cause mortality in older people.

BACKGROUND: Current guidelines for healthcare of community-dwelling older people advocate screening for frailty to predict adverse health outcomes, but there is no consensus on the optimum instrument to use in such settings. The objective of this systematic review of population studies was to compare the ability of the frailty index (FI) and frailty phenotype (FP) instruments to predict all-cause mortality in older people. METHODS: Studies published before 27 July 2022 were identified using Ovid MEDLINE, Embase, Scopus, Web of Science and CINAHL databases. The eligibility criteria were population-based prospective studies of community-dwelling older adults (aged 65 years or older) and evaluation of both the FI and FP for prediction of all-cause mortality. The Scottish Intercollegiate Guidelines Network's Methodology checklist was used to assess study quality. The areas under the receiver operator characteristic curves (AUC) were compared, and the proportions of included studies that achieved acceptable discriminatory power (AUC>0.7) were calculated for each frailty instrument. The results were stratified by the use of continuous or categorical formats of each instrument. The review was reported in accordance with the PRISMA and SWiM guidelines. RESULTS: Among 8 studies (range: 909 to 7713 participants), both FI and FP had comparable predictive power for all-cause mortality. The AUC values ranged from 0.66 to 0.84 for FI continuous, 0.60 to 0.80 for FI categorical, 0.63 to 0.80 for FP continuous and 0.57 to 0.79 for FP categorical. The proportion of studies achieving acceptable discriminatory power were 75%, 50%, 63%, and 50%, respectively. The predictive ability of each frailty instrument was unaltered by the number of included items. CONCLUSIONS: Despite differences in their content, both the FI and FP instruments had modest but comparable ability to predict all-cause mortality. The use of continuous rather than categorical formats in either instrument enhanced their ability to predict all-cause mortality.

Tailored Biocompatible Polyurethane-Poly(ethylene glycol) Hydrogels as a Versatile Nonfouling Biomaterial.

Polyurethane-based hydrogels are relatively inexpensive and mechanically robust biomaterials with ideal properties for various applications, including drug delivery, prosthetics, implant coatings, soft robotics, and tissue engineering. In this report, a simple method is presented for synthesizing and casting biocompatible polyurethane-poly(ethylene glycol) (PU-PEG) hydrogels with tunable mechanical properties, nonfouling characteristics, and sustained tolerability as an implantable material or coating. The hydrogels are synthesized via a simple one-pot method using commercially available precursors and low toxicity solvents and reagents, yielding a consistent and biocompatible gel platform primed for long-term biomaterial applications. The mechanical and physical properties of the gels are easily controlled by varying the curing concentration, producing networks with complex shear moduli of 0.82-190 kPa, similar to a range of human soft tissues. When evaluated against a mechanically matched poly(dimethylsiloxane) (PDMS) formulation, the PU-PEG hydrogels demonstrated favorable nonfouling characteristics, including comparable adsorption of plasma proteins (albumin and fibrinogen) and significantly reduced cellular adhesion. Moreover, preliminary murine implant studies reveal a mild foreign body response after 41 days. Due to the tunable mechanical properties, excellent biocompatibility, and sustained in vivo tolerability of these hydrogels, it is proposed that this method offers a simplified platform for fabricating soft PU-based biomaterials for a variety of applications.

An Overview of Methods and Exemplars of the Use of Mendelian Randomisation in Nutritional Research.

Objectives: It is crucial to elucidate the causal relevance of nutritional exposures (such as dietary patterns, food intake, macronutrients intake, circulating micronutrients), or biomarkers in non-communicable diseases (NCDs) in order to find effective strategies for NCD prevention. Classical observational studies have found evidence of associations between nutritional exposures and NCD development, but such studies are prone to confounding and other biases. This has direct relevance for translation research, as using unreliable evidence can lead to the failure of trials of nutritional interventions. Facilitated by the availability of large-scale genetic data, Mendelian randomization studies are increasingly used to ascertain the causal relevance of nutritional exposures and biomarkers for many NCDs. Methods: A narrative overview was conducted in order to demonstrate and describe the utility of Mendelian randomization studies, for individuals with little prior knowledge engaged in nutritional epidemiological research. Results: We provide an overview, rationale and basic description of the methods, as well as strengths and limitations of Mendelian randomization studies. We give selected examples from the contemporary nutritional literature where Mendelian randomization has provided useful evidence on the potential causal relevance of nutritional exposures. Conclusions: The selected exemplars demonstrate the importance of well-conducted Mendelian randomization studies as a robust tool to prioritize nutritional exposures for further investigation.

Skeletal muscle blood flow during exercise is reduced in a rat model of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is characterized by exercise intolerance. Muscle blood flow may be reduced during exercise in PAH; however, this has not been directly measured. Therefore, we investigated blood flow during exercise in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Sprague-Dawley rats (∼200 g) were injected with 60 mg/kg MCT (MCT, n = 23) and vehicle control (saline; CON, n = 16). Maximal rate of oxygen consumption (V̇o2max) and voluntary running were measured before PH induction. Right ventricle (RV) morphology and function were assessed via echocardiography and invasive hemodynamic measures. Treadmill running at 50% V̇o2max was performed by a subgroup of rats (MCT, n = 8; CON, n = 7). Injection of fluorescent microspheres determined muscle blood flow via photo spectroscopy. MCT demonstrated a severe phenotype via RV hypertrophy (Fulton index, 0.61 vs. 0.31; P < 0.001), high RV systolic pressure (51.5 vs. 22.4 mmHg; P < 0.001), and lower V̇o2max (53.2 vs. 71.8 mL·min-1·kg-1; P < 0.0001) compared with CON. Two-way ANOVA revealed exercising skeletal muscle blood flow relative to power output was reduced in MCT compared with CON (P < 0.001), and plasma lactate was increased in MCT (10.8 vs. 4.5 mmol/L; P = 0.002). Significant relationships between skeletal blood flow and blood lactate during exercise were observed for individual muscles (r = -0.58 to -0.74; P < 0.05). No differences in capillarization were identified. Skeletal muscle blood flow is significantly reduced in experimental PH. Reduced blood flow during exercise may be, at least in part, consequent to reduced exercise intensity in PH. This adds further evidence of peripheral muscle dysfunction and exercise intolerance in PAH.

The Presence of Biofilms in Instrumented Spinal Fusions.

Study Design: Prospective observational cohort study. Objective: To determine whether biofilms exist on spinal instrumentation recovered during revision surgery in which microbial cultures were negative. Background: Biofilm bacteria are extremely difficult to detect by conventional culture methods used in the standard hospital setting. Chronic infections in which bacteria form biofilms have been demonstrated to slow healing and prevent bony fusion. These slime encased microbial communities serve to isolate the bacteria from the body's immune responses, while simultaneously providing metabolic resistance to antimicrobial therapy. Methods: Traditional debridement wound cultures were taken from each specimen and sent for microbiological analyses. Bacterial DNA testing was performed using polymerase chain reaction (PCR) electrospray ionization-mass spectrometry (ESI-MS). Based on the PCR/ESI-MS results, specific crossed immune electrophoresis was used to detect the bacterial species within biofilms observed on the removed instrumentation. In addition, fluorescent in situ hybridization (FISH) probes corresponding to the bacterial species identified by PCR/ESI-MS were used with confocal microscopy to visualize and confirm the infecting bacteria. Results: Fifteen patients presented for surgical revision of thoracolumbar spinal implantation: four for clinical suspicion of infection, six for adjacent segment disease (ASD), one with ASD and pseudoarthrosis (PA), three with PA, and one for pain. Infections were confirmed with PCR/ESI-MS for all four patients who presented with clinical infection, and for five of the patients for whom infection was not clinically suspected. Of the presumed non-infected implants, 50% demonstrated the presence of infectious biofilms. Half of the revisions due to pseudoarthrosis were shown to harbour biofilms. The revisions that were performed for pain demonstrated robust biofilms but did not grow bacteria on traditional culture media. Conclusions: Culture is inadequate as a diagnostic modality to detect indolent/subclinical biofilm infections of spinal instrumentation. The PCR/ESI-MS results for bacterial detection were confirmed using species-specific microscopic techniques for both bacterial nucleic acids and antigens. Biofilms may contribute to pseudoarthrosis and back pain in postoperative wounds otherwise considered sterile.

Understanding General Surgery Applicant Expectations and Perceptions in the Virtual Interview Process.

OBJECTIVE: The COVID-19 pandemic has played a lasting role on residency recruitment through the virtual interview process. The objective of this study was to 1) examine general surgery applicants' priorities and perceptions following pre-interview virtual open houses and 2) to assess applicant expectations and efficacy of the virtual interview day process. DESIGN/SETTING/PARTICIPANTS: This study utilized two voluntary and anonymous cross-sectional surveys administered via email to evaluate the virtual interview process of a general surgery residency program. The first was administered to registrants following completion of three open houses of various topics. The second was administered following each interview day. The post-open house survey had 78 respondents, two excluded for no open house attendance. The post-interview survey was completed by 44 applicants (62.9% response rate). RESULTS: Majority of respondents reported that attending virtual open houses made them want to apply to (90.9%) and improved their perception of the program (94.7%). Applicants who felt a sense of obligation to attend open houses (68.4%) were significantly more likely to feel that they contributed to the stress and time commitment of applications (81.8% vs 18.2%, p=0.028). Interview expectations were identified in recurrent themes: 1. Clear organization with breaks, 2. Interactive resident sessions, 3. Meetings with program leadership, 4. Additional information unavailable on other resources. The pre-interview social and interview day improved 90.2% of the applicants' perceptions of the program. The interview significantly improved applicants' ability to assess nearly all aspects of the program, notably resident camaraderie and culture (30.8% vs 97.4%, p=0.01) and strengths and weaknesses (30.8% vs 92.3%, p=0.04). CONCLUSIONS: While virtual open houses can improve applicants' perceptions and desire to apply to a program, the associated stress and obligation should be considered. Virtual interviews should provide information unavailable using other resources and provide avenues for conveying the resident culture and camaraderie.