Leukocytes, microRNA, and complement activity in raw, heat-treated, and frozen colostrum and their dynamics as colostrum transitions to mature milk in dairy cows.

The objectives of this study were to evaluate the abundance and viability of leukocytes, the abundance of microRNA, and the activity of the complement pathway in (1) colostrum following heat-treatment or freezing, and (2) colostrum, transition milk, and mature milk. In experiment 1, composite colostrum samples were harvested from individual cows (n = 14) on a commercial dairy farm in NY and split into 3 aliquots using single-use colostrum bags. One aliquot was immediately cooled on ice following harvest (RAW) and stored at 4°C overnight, one was heat-treated for 60 min at 60°C (HT) before being cooled on ice and stored at 4°C overnight, and one was frozen at -20°C overnight (FR). The following morning, all samples were warmed to 40°C before further processing. In experiment 2, cows were sampled in a longitudinal study where composite samples were collected from colostrum (first milking, n = 23), transition milk (3 to 4 d postpartum, n = 13), and mature milk (6 to 7 d postpartum, n = 13). In both experiments colostrum was harvested from the first milking within 8 h of calving and samples were processed within 14 h of collection. Colostral leukocytes were isolated before viability was determined by trypan blue exclusion and manual differential cell counts were performed. Extracellular vesicles were isolated from whey by ultracentrifugation to isolate and quantify microRNA. Activity of the alternative complement pathway was determined in casein-depleted whey by semi-solid phase hemolysis assay. Somatic cell counts were determined for all raw samples. Macrophages and neutrophils made up the greatest proportion of leukocytes in colostrum followed by lymphocytes. Lymphocyte proportion increased as colostrum transitioned to mature milk, but overall somatic cell numbers declined concurrently. Viable cells were not isolated from HT or FR samples. Abundance of microRNA isolated from transition and mature milk was decreased compared with colostrum, did not differ between HT and RAW, but was increased in FR compared with RAW. Alternative complement pathway activity was decreased in HT, but not FR compared with RAW, and was not measurable in transition or mature milk. Postharvest heat-treatment and freezing of colostrum eliminated viable colostral leukocytes and affected microRNA abundance and complement activity. Leukocyte proportions, microRNA abundance, and complement activity changed as colostrum transitioned to mature milk. Although there were clear changes in the colostral components under study in relation to treatment and transition to mature milk, the biological significance of the described treatment effects and temporal changes were not investigated here.

Intermittent low dose carbon monoxide inhalation does not influence glucose regulation in overweight adults: a randomized controlled crossover trial.

NEW FINDINGS: What is the central question of this study? Low dose carbon monoxide (CO) inhalation plays a role in regulating proteins involved in glucose metabolism; does low dose CO improve glucose and insulin responses to an oral glucose tolerance test in overweight adults? What is the main finding and its importance? Five days of intermittent CO inhalation does not alter the glucose or insulin responses to ingestion of a glucose bolus in overweight adults. Low dose CO is utilized in various physiological assessment procedures; these findings allow researchers and clinicians to utilize these procedures without concern of altering glucose metabolism. ABSTRACT: Low dose carbon monoxide (CO) inhalation upregulates several proteins important for glucose metabolism. Such changes could be clinically significant and may be relevant to those who use CO as a research tool. We hypothesized that low dose CO inhalation would improve glucose and insulin responses to an oral glucose bolus in overweight humans. Eleven young adults (5 men, 6 women; body mass index: 25-35 kg m-2 ) were included in this randomized, placebo-controlled, single-blinded crossover study. Following screening, participants completed two 7-day protocols with a 4-week washout. Twenty-four hours prior to and following five consecutive days of either once daily CO (men: 1.2 ml (kg body mass)-1 ; women: 1.0 ml (kg body mass)-1 ) or placebo (room air) inhalation, participants underwent oral glucose tolerance tests (OGTT). For key outcome variables, there were no significant main effects or interactions across condition or time point (mean ± SD), including fasting glucose (mg dl-1 : pre-placebo: 85.2 ± 10.1; post-placebo: 82.9 ± 10.6; pre-CO: 83.6 ± 7.7; post-CO: 84.0 ± 9.0), 2 h post glucose (mg dl-1 : pre-placebo: 100.9 ± 20.0; post-placebo: 98.7 ± 13.1; pre-CO: 94.2 ± 23.2; post-CO: 94.4 ± 14.9), or the Matsuda index (pre-placebo: 16.1 ± 11.5; post-placebo: 20.3 ± 24.7; pre-CO: 15.6 ± 15.3; post-CO: 17.5 ± 16.8). In conclusion, 5 days of low dose CO administration did not influence glucose and insulin responses to an OGTT in overweight adults. Low dose CO inhalation is utilized in a variety of physiological assessment procedures; these findings allow researchers to utilize these procedures without concern of altering glucose metabolism.

Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease.

Despite more than a century of research, the aetiology of sporadic Alzheimer's disease (AD) remains unclear and finding disease modifying treatments for AD presents one of the biggest medical challenges of our time. AD pathology is characterized by deposits of aggregated amyloid beta (Aß) in amyloid plaques and aggregated tau in neurofibrillary tangles. These aggregates begin in distinct brain regions and spread throughout the brain in stereotypical patterns. Neurodegeneration, comprising loss of synapses and neurons, occurs in brain regions with high tangle pathology, and an inflammatory response of glial cells appears in brain regions with pathological aggregates. Inheriting an apolipoprotein E ε4 (APOE4) allele strongly increases the risk of developing AD for reasons that are not yet entirely clear. Substantial amounts of evidence support a role for APOE in modulating the aggregation and clearance of Aß, and data have been accumulating recently implicating APOE4 in exacerbating neurodegeneration, tau pathology and inflammation. We hypothesize that APOE4 influences all the pathological hallmarks of AD and may sit at the interface between neurodegeneration, inflammation and the spread of pathologies through the brain. Here, we conducted a systematic search of the literature and review evidence supporting a role for APOE4 in neurodegeneration and inflammation. While there is no direct evidence yet for APOE4 influencing the spread of pathology, we postulate that this may be found in future based on the literature reviewed here. In conclusion, this review highlights the importance of understanding the role of APOE in multiple important pathological mechanisms in AD.

Contributions to lateral balance control in ambulatory older adults.

BACKGROUND: In older adults, impaired control of standing balance in the lateral direction is associated with the increased risk of falling. Assessing the factors that contribute to impaired standing balance control may identify areas to address to reduce falls risk. AIM: To investigate the contributions of physiological factors to standing lateral balance control. METHODS: Two hundred twenty-two participants from the Pittsburgh site of the Health, Aging and Body Composition Study had lateral balance control assessed using a clinical sensory integration balance test (standing on level and foam surface with eyes open and closed) and a lateral center of pressure tracking test using visual feedback. The center of pressure was recorded from a force platform. Multiple linear regression models examined contributors of lateral control of balance performance, including concurrently measured tests of lower extremity sensation, knee extensor strength, executive function, and clinical balance tests. Models were adjusted for age, body mass index, and sex. RESULTS: Larger lateral sway during the sensory integration test performed on foam was associated with longer repeated chair stands time. During the lateral center of pressure tracking task, the error in tracking increased at higher frequencies; greater error was associated with worse executive function. The relationship between sway performance and physical and cognitive function differed between women and men. DISCUSSION: Contributors to control of lateral balance were task-dependent. Lateral standing performance on an unstable surface may be more dependent upon general lower extremity strength, whereas visual tracking performance may be more dependent upon cognitive factors. CONCLUSIONS: Lateral balance control in ambulatory older adults is associated with deficits in strength and executive function.

Brain natriuretic peptide and insulin resistance in older adults.

AIMS: Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established. METHODS: N-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance. RESULTS: Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P < 0.001 for all four indices). Although the genetic score was strongly related to measured NT-proBNP levels amongst European Americans (F statistic = 71.08), we observed no association of genetically determined NT-proBNP with insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP). CONCLUSIONS: In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study.

Outcomes for Patients with apparent Chronic Idiopathic Pelvic Pain and associated Pelvic Floor Disorders undergoing Laparoscopic Ventral Mesh Rectopexy.

This article has been temporarily withdrawn, with the agreement of all authors and the journal editor, whilst an investigated is being carried out by the North Bristol NHS Trust and the General Medical Council following some concerns raised.

Neurophysiological assessment of acute pain in infants: a scoping review of research methods.

A systematic scoping search to describe the neurophysiological methods used in infant acute pain assessment research was conducted. Of the 2411 abstracts screened, 19 articles were retained. Nine studies utilised near-infrared spectroscopy (NIRS), two utilised functional magnetic resonance imaging (fMRI), and eight utilised electroencephalography (EEG). There was methodological variability in studies utilising NIRS, whereas EEG and fMRI studies reported consistent methods. Of the eight EEG studies, six identified a nociceptive-specific event-related potential. CONCLUSION: While more methodologically rigorous studies are needed, ERPs appear to hold some promise as indicators of infant nociception during clinical procedures to supplement existing measures.

Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults.

WHAT IS KNOWN AND OBJECTIVE: There are few studies examining both drug-drug and drug-disease interactions in older adults. Therefore, the objective of this study was to describe the prevalence of potential drug-drug and drug-disease interactions and associated factors in community-dwelling older adults. METHODS: This cross-sectional study included 3055 adults aged 70-79 without mobility limitations at their baseline visit in the Health Aging and Body Composition Study conducted in the communities of Pittsburgh PA and Memphis TN, USA. The outcome factors were potential drug-drug and drug-disease interactions as per the application of explicit criteria drawn from a number of sources to self-reported prescription and non-prescription medication use. RESULTS: Over one-third of participants had at least one type of interaction. Approximately one quarter (25·1%) had evidence of had one or more drug-drug interactions. Nearly 10·7% of the participants had a drug-drug interaction that involved a non-prescription medication. % The most common drug-drug interaction was non-steroidal anti-inflammatory drugs (NSAIDs) affecting antihypertensives. Additionally, 16·0% had a potential drug-disease interaction with 3·7% participants having one involving non-prescription medications. The most common drug-disease interaction was aspirin/NSAID use in those with history of peptic ulcer disease without gastroprotection. Over one-third (34·0%) had at least one type of drug interaction. Each prescription medication increased the odds of having at least one type of drug interaction by 35-40% [drug-drug interaction adjusted odds ratio (AOR) = 1·35, 95% confidence interval (CI) = 1·27-1·42; drug-disease interaction AOR = 1·30; CI = 1·21-1·40; and both AOR = 1·45; CI = 1·34-1·57]. A prior hospitalization increased the odds of having at least one type of drug interaction by 49-84% compared with those not hospitalized (drug-drug interaction AOR = 1·49, 95% CI = 1·11-2·01; drug-disease interaction AOR = 1·69, CI = 1·15-2·49; and both AOR = 1·84, CI = 1·20-2·84). WHAT IS NEW AND CONCLUSION: Drug interactions are common among community-dwelling older adults and are associated with the number of medications and hospitalization in the previous year. Longitudinal studies are needed to evaluate the impact of drug interactions on health-related outcomes.

Impact of dietary plane of energy during the dry period on lipoprotein parameters in the transition period in dairy cattle.

The high energy demands of dairy cows during the transition period from late gestation into early lactation can place them at an increased risk for the development of metabolic and infectious diseases. Modification of the dry period diet has been investigated as a preventive means to minimize the detrimental aspects of metabolic shifts during the transition period. Studies investigating the impact of dry period diet on lipid parameters during the transition period have largely focused on markers of lipolysis and ketogenesis. Total cholesterol declines during the periparturient period and increases in early lactation. The impact total energy in the dry period diet has on the ability of the cow to maintain total serum cholesterol, as well as its natural high-density lipoprotein-rich status, during this metabolically challenging window is not clear. The impact of lipoproteins on inflammation and immune function may have a clinical impact on the cow's ability to ward off production-related diseases. In this study, we hypothesized that the provision of adequate, but not excessive, total metabolizable energy, would better allow the cow to maintain total cholesterol and a higher relative proportion of HDL throughout the transition period. Cows were allocated to one of three dry period dietary treatment groups following a randomized block design. Total serum triglycerides, cholesterol and lipoprotein fractions were measured on a weekly basis from approximately 7 weeks pre-calving to 6 weeks post-calving. The cows on the high energy diet maintained total serum cholesterol as compared to the cows provided a lower energy diet, but there was no significant increase in the LDL fraction of lipoproteins between diet treatment groups.

Maternal and newborn outcomes among women with schizophrenia: a retrospective population-based cohort study.

OBJECTIVE: More women with schizophrenia are becoming pregnant, such that contemporary data are needed about maternal and newborn outcomes in this potentially vulnerable group. We aimed to quantify maternal and newborn health outcomes among women with schizophrenia. DESIGN: Retrospective cohort study. SETTING: Population based in Ontario, Canada, from 2002 to 2011. POPULATION: Ontario women aged 15-49 years who gave birth to a liveborn or stillborn singleton infant. METHODS: Women with schizophrenia (n = 1391) were identified based on either an inpatient diagnosis or two or more outpatient physician service claims for schizophrenia within 5 years prior to conception. The reference group comprised 432 358 women without diagnosed mental illness within the 5 years preceding conception in the index pregnancy. MAIN OUTCOME MEASURES: The primary maternal outcomes were gestational diabetes mellitus, gestational hypertension, pre-eclampsia/eclampsia, and venous thromboembolism. The primary neonatal outcomes were preterm birth, and small and large birthweight for gestational age (SGA and LGA). Secondary outcomes included additional key perinatal health indicators. RESULTS: Schizophrenia was associated with a higher risk of pre-eclampsia (adjusted odds ratio, aOR 1.84; 95% confidence interval, 95% CI 1.28-2.66), venous thromboembolism (aOR 1.72, 95% CI 1.04-2.85), preterm birth (aOR 1.75, 95% CI 1.46-2.08), SGA (aOR 1.49, 95% CI 1.19-1.86), and LGA (aOR 1.53, 95% CI 1.17-1.99). Women with schizophrenia also required more intensive hospital resources, including operative delivery and admission to a maternal intensive care unit, paralleled by higher neonatal morbidity. CONCLUSIONS: Women with schizophrenia are at higher risk of multiple adverse pregnancy outcomes, paralleled by higher neonatal morbidity. Attention should focus on interventions to reduce the identified health disparities.

Stress in the wild: chronic predator pressure and acute restraint affect plasma DHEA and corticosterone levels in a songbird.

The effects of chronic stressors on glucocorticoid levels are well described in laboratory rodents, but far less is known about the effects of chronic stressors on wild animals or on dehydroepiandrosterone (DHEA) levels. DHEA can be produced by the adrenal cortex and has prominent antiglucocorticoid properties. Here, we examined wild songbirds to elucidate the relationship between chronic predator pressure and plasma DHEA and corticosterone levels. We measured circulating steroid levels at baseline and after acute restraint in the breeding and nonbreeding seasons. During the breeding season, males in low predator pressure (LPP) environments had higher baseline DHEA levels than males in high predator pressure (HPP) environments. Also, acute restraint decreased DHEA levels in LPP males only but increased corticosterone levels in HPP and LPP males similarly. During the nonbreeding season, DHEA and corticosterone levels were lower than during the breeding season, and acute restraint decreased DHEA levels in both HPP and LPP males. Unlike males, breeding females showed no effect of predator pressure on baseline DHEA or corticosterone levels. These data suggest that naturalistic chronic and acute stressors affect circulating DHEA and corticosterone levels in wild animals and highlight the importance of using multiple endpoints when studying the physiological effects of chronic stress.

The effect of digital interventions on related health literacy and skills for individuals living with chronic diseases: A systematic review and meta-analysis.

BACKGROUND: Chronic diseases are a leading cause of death and disease burden globally. Digital interventions could be an approach to improve patients' ability to find, evaluate, and use health information. OBJECTIVES: The main objective was to conduct a systematic review to determine the effect of digital interventions on digital health literacy for patients living with chronic disease. Secondary objectives were to provide an overviewof the design and delivery characteristics of interventions that impact digital health literacy in people with chronic disease. METHODS: Randomized controlled trials examining digital health literacy (and related components) for individuals with cardiovascular disease, chronic lung disease, osteoarthritis, diabetes, chronic kidney disease, and HIV were identified. This review was conducted following the PRIMSA guidelines. Certainty was assessed using GRADE and the Cochrane risk of bias tool. Meta-analyses were conducted using Review Manager 5.1. The protocol was registered on PROSPERO (CRD42022375967). RESULTS: 9386 articles were identified and 17 articles representing 16 unique trials were included. Studies evaluated 5138 individuals with one or more chronic conditions (50% women, ages 42 ± 7-71 ± 12 years). The most targeted conditions were cancer, diabetes, cardiovascular disease, and HIV. Interventions included: skills training, websites, electronic personal health records, remote patient monitoring, and education. The effects of the interventions were related to: (i) digital health literacy, (ii) health literacy, (iii) health information skills, (iv) technology skills and access, and (v) self-management and participation in care. A meta-analysis of three studies identified the effect of digital interventions was better than usual care for eHealth literacy (1.22 [CI 0.55, 1.89], p < 0.001). CONCLUSIONS: The evidence of the effects of digital interventions on related health literacy is limited. Existing studies reflect the heterogeneity in study design, population, and outcome measures. There is a need for further studies on the effects of digital interventions on related health literacy for individuals with chronic conditions.

Dietary antioxidants and forced expiratory volume in 1 s decline: the Health, Aging and Body Composition study.

Increased antioxidant defences are hypothesised to decrease age- and smoking-related decline in lung function. The relationship between dietary antioxidants, smoking and forced expiratory volume in 1 s (FEV(1)) was investigated in community-dwelling older adults in the Health, Aging and Body Composition study. 1,443 participants completed a food frequency questionnaire, self-reported smoking history and had measurements taken of FEV(1) at both baseline and after 4 yrs of follow-up. The association of dietary intake of nutrients and foods with antioxidant properties and rate of FEV(1) decline was investigated using hierarchical linear regression models. In continuing smokers (current smokers at both time-points), higher vitamin C intake and higher intake of fruit and vegetables were associated with an 18 and 24 mL · yr(-1) slower rate of FEV(1) decline compared with a lower intake (p < 0.0001 and p = 0.003, respectively). In quitters (a current smoker at study baseline who had quit during follow-up), higher intake was associated with an attenuated rate of decline for each nutrient studied (p ≤ 0.003 for all models). In nonsmoking participants, there was little or no association of diet and rate of decline in FEV(1). The intake of nutrients with antioxidant properties may modulate lung function decline in older adults exposed to cigarette smoke.

Shorter telomeres are associated with obesity and weight gain in the elderly.

OBJECTIVE: Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study. DESIGN: Levels of adiposity were assessed in six ways (obesity status, body mass index (BMI), the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline, and three of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up. RESULTS: At baseline, TL was negatively associated with % body fat (ß=-0.35±0.09, P=0.001) and subcutaneous fat (ß=-2.66±1.07, P=0.01), and positively associated with leptin after adjusting for % body fat (ß=0.32±0.14, P=0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (ß=0.48±0.20, P=0.01) and % body fat (ß=0.42±0.23, P=0.05). CONCLUSION: Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and may warrant more prospective studies.

Genetic analysis of serum osteocalcin and bone mineral in multigenerational Afro-Caribbean families.

UNLABELLED: Osteocalcin is a major component of bone matrix. Concentrations of total, carboxylated, and uncarboxylated osteocalcin, are highly heritable and genetically correlated with bone mineral content (BMC) within African ancestry families. INTRODUCTION: Osteocalcin (OC) is a protein constituent of bone matrix and a marker of bone formation. We characterized the heritability of serum OC measures and identified genomic regions potentially involved in the regulation of OC via high-density genome-wide linkage analysis in African ancestry individuals. METHODS: African ancestry individuals (n = 459) were recruited, without regard to health status, from seven probands (mean family size = 66; 4,373 relative pairs). Residual heritability of serum OC measures was estimated and multipoint quantitative trait linkage analysis was performed using pedigree-based maximum likelihood methods. RESULTS: Residual heritabilities of total OC, uncarboxylated OC, carboxylated OC and percent uncarboxylated OC were 0.74 ± 0.10, 0.89 ± 0.08, 0.46 ± 0.10 and 0.41 ± 0.09, respectively. All OC measures were genetically correlated with whole body BMC. We obtained strong evidence of bivariate linkage for percent uncarboxylated OC and whole body BMC on chromosome 17 (logarithm of the odds [LOD] = 3.15, 99 cM). CONCLUSIONS: All forms of OC were highly heritable and genetically correlated with total body BMC in these African ancestry families. The identified linkage region contains several candidate genes for bone and energy metabolism including COL1A1 and TNFRSF11A. Further studies of this genomic region may reveal novel insight into the genetic regulation of OC and bone mineralization.

Using the Johns Hopkins' Aggregated Diagnosis Groups (ADGs) to predict 1-year mortality in population-based cohorts of patients with diabetes in Ontario, Canada.

AIMS: There are limited validated methods to ascertain comorbidities for risk adjustment in ambulatory populations of patients with diabetes using administrative health-care databases. The objective was to examine the ability of the Johns Hopkins' Aggregated Diagnosis Groups to predict mortality in population-based ambulatory samples of both incident and prevalent subjects with diabetes. METHODS: Retrospective cohorts constructed using population-based administrative data. The incident cohort consisted of all 346,297 subjects diagnosed with diabetes between 1 April 2004 and 31 March 2008. The prevalent cohort consisted of all 879,849 subjects with pre-existing diabetes on 1 January, 2007. The outcome was death within 1 year of the subject's index date. RESULTS: A logistic regression model consisting of age, sex and indicator variables for 22 of the 32 Johns Hopkins' Aggregated Diagnosis Group categories had excellent discrimination for predicting mortality in incident diabetes patients: the c-statistic was 0.87 in an independent validation sample. A similar model had excellent discrimination for predicting mortality in prevalent diabetes patients: the c-statistic was 0.84 in an independent validation sample. Both models demonstrated very good calibration, denoting good agreement between observed and predicted mortality across the range of predicted mortality in which the large majority of subjects lay. For comparative purposes, regression models incorporating the Charlson comorbidity index, age and sex, age and sex, and age alone had poorer discrimination than the model that incorporated the Johns Hopkins' Aggregated Diagnosis Groups. CONCLUSIONS: Logistical regression models using age, sex and the John Hopkins' Aggregated Diagnosis Groups were able to accurately predict 1-year mortality in population-based samples of patients with diabetes.

The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty.

BACKGROUND: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes. OBJECTIVES: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers. SETTING: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center. PARTICIPANTS: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL. INTERVENTION: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days. MEASUREMENTS: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial. RESULTS: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board. CONCLUSION: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.

Small nuclear RNAs and pre-mRNA splicing.

Genetic and biochemical studies have recently shown that the splice sites in nuclear pre-mRNAs are aligned for the transesterification reactions through a collaboration between U5 and U6 small nuclear RNAs, which form the heart of a network of RNA-based interactions in the active spliceosome.

The risk of Parkinson disease associated with urate in a community-based cohort of older adults.

BACKGROUND/AIMS: Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults. METHODS: The association of baseline urate (µmol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 µmol/l), middle (300-500 µmol/l), and high (>500 µmol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD. RESULTS: Women had significantly lower urate concentrations than did men [316.8 µmol/l (SD 88.0) vs. 367.4 µmol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 µmol/l (OR 1.69, 95% CI 1.03-2.78) but not for urate >500 µmol/l (OR 1.55, 95% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 µmol/l, and across the entire range a convex quadratic term was significant. CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.