Dietary NO3- does not enhance endothelial dependent cutaneous vascular conductance in older women.

Prior work has yet to determine whether the reduction of dietary nitrate (NO3-) to NO, via the enterosalivary pathway, may modify cutaneous vascular conductance (CVC) responses to local heating in older women. Changes occurring with the transition to menopause related to hormonal flux, increased adiposity, and/or decreased physical activity may further compound the negative influence of aging on nitric oxide (NO)-dependent CVC. Herein, we characterized changes in NO-dependent CVC following acute ingestion of 140 mL of NO3--rich beetroot juice in 24 older women (age: 65 ± 5 y, BMI: 31.2 ± 3.7 kg/m2). Red blood cell (RBC) flux was measured continuously via laser-Doppler flowmetry on the dorsal aspect of the forearm during local skin heating to 39 °C/44 °C before and 3 h after NO3- ingestion. NO-dependent changes in CVC were calculated as RBC flux/mean arterial blood pressure at 39 °C and normalized as a proportion of maximal CVC at 44 °C (%CVCmax). Changes (Δ) in fractional exhaled NO (FeNO) following NO3- ingestion were used an index of NO bioavailability. Despite increased FeNO (+81 ± 70 %, P < 0.001), %CVCmax at 39 °C was reduced (-16 ± 10 %, P < 0.001) following NO3- ingestion. A greater reduction in %CVCmax was weakly to moderately associated with higher body fat% (r = 0.45 [0.05-0.72], P = 0.029), central adiposity% (r = 0.50 [0.13-0.75], P = 0.012), neutrophil% (r = 0.42 [0.02-0.70], P = 0.041), and higher neutrophil to lymphocyte ratio (r = 0.49 [0.11-0.75], P = 0.016). These findings demonstrate a single dose of dietary NO3- does not promote CVC responses to local heating in sedentary older women with overweight and obesity. Correlation with multiple biomarkers suggest systemic inflammation may be involved.

Walking net V ˙ O2 rises with advancing age in older women: where to go from here?

PURPOSE: Walking net V ˙ O2 tends to increase with advancing age; however, factors contributing to this relationship have not been widely described. The implications of such findings could inform targeted strategies to promote independent mobility in older adults. Herein, we evaluated the relationship between net V ˙ O2 and age at two submaximal workloads while exploring potential moderators of this relationship. METHODS: Secondary analyses were performed on 35 older (65 ± 3 years) women who completed a battery of physical assessments including fixed-speed, non-graded and graded (+ 2.5%) treadmill walking with indirect calorimetry to determine net V ˙ O2. Maximal oxygen uptake ( V ˙ O2max), knee extensor maximal isometric voluntary contraction (MVC), peak rate of torque development (RTD), and plantar flexor range-of-motion (PFROM) were also measured. RESULTS: Bivariate correlations showed non-graded (r = 0.403, p = 0.017) and graded (r = 0.413, p = 0.014) net V ˙ O2 were positively related to age. Notably, these relationships strengthened after adjusting for V ˙ O2max. Regression modeling showed age, RTD:MVC ratio (composite of muscle performance), and PFROM together explained 49% and 34% of the variance in non-graded and graded net V ˙ O2, respectively. Further analyses suggested knee extensor MVC moderates the relationship between non-graded net V ˙ O2 and age, accounting for 9% of the variance [ΔR2 = 0.090, F (1,31) = 4.13, p = 0.05]. CONCLUSION: These data support the premise that, in older women, walking net V ˙ O2 rises with advancing age, and additionally, the RTD:MVC ratio and PFROM are independent correlates of non-graded net V ˙ O2. Exercise interventions with a high degree of training specificity including explosive, velocity-based elements may promote independent mobility in older women.

Osteoporosis screening in Australian community pharmacies: A mixed methods study.

ISSUES ADDRESSED: Osteoporosis and poor bone health impact a large proportion of the Australian population, but is drastically underdiagnosed and undertreated. Community pharmacies are a strategic location for osteoporosis screening services due to their accessibility and the demographic profile of customers. The aim of this study was to develop, implement and evaluate a community pharmacy health promotion service centred on encouraging consumers to complete an anonymous osteoporosis screening survey called Know Your Bones. METHODS: The implementation process was documented using the REAIM (reach, effectiveness, adoption, implementation, maintenance) framework. Uptake of the Know Your Bones screening tool was monitored anonymously with website traffic. Surveys and interviews were designed to capture consumer outcomes after screening. Semi-structured interviews were conducted with Australian community pharmacy stakeholders during design and implementation phases to explore their perspectives of the barriers and facilitators. RESULTS: The service was implemented in 27 community pharmacies. There were 448 visits to the screening website. Interviews were conducted with 41 stakeholders. There were a range of factors that appeared to influence implementation of the service. Perceived acceptability was critical, which depended on staff training, pharmacists' altruism, and remuneration. Staff relied heavily on their existing close relationships with consumers. No consumers completed non-anonymous surveys or agreed to participate in interviews post-screening. CONCLUSION: Using an implementation science approach, a community pharmacy osteoporosis screening service for the Australian context was designed and found to be acceptable to pharmacy staff and effective in reaching the target population. SO WHAT?: This low-cost and non-invasive health promotion has potential to sustainably increase national screening rates for osteoporosis.

Estimation of sparse functional quantile regression with measurement error: a SIMEX approach.

Quantile regression is a semiparametric method for modeling associations between variables. It is most helpful when the covariates have complex relationships with the location, scale, and shape of the outcome distribution. Despite the method's robustness to distributional assumptions and outliers in the outcome, regression quantiles may be biased in the presence of measurement error in the covariates. The impact of function-valued covariates contaminated with heteroscedastic error has not yet been examined previously; although, studies have investigated the case of scalar-valued covariates. We present a two-stage strategy to consistently fit linear quantile regression models with a function-valued covariate that may be measured with error. In the first stage, an instrumental variable is used to estimate the covariance matrix associated with the measurement error. In the second stage, simulation extrapolation (SIMEX) is used to correct for measurement error in the function-valued covariate. Point-wise standard errors are estimated by means of nonparametric bootstrap. We present simulation studies to assess the robustness of the measurement error corrected for functional quantile regression. Our methods are applied to National Health and Examination Survey data to assess the relationship between physical activity and body mass index among adults in the United States.

Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis.

OBJECTIVES: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation. METHODS: We stimulated purified monocytes and whole peripheral blood mononuclear cells (PBMCs) from patients with GPA, patients with MPA or healthy controls with PR3 or MPO and visualised MGC and granuloma-like structure formation using light, confocal and electron microscopy, as well as measuring the cell cytokine production. We investigated the expression of PR3 binding partners on monocytes and tested the impact of their inhibition. Finally, we injected zebrafish with PR3 and characterised granuloma formation in a novel animal model. RESULTS: In vitro, PR3 promoted monocyte-derived MGC formation using cells from patients with GPA but not from patients with MPA, and this was dependent on soluble interleukin 6 (IL-6), as well as monocyte MAC-1 and protease-activated receptor-2, found to be overexpressed in the cells of patients with GPA. PBMCs stimulated by PR3 formed granuloma-like structures with central MGC surrounded by T cells. This effect of PR3 was confirmed in vivo using zebrafish and was inhibited by niclosamide, a IL-6-STAT3 pathway inhibitor. CONCLUSIONS: These data provide a mechanistic basis for granuloma formation in GPA and a rationale for novel therapeutic approaches.

Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28.

RAB28 is a farnesylated, ciliary G-protein. Patient variants in RAB28 are causative of autosomal recessive cone-rod dystrophy (CRD), an inherited human blindness. In rodent and zebrafish models, the absence of Rab28 results in diminished dawn, photoreceptor, outer segment phagocytosis (OSP). Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels. This study further elucidated the molecular mechanisms by which Rab28 controls OSP and inherited blindness. Proteomic profiling identified factors whose expression in the eye or whose expression at dawn and dusk peaks of OSP is dysregulated by loss of Rab28. Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish, suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28-OSP. Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11-cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae (p < .05). These data give further understanding on the molecular mechanisms of RAB28-associated CRD, highlighting roles of Rab28 in both peaks of OSP, in vitamin A metabolism and in retinoid recycling.

Evaluation of in vivo staging of amyloid deposition in cognitively unimpaired elderly aged 78-94.

Amyloid-beta (Aß) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to 18F-flutemetamol PET data to determine an unbiased regional covariance pattern of tracer uptake across grey matter regions. PET staging schemes were applied to the data and compared to the PCA output. Concentration of p-tau181 was measured in blood plasma. The PCA revealed three distinct components accounting for 91.2% of total SUV variance. PC1 driven by the large common variance of uptake in neocortical and striatal regions was significantly positively correlated with global SUVRs, APOE4 status and p-tau181 concentration. PC2 represented mainly non-specific uptake in typical amyloid-PET reference regions, and PC3 the occipital lobe. Application of the staging schemes demonstrated that the majority of the CU cohort (up to 93%) were classified as having pathological amount and distribution of Aß. Good correspondence existed between binary (+/-) classification and later amyloid stages, however, substantial differences existed between schemes for low stages with 8-17% of individuals being unstageable, i.e., not following the sequential progression of Aß deposition. In spite of the difference in staging outcomes there was broad spatial overlap between earlier stages and PC1, most prominently in default mode network regions. This study critically evaluated the utility of in vivo amyloid staging from a single PET scan in CU elderly and found that early amyloid stages could not be consistently classified. The majority of the cohort had pathological Aß, thus, it remains an open topic what constitutes abnormal brain Aß in the oldest-old and what is the best method to determine that.

Correlated cryogenic fluorescence microscopy and electron cryo-tomography shows that exogenous TRIM5α can form hexagonal lattices or autophagy aggregates in vivo.

Members of the tripartite motif (TRIM) protein family have been shown to assemble into structures in both the nucleus and cytoplasm. One TRIM protein family member, TRIM5α, has been shown to form cytoplasmic bodies involved in restricting retroviruses such as HIV-1. Here we applied cryogenic correlated light and electron microscopy, combined with electron cryo-tomography, to intact mammalian cells expressing YFP-rhTRIM5α and found the presence of hexagonal nets whose arm lengths were similar to those of the hexagonal nets formed by purified TRIM5α in vitro. We also observed YFP-rhTRIM5α within a diversity of structures with characteristics expected for organelles involved in different stages of macroautophagy, including disorganized protein aggregations (sequestosomes), sequestosomes flanked by flat double-membraned vesicles (sequestosome:phagophore complexes), sequestosomes within double-membraned vesicles (autophagosomes), and sequestosomes within multivesicular autophagic vacuoles (amphisomes or autolysosomes). Vaults were also seen in these structures, consistent with their role in autophagy. Our data 1) support recent reports that TRIM5α can form both well-organized signaling complexes and nonsignaling aggregates, 2) offer images of the macroautophagy pathway in a near-native state, and 3) reveal that vaults arrive early in macroautophagy.

Montage electron tomography of vitrified specimens.

Cryo-electron tomography provides detailed views of macromolecules in situ. However, imaging a large field of view to provide more cellular context requires reducing magnification during data collection, which in turn restricts the resolution. To circumvent this trade-off between field of view and resolution, we have developed a montage data collection scheme that uniformly distributes the dose throughout the specimen. In this approach, sets of slightly overlapping circular tiles are collected at high magnification and stitched to form a composite projection image at each tilt angle. These montage tilt-series are then reconstructed into massive tomograms with a small pixel size but a large field of view. For proof-of-principle, we applied this method to the thin edge of HeLa cells. Thon rings to better than 10 Å were detected in the montaged tilt-series, and diverse cellular features were observed in the resulting tomograms. These results indicate that the additional dose required by this technique is not prohibitive to performing structural analysis to intermediate resolution across a large field of view. We anticipate that montage tomography will prove particularly useful for lamellae, increase the likelihood of imaging rare cellular events, and facilitate visual proteomics.

Trajectories of objectively measured physical function among older breast cancer survivors in comparison with cancer-free controls.

PURPOSE: Aging associated with progressive declines in physical function is well-known; however, it is unclear how breast cancer diagnosis affects the trajectories of physical function over a long period of time. The current study examined the trajectories in objective measures of physical function over 20 years for women with breast cancer and matched controls. METHODS: 2712 community-dwelling women (452 breast cancer cases and 1:5 matched cancer-free controls) aged 65 years or older at baseline (1986-1988) within the Study of Osteoporotic Fractures were followed for 20 years. Objective physical function was assessed up to 9 times, including hand grip strength, timed chair stand, gait speed and quadriceps strength. Linear mixed models were used to model physical function changes in terms of secular time trend, group (cases or controls), period (pre-and post-diagnosis status), and their interaction terms. RESULTS: We observed all measures of physical function declined over time. While no differences in trends between cases and controls during the pre-diagnosis period were observed, after cancer diagnosis, grip strength and gait speed declined significantly faster in cases than controls. Quadriceps strength significantly decreased ~ 7 pounds shortly after breast cancer diagnosis, and then improved over time. CONCLUSION: Our study revealed that older breast cancer survivors relative to older women without cancer had significantly worse declines in grip strength and gait speed. Breast cancer survivors also had a sharp, short-term drop followed by gradual improvement over time in quadriceps strength. These findings suggest exercise training targeting muscle strength and mobility would be beneficial among older breast cancer survivors.

Three-dimensional insights into human enveloped viruses in vitro and in situ.

Viruses can be enveloped or non-enveloped, and require a host cell to replicate and package their genomes into new virions to infect new cells. To accomplish this task, viruses hijack the host-cell machinery to facilitate their replication by subverting and manipulating normal host cell function. Enveloped viruses can have severe consequences for human health, causing various diseases such as acquired immunodeficiency syndrome (AIDS), seasonal influenza, COVID-19, and Ebola virus disease. The complex arrangement and pleomorphic architecture of many enveloped viruses pose a challenge for the more widely used structural biology techniques, such as X-ray crystallography. Cryo-electron tomography (cryo-ET), however, is a particularly well-suited tool for overcoming the limitations associated with visualizing the irregular shapes and morphology enveloped viruses possess at macromolecular resolution. The purpose of this review is to explore the latest structural insights that cryo-ET has revealed about enveloped viruses, with particular attention given to their architectures, mechanisms of entry, replication, assembly, maturation and egress during infection. Cryo-ET is unique in its ability to visualize cellular landscapes at 3-5 nanometer resolution. Therefore, it is the most suited technique to study asymmetric elements and structural rearrangements of enveloped viruses during infection in their native cellular context.

ARTE index revisited: linking biomarkers of cardiometabolic health with free-living physical activity in postmenopausal women.

Activity-related energy expenditure (AEE) correlates with physical activity volume; however, between-person differences in body size and walking economy (net V̇o2) can influence AEE. The ratio of total energy expenditure (TEE) and resting energy expenditure (REE) estimates physical activity level (PAL) relative to body mass, yet does not account for variance in walking economy. The activity-related time equivalent (ARTEwalk) circumvents such constraints by adjusting for individual-specific walking economy. Herein, we compared AEE, PAL, and ARTEwalk index in a cohort (n = 81) of postmenopausal women while examining possible associations with biomarkers of cardiometabolic health. Secondary analyses were performed on postmenopausal women dichotomized above/below age group 50th percentile for body fat percent. TEE was reduced by 10% for the thermogenesis of digestion wherein AEE was calculated by subtracting REE from adjusted TEE. PAL was calculated as the ratio of TEE/REE. AEE was divided by the mean net energy expenditure of nongraded walking to calculate the ARTEwalk index. Between-group differences were not detected for AEE or PAL. However, the ARTEwalk index revealed that participants with less adiposity were more physically active (258 ± 149 vs. 198 ± 115 min·day-1; P = 0.046; g = 0.46). AEE and PAL did not correlate with cardiorespiratory fitness or biomarkers of cardiometabolic health. Cardiorespiratory fitness (r = 0.32), arterial elasticity (r = 0.24), total cholesterol/HDL-c ratio (r = -0.22), and body fat% (r = -0.24) were correlated with ARTEwalk. The ARTEwalk index may offer utility in detecting possible differences in physical activity volume among postmenopausal women and appears better associated with cardiometabolic biomarkers compared with AEE or PAL.

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study.

BACKGROUND: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD. METHODS: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen. RESULTS: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory. CONCLUSION: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk.

Evidence for impaired chronotropic responses to and recovery from 6-minute walk test in women with post-acute COVID-19 syndrome.

NEW FINDINGS: What is the central question of this study? Are chronotropic responses to a 6-minute walk test different in women with post-acute coronavirus disease 2019 (COVID-19) syndrome compared with control subjects? What is the main finding and its importance? Compared with control subjects, the increase in heart rate was attenuated and recovery delayed after a 6-minute walk test in participants after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Women reporting specific symptoms at time of testing had greater impairments compared with control subjects and SARS-CoV-2 participants not actively experiencing these symptoms. Such alterations have potential to constrain not only exercise tolerance but also participation in free-living physical activity in women during post-acute recovery from COVID-19. ABSTRACT: The short-term cardiopulmonary manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are well defined. However, the implications of cardiopulmonary sequelae, persisting beyond acute illness, on physical function are largely unknown. Herein, we characterized heart rate responses to and recovery from a 6-minute walk test (6MWT) in women ∼3 months after mild-to-moderate SARS-CoV-2 infection compared with non-infected control subjects. Forty-five women (n = 29 SARS-CoV-2; n = 16 controls; age = 56 ± 11 years; body mass index = 25.8 ± 6.0 kg/m2 ) completed pulmonary function testing and a 6MWT. The SARS-CoV-2 participants demonstrated reduced total lung capacity (84 ± 8 vs. 93 ± 13%; P = 0.006), vital capacity (87 ± 10 vs. 93 ± 10%; P = 0.040), functional residual capacity (75 ± 16 vs. 88 ± 16%; P = 0.006) and residual volume (76 ± 18 vs. 93 ± 22%; P = 0.001) compared with control subjects. No between-group differences were observed in 6MWT distance (P = 0.194); however, the increase in heart rate with exertion was attenuated among SARS-CoV-2 participants compared with control subjects (+52 ± 20 vs. +65 ± 18 beats/min; P = 0.029). The decrease in heart rate was also delayed for minutes 1-5 of recovery among SARS-CoV-2 participants (all P < 0.05). Women reporting specific symptoms at the time of testing had greater impairments compared with control subjects and SARS-CoV-2 participants not actively experiencing these symptoms. Our findings provide evidence for marked differences in chronotropic responses to and recovery from a 6MWT in women several months after acute SARS-CoV-2 infection.

Moving beyond inclusion: Methodological considerations for the menstrual cycle and menopause in research evaluating effects of dietary nitrate on vascular function.

Recent reports have acknowledged the underrepresentation of women in the field of dietary nitrate (NO3-) research. Undoubtedly, greater participation from women is warranted to clarify potential sex differences in the responses to dietary NO3- interventions. However, careful consideration for the effects of sex hormones - principally 17ß-estradiol - on endogenous nitric oxide (NO) synthesis and dietary NO3- reductase capacity is necessary for improved interpretation and reproducibility of such investigations. From available literature, we present a narrative review describing how hormonal variations across the menstrual cycle, as well as with menopause, may impact NO biosynthesis catalyzed by NO synthase enzymes and NO3- reduction via the enterosalivary pathway. In doing so, we address methodological considerations related to the menstrual cycle and hormonal contraceptive use relevant for the inclusion of premenopausal women along with factors to consider when testing postmenopausal women. Adherence to such methodological practices may explicate the utility of dietary NO3- supplementation as a means to improve vascular function among women across the lifespan.

Amyloid-ß and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer's disease polygenic risk score.

BACKGROUND: What combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-ß pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. METHODS: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-ß status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-ß status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-ß status, and their interaction on changes in cognitive functioning over time. RESULTS: Fifty-two participants (19%) had abnormal amyloid-ß, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-ß status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-ß status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-ß×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE ß(SE)=-0.05(0.02); AD-PRS ß(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-ß status and AD-PRS predicted a steeper decline in memory functioning (amyloid-ß ß(SE)=-0.07(0.04); AD-PRS ß(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-ß status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-ß abnormal individuals only (ß(SE)=-0.13(0.06); ß(SE)=-0.22(0.07), respectively). CONCLUSION: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-ß only. Furthermore, independent of amyloid-ß status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

Provision of a comprehensive medicines review is associated with lower mortality risk for residents of aged care facilities: a retrospective cohort study.

BACKGROUND: no studies have examined the impact of residential medication management review (RMMR, a 24-year government subsidised comprehensive medicines review program) in Australian residential aged care facilities (RACFs) on hospitalisation or mortality. OBJECTIVE: to examine associations between RMMR provision in the 6-12 months after RACF entry and the 12-month risk of hospitalisation and mortality among older Australians in RACFs. DESIGN: retrospective cohort study. SUBJECTS: individuals aged 65-105 years taking at least one medicine, who entered an RACF in three Australian states between 1 January 2012 and 31 December 2015 and spent at least 6 months in the RACF (n = 57,719). METHODS: Cox regression models estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for associations between RMMR provision and mortality. Adjusted subdistribution hazard ratios were estimated for associations between RMMR provision and next (i) emergency department (ED) presentation or unplanned hospitalisation or (ii) fall-related ED presentation or hospitalisation. RESULTS: there were 12,603 (21.8%) individuals who received an RMMR within 6-12 months of RACF entry, of whom 22.2% (95%CI 21.4-22.9) died during follow-up, compared with 23.3% (95%CI 22.9-23.7) of unexposed individuals. RMMR provision was associated with a lower risk of death due to any cause over 12-months (aHR 0.96, 95%CI 0.91-0.99), but was not associated with ED presentations or hospitalisations for unplanned events or falls. CONCLUSIONS: provision of an RMMR in the 6-12 months after RACF entry is associated with a 4.4% lower mortality risk over 12-months but was not associated with changes in hospitalisations for unplanned events or falls.

Medicines use before and after comprehensive medicines review among residents of long-term care facilities: a retrospective cohort study.

BACKGROUND: Residential Medication Management Review (RMMR) is a subsidized comprehensive medicines review program for individuals in Australian residential aged care facilities (RACFs). This study examined weekly trends in medicines use in the four months before and after an RMMR and among a comparison group of residents who did not receive an RMMR. METHODS: This retrospective cohort study included individuals aged 65 to 105 years who first entered permanent care between 1/1/2012 and 31/12/2016 in South Australia, Victoria, or New South Wales, and were taking at least one medicine. Individuals with an RMMR within 12 months of RACF entry were classified into one of three groups: (i) RMMR within 0 to 3 months, (ii) 3 to 6 months, or (iii) within 6 to 12 months of RACF entry. Individuals without RMMRs were included in the comparison group. Weekly trends in the number of defined daily doses per 1000 days were determined in the four months before and after the RMMR (or assigned index date in the comparison group) for 14 medicine classes. RESULTS: 113909 individuals from 1979 RACFs were included, of whom 55021 received an RMMR. Across all three periods examined, decreased use of statins and proton pump inhibitors was observed post-RMMR in comparison to those without RMMRs. Decreases in calcium channel blockers, benzodiazepines/zopiclone, and antidepressants were observed following RMMR provision in the 3-6 and 6-12 months after RACF entry. Negligible changes in antipsychotic use were also observed following an RMMR in the 6-12 months after RACF entry by comparison to those without RMMRs. No changes in use of opioids, ACE inhibitors/sartans, beta blockers, loop diuretics, oral anticoagulants, or medicines for osteoporosis, diabetes or the cognitive symptoms of dementia were observed post-RMMR. CONCLUSIONS: For six of the 14 medicine classes investigated, modest changes in weekly trends in use were observed after the provision of an RMMR in the 6-12 months after RACF entry compared to those without RMMRs. Findings suggest that activities such as medicines reconciliation may be prioritized when an RMMR is provided on RACF entry, with deprescribing more likely after an RMMR the longer a resident has been in the RACF.

Australian care givers' knowledge of and attitudes towards paediatric fever management.

AIM: Non-evidence-based practice and inappropriate paediatric fever management by care givers is common. The aim of this study was to survey a large sample of Australian parents and care givers utilising a validated Fever Management Tool, to determine the current knowledge, beliefs and attitudes of Australian care givers regarding fever management. METHODS: This study employed a cross-sectional survey conducted via a third-party market research company. Univariate analysis of demographic factors and their influence on knowledge scores were tested. A multivariate linear regression model was specified using all available independent univariate predicators to determine the demographic factors influencing care givers fever knowledge. RESULTS: Data from 1000 questionnaires were analysed. The participants' total knowledge scores were evenly distributed with a mean score of 15.4/29 correct answers in the True/False questionnaire, a median score of 16 and a standard deviation of 4.27. It highlighted that Australian care givers had poor knowledge in questions related to 'teething', 'physical cooling methods' and 'medication dosing'. In the multivariate analysis, 28.9% of the total variance was explained (R2 value = 0.289, P < 0.001) with 5 of 11 factors contributing. CONCLUSION: Overall, this cross-sectional survey has provided a strong understanding of the current knowledge, attitude and beliefs of Australian care givers in regards to fever management in their children. Total knowledge of fever management was generally poor in Australia with many participants harbouring misconceptions and non-evidence-based practices. Future interventions improving fever management practices should be tailored to the specific weaknesses faced by Australian care givers in order to promote long term change.

The role of community pharmacists in delivering interventions for osteoporosis: A systematic review.

BACKGROUND: Osteoporosis is a major public health concern, given that disease prevalence is expected to substantially increase due to the aging population. Community pharmacists can play a key role in the identification and management of chronic diseases. OBJECTIVES: The purpose of this systematic review was to present an overview of the literature on the role of community pharmacists in providing osteoporosis interventions to patients. The secondary objective was to assess the impact of these interventions on patient outcomes. METHODS: A literature search was conducted in Embase, CINAHL, Scopus, MEDLINE, and Web of Science from database inception to March 2021. The search was limited to human studies in the English language. Primary studies were included if they described or assessed a patient-directed osteoporosis intervention conducted by community pharmacists. The following data were extracted and tabulated: citation, study location, study design, subject, number of participants, nature of intervention, classification of intervention, outcome measures, measurement methods, findings, and effect. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2) and Risk of Bias in Non-randomized Studies (ROBINS-I). RESULTS: Twenty-one studies were included in this review. The main interventions were education, screening, and medication management. Nineteen of these studies reported patient outcomes, all yielding positive outcomes. Outcomes included increased physician follow-up, risk factor reduction, increased osteoporosis knowledge, increased medication adherence, identification of medication-related problems, and positive patient-reported experience measures (PREMs). Three studies were considered to have a moderate risk of bias, whereas the remaining 18 studies had a high risk of bias. CONCLUSION: There is some evidence that pharmacist-led osteoporosis interventions have a positive impact on patient outcomes. More high-quality studies using objective outcome measures are needed to determine whether this translates into clinical outcomes such as decreased hospitalization and fractures.