A novel DNA methylation-based surrogate biomarker for chronic systemic inflammation (InfLaMeS): results from the Health and Retirement Study.

Chronic low-grade systemic inflammation is a risk factor for chronic diseases and mortality and is an important biomarker in health research. DNA methylation (DNAm) surrogate biomarkers are valuable exposure, risk factor and health outcome predictors in studies where the measures cannot be measured directly and often perform as well or better than direct measure. We generated a DNAm surrogate biomarker for chronic, systemic inflammation from a systemic inflammation latent variable of seven inflammatory markers and evaluated its performance relative to measured inflammatory biomarkers in predicting several age-associated outcomes of interest, including mortality, activities of daily living and multimorbidity in the Health and Retirement Study (HRS). The DNAm surrogate, Inflammation Latent Variable Methylation Surrogate (InfLaMeS), correlated with seven individual inflammation markers (r= -0.2-0.6) and performed as well or better to the systemic inflammation latent variable measure when predicting multimorbidity, disability, and 4-year mortality in HRS. Findings were validated in an external cohort, The Irish Longitudinal Study of Ageing. These results suggest that InfLaMeS provides a robust alternative to measured blood-chemistry measures of inflammation with broad applicability in instances where values of inflammatory markers are not measured but DNAm data is available.

Enterocytozoon bieneusi, a human pathogen.

Although brought to the forefront in the 1980s with the AIDS pandemic, microsporidia infecting humans are still little known. Enterocytozoon bieneusi, by far the most frequent microsporidia species causing diseases in humans, is responsible for intestinal illness in both non- and immunocompromised patients. This species presents an astonishing genetic diversity with more than 500 genotypes described, some of which have a strong zoonotic potential. Indeed, E. bieneusi infects a broad array of hosts, from wild to domestic animals. This emerging eukaryotic pathogen has thus been associated with foodborne/waterborne outbreaks. Several molecular assays have been developed to enhance its diagnosis or for epidemiological purposes, providing valuable new data. Here, we propose an overview of the current knowledge on this major species among the microsporidia, so far rather neglected in human medicine.

Tlr7 drives sex- and tissue-dependent effects in Sjögren's disease.

Primary Sjögren's disease (pSD) is a systemic autoimmune disease that has the strongest female predilection of all autoimmune diseases. The underlying mechanisms that govern this sexual dimorphism, however, remain poorly understood. We hypothesized that pSD females would exhibit more robust disease as compared to males, and that Tlr7 controls distinct disease manifestations in males and females. Using a well-established pSD mouse model, we harvested exocrine glands, and pulmonary and renal tissue from males and females and quantified the inflammation present. We then collected salivary glands, spleens, and cervical lymph nodes and performed flow cytometry to assess immune populations implicated in disease. We also harvested sera to examine total and autoreactive antibodies. Our data revealed that pSD mice displayed sex-biased disease, as pSD females showed decreased dacryoadenitis, but increased nephritis as compared to males. Moreover, females exhibited increased proportions of germinal center B cells and CD4+ activated/memory T cells in the periphery. Additionally, salivary gland immune populations were altered in a sex-dependent manner in pSD. Females with pSD also displayed elevated total and autoreactive IgG as compared to males. Additionally, splenic B cell Tlr7 expression was increased in females. We next generated pSD mice that lacked Tlr7 systemically and found that ablation of Tlr7 was primarily protective in pSD females, while Tlr7-deficient pSD males showed heightened disease. Thus, pSD mice display sex-biased disease and these dichotomous manifestations are governed by Tlr7 activation. This study identifies Tlr7 as a druggable target for pSD, and highlights the importance of studying pSD disease mechanisms in both sexes.

Vitamin D, periodontitis and tooth loss in older Irish adults.

The aim of this study is to investigate whether 25-hydroxyvitamin D (25(OH)D) is associated with periodontitis and tooth loss in older adults. A total of 2346 adults underwent a detailed dental examination as part of the health assessment of a national population study - The Irish Longitudinal Study of Ageing. 25(OH)D analysis was performed on frozen non-fasting total plasma using LC-MS. The analysis included both multiple logistic regression and multinominal logistic regression to investigate associations between 25(OH)D concentration, periodontitis and tooth loss, adjusting for a range of potential confounders. Results of the analysis found the mean age of participants was 65·3 years (sd 8·2) and 55·3 % of the group were female. Based on the quintile of 25(OH)D concentration, participants in the lowest v. highest quintile had an OR of 1·57 (95 % CI 1·16, 2·13; P < 0·01) of having periodontitis in the fully adjusted model. For tooth loss, participants in the lowest v. highest quintile of 25(OH)D had a RRR of 1·55 (95 % CI 1·12, 2·13; P < 0·01) to have 1-19 teeth and a RRR of 1·96 (95 % CI 1·20, 3·21; P < 0·01) to be edentulous, relative to those with ≥ 20 teeth in the fully adjusted models. These findings demonstrate that in this cross-sectional study of older men and women from Ireland, 25(OH)D concentration was associated with both periodontitis and tooth loss, independent of other risk factors.

Use of open fires or closed solid fuel appliances for residential heating and cognitive decline in older adults.

OBJECTIVES: Use of solid fuel appliances is a major contributor to air pollution. Indoor solid fuel burning for cooking and heating in lower-middle income countries is associated with lower cognitive function and faster decline. Less is known, however, about the potential risk to brain health from burning solid fuels in open fires and closed appliances for heating purposes only, particularly in higher income countries. The current study aimed to investigate the association between burning solid fuels for home heating and cognitive decline in older Irish adults, also testing whether results differ by sex/gender. DESIGN AND PARTICIPANTS: The sample consisted of 4,537 participants aged 50 and older from The Irish Longitudinal Study on Ageing, a population-based cohort study. Participants were surveyed every two years between 2012 and 2018. Solid fuel use in 2012 (Wave 2) and cognitive function (word recall and verbal fluency) at waves 2, 3, 4 and 5 were analysed. Hierarchical linear mixed effects regression models were used to examine the association between solid fuel use and cognitive decline, controlling for multiple confounders. RESULTS: There was a significant main effect of solid fuel use on cognitive function, such that individuals who reported using a solid fuel appliance or open fire as a main source of heating had lower cognitive scores than those who did not report such use at all waves, but there was no difference in the slope of the trajectory over time and no clear sex differences. CONCLUSIONS: Older Irish adults who reported burning solid fuels (in an open fire or closed appliance) as a main way source of home heating had lower observed cognitive function across 6 years in TILDA but no evident faster decline than non-users. These findings further expand the evidence base on indoor air pollution and brain health.

Social disconnection correlates of a "Wish to Die" among a large community-dwelling cohort of older adults.

Introduction: Social disconnection and deaths by suicide among older adults are both important public health concerns, particularly in the context of ageing populations. The association between death ideation and behaviours, and social disconnection is well established and both functional and structural social relationships have been identified as predictive of suicide-related thoughts and behaviours. The "Wish to Die" (WTD) involves thoughts of or wishes for one's own death or that one would be better off dead is a commonly used indicator to capture death ideation. It has been shown to be as predictive as active ideation of future suicide attempt. Methods: Data were from a large cohort of community-dwelling older adults aged 50+, The Irish Longitudinal Study on Ageing (TILDA). Cross-sectional analyses of the association between numerous markers of social disconnection (loneliness, social isolation, living alone, marital status, social participation, volunteering, and attending religious service) and WTD were conducted. Results: Multiple markers of social disconnection were associated with a "wish to die". However, loneliness was the strongest risk factor while attendance of religious services was an important protective behaviour. Discussion: There is a strong association between social disconnection and a WTD among older adults. There is also a strong association between depression and a WTD, while attending religious services or similarly prosocial settings may protect older adults from experiencing negative thoughts about dying.

Which Components of the Haemodynamic Response to Active Stand Predict Cardiovascular Disease and Mortality? Data From The Irish Longitudinal Study on Ageing.

Background: An integrated haemodynamic response during standing may serve as an integrative marker of neuro-cardiovascular function. Individual components of both heart rate (HR) and blood pressure (BP) responses to active stand (AS) have been linked with cardiovascular disease (CVD) and mortality. We assessed longitudinal associations between entire HR/BP response curves during AS, incident CVD and mortality over 12 years. Methods: Beat-to-beat measurements of dynamic HR/BP responses to AS were conducted in 4,336 individuals (61.5±8.2 years; 53.7% female). Functional Principal Components Analysis was applied to HR/BP response curves and their association with CVD and mortality assessed. We hypothesised that integrating BP/HR information from the entire haemodynamic response curve may uncover novel associations with both CVD and mortality. Results: Higher systolic BP (SBP) before AS and blunted recovery of SBP during AS was associated with all-cause mortality over 12-years (Hazard Ratio [HR]: 1.14; 1.04, 1.26; p=0.007). Higher baseline/peak HR and lower HR from 30 seconds post stand onwards were associated with lower mortality due to circulatory causes (HR: 0.78; 0.64, 0.95; p = 0.013). Higher HR throughout AS was associated with mortality from other causes (HR: 1.48; 1.22, 1.80; p<0.001). Findings persisted on robust covariate adjustment. Conclusions: We observed distinct relationships between HR/BP responses to AS and 12-year incident CVD and mortality. Integrating the entire haemodynamic response may reveal more nuanced relationships between HR/BP responses to AS, CVD and mortality - serving as an integrative marker of neuro-cardiovascular health in midlife and beyond.

Development of a Medication-Use Evaluation Template for Andexanet Alfa in the Reversal of Anticoagulation With Factor Xa Inhibitors.

Medication-use evaluations are meant to ensure that medication-use processes are consistent with prevailing standards of care, assure optimal use of therapy, and reduce the risk of medication-related problems. Reversal agents for direct oral anticoagulants are a worthy focus for medication-use evaluations for reasons of efficacy, safety, and cost. A multidisciplinary team of experts developed 2 medication-use evaluation templates illustrating the application of professional society guidelines to the appropriate use of andexanet alfa.

Cardiovascular Autonomic Function and Progression of Age-Related Macular Degeneration in The Irish Longitudinal Study of Ageing (TILDA).

Purpose: To examine if changes in hemodynamic measures during an orthostatic challenge were associated with progression of age-related macular degeneration (AMD) over a 4-year period in The Irish Longitudinal Study on Ageing. Methods: Participants with AMD who underwent an active stand (AS) test at wave 1 (2009/2010) and retinal photographs at both wave 1 and wave 3 (2014/2015) were included (N = 159: 121 with no AMD progression and 38 with progression). Beat-to-beat hemodynamic data were non-invasively collected using a Finometer MIDI device during the AS at wave 1, recording systolic blood pressure (sBP), diastolic blood pressure (dBP), mean arterial pressure (MAP), and heart rate. Cardiac output, stroke volume, and total peripheral resistance (TPR) were derived from these measures. Baseline characteristics were compared between groups with and without AMD progression. Mixed-effects linear regression models were used to assess the association between changes in hemodynamic parameters during the AS and AMD progression, controlling for known AMD-associated risk factors. Results: At baseline, increasing age and lower dBP were significantly associated with AMD progression. Mixed-effects models for the period between standing and 10 seconds post-stand revealed significant associations with AMD progression with a steeper drop in dBP and a slower drop in TPR. Between 10 and 20 seconds post-stand, AMD progression was significantly associated with less pronounced reduction in heart rate. Conclusions: These observational data suggest that impaired hemodynamic responses within the first 20 seconds of orthostasis may be associated with the progression of AMD.

Primary care payment models and avoidable hospitalizations in Ontario, Canada: A multivalued treatment effects analysis.

Improving access to primary care physicians' services may help reduce hospitalizations due to Ambulatory Care Sensitive Conditions (ACSCs). Ontario, Canada's most populous province, introduced blended payment models for primary care physicians in the early- to mid-2000s to increase access to primary care, preventive care, and better chronic disease management. We study the impact of payment models on avoidable hospitalizations due to two incentivized ACSCs (diabetes and congestive heart failure) and two non-incentivized ACSCs (angina and asthma). The data for our study came from health administrative data on practicing primary care physicians in Ontario between 2006 and 2015. We employ a two-stage estimation strategy on a balanced panel of 3710 primary care physicians (1158 blended-fee-for-service (FFS), 1388 blended-capitation models, and 1164 interprofessional team-based practices). First, we account for the differences in physician practices using a generalized propensity score based on a multinomial logit regression model, corresponding to three primary care payment models. Second, we use fractional regression models to estimate the average treatment effects on the treated outcome (i.e., avoidable hospitalizations). The capitation-based model sometimes increases avoidable hospitalizations due to angina (by 7 per 100,000 patients) and congestive heart failure (40 per 100,000) relative to the blended-FFS-based model. Switching capitation physicians into interprofessional teams mitigates this effect, reducing avoidable hospitalizations from congestive heart failure by 30 per 100,000 patients and suggesting better access to primary care and chronic disease management in team-based practices.

Examining mental health and autonomic function as putative mediators of the relationship between sleep and trajectories of cognitive function: findings from the Irish longitudinal study on ageing (TILDA).

OBJECTIVES: This study investigates the mediating roles of autonomic function and mental health in the association between sleep and cognitive decline in adults aged 50 and above. METHOD: A total of 2,697 participants with observations on sleep and mediators at baseline and repeated measures of cognitive function (MMSE) were included. Clusters of individuals with similar cognitive trajectories (high-stable, mid-stable and low-declining) were identified. Multinomial logistic regressions were used to estimate the likelihood of membership to each trajectory group based on sleep duration and disturbance. Finally, mediation analysis tested potential mediating effects of autonomic function and mental health underpinning the sleep-cognition relationship. RESULTS: Short (p = .028), long (p =.019), and disturbed sleep (p =.008) increased the likelihood of a low-declining cognitive trajectory. Mental health measures fully attenuated relationships between cognitive decline and short or disturbed sleep but not long sleep. No autonomic function mediation was observed. CONCLUSION: Older adults with short or disturbed sleep are at risk of cognitive decline due to poor mental health. Individuals with long sleep are also at risk, however, the acting pathways remain to be identified. These outcomes have clinical implications, potentially identifying intervention strategies targeting mental health and sleep as prophylactic measures against dementia.

ΔNp63 regulates Sfrp1 expression to direct salivary gland branching morphogenesis.

Branching morphogenesis is a complex process shared by many organs including the lungs, kidney, prostate, as well as several exocrine organs including the salivary, mammary and lacrimal glands. This critical developmental program ensures the expansion of an organ's surface area thereby maximizing processes of cellular secretion or absorption. It is guided by reciprocal signaling from the epithelial and mesenchymal cells. While signaling pathways driving salivary gland branching morphogenesis have been relatively well-studied, our understanding of the underlying transcriptional regulatory mechanisms directing this program, is limited. Here, we performed in vivo and ex vivo studies of the embryonic mouse submandibular gland to determine the function of the transcription factor ΔNp63, in directing branching morphogenesis. Our studies show that loss of ΔNp63 results in alterations in the differentiation program of the ductal cells which is accompanied by a dramatic reduction in branching morphogenesis that is mediated by dysregulation of WNT signaling. We show that ΔNp63 modulates WNT signaling to promote branching morphogenesis by directly regulating Sfrp1 expression. Collectively, our findings have revealed a novel role for ΔNp63 in the regulation of this critical process and offers a better understanding of the transcriptional networks involved in branching morphogenesis.

White matter fibre density in the brain's inhibitory control network is associated with falling in low activity older adults.

Recent research has indicated that the relationship between age-related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self-reported frequency of falling over a 4-year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical-subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross-sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity.

Multicenter evaluation of the Toxoplasma gondii Real-TM (Sacace) kit performance for the molecular diagnosis of toxoplasmosis.

The molecular detection of Toxoplasma gondii DNA is a key tool for the diagnosis of disseminated and congenital toxoplasmosis. This multicentric study from the Molecular Biology Pole of the French National Reference Center for toxoplasmosis aimed to evaluate Toxoplasma gondii Real-TM PCR kit (Sacace). The study compared the analytical and clinical performances of this PCR assay with the reference PCRs used in proficient laboratories. PCR efficiencies varied from 90% to 112%; linearity zone extended over four log units (R2 > 0.99) and limit of detection varied from 0.01 to ≤1 Tg/mL depending on the center. Determined on 173 cryopreserved DNAs from a large range of clinical specimens, clinical sensitivity was 100% [106/106; 95 confidence interval (CI): 96.5%-100%] and specificity was 100% (67/67; 95 CI: 94.6%-100%). The study revealed two potential limitations of the Sacace PCR assay: the first was the inconsistency of the internal control (IC) when added to the PCR mixture. This point was not found under routine conditions when the IC was added during the extraction step. The second is a lack of practicality, as the mixture is distributed over several vials, requiring numerous pipetting operations. Overall, this study provides useful information for the molecular diagnosis of toxoplasmosis; the analytical and clinical performances of the Sacace PCR kit were satisfactory, the kit having sensitivity and specificity similar to those of expert center methods and being able to detect low parasite loads, at levels where multiplicative analysis gives inconsistently positive results. Finally, the study recommends multiplicative analysis in particular for amniotic fluids, aqueous humor, and other single specimens.

Frailty on the island of Ireland: evidence from the NICOLA and TILDA studies.

BACKGROUND: Aimed to compare the prevalence, characteristics, and associated mortality risk of frailty in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Secondary analysis of the first wave of two nationally representative cohorts, the Northern Ireland Cohort for the Longitudinal Study of Ageing or NICOLA study (N = 8504) and the Irish Longitudinal Study on Ageing or TILDA study (N = 8504). Frailty was assessed using a harmonized accumulation deficits frailty index (FI) containing 30 items. FI scores classified individuals as non-frail (<0.10), pre-frail (0.10-0.24) and frail (≥0.25). Linkage to respective administrative data sources provided mortality information with a follow-up time of 8 years. RESULTS: The prevalence of frailty was considerably higher in NI compared with the ROI (29.0% compared with 15.0%), though pre-frailty was slightly lower (35.8% and 37.3%, respectively). Age, female sex, and lower socio-economic status were consistently associated with a higher likelihood of both pre-frailty and frailty. In the pooled analysis, both frailty and pre-frailty were higher in NI (RR = 2.68, 95% CIs 2.45, 2.94 and RR = 1.30, 95% CIs 1.21, 1.40, respectively). Frailty was associated with an increased mortality risk in both cohorts, even after full adjustment for all other characteristics, being marginally higher in TILDA than in NICOLA (HR = 2.43, 95% CIs 2.03, 2.91 vs. HR = 2.31, 95% CIs 1.90, 2.79). CONCLUSIONS: Frailty is a major public health concern for both jurisdictions. Further research and monitoring are required to elucidate why there is a higher prevalence in NI and to identify factors in early life that may be driving these differences.

Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

The Impact of Type 2 Diabetes on Peripheral and Cerebral Hemodynamic Responses to Active Stand.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is an established risk factor for cognitive impairment, the underlying mechanisms remain poorly explored. One potential mechanism may be through effects of T2DM on cerebral perfusion. The current study hypothesized that T2DM is associated with altered peripheral and central hemodynamic responses to orthostasis, which may in turn be associated with cognitive impairment in T2DM. METHODS: A novel use of function-on-scalar regression, which allows the entire hemodynamic response curve to be modeled, was employed to assess the association between T2DM and hemodynamic responses to orthostasis. Logistic regression was used to assess the relationship between tissue saturation index (TSI), T2DM, and cognitive impairment. All analyses used cross-sectional data from Wave 3 of The Irish Longitudinal Study on Ageing (TILDA). RESULTS: Of 2 984 older adults (aged 64.3 ±â€…8.0; 55% female), 189 (6.3%) had T2DM. T2DM was associated with many features that are indicative of autonomic dysfunction including a blunted peak heart rate and lower diastolic blood pressure. T2DM was associated with reduced TSI and also with greater odds of impaired performance on the Montreal Cognitive Assessment (odds ratio [OR]: 1.62; confidence interval [CI: 1.07, 2.56]; p = .019). Greater TSI was associated with lower odds of impaired performance (OR: 0.90, CI [0.81-0.99]; p = .047). CONCLUSIONS: T2DM was associated with impaired peripheral and cerebral hemodynamic responses to active stand. Both T2DM and reduced cerebral perfusion were associated with impaired cognitive performance. Altered cerebral perfusion may represent an important mechanism linking T2DM and adverse brain health outcomes in older adults.

Landscape of Métis health and wellness: protocol for a scoping review.

INTRODUCTION: In Canada, Métis people are one of three distinct Indigenous peoples whose rights are recognised and affirmed in Section 35 of the federal Constitution Act, 1982. In line with Métis people having a unique culture, history, language and way of life, a distinctions-based approach is critical to understand the current landscape of Métis-specific health. In this paper, we present a scoping review protocol to describe this research landscape in Canada led by the Métis Nation of Ontario (MNO). METHODS AND ANALYSIS: This scoping review protocol is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews reporting guidelines and follows Arksey and O'Malley's scoping review methodology. We will search electronic databases (Scopus, MEDLINE, Embase, Web of Science, CINAHL, APA PsycINFO, Anthropology Plus, Bibliography of Indigenous Peoples of North America, Canadian Business and Current Affairs, Indigenous Studies Portal, Informit Indigenous Collection, Collaborative Indigenous Garden, PubMed, ProQuest), grey literature sources and reference lists from selected papers. Two reviewers (HMB and SK) will double-blind screen all titles/abstracts and full-text studies for inclusion. Any health-related study or health report that includes a Métis-specific health, well-being or Métis social determinant of health outcome will be included. Relevant variables will be extracted following an iterative process whereby the data charting will be reviewed and updated. ETHICS AND DISSEMINATION: Findings from this scoping review will be shared back through the MNO's existing community-based communication channels. Traditional academic dissemination will also be pursued. Research ethics board approval is not required, since data are from peer-reviewed publications or publicly shared health reports and knowledge translation products.