Altered Tau Kinase Activity in rTg4510 Mice after a Single Interfaced CHIMERA Traumatic Brain Injury.

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative diseases. In this study, we used the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) to investigate the effects of a single high-energy TBI in rTg4510 mice, a mouse model of tauopathy. Fifteen male rTg4510 mice (4 mo) were impacted at 4.0 J using interfaced CHIMERA and were compared to sham controls. Immediately after injury, the TBI mice showed significant mortality (7/15; 47%) and a prolonged duration of loss of the righting reflex. At 2 mo post-injury, surviving mice displayed significant microgliosis (Iba1) and axonal injury (Neurosilver). Western blotting indicated a reduced p-GSK-3ß (S9):GSK-3ß ratio in TBI mice, suggesting chronic activation of tau kinase. Although longitudinal analysis of plasma total tau suggested that TBI accelerates the appearance of tau in the circulation, there were no significant differences in brain total or p-tau levels, nor did we observe evidence of enhanced neurodegeneration in TBI mice compared to sham mice. In summary, we showed that a single high-energy head impact induces chronic white matter injury and altered GSK-3ß activity without an apparent change in post-injury tauopathy in rTg4510 mice.

The sodium-glucose cotransporter-2 inhibitor canagliflozin does not increase risk of non-genital skin and soft tissue infections in people with type 2 diabetes mellitus: A pooled post hoc analysis from the CANVAS Program and CREDENCE randomized double-blind trials.

AIMS: To assess whether the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin affects risk of non-genital skin and soft tissue infections (SSTIs). MATERIALS AND METHODS: We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator-reported adverse events were assessed by two blinded authors following predetermined criteria for non-genital SSTIs. Risks of non-genital SSTIs, overall and within prespecified subgroups, and risk of non-genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non-genital SSTIs were assessed using multivariable Cox regression models. RESULTS: Overall, 903 of 14 531 participants (6%) experienced non-genital SSTIs over a median follow-up of 26 months. No difference was observed in non-genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person-years vs. 23.9 events/1000 person-years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non-genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94-1.19 [P = 0.32] and HR 1.18, 95% CI 0.88-1.60 [P = 0.27], respectively). Baseline factors independently associated with non-genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. CONCLUSIONS: Canagliflozin did not affect risk of non-genital SSTIs or non-genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor-mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial.

RATIONALE & OBJECTIVE: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study. STUDY DESIGN: Secondary analysis of a randomized controlled trial. SETTING & PARTICIPANTS: Participants in the CREDENCE trial. INTERVENTION: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo. OUTCOMES: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models. RESULTS: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for interaction). No differences in safety outcomes by age group or sex were observed. LIMITATIONS: This was a post hoc analysis with multiple comparisons. CONCLUSIONS: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants. FUNDING: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical. TRIAL REGISTRATION: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Risk Factors for Fracture in Patients with Coexisting Chronic Kidney Disease and Type 2 Diabetes: An Observational Analysis from the CREDENCE Trial.

Background: The fracture pathophysiology associated with type 2 diabetes and chronic kidney disease (CKD) is incompletely understood. We examined individual fracture predictors and prediction sets based on different pathophysiological hypotheses, testing whether any of the sets improved prediction beyond that based on traditional osteoporotic risk factors. Methods: Within the CREDENCE cohort with adjudicated fracture outcomes, we assessed the association of individual factors with fracture using Cox regression models. We used the Akaike information criteria (AIC) and Schwartz Bayes Criterion (SBC) to assess six separate variable sets based on hypothesized associations with fracture, namely, traditional osteoporosis, exploratory general population findings, cardiovascular risk, CKD-mineral and bone disorder, diabetic osteodystrophy, and an all-inclusive set containing all variables. Results: Fracture occurred in 135 (3.1%) participants over a median 2.35 [1.88-2.93] years. Independent fracture predictors were older age (hazard ratio [HR] 1.04, confidence interval [CI] 1.01-1.06), female sex (HR 2.49, CI 1.70-3.65), previous fracture (HR 2.30, CI 1.58-3.34), Asian race (HR 1.74, CI 1.09-2.78), vitamin D therapy requirement (HR 2.05, CI 1.31-3.21), HbA1c (HR 1.14, CI 1.00-1.32), prior cardiovascular event (HR 1.60, CI 1.10-2.33), and serum albumin (HR 0.41, CI 0.23-0.74) (lower albumin associated with greater risk). The goodness of fit of the various hypothesis sets was similar (AIC range 1870.92-1849.51, SBC range 1875.60-1948.04). Conclusion: Independent predictors of fracture were identified in the CREDENCE participants with type 2 diabetes and CKD. Fracture prediction was not improved by models built on alternative pathophysiology hypotheses compared with traditional osteoporosis predictors.

Evaluation of step-down oral antibiotic therapy for uncomplicated streptococcal bloodstream infections on clinical outcomes.

BACKGROUND: Despite the severity and frequency of streptococcal bloodstream infections (BSIs), the effectiveness of oral definitive therapy remains unknown. The objective of this study was to evaluate the clinical outcomes of step-down oral antibiotics for the treatment of uncomplicated streptococcal BSIs. METHODS: In this retrospective cohort study, adult patients admitted with uncomplicated streptococcal BSI between June 2015 and June 2017 were included. Patients were excluded if they received <48 h of antibiotic therapy; therapy was started >48 h after first positive culture; had complicated infections of endocarditis, bone and joint infections, or central nervous system infections; Pitt bacteremia score (PBS) ⩾ 4; or failed to respond to effective therapy necessitating continued intravenous (IV) therapy. Patients were grouped by receipt of step-down oral antibiotic therapy (PO group) versus continued IV therapy (IV group). Outcomes included hospital length of stay (LOS), 30-day recurrence of BSI, 30-day readmission, 30-day all-cause mortality, and catheter-related or drug-related adverse events (AEs). RESULTS: Of 244 patients included, 40% received step-down oral therapy (n = 98). Overall, the most common source of BSI was pneumonia (22%), followed by skin and soft tissue infections (SSTI) (18%). Severity of illness measured by intensive care unit (ICU) admission and PBS was similar. The IV group had significantly longer LOS [median 10 (interquartile range [IQR] = 5-21) versus 5 (4-6) days, p < 0.01] compared with the PO group. BSI recurrence, readmission, all-cause mortality within 30 days, and AEs were similar between the groups (p = ns). CONCLUSION: In uncomplicated streptococcal BSI, patients treated with step-down oral antibiotic therapy had significantly shorter LOS compared with continued IV therapy without compromise of clinical outcomes.

The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial.

AIM: Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy. METHODS: The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100 mg daily or placebo. Neuropathy events were defined post-hoc as any reported adverse event consistent with a peripheral or autonomic neuropathy event. The effect of canagliflozin and predictors of neuropathy events were estimated using Cox regression analysis. In sensitivity analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, and non-autonomic neuropathy events. RESULTS: Almost half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years of follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). Independent factors associated with higher risk of experiencing neuropathy events were non-white race, younger age, higher glycated haemoglobin and lower estimated glomerular filtration rate. The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, P = 0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, P = 0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, P = 0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, P = 0.77). The lack of effect on neuropathy events was consistent in subgroup analyses. CONCLUSION: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial. Future large randomized studies with prespecified neuropathy endpoints are required to determine the impact of sodium glucose cotransporter 2 inhibitors on diabetic neuropathy.

Risk factors for incident kidney disease in older adults: an Australian prospective population-based study.

BACKGROUND AND AIM: To determine risk factors for incident chronic kidney disease (CKD) in a large population-based cohort. METHODS: This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely collected databases. The primary outcome was the development of incident CKD, defined as eGFR < 60 mL/min/1.73 m2 . CKD incidence was calculated using Poisson regression. Risk factors for incident CKD were assessed using Cox regression in multivariable models. RESULTS: In 39 574 participants who did not have CKD at enrolment, independent factors associated with developing CKD included: older age, regional residence (HR 1.38 (1.27-1.50) for outer regional vs major city), smoking (1.13 (1.00-1.27) for current smoker vs non-smoker), obesity (1.25 (1.16-1.35) for obese vs normal body mass index), diabetes mellitus (1.41 (1.33-1.50)), hypertension (1.53 (1.44-1.62)), coronary heart disease (1.13 (1.07-1.20)), depression/anxiety (1.16 (1.09-1.24)) and cancer (1.29 (1.20-1.39)). Migrants were less likely to develop CKD compared with people born in Australia (0.88 (0.83-0.94)). Gender, partner status and socioeconomic factors were not independently associated with developing CKD. CONCLUSIONS: This large population-based study found multiple modifiable and non-modifiable factors were independently associated with developing CKD. In the Australian setting, the risk of CKD was higher with regional residence. Differences according to socioeconomic status were predominantly explained by age, comorbidities and harmful health-related behaviours.

Effects of canagliflozin compared with placebo on major adverse cardiovascular and kidney events in patient groups with different baseline levels of HbA1c, disease duration and treatment intensity: results from the CANVAS Program.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. METHODS: We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (<10, 10 to 16, >16 years) and HbA1c (≤53.0 mmol/mol [<7.0%], >53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance <0.05). RESULTS: At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0-18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37. CONCLUSIONS/INTERPRETATION: In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c.

Effect of Hemodiafiltration on the Progression of Neuropathy with Kidney Failure: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Neuropathy is a common complication of kidney disease that lacks proven disease-modifying treatments. Hemodiafiltration improves clearance of uremic toxins and is associated with better nerve function than hemodialysis. We aimed to determine whether hemodiafiltration reduces the progression of neuropathy in people receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study was an open-label, blinded end point assessment, controlled trial that randomized maintenance hemodialysis recipients to hemodiafiltration or high-flux hemodialysis for 48 months or until death or cessation of dialysis at four study centers. The primary outcome was the mean change in the yearly modified total neuropathy score from baseline, with time points weighted equally. RESULTS: A total of 124 participants were randomized and followed for a mean of 41 months. At baseline, neuropathy was present in 91 (73%) participants (modified total neuropathy score greater than or equal to two), and 38 (31%) had moderate to severe neuropathy (modified total neuropathy score 9-28). Convection volume in the hemodiafiltration arm was a median of 24.7 (interquartile range, 22.4-26.5) L. The mean modified total neuropathy score (SEM) worsened by 1.7 (0.4)/28 and 1.2 (0.4)/28 in the hemodiafiltration and hemodialysis groups, respectively, with a mean difference of 0.5 (95% confidence interval, -0.7 to 1.7; P=0.37). There was no difference in survival (hazard ratio, 1.24; 95% confidence interval, 0.61 to 2.51; log rank P=0.55) or any of the prespecified adverse events. There was no difference between groups in the number of participants who suffered an adverse event adjusted by follow-up time (relative risk, 1.05; 95% confidence interval, 0.83 to 1.32; P=0.68). CONCLUSIONS: Neuropathy is still a common complication of kidney disease without disease-altering therapy. Hemodiafiltration did not affect neuropathy progression compared with hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE), ACTRN12609000615280.

Cost-benefit analysis comparing trough, two-level AUC and Bayesian AUC dosing for vancomycin.

OBJECTIVES: Area under the time-concentration curve (AUC) -guided dosing provides better estimates of exposure than vancomycin trough concentrations. Though clinical benefits have been reported, the costs of AUC-guided dosing are uncertain. The objective of this study was to quantify the costs of single-sample Bayesian or two-sample AUC strategies versus trough-guided dosing. METHODS: A cost-benefit analysis from the institutional perspective was conducted using a decision tree to model the probabilities and costs of acute kidney injury (AKI) associated with vancomycin administered over 48 hours up to 21+ days. Costs included vancomycin concentrations, Bayesian software and AKI hospitalization costs, and probabilities were obtained from primary literature. Robustness was assessed via both one-way and probabilistic sensitivity analyses. RESULTS: In the base-case model, two-sample AUC versus trough dosing saved an average of US$ 846 per patient encounter, and single-sample Bayesian AUC versus trough dosing saved an average of US$ 2065 per patient encounter. This translates into annual cost-savings of US$ 846 810 and US$ 2 065 720 for two-sample and single-sample Bayesian methods versus trough dosing, respectively, assuming 1000 vancomycin-treated patients per year. Assuming a budget of US$ 100 000 per year for Bayesian software, an institution would need to treat ≥41 patients with vancomycin for at least 48 hours to break even. CONCLUSIONS: There are significant institutional cost benefits using two-sample AUC or single-sample Bayesian methods over trough dosing, even after accounting for the annual costs of Bayesian programs. The potential to decrease rates of AKI, improve clinical outcomes and reduce costs to the institution strongly warrants consideration of improved dosing methods for vancomycin.

Relationship between measured and prescribed dialysate sodium in haemodialysis: a systematic review and meta-analysis.

BACKGROUND: Dialysate sodium (DNa) prescription policy differs between haemodialysis (HD) units, and the optimal DNa remains uncertain. We sought to summarize the evidence on the agreement between prescribed and delivered DNa, and whether the relationship varied according to prescribed DNa. METHODS: We searched MEDLINE and PubMed from inception to 26 February 2020 for studies reporting measured and prescribed DNa. We analysed results reported in aggregate with random-effects meta-analysis. We analysed results reported by individual sample, using mixed-effects Bland-Altman analysis and linear regression. Pre-specified subgroup analyses included method of sodium measurement, dialysis machine manufacturer and proportioning method. RESULTS: Seven studies, representing 908 dialysate samples from 10 HD facilities (range 16-133 samples), were identified. All but one were single-centre studies. Studies were of low to moderate quality. Overall, there was no statistically significant difference between measured and prescribed DNa {mean difference = 0.73 mmol/L [95% confidence interval (CI) -1.12 to 2.58; P = 0.44]} but variability across studies was substantial (I2 = 99.3%). Among individually reported samples (n = 295), measured DNa was higher than prescribed DNa by 1.96 mmol/L (95% CI 0.23-3.69) and the 95% limits of agreement ranged from -3.97 to 7.88 mmol/L. Regression analysis confirmed a strong relationship between prescribed and measured DNa, with a slope close to 1:1 (ß = 1.16, 95% CI 1.06-1.27; P < 0.0001). CONCLUSIONS: A limited number of studies suggest that, on average, prescribed and measured DNa are similar. However, between- and within-study differences were large. Further consideration of the precision of delivered DNa is required to inform rational prescribing.

Prevalence, incidence and risk factors of diabetes in Australian adults aged ≥45 years: A cohort study using linked routinely-collected data.

AIMS: To use linked routinely-collected health data to estimate diabetes prevalence and incidence in an Australian cohort of adults aged ≥45 years, and examine risk factors associated with incident disease. RESEARCH DESIGN AND METHODS: The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45) Study is a linked data study that combines baseline questionnaire responses from the population-based 45 and Up Study (2006-2009, n = 267,153) with multiple routinely-collected health databases up to December 2014. Among participants with ≥1 linked result for any laboratory test, diabetes status was determined from multiple data sources according to standard biochemical criteria, use of glucose-lowering medication or self-report, and the prevalence and incidence rate calculated. Independent risk factors of incident diabetes were examined using multivariable Cox regression. RESULTS: Among 152,169 45 and Up Study participants with ≥1 linked laboratory result in the EXTEND45 database (mean age 63.0 years; 54.9% female), diabetes prevalence was 10.8% (95% confidence interval [CI] 10.6%-10.9%). Incident disease in those without diabetes at baseline (n = 135,810; mean age 62.5 years; 56.1% female) was 10.0 per 1,000 person-years (95% CI 9.8-10.2). In all age groups, diabetes incidence was lower in women compared to men, an association that persisted in the fully adjusted analyses. Other independent risk factors of diabetes were older age, being born outside of Australia (with the highest rate of 19.2 per 1,000 person-years observed in people born in South and Central Asia), lower education status, lower annual household income, residence in a major city, family history of diabetes, personal history of cardiovascular disease or hypertension, higher body mass index, smoking and long sleeping hours. CONCLUSIONS: Our study represents an efficient approach to assessing diabetes frequency and its risk factors in the community. The infrastructure provided by the EXTEND45 Study will be useful for diabetes surveillance and examining other important clinical and epidemiological questions.

EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (the EXTEND45 Study): Protocol for an Australian Linked Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) and diabetes are the major causes of death and disability worldwide. They are associated with high health service utilization persisting over many years. Their slow progression and wide clinical variation make them eminently suitable for study in population-based cohorts. However, current understanding of their prevalence, incidence, and progression is largely based on studies conducted in clinical populations. OBJECTIVE: This study aims to establish a novel link between an existing population-based cohort (the 45 and Up Study) and routinely collected laboratory and administrative data to facilitate research across the full disease spectrum of CKD and diabetes. METHODS: In the EXTEND45 Study (EXamining OuTcomEs in chroNic Disease in the 45 and Up Study), baseline questionnaire responses of over 260,000 participants of the 45 and Up Study aged ≥45 years living in New South Wales (NSW), collected between January 2006 and December 2009, are linked to data from laboratory service providers as well as national- and state-based administrative datasets via probabilistic linkage. Routinely collected data were obtained for participants who could be linked between January 2005 and July 2013. Laboratory data will enable the identification of early cases of chronic disease and the assessment of clinically relevant biochemical targets during the disease course. Health administrative datasets will allow for the examination of health service use, pharmacological management, and clinical outcomes. RESULTS: The study received ethics approval from the NSW Population and Health Services Research Ethics Committee in February 2014. Data linkage for 267,153 of the 45 and Up Study participants was completed in June 2016, with congruent linkage achieved for 265,086 (99.23%) individuals. To date, the CKD and diabetes cohorts have been identified (published elsewhere), and a diverse portfolio of research projects relating to disease burden, risk factors, health outcomes, and health service utilization is in development. CONCLUSIONS: The EXTEND45 Study represents an unparalleled opportunity to perform extensive research into diseases of considerable public health and clinical importance. Strengths include the population-based nature of the cohort and the availability of longitudinal information on the complete disease pathway for affected individuals. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/15646.

Incidence and Associations of Chronic Kidney Disease in Community Participants With Diabetes: A 5-Year Prospective Analysis of the EXTEND45 Study.

OBJECTIVE: To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in people with diabetes. RESEARCH DESIGN AND METHODS: We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006-2014) that linked the Sax Institute's 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement <60 mL/min/1.73 m2 recorded during the follow-up period. Participants with eGFR < 60 mL/min/1.73 m2 at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR <60 mL/min/1.73 m2 and multivariable Cox regression to examine factors associated with the study outcome. RESULTS: Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR <60 mL/min/1.73 m2 over a median follow-up time of 5.7 years (interquartile range, 3.0-5.9 years). The eGFR <60 mL/min/1.73 m2 incidence rate per 100 person-years was 6.0 (95% CI 5.7-6.3) overall, 1.5 (1.3-1.9) in participants aged 45-54 years, 3.7 (3.4-4.0) for 55-64 year olds, 7.6 (7.1-8.1) for 65-74 year olds, 15.0 (13.0-16.0) for 75-84 year olds, and 26.0 (22.0-32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase; 95% CI 1.19-1.26), geography (outer regional and remote versus major city: 1.36; 1.17-1.58), obesity (obese class III versus normal: 1.44; 1.16-1.80), and the presence of hypertension (1.52; 1.33-1.73), coronary heart disease (1.13; 1.02-1.24), cancer (1.30; 1.14-1.50), and depression/anxiety (1.14; 1.01-1.27). CONCLUSIONS: In participants with diabetes, the incidence of an eGFR <60 mL/min/1.73 m2 was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.

Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Background Several trials have demonstrated protective effects from inhibition of sodium-glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results We included 4 large-scale trials of sodium-glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs. There were 38 723 patients from 4 trials, with a mean 2.9 years of follow-up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI, 0.82-0.94; P<0.001) and no evidence that the effects of sodium-glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction >0.252; I2<25%). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction>0.302; I2<10%), cardiovascular death (all P interaction>0.167; I2<50%), and death from any cause (all P interaction>0.354; I2=0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function (P interaction=0.020; I2=81%). Conclusions Sodium-glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.

Effect of Treatment on Damage and Hospitalization in Elderly Patients with Microscopic Polyangiitis and Granulomatosis with Polyangiitis.

OBJECTIVE: Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown. METHODS: Consecutive patients from Sweden, the United Kingdom, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide (CYC), rituximab (RTX), and corticosteroids the first 3 months was registered. Outcomes up to 2 years from diagnosis included Vasculitis Damage Index (VDI), hospitalization, and cause of death. RESULTS: Treatment data were available for 167 of 202 patients. At 2 years, 4% had no items of damage. There was a positive association between VDI score at 2 years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using CYC or RTX. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. Myeloperoxidase-antineutrophil cytoplasmic antibody positivity and lower creatinine levels decreased the odds of readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose. CONCLUSION: Immunosuppressive treatment with CYC or RTX in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first 3 months was associated with treatment-related damage and fatal infections.

Addressing common barriers in adult immunizations: a review of interventions.

Introduction: Low levels of adult vaccination have been documented in the United States and globally. Research has been conducted to identify reasons for low immunization rates; however, the most useful studies are those that implemented interventions for identified barriers to evaluate their impact on rates of immunization. Identifying successful interventions provides immunization providers with evidence-based methods that can be utilized to increase the uptake of recommended vaccines.Areas covered: This review focuses on known barriers to adult immunizations and the interventions available in the literature to overcome these barriers. It outlines interventions that may increase vaccine uptake in the adult population through addressing barriers related to lack of vaccine knowledge, cost, access, provider and practice-based challenges, and racial and ethnic disparities.Expert opinion: Improving adult immunization rates is critical to protecting a population against vaccine-preventable diseases. Those interventions that appeared to increase immunization rates in the adult population included education and reminders about vaccination using text and telephone calls, low-cost or subsidized vaccines, easy access to immunization services, and understanding the cultural and social needs of different racial and ethnic populations. It is likely that an evidence-based multimodal approach using different categories of interventions is necessary to significantly improve adult immunization rates.