Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

Differences between pure desmoplastic melanoma and superficial spreading melanoma in terms of survival, distribution and other clinicopathologic features.

BACKGROUND: Pure desmoplastic melanoma (pDM) is an uncommon subtype of malignant melanoma with comparative high rates of local recurrence and low rates of sentinel lymph node positivity. The melanoma-specific survival (MSS) of pDM compared to other melanoma subtypes is unclear, with conflicting reports and lack of multivariable analyses. OBJECTIVES: We aimed to describe clinicopathological characteristics of a cohort of patients with pDM and to compare the MSS of pDM with superficial spreading melanoma (SSM). METHODS: A prospective cohort study was performed of all primary invasive cutaneous pDM with known tumour location and thickness reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 119 primary cutaneous invasive pDMs from 3570 total invasive cutaneous melanomas were included. Compared to 2272 SSMs, and due largely to their greater average thickness, patients with pDM had worse MSS (unadjusted hazard ratio, HR, 2.56, 95% confidence interval, CI, 1.56-4.22). After adjustment for clinicopathologic factors (including thickness, ulceration, mitotic rate, age and sex), there was evidence that patients with pDM had an improved MSS (adjusted HR, 0.49; 95% CI, 0.28-0.87). Median thickness of head and neck pDM was greater than non-head and neck pDM (P < 0.001). There was reduced univariable MSS in head and neck pDM compared to the rest of the body. CONCLUSIONS: Decreased univariable MSS of patients with pDM compared to SSM was explained by the increased frequency of adverse clinicopathologic features at diagnosis, in particular the greater Breslow thickness of pDM. After adjustment, patients with pDM had half the chance of melanoma-specific death compared to SSM. Head and neck pDM were thicker at diagnosis compared to the rest of the body, which may account for its poorer survival compared to the rest of the body.

Efficient Fusion at Neutral pH by Human Immunodeficiency Virus gp41 Trimers Containing the Fusion Peptide and Transmembrane Domains.

Human immunodeficiency virus (HIV) is membrane-enveloped, and an initial infection step is joining/fusion of viral and cell membranes. This step is catalyzed by gp41, which is a single-pass integral viral membrane protein. The protein contains an ∼170-residue ectodomain located outside the virus that is important for fusion and includes the fusion peptide (FP), N-helix, loop, C-helix, and viral membrane-proximal external region (MPER). The virion initially has noncovalent complexes between three gp41 ectodomains and three gp120 proteins. A gp120 contains ∼500 residues and functions to identify target T-cells and macrophages via binding to specific protein receptors of the target cell membrane. gp120 moves away from the gp41 ectodomain, and the ectodomain is thought to bind to the target cell membrane and mediate membrane fusion. The secondary and tertiary structures of the ectodomain are different in the initial complex with gp120 and the final state without gp120. There is not yet imaging of gp41 during fusion, so the temporal relationship between the gp41 and membrane structures is not known. This study describes biophysical and functional characterization of large gp41 constructs that include the ectodomain and transmembrane domain (TM). Significant fusion is observed of both neutral and anionic vesicles at neutral pH, which reflects the expected conditions of HIV/cell fusion. Fusion is enhanced by the FP, which in HIV/cell fusion likely contacts the host membrane, and the MPER and TM, which respectively interfacially contact and traverse the HIV membrane. Initial contact with vesicles is made by protein trimers that are in a native oligomeric state that reflects the initial complex with gp120 and also is commonly observed for the ectodomain without gp120. Circular dichroism data support helical structure for the N-helix, C-helix, and MPER and nonhelical structure for the FP and loop. Distributions of monomer, trimer, and hexamer states are observed by size-exclusion chromatography (SEC), with dependences on solubilizing detergent and construct. These SEC and other data are integrated into a refined working model of HIV/cell fusion that includes dissociation of the ectodomain into gp41 monomers followed by folding into hairpins that appose the two membranes, and subsequent fusion catalysis by trimers and hexamers of hairpins. The monomer and oligomer gp41 states may therefore satisfy dual requirements for HIV entry of membrane apposition and fusion.

Baseline characteristics of participants in the Kerala Diabetes Prevention Program: a cluster randomized controlled trial of lifestyle intervention in Asian Indians.

AIMS: To describe the baseline characteristics of participants in the Kerala Diabetes Prevention Program. METHODS: The Kerala Diabetes Prevention Program is a cluster randomized controlled trial of lifestyle intervention for prevention of Type 2 diabetes mellitus in India. Participants in the study were those aged 30-60 years who had an Indian Diabetes Risk Score ≥ 60 and who were without Type 2 diabetes on oral glucose tolerance test. Data on demographic, lifestyle, clinical and biochemical characteristics were collected using standardized tools. RESULTS: A total of 2586 individuals were screened with the Indian Diabetes Risk Score, of these 1529 people (59.1%) had a score ≥ 60, of whom 1209 (79.1%) underwent an oral glucose tolerance test. A total of 202 individuals (16.7%) had undiagnosed Type 2 diabetes and were excluded, and the remaining 1007 individuals were enrolled in the trial (control arm, n = 507; intervention arm, n = 500). The mean participant age was 46.0 ± 7.5 years, and 47.2% were women. The mean Indian Diabetes Risk Score was 67.1 ± 8.4. More than two-thirds (69.0%) had prediabetes and 31.0% had normal glucose tolerance. The prevalence of cardiometabolic risk factors was high, including current tobacco use (34.4% in men), current alcohol use (39.3% in men), no leisure time exercise (98.0%), no daily intake of fruit and vegetables (78.7%), family history of diabetes (47.9%), overweight or obesity (68.5%), hypertension (22.3%) and dyslipidemia (85.4%). CONCLUSIONS: The Kerala Diabetes Prevention Program recruited participants using a diabetes risk score. A large proportion of the participants had prediabetes and there were high rates of cardiometabolic risk factors. The trial will evaluate the effectiveness of lifestyle intervention in a population selected on the basis of a diabetes risk score.

Medication safety in the operating room: literature and expert-based recommendations.

Human error poses significant risk for hospitalized patients causing an estimated 100,000 to 400,000 deaths in the USA annually. Medication errors contribute, with error occurring in 5.3% of medication administrations during surgery. In this study 70.3% of medication errors were deemed preventable. Given the paucity of randomized controlled studies, we undertook a rigorous review of the literature to identify recommendations supported by expert opinions. An extensive literature search pertaining to medication error, medication safety, operating room, and anaesthesia was performed. The National Guidelines Clearinghouse was searched for any anaesthesia or operating room medication safety guidelines.A total of 74 articles were included. Recommendations were tabulated and assigned points based on a scale revised from a prior study. A total of 138 unique recommendations were identified, with point tallies ranging from 4 to 190. An in-person focus meeting occurred, where the 138 recommendations were reviewed, combined and condensed. A modified Delphi process was used to eliminate items found to be unimportant or those unable to be quantified (e.g. "minimize fatigue"). A total of 35 specific recommendations remained. Adverse events as a result of medication errors occur frequently in the operative setting. There are few rigorous studies to direct medication safety strategies, but this should not lead us to do nothing. The overwhelming consensus regarding best practices should be accepted, and the recommendations implemented. Our list of recommended strategies can hopefully be used to assess local vulnerabilities and institute system solutions.

Associations of hospital characteristics with nosocomial pneumonia after cardiac surgery can impact on standardized infection rates.

To identify hospital-level factors associated with post-cardiac surgical pneumonia for assessing their impact on standardized infection rates (SIRs), we studied 43 691 patients in a cardiac surgery registry (2001-2011) in 16 hospitals. In a logistic regression model for pneumonia following cardiac surgery, associations with hospital characteristics were quantified with adjustment for patient characteristics while allowing for clustering of patients by hospital. Pneumonia rates varied from 0·7% to 12·4% across hospitals. Seventy percent of variability in the pneumonia rate was attributable to differences in hospitals in their long-term rates with the remainder attributable to within-hospital differences in rates over time. After adjusting for patient characteristics, the pneumonia rate was found to be higher in hospitals with more registered nurses (RNs)/100 intensive-care unit (ICU) admissions [adjusted odds ratio (aOR) 1·2, P = 0·006] and more RNs/available ICU beds (aOR 1·4, P < 0·001). Other hospital characteristics had no significant association with pneumonia. SIRs calculated on the basis of patient characteristics alone differed substantially from the same rates calculated on the basis of patient characteristics and the hospital characteristic of RNs/100 ICU admissions. Since SIRs using patient case-mix information are important for comparing rates between hospitals, the additional allowance for hospital characteristics can impact significantly on how hospitals compare.

ASPREE-D: Aspirin for the prevention of depression in the elderly.

BACKGROUND: Not only is depression associated with increased inflammation but inflammation is a risk factor for the genesis of depression. Many of the environmental risk factors for depression are transduced through inflammatory signaling. Anti-inflammatory agents show promise for the management of depression in preclinical, epidemiological, and early clinical studies. This opens the door to the potential for anti-inflammatory agents to treat and prevent depression. There are no evidence-based pharmacotherapies for depression prevention. METHOD: ASPREE-D, aspirin in the prevention of depression in the elderly, is a sub study of ASPREE, which explores the potential of aspirin to prevent a range of inflammation related disorders in the elderly. With a sample size of 19,114, and a duration of 5 years, this placebo controlled study will be one of the largest randomized controlled trials in psychiatry and will provide definitive evidence on the ability of aspirin to prevent depression. RESULTS: This paper presents the rationale for the study and presents a summary of the study design. CONCLUSIONS: ASPREE-D may not only define novel therapy but will provide mechanistic proof of concept of the role of inflammation in depression.

Cardiovascular risk outcome and program evaluation of a cluster randomised controlled trial of a community-based, lay peer led program for people with diabetes.

BACKGROUND: The 2013 Global Burden of Disease Study demonstrated the increasing burden of diabetes and the challenge it poses to the health systems of all countries. The chronic and complex nature of diabetes requires active self-management by patients in addition to clinical management in order to achieve optimal glycaemic control and appropriate use of available clinical services. This study is an evaluation of a "real world" peer support program aimed at improving the control and management of type 2 diabetes (T2DM) in Australia. METHODS: The trial used a randomised cluster design with a peer support intervention and routine care control arms and 12-month follow up. Participants in both arms received a standardised session of self-management education at baseline. The intervention program comprised monthly community-based group meetings over 12 months led by trained peer supporters and active encouragement to use primary health care and other community resources and supports related to diabetes. Clinical, behavioural and other measures were collected at baseline, 6 and 12 months. The primary outcome was the predicted 5 year cardiovascular disease risk using the United Kingdom Prospective Diabetes Study (UKPDS) Risk Equation at 12 months. Secondary outcomes included clinical measures, quality of life, measures of support, psychosocial functioning and lifestyle measures. RESULTS: Eleven of 12 planned groups were successfully implemented in the intervention arm. Both the usual care and the intervention arms demonstrated a small reduction in 5 year UKPDS risk and the mean values for biochemical and anthropometric outcomes were close to target at 12 months. There were some small positive changes in self-management behaviours. CONCLUSIONS: The positive changes in self-management behaviours among intervention participants were not sufficient to reduce cardiovascular risk, possibly because approximately half of the study participants already had quite well controlled T2DM at baseline. Future research needs to address how to enhance community based programs so that they reach and benefit those most in need of resources and supports to improve metabolic control and associated clinical outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000469213 . Registered 16 June 2009.

The role of BRAF mutations in primary melanoma growth rate and survival.

BACKGROUND: The clinical behaviour and prognosis of primary melanomas harbouring BRAF mutations is not fully understood. OBJECTIVES: To investigate the effect of mutation status on primary melanoma growth rate and melanoma-specific survival (MSS). METHODS: A prospective cohort of 196 patients with stage I-III primary cutaneous melanoma were followed for a median of 92 months, pre-dating the institution of BRAF inhibitor therapy. Clinicopathological variables were correlated with mutation status and hazard ratios (HRs) estimated for MSS. RESULTS: Of 196 tumours, 77 (39.2%) were BRAF V600E, 10 (5.1%) BRAF V600K and 33 (16.8%) were NRAS mutant. BRAF V600E mutant melanomas were associated with favourable clinical characteristics and tended to be slower growing compared with BRAF V600K, NRAS mutant or BRAF/NRAS wild-type tumours (0.12 mm per month, 0.61 mm per month, 0.36 mm per month and 0.23 mm per month, respectively; P = 0.05). There were 39 melanoma deaths, and BRAF mutant melanomas were associated with poorer MSS in stage I-III disease [HR 2.60, 95% confidence interval (CI) 1.20-5.63; P = 0.02] and stage I-II disease (HR 3.39, 95% CI 1.12-10.22; P = 0.03) after adjusting for other prognostic variables. Considered separately, BRAF V600E mutant melanomas were strongly associated with MSS independently of thickness and nodal status (HR 3.89, 95% CI 1.67-9.09; P < 0.01) but BRAF V600K mutant tumours were not (HR 1.19, 95% CI 0.36-3.92; P = 0.77). CONCLUSIONS: The presence of a BRAF mutation does not necessarily 'drive' more rapid tumour growth but is associated with poorer MSS in patients with early-stage disease.

External validation and updating of a prediction model for nosocomial pneumonia after coronary artery bypass graft surgery.

The generalizability of a prediction model from North America for incident nosocomial pneumonia following coronary artery bypass graft surgery was assessed for 23247 patients on the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) registry. The performance of the North American model was evaluated using measures of calibration and discrimination. The model had reasonable discrimination (area under the receiver-operating characteristic curve, AUC=0·69), but unsatisfactory calibration (Hosmer-Lemeshow test, P<0·001) in the ANZSCTS patients. An update of the model coefficients yielded a model with AUC=0·71 and good calibration (P=0·46).

The impact of sport and active recreation injuries on physical activity levels at 12 months post-injury.

The aim of this study was to evaluate the impact of serious sport and active recreation injury on 12-month physical activity levels. Adults admitted to hospital with sport and active recreation-related injuries, and captured by the Victorian Orthopaedic Trauma Outcomes Registry were recruited to the study. Changes between preinjury and 12 month post-injury physical activity was assessed using the short International Physical Activity Questionnaire (IPAQ). Independent demographic, injury, and hospital variables were assessed for associations with changes in physical activity levels, using multivariate linear regression. A total of 324 patients were recruited, of which 98% were followed up at 12 months. Mean short IPAQ scores decreased from 7650 METS (95% CI: 7180, 8120) preinjury to 3880 METS; (95% CI: 3530, 4250) post-injury, independent of functional recovery. Education level and occupation group were the only variables independently associated with changes in physical activity levels post-injury. These results highlighted that sport and active recreation injuries lead to significant reductions in physical activity levels. Hence, the prevention of sport and active recreation injuries is important when considering promotion of activity at a population level.

Most individuals with treated blood pressures above target receive only one or two antihypertensive drug classes.

BACKGROUND: A significant proportion of individuals taking antihypertensive therapies fail to achieve blood pressures <140/90 mmHg. In order to develop strategies for improved treatment of blood pressure, we examined the association of blood pressure control with antihypertensive therapies and clinical and lifestyle factors in a cohort of adults at increased cardiovascular risk. METHODS: A cross-sectional study of 3994 adults from Melbourne and Shepparton, Australia enrolled in the SCReening Evaluation of the Evolution of New Heart Failure (SCREEN-HF) study. Inclusion criteria were age ≥60 years with one or more of self-reported ischaemic or other heart disease, atrial fibrillation, cerebrovascular disease, renal impairment or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known heart failure or cardiac abnormality on echocardiography or other imaging. The main outcome measures were the proportion of participants receiving antihypertensive therapy with blood pressures ≥140/90 mmHg and the association of blood pressure control with antihypertensive therapies and clinical and lifestyle factors. RESULTS: Of 3623 participants (1975 men and 1648 women) receiving antihypertensive therapy, 1867 (52%) had blood pressures ≥140/90 mmHg. Of these 1867 participants, 1483 (79%) were receiving only one or two antihypertensive drug classes. Blood pressures ≥140/90 mmHg were associated with increased age, male sex, waist circumference and log amino-terminal-pro-B-type natriuretic peptide levels. CONCLUSIONS: Most individuals with treated blood pressures above target receive only one or two antihypertensive drug classes. Prescribing additional antihypertensive drug classes and lifestyle modification may improve blood pressure control in this population of individuals at increased cardiovascular risk.

Correlates of Meal Skipping in Community Dwelling Older Adults: A Cross-Sectional Study.

In this cross-sectional analysis of 10,071 community dwelling adults aged ≥70 years, we examined factors associated with meal skipping (self-reported) using multivariable logistic regression. Prevalence of meal skipping in this study was 19.5%. The adjusted odds (aOR [95%CI]) of meal skipping were lower in those 85+ years (vs. 70-74.9 years, 0.56 [0.45-0.70]), and in those in regional areas (vs. urban area, 0.81 [0.72-0.92]). Higher odds of meal skipping were observed for those living alone (vs. living with someone, 1.84 [1.64-2.05]), current smokers (vs. non-smokers, 2.07 [1.54-2.80]), consumers of high amounts of alcohol (vs. abstainers 1.93 [1.35-2.75]), those with poor oral health (vs. excellent oral health, 1.71 [1.07 -2.73]) diabetes (vs. not 1.26 [1.06-1.50]), or frailty (vs. not, 1.63 [1.09-2.43]). This study identified socio-demographic, social, behavioural and biomedical correlates of meal skipping in later life, which may assist in targeting interventions to address meal skipping.

Self-reported oral health status, edentulism and all-cause mortality risk in 12 809 Australian older adults: a prospective cohort study.

OBJECTIVE: To investigate the association between oral health status and all-cause mortality in older adults using prospective cohort study design. SETTING AND PARTICIPANTS: In total, 12 809 adults aged ≥70 years (54.3% females) were participants of the ASPREE Longitudinal Study of Older Persons (ALSOP). METHODS: Participants self-reported the presence of natural teeth and oral health status. The association of self-reported oral health, edentulism and the integrative measure of the two with all-cause mortality were explored using the Cox-regression models adjusted for age, gender, socio-economic status, health-related behaviours, weight status, aspirin and polypharmacy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. RESULTS: In total, 22.2% of participants reported edentulism and 13.8% had fair/poor oral health. After adjustment for confounders, risk of all-cause mortality was higher among those with edentulism (vs. no edentulism) HR (95% CI) 1.43 (1.18, 1.73); and those with edentulism and reporting poor/fair oral health HR (95% CI) 1.69 (1.02, 2.82), or with no edentulism but reporting poor/fair oral health HR (95% CI) 1.46 (1.19-1.80) vs. no edentulism and reporting good/very good/excellent oral health. No association was observed between self-reported oral health alone and all-cause mortality. CONCLUSIONS: The risk of all-cause mortality was 69% higher among older adults reporting both edentulism and poor/fair oral health compared with those with teeth and more favourable self-reported oral health. © 2023 Australian Dental Association.

Doubly robust estimators of causal exposure effects with missing data in the outcome, exposure or a confounder.

We consider the estimation of the causal effect of a binary exposure on a continuous outcome. Confounding and missing data are both likely to occur in practice when observational data are used to estimate this causal effect. In dealing with each of these problems, model misspecification is likely to introduce bias. We present augmented inverse probability weighted (AIPW) estimators that account for both confounding and missing data, with the latter occurring in a single variable only. These estimators have an element of robustness to misspecification of the models used. Our estimators require two models to be specified to deal with confounding and two to deal with missing data. Only one of each of these models needs to be correctly specified. When either the outcome or the exposure of interest is missing, we derive explicit expressions for the AIPW estimator. When a confounder is missing, explicit derivation is complex, so we use a simple algorithm, which can be applied using standard statistical software, to obtain an approximation to the AIPW estimator.

Development of donor yield models.

Increasing donor yield, or the number of organs transplanted per donor, has been a focus of the transplant community in recent years. However, an exclusive focus on observed yield, unadjusted for the donor characteristics, ignores important differences between donors and donor case mixes in donation service areas (DSAs). We analyzed deceased donor registry data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients from January 2006 to December 2009 (N = 32 116 donors). Overall yields and kidney yields were modeled using ordinal logistic regression, and logistic regression was used to model heart, lung, pancreas and liver yields. Donor characteristics, including demographics, historical information and positive serology were related to overall and organ-specific yield. This study shows the potential value of the yield models as evaluation metrics and as tools that can inform DSA-wide practices in donor management and can improve organ utilization.

Transplanting kidneys without points for HLA-B matching: consequences of the policy change.

In 2003, the US kidney allocation system was changed to eliminate priority for HLA-B similarity. We report outcomes from before and after this change using data from the Scientific Registry of Transplant Recipients (SRTR). Analyses were based on 108 701 solitary deceased donor kidney recipients during the 6 years before and after the policy change. Racial/ethnic distributions of recipients in the two periods were compared (chi-square); graft failures were analyzed using Cox models. In the 6 years before and after the policy change, the overall number of deceased donor transplants rose 23%, with a larger increase for minorities (40%) and a smaller increase for non-Hispanic whites (whites) (8%). The increase in the proportion of transplants for non-whites versus whites was highly significant (p < 0.0001). Two-year graft survival improved for all racial/ethnic groups after implementation of this new policy. Findings confirmed prior SRTR predictions. Following elimination of allocation priority for HLA-B similarity, the deficit in transplantation rates among minorities compared with that for whites was reduced but not eliminated; furthermore, there was no adverse effect on graft survival.

Maximizing efficiency and cost-effectiveness of Type 2 diabetes screening: the AusDiab study.

AIMS: To evaluate how to most efficiently screen populations to detect people at high risk of incident Type 2 diabetes and those with prevalent, but undiagnosed, Type 2 diabetes. METHODS: Data from 5814 adults in the Australian Diabetes, Obesity and Lifestyle study were used to examine four different types of screening strategies. The strategies incorporated various combinations of cut-points of fasting plasma glucose, the non-invasive Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK1) and a modified version of the tool incorporating fasting plasma glucose (AUSDRISK2). Sensitivity, specificity, positive predictive value, screening costs per case of incident or prevalent undiagnosed diabetes identified and intervention costs per case of diabetes prevented or reverted were compared. RESULTS: Of the four strategies that maximized sensitivity and specificity, use of the non-invasive AUSDRISK1, followed by AUSDRISK2 in those found to be at increased risk on AUSDRISK1, had the highest sensitivity (80.3%; 95% confidence interval 76.6-84.1%), specificity (78.1%; 95% confidence interval 76.9-79.2%) and positive predictive value (22.3%; 95% confidence interval 20.2-24.4%) for identifying people with either prevalent undiagnosed diabetes or future incident diabetes. It required the fewest people (24.1%; 95% confidence interval 23.0-25.2%) to enter lifestyle modification programmes, and also had the lowest intervention costs and combined costs of running screening and intervention programmes per case of diabetes prevented or reverted. CONCLUSIONS: Using a self-assessed diabetes risk score as an initial screening step, followed by a second risk score incorporating fasting plasma glucose, would maximize efficiency of identifying people with undiagnosed Type 2 diabetes and those at high risk of future diabetes.