Histone H1.0 couples cellular mechanical behaviors to chromatin structure.

Tuning of genome structure and function is accomplished by chromatin-binding proteins, which determine the transcriptome and phenotype of the cell. Here we investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that histone H1.0, which compacts nucleosomes into higher-order chromatin fibers, controls genome organization and cellular stress response. We show that histone H1.0 has privileged expression in fibroblasts across tissue types and that its expression is necessary and sufficient to induce myofibroblast activation. Depletion of histone H1.0 prevents cytokine-induced fibroblast contraction, proliferation and migration via inhibition of a transcriptome comprising extracellular matrix, cytoskeletal and contractile genes, through a process that involves locus-specific H3K27 acetylation. Transient depletion of histone H1.0 in vivo prevents fibrosis in cardiac muscle. These findings identify an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling force generation, nuclear organization and gene transcription.

Pharmacology of drugs used in autoimmune dermatopathies in cats and dogs: A narrative review.

Immunosuppressive drugs are the mainstay of treatment for many feline and canine autoimmune skin diseases, either as monotherapy or in combination with other drugs. Treatment with these drugs is often lifelong and may have long-term consequences on the affected animal's overall quality-of-life. Clinicians need to understand the pharmacology of immunosuppressants in planning and executing the treatment regimen for the best possible clinical outcome, as well as reducing the risk of adverse effects. This review paper will focus on the mechanism of action, pharmacokinetics and pharmacodynamics, clinical uses and adverse effects of immunosuppressive drugs used to treat autoimmune dermatoses in cats and dogs. These include glucocorticoids, ciclosporin A, azathioprine, chlorambucil, mycophenolate mofetil, oclacitinib and Bruton's tyrosine kinase inhibitors.

Les médicaments immunosuppresseurs constituent la base de la thérapeutique de nombreuses dermatoses auto­immunes félines et canines, soit en monothérapie, soit en association avec d'autres médicaments. Le traitement par ces médicaments dure souvent toute la vie et peut avoir des conséquences à long terme sur la qualité de vie globale de l'animal affecté. Les cliniciens doivent comprendre la pharmacologie des immunosuppresseurs afin de planifier et de mettre en place le plan thérapeutique, afin d'obtenir le meilleur résultat clinique possible et de réduire le risque d'effets indésirables. Cet article de synthèse cible le mécanisme d'action, la pharmacocinétique et la pharmacodynamie, les utilisations cliniques et les effets indésirables des médicaments immunosuppresseurs utilisés pour traiter les dermatoses auto­immunes chez les chats et les chiens. Ces médicaments comprennent les glucocorticoïdes, la ciclosporine A, l'azathioprine, le chlorambucil, le mycophénolate mofétil, l'oclacitinib et les inhibiteurs de la tyrosine kinase de Bruton.

Os medicamentos imunossupressores são a base do tratamento para muitas doenças de pele autoimunes felinas e caninas, seja em monoterapia ou em combinação com outros medicamentos. O tratamento com esses medicamentos costuma durar toda a vida e pode ter consequências a longo prazo na qualidade de vida geral do animal afetado. Os clínicos precisam compreender a farmacologia dos imunossupressores para planejar e executar o protocolo de tratamento para se obter o melhor resultado clínico possível, assim como reduzir o risco de efeitos adversos. Este artigo de revisão será focado no mecanismo de ação, farmacocinética e farmacodinâmica, indicações clínicas e efeitos adversos de medicamentos imunossupressores usados para tratar dermatoses autoimunes em cães e gatos. Estes incluem glucocorticóides, ciclosporina A, azatioprina, clorambucil, micofenolato de mofetila, oclacitinib e inibidores da tirosina quinase de Bruton.

Los tratamientos inmunosupresores son la línea de tratamiento principal en muchas enfermedades autoinmunes de la piel de perros y gatos, bien como monoterapia o en combinación con otros fármacos. El tratamiento con estos fármacos es a menudo de larga duración o de por vida y puede tener consecuencias adversas de larga duración en la calidad de vida de los animales. Los veterinarios clínicos tienen que entender la farmacología de los inmunosupresores durante la planificación y ejecución de los tratamientos para obtener los resultados más beneficiosos y reducir los efectos adversos. Este artículo de revisión está enfocado en los mecanismos de acción, farmacocinética, farmacodinámica, usos clínicos y efectos adversos de tratamientos inmunosupresores utilizados en perros y gatos para tratar dermatopatías inmunomediadas de la piel. Se incluyen glucocorticoides, ciclosporina A, azatioprina, clorambucilo, mofetil micofenolato, oclacitinib e inhibidores de la tirosina quinasa de Bruton.

Sox9-coordinated cellular neighborhoods generate fibrosis.

Poorly regenerative organs deposit scar tissue to mend damage. Aggarwal et al. establish that transient Sox9 activity is necessary for early proximal tubule epithelial regeneration, while Trogisch et al. and Aggarwal et al. show that persistent Sox9 activity in epithelial and endothelial cells activates fibroblasts creating fibrotic microdomains in multiple organs.

Understanding Health Beliefs and Health Behaviors in Older Adults at Risk for Alzheimer's Disease.

Background: There are significant public health benefits to delaying the onset of Alzheimer's disease (AD) in individuals at risk. However, adherence to brain healthy behaviors is low. The Health Belief Model proposes that specific beliefs are mediators of behavior change. Objective: To characterize health belief measures from the Science of Behavior Change Research Network (SBCRN) in an older adult population and associations between health beliefs, AD risk, and current health behaviors. Methods: A total of 172 individuals from the Rhode Island AD Prevention Registry participated. SBCRN health belief measures included assessments of future time perspective, self-efficacy, deferment of gratification, and consideration of future consequences. Outcome measures included individual AD risk index score, dementia risk awareness, and lifestyle behaviors including physical, cognitive, and social activity. Results: Participants who were older had higher scores for AD risk, lower future time perspective, and lower generalized self-efficacy (all at p <  0.001). Higher generalized self-efficacy was related to increased physical activity (p <  0.010). Higher future time perspective (p <  0.001) and generalized self-efficacy (p = 0.48) were associated with lower AD risk score. Subjective cognitive decline (SCD) was associated with lower self-efficacy, ability to delay gratification, and a less expansive future time perspective. Conclusions: Greater self-efficacy and perceived future time remaining were associated with lower AD risk and greater engagement in physical activity. SCD was associated with health beliefs that may negatively affect engagement in positive brain health behaviors. Assessment of and psychoeducation about these intrapersonal health belief constructs may be important targets for behavioral interventions to reduce AD risk.

Medication management error types: Associations with mild cognitive impairment subtype.

Objective: Medication management errors are suspected to be prevalent among older adults with mild cognitive impairment (MCI). This study examined types of simulated medication-taking errors in cognitively normal older adults (CN; n = 131), single domain amnestic MCI (sdMCI, n = 91), and multi-domain MCI (mdMCI, n = 44). Errors were measured using the medication management ability assessment (MMAA). Methods: 266 participants seen for neuropsychological evaluation (94.4% White, 57.9% female, average age = 72, average education = 14 years) completed the MMAA (version 4.1), a performance-based task of medication management. Group differences in MMAA total scores, accuracy, and error types were evaluated using Kruskall-Wallis H tests. This study was the first to explore a newly operationalized error, perseverations, caused by taking a specific dose ≥2 times during the simulation. Results: CN and sdMCI groups had higher MMAA total scores than individuals with mdMCI, indicating better overall performance. The mdMCI group made a higher number of omission errors (missed pills) than other groups, but no differences were found for commission errors (extra pills). The sdMCI group made more perseverative errors compared to the CN group. Conclusions: Individuals with mdMCI made more simulated medication management errors than CN and sdMCI groups, indicating that they may be most vulnerable to difficulties in medication management. In contrast, sdMCI individuals were more likely to make perseverative errors, which may reflect a tendency towards overcompensation of memory loss. Future studies should assess whether MMAA performance is associated with patterns of real-world medication-taking in more diverse samples of older adults.

MYBPC3-c.772G>A mutation results in haploinsufficiency and altered myosin cycling kinetics in a patient induced stem cell derived cardiomyocyte model of hypertrophic cardiomyopathy.

Approximately 40% of hypertrophic cardiomyopathy (HCM) mutations are linked to the sarcomere protein cardiac myosin binding protein-C (cMyBP-C). These mutations are either classified as missense mutations or truncation mutations. One mutation whose nature has been inconsistently reported in the literature is the MYBPC3-c.772G > A mutation. Using patient-derived human induced pluripotent stem cells differentiated to cardiomyocytes (hiPSC-CMs), we have performed a mechanistic study of the structure-function relationship for this MYBPC3-c.772G > A mutation versus a mutation corrected, isogenic cell line. Our results confirm that this mutation leads to exon skipping and mRNA truncation that ultimately suggests ∼20% less cMyBP-C protein (i.e., haploinsufficiency). This, in turn, results in increased myosin recruitment and accelerated myofibril cycling kinetics. Our mechanistic studies suggest that faster ADP release from myosin is a primary cause of accelerated myofibril cross-bridge cycling due to this mutation. Additionally, the reduction in force generating heads expected from faster ADP release during isometric contractions is outweighed by a cMyBP-C phosphorylation mediated increase in myosin recruitment that leads to a net increase of myofibril force, primarily at submaximal calcium activations. These results match well with our previous report on contractile properties from myectomy samples of the patients from whom the hiPSC-CMs were generated, demonstrating that these cell lines are a good model to study this pathological mutation and extends our understanding of the mechanisms of altered contractile properties of this HCM MYBPC3-c.772G > A mutation.

Anticholinergic and sedative medication use in older patients with cognitive concerns.

BACKGROUND: Anticholinergic (AC) and sedative medications are a risk factor for cognitive impairment. This study sought to characterize AC and sedative use in older patients seen for outpatient neuropsychological evaluation and evaluate their associations with different cognitive domains. We hypothesized that AC and sedative use would be associated with worse attention/processing speed (AP), executive functioning (EF), and memory. METHODS: We conducted a cross-sectional chart review of 392 patients (mean [M] age = 72 ± 7.7 years, range = 54-91). Medications were characterized by number of AC medications (≥1 on the Anticholinergic Cognitive Burden Scale [ACB]), number of sedative medications, and polypharmacy (≥5 daily medications). Demographically adjusted composites were calculated for AP, EF, and memory. Bivariate Pearson correlations assessed relationships between medication use and cognition. Multivariate linear regressions evaluated significant medication-cognition associations, controlling for total medications, medical comorbidities, and estimated premorbid cognitive functioning. RESULTS: Polypharmacy was common (80%; n = 314). Most patients (70%; n = 275) used ≥1 sedative medications (range = 0-9). Over half (63%; n = 248) used ≥1 AC drugs (range = 0-7), yet ACB scores were ≤2 in 74% of patients. Sedative use was negatively correlated with AP (r = -0.134, p = 0.008) and EF (r = -0.105, p = 0.04). ACB scores were negatively correlated with AP (r = -0.106, p = 0.037). Sedatives and a priori covariates significantly predicted AP performance (R2 = 0.127, p < 0.001); using more sedative medications was uniquely associated with worse AP (ß = -0.426, p = 0.049). No significant associations were found with memory. CONCLUSION: AC and sedative medications and polypharmacy were prevalent in this sample of older patients. Though both drug classes had negative relationships with AP and EF, sedatives had a particularly negative association with AP. Contrary to our hypotheses, memory was not associated with medication use; however, anticholinergic burden was low within the sample, and AP and EF deficits may masquerade as memory problems.

Compensatory Strategy Intervention: What Older Patients Want and Why.

OBJECTIVE: Compensatory strategies can improve performance of instrumental activities of daily living in people with cognitive impairment. This study investigated patient interest in compensatory strategy interventions and preference for various intervention formats. METHODS: Semi-structured qualitative interviews with 38 older adults with cognitive impairment queried motivation to improve strategy use and interest in intervention formats/delivery methods. Two coders used thematic analysis to determine rates of interest in each intervention type and explore patient-reported barriers and facilitators to motivation and intervention models. RESULTS: Most of the samples reported motivation to enhance compensatory strategy use. Degree of motivation was driven by current experiences with strategy use, perceived benefit of potential changes, intrinsic desire to improve life and self, and current perceived need. The vast majority were interested in hour-long, multi-session, instructor-led interventions. Just over half of the sample was interested in a self-directed virtual program, and just under half was interested in involving family/friends. Facilitators and barriers to interest in intervention formats and delivery methods varied based on participants' previous experiences, preferred learning style, content, and time commitment of the intervention, and perceived current need for intervention. One-fifth of the sample expressed no interest in any intervention type, though they expressed openness to assistance in the future as needed. CONCLUSIONS: Older adults with cognitive impairment are generally motivated to enhance their compensatory strategy use. Clinicians/researchers designing compensatory strategy interventions should consider instructor-led formats, present individualized benefits of interventions, and demonstrate the benefits of both preventative and remedial intervention to optimize patient engagement.

MBNL1 Regulates Programmed Postnatal Switching Between Regenerative and Differentiated Cardiac States.

BACKGROUND: Discovering determinants of cardiomyocyte maturity is critical for deeply understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration, but elucidation of endogenous developmental regulators of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. MBNL1 (muscleblind-like 1) regulates fibroblast, thymocyte, and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. METHODS: MBNL1 gain- and loss-of-function mouse models were studied at several developmental time points and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro assays to determine the mechanisms through which MBNL1 exerts its effects. RESULTS: MBNL1 is coexpressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deficiency was insufficient to promote regeneration in the adult heart because of cell cycle checkpoint activation. CONCLUSIONS: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Targeting loss of cardiomyocyte maturity and downregulation of cell cycle inhibitors through MBNL1 deletion was not sufficient to promote adult regeneration.

What is 'physiological birth'? A scoping review of the perspectives of women and care providers.

PROBLEM: Physiological birth was defined by the World Health Organization in 1997, however, clinical practices in childbirth have changed considerably since this time. BACKGROUND: Ambiguous terms in healthcare such as 'physiological birth' may cause confusion amongst care providers and consumers. AIM: To identify what is known about physiological birth, and how perceptions of physiological birth manifest in current literature. METHODS: This review followed the Joanna Briggs Institute methodology for scoping reviews and the PRISMA-ScR checklist. Four databases were searched using keywords relating to physiological birth. Relevant studies were identified using agreed criteria, and data were extracted and synthesised. RESULTS: A total of 24 studies met the inclusion criteria for this review. Three connected factors were identified: (1) Physiological birth in a risk-averse system, (2) Dominant voices in birth, and (3) Lack of exposure to physiological birth. No unified universal definition of physiological birth was identified in the literature. DISCUSSION: 'Physiological birth' as a term lacks consistency. A risk-averse healthcare system could be a barrier to physiological birth. Dominant voices in the birthing space can dictate the way birth occurs. Lack of exposure to physiological birth may diminish the acquisition and maintenance of important skills and knowledge among care providers. Recognising the factors important to women could lead to a positive birth experience. CONCLUSION: Excluding a woman's subjective experience from health professionals' understanding of physiological birth increases the likelihood of risk management being the paramount objective in clinical decision-making. We propose it is timely to align clinical understanding of physiological birth with midwifery's woman-centred professional philosophy.

Hemadsorption extracorporeal therapy removes cytokines ex vivo in horses.

OBJECTIVE: Plasma cytokine adsorption has shown benefit as an adjunctive therapy in human sepsis but has yet to be investigated in horses. We hypothesized that ex vivo filtration of equine plasma with a novel cytokine adsorption device would significantly reduce concentrations of lipopolysaccharide-stimulated cytokines. We also hypothesized that the device would adsorb medications commonly used to treat sepsis. ANIMALS: 8 horses owned by North Carolina State University. METHODS: Four liters of heparinized whole blood was collected from healthy adult horses (n = 8) and stimulated with lipopolysaccharide (100 ng/mL) for 6 hours (37 °C.) from June 4, 2023, to December 15, 2023. Plasma was filtered through a cytokine adsorption device or sham circuit. Samples were collected at 11 time points for multiplex cytokine analysis. Chemistry analysis was performed before and after filtration. To investigate the impact of the device on medication concentrations, equine plasma containing potassium penicillin, gentamicin, and flunixin meglumine was filtered through the cytokine adsorption device or sham for 6 hours. Drug concentrations before and after filtration were determined by ultra-high-performance liquid chromatography. Prefiltration versus postfiltration sample concentrations were analyzed by Student paired t test using GraphPad Prism 9.0 (P < .05). RESULTS: Filtration of lipopolysaccharide-stimulated equine plasma (n = 8) for 6 hours resulted in significant mean reductions in the cytokines IL-10, IL-5, IL-8, tumor necrosis factor-α (TNF-α), and IL-1ß, as well as albumin. Drug concentrations of potassium penicillin, gentamicin, and flunixin meglumine were also significantly reduced by filtration. CLINICAL RELEVANCE: This work provides proof of concept for further investigation of extracorporeal cytokine adsorption as a potential adjunct treatment for equine sepsis.

Association between neuropsychological assessment and amyloid status in a clinical setting.

OBJECTIVE: Large research cohorts show robust associations between neuropsychological tests and Alzheimer's disease (AD) biomarkers, but studies in clinical settings are limited. The increasing availability of AD biomarkers to the practicing clinician makes it important to understand the relationship between comprehensive clinical neuropsychological assessment and biomarker status. This study examined concordance between practicing clinical neuropsychologists' diagnostic impressions and AD biomarker status in patients seen at an outpatient medical center, with a secondary aim of defining the characteristics of discordant cases. METHOD: Participants (N = 79) seen for clinical neuropsychological assessment who subsequently underwent lumbar puncture or amyloid positron emission tomography imaging were identified via retrospective chart review. Concordance between clinical neuropsychological diagnosis (non-AD, indeterminate, possible/probable AD) and AD biomarker status (negative, indeterminate, positive) was determined. Individual test score data were used to examine between-group differences based on amyloid status. RESULTS: AD biomarker positive and negative patients did not differ on individual neuropsychological tests after correcting for multiple comparisons, though the small number of AD biomarker indeterminate individuals performed better than biomarker positive patients. However, there was 76.7% concordance between neuropsychologists' diagnostic impressions and AD biomarker status (88% sensitivity and 55% specificity of neuropsychological assessment in detecting AD biomarker status). AD biomarker negative patients diagnosed as possible/probable AD (discordant) versus non-AD (concordant) had significantly lower Neuropsychological Assessment Battery Story Delayed Recall, higher Wechsler Adult Intelligence Scale-Fourth Edition Coding, and higher Trail-Making A (i.e., an amnestic memory profile). CONCLUSIONS: Comprehensive neuropsychological assessment showed modest concordance with AD biomarker status in patients seen in an outpatient medical center for routine clinical care. Low specificity for the clinical diagnosis of AD could be explained by the multiplicity of etiologies that cause memory impairment (i.e., TAR DNA-binding protein 43, suspected non-AD pathology). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

How poverty is measured impacts who gets classified as impoverished.

We test whether the classification of households into poverty categories is meaningfully influenced by the poverty measurement approach that is employed. These classification techniques are widely used by governments, non-profit organizations, and development agencies for policy design and implementation. Using primary data collected in Ethiopia, Ghana, and Uganda, we find almost no agreement in how four commonly used approaches rank 16,150 households in terms of poverty status. This result holds for each country, for urban and rural households, and across the entire socio-economic distribution. Households' poverty rankings differ by an entire quartile on average. Conclusions about progress toward poverty alleviation goals may depend in large part on how poverty is measured.

International collaboration between low-middle-income and high-income institutions to improve radiation therapy care delivery.

INTRODUCTION: The Philippines is a lower-middle-income island country with over 153 000 new cancer diagnosis each year. Despite many patients needing radiotherapy as part of disease management, there remains limitations to access. Currently, the Philippines has 50 linear accelerator facilities serving a population of 110 million. However, given the recommendation of 1 linear accelerator for every 250 thousand people, it is evident that the demand for accessible radiotherapy resources is significantly underserved in the country. This paper outlines the collaboration between GenesisCare Solutions (GCS) and Fairview Cancer Center (FCC) to address efficiency and access within the radiotherapy department at FCC. METHODS: Through international collaboration between GCS and FCC, areas for improvement were identified and categorized into four domains: Dosimetry quality, Patient workflow, Data & Reporting, and Information Technology (IT) Infrastructure. Action plans were developed then implemented. A baseline measurement was obtained for each domain, and post-implementation evaluation undertaken at 3 months, 6 months, and 12 months. Data captured within the electronic medical record system was extrapolated, and average treatment times were established for pre- and post-engagement. A paired, 2-tailed t-test was used for statistical analysis of outcome parameters using IBM SPSS version 23 for all statistics. RESULTS: Twelve months post-initial engagement, all four domains saw positive outcomes. Improved plan quality linked to Intensity Modulated Radiotherapy (IMRT) utilization rates saw an increase from 20% to 54%. A significant reduction in patient average wait times was also observed, from 27 to 17 min (p ≤ 0.001). Prior to engagement, tracking patient demographics and diagnosis was not prioritized, post engagement an average of 92% diagnosis entry compliance was achieved. CONCLUSION: Through the collaboration of GCS and FCC, objectives in all action plan domains were achieved, highlighting the benefits of collaboration between low-middle-income and high-income institutions.

Association of social determinants of health International Classification of Disease, Tenth Edition clinical modification codes with outcomes for emergency general surgery and trauma admissions.

BACKGROUND: Patients with Acute Care Surgery needs (ie, emergency general surgery diagnosis or trauma admission) are at particularly high risk for nonmedical patient-related factors that can be important drivers of healthcare outcomes. These social determinants of health are typically ascertained at the geographic area level (ie, county or neighborhood) rather than at the individual patient level. Recently, the International Classification of Diseases Tenth Revision, Tenth Edition created codes to capture health hazards related to patient socioeconomic and psychosocial circumstances. We sought to characterize the impact of these social determinants of health-related codes on perioperative outcomes among patients with acute care surgery needs. METHODS: Patients diagnosed between 2017 and 2020 with acute care surgery needs (ie, emergency general surgery diagnosis or a trauma admission) were identified in the California Department of Healthcare Access and information Patient Discharge database. Data on concomitant social determinants of health-related codes (International Classification of Diseases Tenth Revision, Tenth Edition Z55-Z65), which designated health hazards related to socioeconomic and psychosocial (socioeconomic and psychosocial, respectively) circumstances, were obtained. After controlling for patient factors, including age, sex, race, payer type, and admitting hospital, the association of socioeconomic and psychosocial codes with perioperative outcomes and hospital disposition was analyzed. RESULTS: Among 483,280 with an acute care surgery admission (emergency general surgery: n = 289,530, 59.9%; trauma: n = 193,705, 40.1%) mean age was 56.5 years (standard deviation: 21.5) and 271,911 (56.3%) individuals were male. Overall, 16,263 (3.4%) patients had a concomitant socioeconomic and psychosocial diagnosis code. The percentage of patients with a concurrent social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis increased throughout the study period from 2.6% in 2017 to 4.4% in 2020. Patients that were male (odds ratio 1.89; 95% confidence interval 1.82, 1.96), insured by Medicaid (odds ratio 5.43; 95% confidence interval 5.15, 5.72) or self-pay (odds ratio 3.04; 95% confidence interval 2.75, 3.36) all had higher odds of having an social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis. Black race did not have a significant association with an social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis (odds ratio 0.99; 95% confidence interval 0.94, 1.04); however, Hispanic (odds ratio 0.44; 95% confidence interval 0.43, 0.46) and Asian (odds ratio 0.40; 95% confidence interval 0.36, 0.44) race/ethnicity was associated with a lower odds of having an social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis. After controlling for competing risk factors on multivariable analyses, the risk-adjusted probability of hospital postoperative death was 3.1% (95% confidence interval 2.8, 3.4) among patients with a social determinants of health diagnosis versus 5.9% (95% confidence interval 5.9, 6.0) (odds ratio 0.48; 95% confidence interval 0.44, 0.54) among patients without a social determinants of health diagnosis. Risk-adjusted complications were 26.7% (95% confidence interval 26.1, 37.3) among patients with a social determinants of health diagnosis compared with 31.9% (95% confidence interval 31.7, 32.0) (odds ratio 0.74; 95% confidence interval 0.71, 0.77) among patients without a social determinants of health diagnosis. CONCLUSION: International Classification of Diseases Tenth Revision, Tenth Edition social determinants of health code use was low, with only 3.4% of patients having documentation of a socioeconomic and psychosocial circumstance. The presence of an International Classification of Diseases Tenth Revision, Tenth Edition social determinants of health code was not associated with greater odds of complications or death; however, it was associated with longer length of stay and higher odds of being discharged to a skilled nursing facility.

Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting.

BACKGROUND: Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models. METHODS: Gene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin. RESULTS: TFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice. CONCLUSIONS: TfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.

Providing health sciences education through virtual reality experiences.

In 2020 - 2021 the Robert B. Greenblatt, M.D. Library at Augusta University implemented two projects leveraging virtual reality (VR) technology to provide immersive experiential learning opportunities for health sciences students. The projects shared some commonalities in spite of having differing objectives and desired outcomes. These common facets led to the success of both projects and will be helpful for other institutions considering implementing VR projects.

Economic Evaluation of Exercise or Cognitive and Social Enrichment Activities for Improved Cognition After Stroke.

Importance: Cognitive impairment is prevalent in survivors of stroke, affecting approximately 30% of individuals. Physical exercise and cognitive and social enrichment activities can enhance cognitive function in patients with chronic stroke, but their cost-effectiveness compared with a balance and tone program is uncertain. Objective: To conduct a cost-effectiveness and cost-utility analysis of multicomponent exercise or cognitive and social enrichment activities compared with a balance and tone program. Design, Setting, and Participants: This economic evaluation used a Canadian health care systems perspective and the Vitality study, a randomized clinical trial aimed at improving cognition after stroke with a 6-month intervention and a subsequent 6-month follow-up (ie, 12 months). The economic evaluation covered the duration of the Vitality trial, between June 6, 2014, and February 26, 2019. Participants were community-dwelling adults aged 55 years and older who experienced a stroke at least 12 months prior to study enrollment in the Vancouver metropolitan area, British Columbia, Canada. Data were analyzed from June 1, 2022, to March 31, 2023. Interventions: Participants were randomly assigned to twice-weekly classes for 1 of the 3 groups: multicomponent exercise program, cognitive and social enrichment activities program, or a balance and tone program (control). Main Outcomes and Measures: The primary measures for the economic evaluation included cost-effectiveness (incremental costs per mean change in cognitive function, evaluated using the Alzheimer Disease Assessment Scale-Cognitive-Plus), cost-utility (incremental cost per quality-adjusted life-year gained), intervention costs, and health care costs. Since cognitive benefits 6 months after intervention cessation were not observed in the primary randomized clinical trial, an economic evaluation at 12 months was not performed. Results: Among 120 participants (mean [SD] age, 71 [9] years; 74 [62%] male), 34 were randomized to the multicomponent exercise program, 34 were randomized to the social and cognitive enrichment activities program, and 52 were randomized to the balance and tone control program. At the end of the 6-month intervention, the cost per mean change in Alzheimer Disease Assessment Scale-Cognitive-Plus score demonstrated that exercise was more effective and costlier compared with the control group in terms of cognitive improvement with an incremental cost-effectiveness ratio of CAD -$8823. The cost per quality-adjusted life-year gained for both interventions was negligible, with exercise less costly (mean [SD] incremental cost, CAD -$32 [$258]) and cognitive and social enrichment more costly than the control group (mean [SD] incremental cost, CAD $1018 [$378]). The balance and tone program had the lowest delivery cost (CAD $777), and the exercise group had the lowest health care resource utilization (mean [SD] $1261 [$1188]) per person. Conclusions and Relevance: The findings of this economic evaluation suggest that exercise demonstrated potential for cost-effectiveness to improve cognitive function in older adults with chronic stroke during a 6-month intervention.

Supporting physical activity for mobility in older adults with mobility limitations (SuPA Mobility): study protocol for a randomized controlled trial.

BACKGROUND: Limited mobility in older adults consistently predicts both morbidity and mortality. As individuals age, the rates of mobility disability increase from 1.0% in people aged 15-24 to 20.6% in adults over 65 years of age. Physical activity can effectively improve mobility in older adults, yet many older adults do not engage in sufficient physical activity. Evidence shows that increasing physical activity by 50 min of moderate intensity physical activity in sedentary older adults with mobility limitations can improve mobility and reduce the incidence of mobility disability. To maximize the healthy life span of older adults, it is necessary to find effective and efficient interventions that can be delivered widely to prevent mobility limitations, increase physical activity participation, and improve quality of life in older adults. We propose a randomized controlled trial to assess the effect of a physical activity health coaching intervention on mobility in older adults with mobility limitations. METHODS: This randomized controlled trial among 290 (145 per group) community-dwelling older adults with mobility limitations, aged 70-89 years old, will compare the effect of a physical activity health coaching intervention versus a general healthy aging education program on mobility, as assessed with the Short Physical Performance Battery. The physical activity health coaching intervention will be delivered by exercise individuals who are trained in Brief Action Planning. The coaches will use evidence-based behavior change techniques including goal-setting, action planning, self-monitoring, and feedback to improve participation in physical activity by a known dose of 50 min per week. There will be a total of 9 health coaching or education sessions delivered over 26 weeks with a subsequent 26-week follow-up period, wherein both groups will receive the same duration and frequency of study visits and activities. DISCUSSION: The consequences of limited mobility pose a significant burden on the quality of life of older adults. Our trial is novel in that it investigates implementing a dose of physical activity that is known to improve mobility in older adults utilizing a health coaching intervention. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT05978336; registered on 28 July 2023.

Pharmacokinetic-pharmacodynamic cutoff values for benzylpenicillin in horses to support the establishment of clinical breakpoints for benzylpenicillin antimicrobial susceptibility testing in horses.

Introduction: The aim of this international project was to establish a species-specific Clinical Breakpoint for interpretation of Antimicrobial Susceptibility Testing of benzylpenicillin (BP) in horses. Methods: A population pharmacokinetic model of BP disposition was developed to compute PK/PD cutoff values of BP for different formulations that are commonly used in equine medicine around the world (France, Sweden, USA and Japan). Investigated substances were potassium BP, sodium BP, procaine BP, a combination of procaine BP and benzathine BP and penethamate, a prodrug of BP. Data were collected from 40 horses that provided 63 rich profiles of BP corresponding to a total of 1022 individual BP plasma concentrations. Results: A 3-compartment disposition model was selected. For each of these formulations, the PK/PD cutoff was estimated for different dosage regimens using Monte Carlo simulations. The fAUC/MIC or fT>MIC were calculated with a free BP fraction set at 0.4. For fAUC/MIC, a target value of 72 h (for a 72h treatment) was considered. For fT>MIC, efficacy was assumed when free plasma concentrations were above the explored MIC (0.0625-2 mg/L) for 30 or 40 % of the dosing interval. For continuous infusion, a fT>MIC of 90 % was considered. It was shown that a PK/PD cutoff of 0.25 mg/L can be achieved in 90 % of horses with routine regimen (typically 22,000 IU/kg or 12.4 mg/kg per day) with IM procaine BP once a day (France, Japan, Sweden but not USA1) and with IM sodium BP at 14.07 mg/kg, twice a day or IV sodium BP infusion of 12.4 mg/kg per day. In contrast, penethamate and the combination of procaine BP and benzathine BP were unable to achieve this PK/PD cutoff not even an MIC of 0.125 mg/L. Discussion: The PK/PD cutoff of 0.25 mg/L is one dilution lower than the clinical breakpoint released by the CLSI (0.5 mg/ L). From our simulations, the CLSI clinical breakpoint can be achieved with IM procaine BP twice a day at 22,000 IU i.e. 12.4 mg/kg.