Unfavorable social determinants of health and risk of mortality in adults with diabetes: findings from the National Health Interview Survey.

INTRODUCTION: Understanding the role of social determinants of health as predictors of mortality in adults with diabetes may help improve health outcomes in this high-risk population. Using population-based, nationally representative data, this study investigated the cumulative effect of unfavorable social determinants on all-cause mortality in adults with diabetes. RESEARCH DESIGN AND METHODS: We used data from the 2013-2018 National Health Interview Survey, linked to the National Death Index through 2019, for mortality ascertainment. A total of 47 individual social determinants of health were used to categorize participants in quartiles denoting increasing levels of social disadvantage. Poisson regression was used to report age-adjusted mortality rates across increasing social burden. Multivariable Cox proportional hazards models were used to assess the association between cumulative social disadvantage and all-cause mortality in adults with diabetes, adjusting for traditional risk factors. RESULTS: The final sample comprised 182 445 adults, of whom 20 079 had diabetes. In the diabetes population, mortality rate increased from 1052.7 per 100 000 person-years in the first quartile (Q1) to 2073.1 in the fourth quartile (Q4). In multivariable models, individuals in Q4 experienced up to twofold higher mortality risk relative to those in Q1. This effect was observed similarly across gender and racial/ethnic subgroups, although with a relatively stronger association for non-Hispanic white participants compared with non-Hispanic black and Hispanic subpopulations. CONCLUSIONS: Cumulative social disadvantage in individuals with diabetes is associated with over twofold higher risk of mortality, independent of established risk factors. Our findings call for action to screen for unfavorable social determinants and design novel interventions to mitigate the risk of mortality in this high-risk population.

Unfavorable social determinants of health and mortality risk by cardiovascular disease status: Findings from a National Study of United States Adults.

BACKGROUND: The association between cumulative burden of unfavorable social determinants of health (SDoH) and all-cause mortality has not been assessed by atherosclerotic cardiovascular disease (ASCVD) status on a population level in the United States. METHODS: We assessed the association between cumulative social disadvantage and all-cause mortality by ASCVD status in the National Health Interview Survey, linked to the National Death Index. RESULTS: In models adjusted for established clinical risk factors, individuals experiencing the highest level of social disadvantage (SDoH-Q4) had over 1.5 (aHR = 1.55; 95%CI = 1.22, 1.96) and 2-fold (aHR = 2.21; 95% CI = 1.91, 2.56) fold increased risk of mortality relative to those with the most favorable social profile (SDoH-Q1), respectively for adults with and without ASCVD; those experiencing co-occurring ASCVD and high social disadvantage had up to four-fold higher risk of mortality (aHR = 3.81; 95%CI = 3.36, 4.32). CONCLUSIONS: These findings emphasize the importance of a healthcare model that prioritizes efforts to identify and address key social and environmental barriers to health and wellbeing, particularly in individuals experiencing the double jeopardy of clinical and social risk.

Polysocial Risk Scores: Implications for Cardiovascular Disease Risk Assessment and Management.

PURPOSE OF REVIEW: To review current evidence, discuss key knowledge gaps and identify opportunities for development, validation and application of polysocial risk scores (pSRS) for cardiovascular disease (CVD) risk prediction and population cardiovascular health management. RECENT FINDINGS: Limited existing evidence suggests that pSRS are promising tools to capture cumulative social determinants of health (SDOH) burden and improve CVD risk prediction beyond traditional risk factors. However, available tools lack generalizability, are cross-sectional in nature or do not assess social risk holistically across SDOH domains. Available SDOH and clinical risk factor data in large population-based databases are under-utilized for pSRS development. Recent advances in machine learning and artificial intelligence present unprecedented opportunities for SDOH integration and assessment in real-world data, with implications for pSRS development and validation for both clinical and healthcare utilization outcomes. pSRS presents unique opportunities to potentially improve traditional "clinical" models of CVD risk prediction. Future efforts should focus on fully utilizing available SDOH data in large epidemiological databases, testing pSRS efficacy in diverse population subgroups, and integrating pSRS into real-world clinical decision support systems to inform clinical care and advance cardiovascular health equity.

Acute effects of an isometric neck warm-up programme on neck performance characteristics and ultrasound-based morphology.

OBJECTIVE: Athletic performance can be enhanced immediately after an isometric warm-up, a phenomenon termed post-activation performance enhancement (PAPE). While isometric warm-ups can improve lower extremity sprint and jump performance, neck-specific isometric warm-ups need development and validation for mild traumatic brain disorders and neck pain. This study examined acute effects of isometric warm-ups on neck performance and morphology. METHODS: Arm 1: Twenty-six adults (13 M:13F) completed neck performance testing before and after a 10-minute neck isometric warm-up or stationary bike (sham) between two visits. Testing included visual-motor reaction time, peak force, rate of force development, force steadiness, and force replication/proprioception measured by a 6-axis load cell. An inclinometer assessed range-of-motion. Paired t-tests and two-way ANOVA examined effects of neck/bike warm-up and interaction effects, respectively. Arm 2: 24 adults (11 M:13F) completed ultrasound scans of cervical muscles: before 20-minute rest (sham), and before/after a 5-min neck isometric warm-up. Longus colli cross-sectional area and sternocleidomastoid/upper trapezius thickness and stiffness, and cervical extensors thickness was assessed. One-way ANOVA compared morphological values at sham, before, and after warm-up. Significance was set at p < 0.05. RESULTS: Isometric neck warm-up increased rate of force development in flexion (p = 0.022), extension (p = 0.001-0.003), right lateral flexion (p = 0.004-0.032), left lateral flexion (p = 0.005-0.014), while peak force improved only in left lateral flexion (p = 0.032). Lateral flexion range-of-motion increased after neck warm-up (p = 0.003-0.026). Similarly, longus colli cross-sectional area (p = 0.016) and sternocleidomastoid thickness (p = 0.004) increased. CONCLUSIONS: Increased neck performance characteristics and morphology are likely due to PAPE effects of isometric neck warm-up. For coaches and athletes, simple isometric contractions could be added to existing warm-ups to reduce prevalence, incidence, and severity of mild traumatic brain injuries and neck pain.

A review and perspective on the neural basis of radiological expertise.

Radiological expertise requires tremendous time, effort, and training. While there has been a myriad of studies focusing on radiological expertise and error, the precise underlying neural mechanism still remains largely unexplored. In this article, we review potential neural mechanisms, namely, the fusiform face area, working memory, and predictive coding and propose experiments to test the predictive coding framework.

Vaccinating against cancer: getting to prime time.

Immunotherapies, such as immune checkpoint inhibitors, cellular therapies, and T-cell engagers, have fundamentally changed our approach to treating cancer. However, successes with cancer vaccines have been more difficult to realize. While vaccines against specific viruses have been widely adopted to prevent the development of cancer, only two vaccines can improve survival in advanced disease: sipuleucel-T and talimogene laherparepvec. These represent the two approaches that have the most traction: vaccinating against cognate antigen and priming responses using tumors in situ. Here, we review the challenges and opportunities researchers face in developing therapeutic vaccines for cancer.

Changes in cortisol and corticosteroid receptors during dynamic salinity challenges in Mozambique tilapia.

In estuarine environments, euryhaline fish maintain a narrow range of internal osmolality despite daily changes in environmental salinity that can range from fresh water (FW) to seawater (SW). The capacity of euryhaline fish to maintain homeostasis in a range of environmental salinities is primarily facilitated by the neuroendocrine system. One such system, the hypothalamic-pituitary-interrenal (HPI) axis, culminates in the release of corticosteroids such as cortisol into circulation. Cortisol functions as both a mineralocorticoid and glucocorticoid in fish because of its roles in osmoregulation and metabolism, respectively. The gill, a key site for osmoregulation, and the liver, the primary storage site for glucose, are known targets of cortisol's actions during salinity stress. While cortisol facilitates acclimation to SW environments, less is known on its role during FW adaptation. In this study, we characterized the responses of plasma cortisol, mRNA expression of pituitary pro-opiomelanocortin (pomc), and mRNA expression of liver and gill corticosteroid receptors (gr1, gr2, and mr) in the euryhaline Mozambique tilapia (Oreochromis mossambicus) under salinity challenges. Specifically, tilapia were subjected to salinity transfer regimes from steady-state FW to SW, SW to FW (experiment 1) or steady state FW or SW to tidal regimen (TR, experiment 2). In experiment 1, fish were sampled at 0 h, 6 h, 1, 2, and 7 d post transfer; while in experiment 2, fish were sampled at day 0 and day 15. We found a rise in pituitary pomc expression and plasma cortisol following transfer to SW while branchial corticosteroid receptors were immediately downregulated after transfer to FW. Moreover, branchial expression of corticosteroid receptors changed with each salinity phase of the TR, suggesting rapid environmental modulation of corticosteorid action. Together, these results support the role of the HPI-axis in promoting salinity acclimation, including in dynamically-changing environments.

Low educational attainment is associated with higher all-cause and cardiovascular mortality in the United States adult population.

INTRODUCTION: Educational attainment is an important social determinant of health (SDOH) for cardiovascular disease (CVD). However, the association between educational attainment and all-cause and CVD mortality has not been longitudinally evaluated on a population-level in the US, especially in individuals with atherosclerotic cardiovascular disease (ASCVD). In this nationally representative study, we assessed the association between educational attainment and the risk of all-cause and cardiovascular (CVD) mortality in the general adult population and in adults with ASCVD in the US. METHODS: We used data from the 2006-2014 National Death Index-linked National Health Interview Survey for adults ≥ 18 years. We generated age-adjusted mortality rates (AAMR) by levels of educational attainment (< high school (HS), HS/General Education Development (GED), some college, and ≥ College) in the overall population and in adults with ASCVD. Cox proportional hazards models were used to examine the multivariable-adjusted associations between educational attainment and all-cause and CVD mortality. RESULTS: The sample comprised 210,853 participants (mean age 46.3), representing ~ 189 million adults annually, of which 8% had ASCVD. Overall, 14.7%, 27%, 20.3%, and 38% of the population had educational attainment < HS, HS/GED, Some College, and ≥ College, respectively. During a median follow-up of 4.5 years, all-cause age-adjusted mortality rates were 400.6 vs. 208.6 and 1446.7 vs. 984.0 for the total and ASCVD populations for < HS vs ≥ College education, respectively. CVD age adjusted mortality rates were 82.1 vs. 38.7 and 456.4 vs 279.5 for the total and ASCVD populations for < HS vs ≥ College education, respectively. In models adjusting for demographics and SDOH, < HS (reference = ≥ College) was associated with 40-50% increased risk of mortality in the total population and 20-40% increased risk of mortality in the ASCVD population, for both all-cause and CVD mortality. Further adjustment for traditional risk factors attenuated the associations but remained statistically significant for < HS in the overall population. Similar trends were seen across sociodemographic subgroups including age, sex, race/ethnicity, income, and insurance status. CONCLUSIONS: Lower educational attainment is independently associated with increased risk of all-cause and CVD mortality in both the total and ASCVD populations, with the highest risk observed for individuals with < HS education. Future efforts to understand persistent disparities in CVD and all-cause mortality should pay close attention to the role of education, and include educational attainment as an independent predictor in mortality risk prediction algorithms.

Non-clinical, quality and environmental impact assessments of cell and gene therapy products: Report on the 5th Asia Partnership Conference of Regenerative Medicine - April 7, 2022.

The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.

Comparison of guidelines for biological ancillary materials used for the manufacture of gene and cellular therapy products in Asia.

BACKGROUND AIMS: Although biologiocal ancillay materials (AMs) have specific risk associated with their derivations, it plays key role to manufature cell and gene therapy (CGT) products. It is important to understand the regulation relevant to AMs for developers. METHODS: The authors investigated the guidelines and pharmacopeia (hereinafter referred to as "guidelines") for biological AMs used for the manufacture of CGT products in Asia (China, India, Japan, Korea and Taiwan). In addition, the authors benchmarked the relevant guidelines in the United States (US) and European Union (EU). RESULTS AND DISCUSSIONS: The guidelines could be classified into two types based on whether specific AMs are scoped: (i) general guidelines for risk assessment of AMs and (ii) guidelines for specific AMs. The authors compared the risk categories for each type of AM provided in the general guidelines between the US and China and the specific requirements for bovine serum and trypsin in the guidelines of China, Japan, Taiwan, US and EU. The authors further compiled in-depth descriptions of the respective regulations in China, India, Japan, Korea and Taiwan. There is limited availability of some guidelines for specific AMs. Moreover, there are no common requirements established across the surveyed countries and regions. Therefore, the authors suggest a risk assessment approach for AMs with consideration of their biological origin and traceability, production steps applied and ability to control or remove AMs from the final medicinal product over the CGT manufacturing process.

Historical Portrayal of Hoarding Disorder in European Literature and Its Relationship to the Economic and Personal Circumstances of the Authors.

In 2013, hoarding disorder was officially recognized as a separate Diagnostic and Statistical Manual psychiatric diagnosis after years of debate. Prior to 2013, hoarding disorder was generally considered a subset of obsessive-compulsive disorder. Though modern medicine has only recently deepened the analysis of hoarding disorder, hoarding was regularly featured as a character trait in numerous European literary works dating back over 700 years. Several prominent European writers incorporated hoarding behavior in the fictional characters they created. Each author's individual social and economic experiences may have been motivators for perpetuating hoarding-like behavior. It can be postulated that specific historical events and economic circumstances in the country at the time of each author's life likely impacted their interpretation of hoarding behaviors, and the authors carried these influences into their portrayal of their fictional characters. This analysis discusses the various portrayals of hoarding in key pieces of literature and seeks to explain the rationale for these authors' inclusion of hoarding traits in their characters.

A Review of the Multi-Systemic Complications of a Ketogenic Diet in Children and Infants with Epilepsy.

Ketogenic diets (KDs) are highly effective in the treatment of epilepsy. However, numerous complications have been reported. During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet. While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone. Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet. With appropriate monitoring and close follow-up to minimize adverse effects, KDs can be effective for patients with intractable epilepsy.

Nonclinical and quality assessment of cell therapy products: Report on the 4th Asia Partnership Conference of Regenerative Medicine, April 15, 2021.

The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.

Food insecurity and cardiovascular disease: Current trends and future directions.

Food insecurity (FI) - a state of limited access to nutritionally adequate food - is notably more prominent among patients with cardiovascular disease (CVD) than the general population. Current research suggests that FI increases the risk of cardiovascular morbidity and mortality through various behavioral and biological pathways. Importantly, FI is more prevalent among low-income households and disproportionately affects households with children, particularly those led by single mothers. These disparities necessitate solutions specifically geared towards helping these high-risk subgroups, who also experience increased risk of CVD associated with FI. Further, individuals with CVD may experience increased risk of FI due to the financial burden imposed by CVD care. While participation in federal aid programs like the Supplemental Nutrition Assistance Program and the Special Supplemental Nutrition Program for Women, Infants, and Children has been associated with cardiovascular health benefits, residual FI and lower dietary quality among many families suggest a need for better outreach and expanded public assistance programs. Healthcare systems and community organizations can play a vital role in screening individuals for FI and connecting them with food and educational resources. While further research is needed to evaluate sociodemographic differences in the FI-CVD relationship, interventions at the policy, health system, and community levels can help address both the burden of FI and its impacts on cardiovascular health.

Chronic plantar fasciitis reduces rearfoot to medial-forefoot anti-phase coordination.

BACKGROUND: It is commonly assumed that abnormal foot biomechanics cause plantar fasciitis; however, this assumption is not well supported. In this study, we investigated rearfoot to medial-forefoot coordination of healthy and plantar fasciitis individuals. We hypothesized that chronic plantar fasciitis individuals would exhibit greater intersegmental rearfoot to medial-forefoot anti-phase coordination and greater coordinative variability than a healthy cohort. METHODS: Twenty-two individuals with chronic plantar fasciitis (symptomatic mean 4.5 years) and 22 healthy individuals participated. Three-dimensional kinematics of the rearfoot and medial forefoot segments were captured using reflective markers for walking trials. After resolving rearfoot and medial-forefoot segment angle data, a modified vector coding method was used to compute coupling angles, anti-phase movements, and coordinative variability. FINDINGS: Compared to healthy individuals, individuals with plantar fasciitis exhibited fewer anti-phase movements (frontal plane: P = 0.003, effect size = 0.38). No group differences were detected in coordinative variability magnitude (sagittal, frontal, transverse, respectively: P = 0.99, 0.72, 0.86; effect sizes = 0.00, 0.12, 0.04). There were significant main effect differences in coupling variability between stance periods (P < 0.0001). INTERPRETATION: Contrary to our hypothesis, these data suggest that a relative reduction of rearfoot to medial-forefoot anti-phase movements with a chronic plantar fasciitis injury indicates a coordinative deficit, and that a greater frequency of anti-phase movements is associated with healthy foot function. Pain, guarding, and/or the state of chronic injury may be impairing fluid inter-segmental motion. Although no group differences were found in coordinative variability, this variability increased around transitions between loading, weight acceptance, and propulsive phases of gait.

Treatment of Severe Ankle and Hindfoot Deformity: Technique Using Femoral Head Allograft for Tibiotalocalcaneal Fusion Using a Cup-and-Cone Reamer.

Limb shortening due to structural bone loss in tibiotalocalcaneal arthrodesis is a concern that can negatively impact the patient's gait and weight-bearing. To aid in preventing the risk of limb shortening, the use of a femoral head allograft and intramedullary nail in tibiotalocalcaneal arthrodesis has been shown to successfully preserve limb length in patients with structural bone deficits. We present our technique using a femoral head allograft with a cup-and-cone reamer for the treatment of severe ankle and hindfoot deformity.

Multi-Immune Agonist Nanoparticle Therapy Stimulates Type I Interferons to Activate Antigen-Presenting Cells and Induce Antigen-Specific Antitumor Immunity.

Cancer immunity is mediated by a delicate orchestration between the innate and adaptive immune system both systemically and within the tumor microenvironment. Although several adaptive immunity molecular targets have been proven clinically efficacious, stand-alone innate immunity targeting agents have not been successful in the clinic. Here, we report a nanoparticle optimized for systemic administration that combines immune agonists for TLR9, STING, and RIG-I with a melanoma-specific peptide to induce antitumor immunity. These immune agonistic nanoparticles (iaNPs) significantly enhance the activation of antigen-presenting cells to orchestrate the development and response of melanoma-sensitized T-cells. iaNP treatment not only suppressed tumor growth in an orthotopic solid tumor model, but also significantly reduced tumor burden in a metastatic animal model. This combination biomaterial-based approach to coordinate innate and adaptive anticancer immunity provides further insights into the benefits of stimulating multiple activation pathways to promote tumor regression, while also offering an important platform to effectively and safely deliver combination immunotherapies for cancer.

DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation.

Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell-engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micrometre-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR T cells, driving local tumour clearance while sparing uninjected tumours in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to substantially impact human primary T cell activation phenotypes. This modular and versatile biomaterial functionalization platform can provide new opportunities for immunotherapies.

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress.

Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial cells can promote chronic inflammation and disease processes like thrombosis, atherosclerosis, and lung injury. In endothelial cells, mitochondria regulate these inflammatory pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that can initiate and exacerbate senescence, a state that promotes inflammation and chronic endothelial dysfunction. Oxidative stress can also activate feedback loops that perpetuate mitochondrial dysfunction, mtROS overproduction, and inflammation. In this review, we provide an overview of phenotypes mediated by mtROS in endothelial cells - such as mitochondrial dysfunction, inflammation, and senescence - as well as how these chronic states may be initiated by SARS-CoV-2 infection of endothelial cells. We also propose that SARS-CoV-2 activates mtROS-mediated feedback loops that cause long-term changes in host redox status and endothelial function, promoting cardiovascular disease and lung injury after recovery from COVID-19. Finally, we discuss the implications of these proposed pathways on long-term vascular health and potential treatments to address these chronic conditions.

Nanoporous Immunoprotective Device for Stem-Cell-Derived ß-Cell Replacement Therapy.

Encapsulation of human embryonic stem-cell-differentiated beta cell clusters (hES-ßC) holds great promise for cell replacement therapy for the treatment of diabetics without the need for chronic systemic immune suppression. Here, we demonstrate a nanoporous immunoprotective polymer thin film cell encapsulation device that can exclude immune molecules while allowing exchange of oxygen and nutrients necessary for in vitro and in vivo stem cell viability and function. Biocompatibility studies show the device promotes neovascular formation with limited foreign body response in vivo. The device also successfully prevented teratoma escape into the peritoneal cavity of mice. Long-term animal studies demonstrate evidence of engraftment, viability, and function of cells encapsulated in the device after 6 months. Finally, in vivo study confirms that the device was able to effectively immuno-isolate cells from the host immune system.