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Obesity is a risk factor for osteoarthritis. Antiretroviral therapy (ART)–treated HIV-infected patients are frequently affected by overweight and obesity, and may be at increased risk of osteoarthritis. BMI however is a measure which does not discriminate adipose from non-adipose body mass, or fat distribution, which may have different effects. This study aimed to examine relationships between body composition and knee cartilage volume, as assessed by magnetic resonance imaging in HIV infection. 35 ART-treated HIV-infected men aged 51.7 years (mean) 7.9 (SD) and 18 healthy men aged 49.5 years (mean) 6.4 (SD) participated. Cartilage volume was measured on magnetic resonance imaging of the dominant knee using validated methods. Body composition was measured using dual x-ray absorptiometry. HIV-infected participants had less total body and gynoid fat (kg) (p = 0.04 and p = 0.007, respectively) and more percent android fat mass and percent trunk fat mass (p = 0.001 and p < 0.001, respectively) than controls. In HIV-infected participants there was an inverse association between total body fat mass and average tibial cartilage volume (R = −8.01, 95% CI −15.66, −0.36). Also, in HIV-infected participants there was an inverse association between android fat mass and average cartilage volume (R = −90.91, 95% CI −158.66, −23.16). This preliminary study found that both total body and android fat mass were inversely related to average knee cartilage volume in ambulant, ART–treated HIV-infected adults. These findings are features of early knee osteoarthritis and this may be of future significance in HIV. [ABSTRACT FROM AUTHOR]

The intention-to-treat (ITT) analysis of the Applying Wolbachia to Eliminate Dengue (AWED) trial estimated a protective efficacy of 77.1% for participants resident in areas randomised to receive releases of wMel-infected Aedes aegypti mosquitoes, an emerging dengue preventive intervention. The limiting assumptions of ITT analyses in cluster randomised trials and the mobility of mosquitoes and humans across cluster boundaries indicate the primary analysis is likely to underestimate the full public health benefit. Using spatiotemporally-resolved data on the distribution of Wolbachia mosquitoes and on the mobility of AWED participants (n = 6306), we perform complier-restricted and per-protocol re-examinations of the efficacy of the Wolbachia intervention. Increased intervention efficacy was estimated in all analyses by the refined exposure measures. The complier-restricted analysis returned an estimated efficacy of 80.7% (95% CI 65.9, 89.0) and the per-protocol analysis estimated 82.7% (71.7, 88.4) efficacy when comparing participants with an estimated wMel exposure of ≥ 80% compared to those with <20%. These reanalyses demonstrate how human and mosquito movement can lead to underestimation of intervention effects in trials of vector interventions and indicate that the protective efficacy of Wolbachia is even higher than reported in the primary trial results., (© 2024. The Author(s).)

Pacific Island countries have experienced periodic dengue, chikungunya and Zika outbreaks for decades. The prevention and control of these mosquito-borne diseases rely heavily on control of Aedes aegypti mosquitoes, which in most settings are the primary vector. Introgression of the intracellular bacterium Wolbachia pipientis (wMel strain) into Ae. aegypti populations reduces their vector competence and consequently lowers dengue incidence in the human population. Here we describe successful area-wide deployments of wMel-infected Ae. aegypti in Suva, Lautoka, Nadi (Fiji), Port Vila (Vanuatu) and South Tarawa (Kiribati). With community support, weekly releases of wMel-infected Ae. aegypti mosquitoes for between 2 to 5 months resulted in wMel introgression in nearly all locations. Long term monitoring confirmed a high, self-sustaining prevalence of wMel infecting mosquitoes in almost all deployment areas. Measurement of public health outcomes were disrupted by the Covid19 pandemic but are expected to emerge in the coming years., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Simmons et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Releases of Wolbachia ( w Mel)-infected Aedes aegypti mosquitoes significantly reduced the incidence of virologically confirmed dengue in a previous cluster randomised trial in Yogyakarta City, Indonesia. Following the trial, w Mel releases were extended to the untreated control areas, to achieve city-wide coverage of Wolbachia., Objective: In this predefined analysis, we evaluated the impact of the wMel deployments in Yogyakarta on dengue hemorrhagic fever (DHF) case notifications and on the frequency of perifocal insecticide spraying by public health teams., Methods: Monthly counts of DHF cases notified to the Yogyakarta District Health Office between January 2006 and May 2022 were modelled as a function of time-varying local wMel treatment status (fully- and partially-treated vs untreated, and by quintile of wMel prevalence). The frequency of insecticide fogging in wMel-treated and untreated areas was analysed using negative binomial regression., Results: Notified DHF incidence was 83% lower in fully treated vs untreated periods (IRR 0.17 [95% CI 0.14, 0.20]), and 78% lower in areas with 80-100% wMel prevalence compared to areas with 0-20% w Mel (IRR 0.23 [0.17, 0.30]). A similar intervention effect was observed at 60-80% wMel prevalence as at 80-100% prevalence (76% vs 78% efficacy, respectively). Pre-intervention, insecticide fogging occurred at similar frequencies in areas later randomised to wMel-treated and untreated arms of the trial. After w Mel deployment, fogging occurred significantly less frequently in treated areas (IRR 0.17 [0.10, 0.30])., Conclusions: Deployments of w Mel-infected Aedes aegypti mosquitoes resulted in an 83% reduction in the application of perifocal insecticide spraying, consistent with lower dengue case notifications in wMel-treated areas. These results show that the Wolbachia intervention effect demonstrated previously in a cluster randomised trial was also measurable from routine surveillance data.

Background: The introduction of Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Randomised and non-randomised studies in multiple countries have shown significant reductions in dengue incidence following field releases of wMel-infected Ae. aegypti. We report the public health outcomes from phased, large-scale releases of wMel-Ae. aegypti mosquitoes throughout three contiguous cities in the Aburrá Valley, Colombia., Methodology/principal Findings: Following pilot releases in 2015-2016, staged city-wide wMel-Ae. aegypti deployments were undertaken in the cities of Bello, Medellín and Itagüí (3.3 million people) between October 2016 and April 2022. The impact of the Wolbachia intervention on dengue incidence was evaluated in two parallel studies. A quasi-experimental study using interrupted time series analysis showed notified dengue case incidence was reduced by 95% in Bello and Medellín and 97% in Itagüí, following establishment of wMel at ≥60% prevalence, compared to the pre-intervention period and after adjusting for seasonal trends. A concurrent clinic-based case-control study with a test-negative design was unable to attain the target sample size of 63 enrolled virologically-confirmed dengue (VCD) cases between May 2019 and December 2021, consistent with low dengue incidence throughout the Aburrá Valley following wMel deployments. Nevertheless, VCD incidence was 45% lower (OR 0.55 [95% CI 0.25, 1.17]) and combined VCD/presumptive dengue incidence was 47% lower (OR 0.53 [95% CI 0.30, 0.93]) among participants resident in wMel-treated versus untreated neighbourhoods., Conclusions/significance: Stable introduction of wMel into local Ae. aegypti populations was associated with a significant and sustained reduction in dengue incidence across three Colombian cities. These results from the largest contiguous Wolbachia releases to-date demonstrate the real-world effectiveness of the method across large urban populations and, alongside previously published results, support the reproducibility of this effectiveness across different ecological settings., Trial Registration: NCT03631719., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Velez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We explored the utility of the standardized infection ratio (SIR) for surgical site infection (SSI) reporting in an Australian jurisdiction., Design: Retrospective chart review., Setting: Statewide SSI surveillance data from 2013 to 2019., Patients: Individuals who had cardiac bypass surgery (CABG), colorectal surgery (COLO), cesarean section (CSEC), hip prosthesis (HPRO), or knee prosthesis (KPRO) procedures., Methods: The SIR was calculated by dividing the number of observed infections by the number of predicted infections as determined using the National Healthcare Safety Network procedure-specific risk models. In line with a minimum precision criterion, an SIR was not calculated if the number of predicted infections was <1., Results: A SIR >0 (≥1 observed SSI, predicted number of SSI ≥1, no missing covariates) could be calculated for a median of 89.3% of reporting quarters for CABG, 75.0% for COLO, 69.0% for CSEC, 0% for HPRO, and 7.1% for KPRO. In total, 80.6% of the reporting quarters, when the SIR was not calculated, were due to no observed infections or predicted infections <1, and 19.4% were due to missing covariates alone. Within hospitals, the median percentage of quarters during which zero infections were observed was 8.9% for CABG, 20.0% for COLO, 25.4% for CSEC, 67.3% for HPRO, and 71.4% for KPRO., Conclusions: Calculating an SIR for SSIs is challenging for hospitals in our regional network, primarily because of low event numbers and many facilities with predicted infections <1. Our SSI reporting will continue to use risk-indexed rates, in tandem with SIR values when predicted number of SSI ≥1., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2023.)

Dengue exhibits focal clustering in households and neighborhoods, driven by local mosquito population dynamics, human population immunity, and fine scale human and mosquito movement. We tested the hypothesis that spatiotemporal clustering of homotypic dengue cases is disrupted by introduction of the arbovirus-blocking bacterium Wolbachia (wMel-strain) into the Aedes aegypti mosquito population. We analysed 318 serotyped and geolocated dengue cases (and 5921 test-negative controls) from a randomized controlled trial in Yogyakarta, Indonesia of wMel deployments. We find evidence of spatial clustering up to 300 m among the 265 dengue cases (3083 controls) in the untreated trial arm. Participant pairs enrolled within 30 days and 50 m had a 4.7-fold increase (compared to 95% CI on permutation-based null distribution: 0.1, 1.2) in the odds of being homotypic (i.e. potentially transmission-related) as compared to pairs occurring at any distance. In contrast, we find no evidence of spatiotemporal clustering among the 53 dengue cases (2838 controls) resident in the wMel-treated arm. Introgression of wMel Wolbachia into Aedes aegypti mosquito populations interrupts focal dengue virus transmission leading to reduced case incidence; the true intervention effect may be greater than the 77% efficacy measured in the primary analysis of the Yogyakarta trial., (© 2022. The Author(s).)

The Applying Wolbachia to Eliminate Dengue (AWED) trial was a parallel cluster randomised trial that demonstrated Wolbachia (wMel) introgression into Ae. aegypti populations reduced dengue incidence. In this predefined substudy, we compared between treatment arms, the relative abundance of Ae. aegypti and Ae. albopictus before, during and after wMel-introgression. Between March 2015 and March 2020, 60,084 BG trap collections yielded 478,254 Ae. aegypti and 17,623 Ae. albopictus. Between treatment arms there was no measurable difference in Ae. aegypti relative abundance before or after wMel-deployments, with a count ratio of 0.96 (95% CI 0.76, 1.21) and 1.00 (95% CI 0.85, 1.17) respectively. More Ae. aegypti were caught per trap per week in the wMel-intervention arm compared to the control arm during wMel deployments (count ratio 1.23 (95% CI 1.03, 1.46)). Between treatment arms there was no measurable difference in the Ae. albopictus population size before, during or after wMel-deployment (overall count ratio 1.10 (95% CI 0.89, 1.35)). We also compared insecticide resistance phenotypes of Ae. aegypti in the first and second years after wMel-deployments. Ae. aegypti field populations from wMel-treated and untreated arms were similarly resistant to malathion (0.8%), permethrin (1.25%) and cyfluthrin (0.15%) in year 1 and year 2 of the trial. In summary, we found no between-arm differences in the relative abundance of Ae. aegypti or Ae. albopictus prior to or after wMel introgression, and no between-arm difference in Ae. aegypti insecticide resistance phenotypes. These data suggest neither Aedes abundance, nor insecticide resistance, confounded the epidemiological outcomes of the AWED trial., Competing Interests: The authors have declared that no competing interests exist.

Background: The introduction of the bacterium Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Evidence of a reduction in dengue case incidence following field releases of wMel-infected Ae. aegypti has been reported previously from a cluster randomised controlled trial in Indonesia, and quasi-experimental studies in Indonesia and northern Australia., Methodology/principal Findings: Following pilot releases in 2015-2016 and a period of intensive community engagement, deployments of adult wMel-infected Ae. aegypti mosquitoes were conducted in Niterói, Brazil during 2017-2019. Deployments were phased across four release zones, with a total area of 83 km2 and a residential population of approximately 373,000. A quasi-experimental design was used to evaluate the effectiveness of wMel deployments in reducing dengue, chikungunya and Zika incidence. An untreated control zone was pre-defined, which was comparable to the intervention area in historical dengue trends. The wMel intervention effect was estimated by controlled interrupted time series analysis of monthly dengue, chikungunya and Zika case notifications to the public health surveillance system before, during and after releases, from release zones and the control zone. Three years after commencement of releases, wMel introgression into local Ae. aegypti populations was heterogeneous throughout Niterói, reaching a high prevalence (>80%) in the earliest release zone, and more moderate levels (prevalence 40-70%) elsewhere. Despite this spatial heterogeneity in entomological outcomes, the wMel intervention was associated with a 69% reduction in dengue incidence (95% confidence interval 54%, 79%), a 56% reduction in chikungunya incidence (95%CI 16%, 77%) and a 37% reduction in Zika incidence (95%CI 1%, 60%), in the aggregate release area compared with the pre-defined control area. This significant intervention effect on dengue was replicated across all four release zones, and in three of four zones for chikungunya, though not in individual release zones for Zika., Conclusions/significance: We demonstrate that wMel Wolbachia can be successfully introgressed into Ae. aegypti populations in a large and complex urban setting, and that a significant public health benefit from reduced incidence of Aedes-borne disease accrues even where the prevalence of wMel in local mosquito populations is moderate and spatially heterogeneous. These findings are consistent with the results of randomised and non-randomised field trials in Indonesia and northern Australia, and are supportive of the Wolbachia biocontrol method as a multivalent intervention against dengue, chikungunya and Zika., Competing Interests: The authors have declared that no competing interest exist.

Background: Aedes aegypti mosquitoes infected with the w Mel strain of Wolbachia pipientis are less susceptible than wild-type A. aegypti to dengue virus infection., Methods: We conducted a cluster-randomized trial involving releases of w Mel-infected A. aegypti mosquitoes for the control of dengue in Yogyakarta, Indonesia. We randomly assigned 12 geographic clusters to receive deployments of w Mel-infected A. aegypti (intervention clusters) and 12 clusters to receive no deployments (control clusters). All clusters practiced local mosquito-control measures as usual. A test-negative design was used to assess the efficacy of the intervention. Patients with acute undifferentiated fever who presented to local primary care clinics and were 3 to 45 years of age were recruited. Laboratory testing was used to identify participants who had virologically confirmed dengue (VCD) and those who were test-negative controls. The primary end point was symptomatic VCD of any severity caused by any dengue virus serotype., Results: After successful introgression of w Mel into the intervention clusters, 8144 participants were enrolled; 3721 lived in intervention clusters, and 4423 lived in control clusters. In the intention-to-treat analysis, VCD occurred in 67 of 2905 participants (2.3%) in the intervention clusters and in 318 of 3401 (9.4%) in the control clusters (aggregate odds ratio for VCD, 0.23; 95% confidence interval [CI], 0.15 to 0.35; P = 0.004). The protective efficacy of the intervention was 77.1% (95% CI, 65.3 to 84.9) and was similar against the four dengue virus serotypes. The incidence of hospitalization for VCD was lower among participants who lived in intervention clusters (13 of 2905 participants [0.4%]) than among those who lived in control clusters (102 of 3401 [3.0%]) (protective efficacy, 86.2%; 95% CI, 66.2 to 94.3)., Conclusions: Introgression of w Mel into A. aegypti populations was effective in reducing the incidence of symptomatic dengue and resulted in fewer hospitalizations for dengue among the participants. (Funded by the Tahija Foundation and others; AWED ClinicalTrials.gov number, NCT03055585; Indonesia Registry number, INA-A7OB6TW.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Histological and epidemiological data suggest that increased signal intensity at the proximal patellar tendon on magnetic resonance imaging is a response to tendon loading. As patellofemoral geometry is a mediator of loading, we examined the association between patellofemoral geometry and the prevalence of increased signal intensity at the patellar tendon in community-based middle-aged adults., Methods: Two hundred-one adults aged 25-60 years in a study of obesity and musculoskeletal health had the patellar tendon assessed from magnetic resonance imaging. Increased signal intensity at the proximal patellar tendon was defined as hyper-intense regions of characteristic pattern, size and distribution on both T1- and T2-weighted sequences. Indices of patellofemoral geometry, including Insall-Salvati ratio, patellofemoral congruence angle, sulcus angle, and lateral condyle-patella angle, were measured from magnetic resonance imaging using validated methods. Binary logistic regression was used to examine the association between patellofemoral geometrical indices and the prevalence of increased signal intensity at the patellar tendon., Results: The prevalence of increased signal intensity at the patellar tendon was 37.3%. A greater Insall-Salvati ratio (odds ratio 0.80, 95% confidence interval 0.66-0.97 per 0.1 change in the ratio, p = 0.02), indicative of a higher-riding patella, and a larger patellofemoral congruence angle (odds ratio 0.91, 95% confidence interval 0.85-0.98 per 5 degree change in the angle, p = 0.01), indicating a more laterally placed patella, were associated with reduced odds of increased signal intensity at the patellar tendon. Sulcus angle and lateral condyle-patella angle were not significantly associated with the odds of increased signal intensity at the patellar tendon., Conclusions: In community-based asymptomatic middle-aged adults, increased signal intensity at the patellar tendon was common and associated with Insall-Salvati ratio and patellofemoral congruence angle, suggesting a biomechanical mechanism. Such work is likely to inform tissue engineering and cell regeneration approaches to improving outcomes in those with tendon pathology.

Background: The AWED (Applying Wolbachia to Eliminate Dengue) trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Yogyakarta, Indonesia, with the aim of measuring the efficacy of Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting. Enrolment began in January 2018 and is ongoing. The original study protocol was published in April 2018. Here, we describe amendments that have been made to the study protocol since commencement of the trial., Methods: The key protocol amendments are (1) a revised study duration with planned end of participant enrolment in August 2020, (2) the addition of new secondary objectives (i) to estimate serotype-specific efficacy of the Wolbachia intervention and (ii) to compare Ae. aegypti abundance in intervention versus untreated clusters, (3) an additional exposure classification for the per-protocol analysis where the Wolbachia exposure index is calculated using only the cluster-level Wolbachia prevalence in the participant's cluster of residence, (4) power re-estimation using a multinomial sampling method that better accounts for randomness in sampling, and (5) the addition of two trial stopping rules to address the potential for persistently low rates of virologically confirmed dengue case enrolment and Wolbachia contamination into untreated clusters. Additional minor changes to the protocol are also described., Discussion: The findings from this study will provide the first experimental evidence for the efficacy of Wolbachia in reducing dengue incidence. Enrolment in the trial will conclude this year (2020) and results will be reported shortly thereafter., Trial Registration: ClinicalTrials.gov, identifier: NCT03055585. Registered on 14 February 2017. Last updated 22 March 2020.

Background: Ae. aegypti mosquitoes stably transfected with the intracellular bacterium Wolbachia pipientis ( w Mel strain) have been deployed for biocontrol of dengue and related arboviral diseases in multiple countries. Field releases in northern Australia have previously demonstrated near elimination of local dengue transmission from Wolbachia -treated communities, and pilot studies in Indonesia have demonstrated the feasibility and acceptability of the method. We conducted a quasi-experimental trial to evaluate the impact of scaled Wolbachia releases on dengue incidence in an endemic setting in Indonesia. Methods: In Yogyakarta City, Indonesia, following extensive community engagement, w Mel Wolbachia -carrying mosquitoes were released every two weeks for 13-15 rounds over seven months in 2016-17, in a contiguous 5 km 2 area (population 65,000). A 3 km 2 area (population 34,000) on the opposite side of the city was selected a priori as an untreated control area. Passive surveillance data on notified hospitalised dengue patients was used to evaluate the epidemiological impact of Wolbachia deployments, using controlled interrupted time-series analysis. Results: Rapid and sustained introgression of w Mel Wolbachia into local Ae. aegypti populations was achieved. Thirty-four dengue cases were notified from the intervention area and 53 from the control area (incidence 26 vs 79 per 100,000 person-years) during 24 months following Wolbachia deployment. This corresponded in the regression model to a 73% reduction in dengue incidence (95% confidence interval 49%,86%) associated with the Wolbachia intervention. Exploratory analysis including 6 months additional post-intervention observations showed a small strengthening of this effect (30 vs 115 per 100,000 person-years; 76% reduction in incidence, 95%CI 60%,86%). Conclusions: We demonstrate a significant reduction in dengue incidence following successful introgression of Wolbachia into local Ae. aegypti populations in an endemic setting in Indonesia. These findings are consistent with previous field trials in northern Australia, and support the effectiveness of this novel approach for dengue control., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Indriani C et al.)

Background: The w Mel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and subsequently shown in laboratory studies to reduce transmission of a range of viruses including dengue, Zika, chikungunya, yellow fever, and Mayaro viruses that cause human disease. Here we report the entomological and epidemiological outcomes of staged deployment of Wolbachia across nearly all significant dengue transmission risk areas in Australia. Methods: The  w Mel strain of  Wolbachia  was backcrossed into the local  Aedes aegypti  genotype (Cairns and Townsville backgrounds) and mosquitoes were released in the field by staff or via community assisted methods. Mosquito monitoring was undertaken and mosquitoes were screened for the presence of  Wolbachia . Dengue case notifications were used to track dengue incidence in each location before and after releases. Results: Empirical analyses of the Wolbachia mosquito releases, including data on the density, frequency and duration of Wolbachia mosquito releases, indicate that Wolbachia can be readily established in local mosquito populations, using a variety of deployment options and over short release durations (mean release period 11 weeks, range 2-22 weeks). Importantly, Wolbachia frequencies have remained stable in mosquito populations since releases for up to 8 years. Analysis of dengue case notifications data demonstrates near-elimination of local dengue transmission for the past five years in locations where Wolbachia has been established. The regression model estimate of Wolbachia intervention effect from interrupted time series analyses of case notifications data prior to and after releases, indicated a 96% reduction in dengue incidence in Wolbachia treated populations (95% confidence interval: 84 - 99%). Conclusion: Deployment of the w Mel strain of Wolbachia into local Ae. aegypti populations across the Australian regional cities of Cairns and most smaller regional communities with a past history of dengue has resulted in the reduction of local dengue transmission across all deployment areas., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Ryan PA et al.)

Background: The w Mel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and subsequently shown in laboratory studies to reduce transmission of a range of viruses including dengue, Zika, chikungunya, yellow fever, and Mayaro viruses that cause human disease. Here we report the entomological and epidemiological outcomes of staged deployment of Wolbachia across nearly all significant dengue transmission risk areas in Australia. Methods: The  w Mel strain of  Wolbachia  was backcrossed into the local  Aedes aegypti  genotype (Cairns and Townsville backgrounds) and mosquitoes were released in the field by staff or via community assisted methods. Mosquito monitoring was undertaken and mosquitoes were screened for the presence of  Wolbachia . Dengue case notifications were used to track dengue incidence in each location before and after releases. Results: Empirical analyses of the Wolbachia mosquito releases, including data on the density, frequency and duration of Wolbachia mosquito releases, indicate that Wolbachia can be readily established in local mosquito populations, using a variety of deployment options and over short release durations (mean release period 11 weeks, range 2-22 weeks). Importantly, Wolbachia frequencies have remained stable in mosquito populations since releases for up to 8 years. Analysis of dengue case notifications data demonstrates near-elimination of local dengue transmission for the past five years in locations where Wolbachia has been established. The regression model estimate of Wolbachia intervention effect from interrupted time series analyses of case notifications data prior to and after releases, indicated a 96% reduction in dengue incidence in Wolbachia treated populations (95% confidence interval: 84 - 99%). Conclusion: Deployment of the w Mel strain of Wolbachia into local Ae. aegypti populations across the Australian regional cities of Cairns and most smaller regional communities with a past history of dengue has resulted in the reduction of local dengue transmission across all deployment areas., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Ryan PA et al.)

Background : A number of new technologies are under development for the control of mosquito transmitted viruses, such as dengue, chikungunya and Zika that all require the release of modified mosquitoes into the environment. None of these technologies has been able to demonstrate evidence that they can be implemented at a scale beyond small pilots. Here we report the first successful citywide scaled deployment of Wolbachia in the northern Australian city of Townsville. Methods : The w Mel strain of Wolbachia was backcrossed into a local Aedes aegypti genotype and mass reared mosquitoes were deployed as eggs using mosquito release containers (MRCs). In initial stages these releases were undertaken by program staff but in later stages this was replaced by direct community release including the development of a school program that saw children undertake releases. Mosquito monitoring was undertaken with Biogents Sentinel (BGS) traps and individual mosquitoes were screened for the presence of Wolbachia with a Taqman qPCR or LAMP diagnostic assay. Dengue case notifications from Queensland Health Communicable Disease Branch were used to track dengue cases in the city before and after release. Results : Wolbachia was successfully established into local Ae. aegypti mosquitoes across 66 km 2 in four stages over 28 months with full community support.  A feature of the program was the development of a scaled approach to community engagement. Wolbachia frequencies have remained stable since deployment and to date no local dengue transmission has been confirmed in any area of Townsville after Wolbachia has established, despite local transmission events every year for the prior 13 years and an epidemiological context of increasing imported cases. Conclusion : Deployment of Wolbachia into Ae. aegypti populations can be readily scaled to areas of ~60km 2 quickly and cost effectively and appears in this context to be effective at stopping local dengue transmission., Competing Interests: No competing interests were disclosed.

Background: Rio de Janeiro and Niterói municipalities in southeastern Brazil experience large dengue epidemics every 2 to 5 years, with >100,000 cases notified in epidemic years. Costs of vector control and direct and indirect costs due to the Aedes -borne diseases dengue, chikungunya and Zika were estimated to total $650 million USD in 2016, but traditional vector control strategies have not been effective in preventing arboviral disease outbreaks. The Wolbachia method is a novel and self-sustaining approach for the biological control of arboviral diseases, in which the transmission potential of Ae. aegypti mosquitoes is reduced by stably transfecting them with the Wolbachia bacterium. This paper describes a study protocol for evaluating the effect of large-scale non-randomised releases of Wolbachia mosquitoes on the incidence of dengue, Zika and chikungunya in the municipalities of Niterói and Rio de Janeiro. This follows a lead-in period since 2014 involving intensive community engagement, regulatory and public approval, entomological surveys, and small-scale pilot releases. Method: The planned releases during 2017-2019 cover a combined area of 121 km2 with a resident population of 1.1 million, across the two cities. Untreated areas with comparable historical dengue profiles and sociodemographic characteristics have been identified a priori as comparative control areas in each municipality. The proposed pragmatic epidemiological approach combines a controlled interrupted time series analysis of routinely notified suspected and laboratory-confirmed arboviral cases, together with monitoring of arbovirus activity utilising outbreak signals routinely used in public health disease surveillance. Discussion: If the current project is successful, this model for control of arboviral disease through Wolbachia releases can be expanded nationally and regionally., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Durovni B et al.)

Background: Rio de Janeiro and Niterói are neighbouring cities in southeastern Brazil which experience large dengue epidemics every 2 to 5 years, with >100,000 cases notified in epidemic years. Costs of vector control and direct and indirect costs due to the Aedes -borne diseases dengue, chikungunya and Zika were estimated to total $650 million USD in 2016, but traditional vector control strategies have not been effective in preventing mosquito-borne disease outbreaks. The Wolbachia method is a novel and self-sustaining approach for the biological control of Aedes -borne diseases, in which the transmission potential of Aedes aegypti mosquitoes is reduced by stably transfecting them with the Wolbachia bacterium ( w Mel strain). This paper describes a study protocol for evaluating the effect of large-scale non-randomised releases of Wolbachia- -infected mosquitoes on the incidence of dengue, Zika and chikungunya in the two cities of Niterói and Rio de Janeiro. This follows a lead-in period since 2014 involving intensive community engagement, regulatory and public approval, entomological surveys, and small-scale pilot releases. Method: The Wolbachia releases during 2017-2019 covered a combined area of 170 km 2 with a resident population of 1.2 million, across Niterói and Rio de Janeiro. Untreated areas with comparable historical dengue profiles and demographic characteristics have been identified a priori as comparative control areas in each city. The proposed pragmatic epidemiological approach combines a controlled interrupted time series analysis of routinely notified suspected and laboratory-confirmed dengue and chikungunya cases, together with monitoring of Aedes -borne disease activity utilising outbreak signals routinely used in public health disease surveillance. Discussion: If the current project is successful, this model for control of mosquito-borne disease through Wolbachia releases can be expanded nationally and regionally., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Durovni B et al.)

Background: Dengue, chikungunya and Zika are viral infections transmitted by Aedes aegypti mosquitoes, and present major public health challenges in tropical regions. Traditional vector control methods have been ineffective at halting disease transmission. The World Mosquito Program has developed a novel approach to arbovirus control using Ae. aegypti stably transfected with the Wolbachia bacterium, which have significantly reduced ability to transmit dengue, Zika and chikungunya in laboratory experiments. Field releases in eight countries have demonstrated Wolbachia establishment in local Ae. aegypti populations. Methods: We describe a pragmatic approach to measuring the epidemiological impact of city-wide Wolbachia deployments in Bello and Medellín, Colombia. First, an interrupted time-series analysis will compare the incidence of dengue, chikungunya and Zika case notifications before and after Wolbachia releases, across the two municipalities. Second, a prospective case-control study using a test-negative design will be conducted in one quadrant of Medellín. Three of the six contiguous release zones in the case-control area were allocated to receive the first Wolbachia deployments in the city and three to be treated last, approximating a parallel two-arm trial for the >12-month period during which Wolbachia exposure remains discordant. Allocation, although non-random, aimed to maximise balance between arms in historical dengue incidence and demographics. Arboviral disease cases and arbovirus-negative controls will be enrolled concurrently from febrile patients presenting to primary care, with case/control status classified retrospectively following laboratory diagnostic testing. Intervention effect is estimated from an aggregate odds ratio comparing Wolbachia -exposure odds among test-positive cases versus test-negative controls. Discussion: The study findings will add to an accumulating body of evidence from global field sites on the efficacy of the Wolbachia method in reducing arboviral disease incidence, and can inform decisions on wider public health implementation of this intervention in the Americas and beyond. Trial registration: ClinicalTrials.gov: NCT03631719. Registered on 15 August 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Velez ID et al.)

Aims: The impact of introducing new classes of glucose-lowering medication (GLM) on diabetes management remains unclear, especially outside North America and Western Europe. Therefore, we aimed to analyse trends in glycaemic control and the usage of new and old GLMs in people with type 2 diabetes from 2006 to 2015., Methods: Summary data from clinical services from nine countries outside North America and Western Europe were collected and pooled for statistical analysis. Each site summarized individual-level data from out-patient medical records for 2006 and 2015. Data included: demographics; HbA1c and fasting plasma glucose levels; and the proportions of patients taking GLM as monotherapy, combination therapy and/or insulin., Results: Between 2006 and 2015, glycaemic control remained stable, although body mass index and duration of diabetes increased in most sites. The proportion of people on GLM increased, and the therapeutic regimens became more complex. There were increases in the use of insulin and triple therapy in most sites, while monotherapy, particularly in relation to sulphonylureas, decreased. Despite the introduction of new GLMs, such as DPP-4 inhibitors, insulin use increased over time., Conclusions: There was no clear evidence that the use of new classes of GLMs was associated with improvements in glycaemic control or reduced the reliance on insulin. These findings were consistent across a range of economic and geographic settings.

Aim: Optimal treatment of cardiovascular disease is essential to decrease mortality among people with diabetes, but information is limited on how actual treatment relates to guidelines. We analysed changes in therapeutic approaches to anti-hypertensive and lipid-lowering medications in people with Type 2 diabetes from 2006 and 2015., Methods: Summary data from clinical services in seven countries outside North America and Western Europe were collected for 39 684 people. Each site summarized individual-level data from outpatient medical records for 2006 and 2015. Data included: demographic information, blood pressure (BP), total cholesterol levels and percentage of people taking statins, anti-hypertensive medication (angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor blockers, thiazide diuretics) and antiplatelet drugs., Results: From 2006 to 2015, mean cholesterol levels decreased in six of eight sites (range: -0.5 to -0.2), whereas the proportion with BP levels > 140/90 mmHg increased in seven of eight sites. Decreases in cholesterol paralleled increases in statin use (range: 3.1 to 47.0 percentage points). Overall, utilization of anti-hypertensive medication did not change. However, there was an increase in the use of angiotensin II receptor blockers and a decrease in angiotensin-converting enzyme inhibitors. The percentage of individuals receiving calcium channel blockers and aspirin remained unchanged., Conclusions: Our findings indicate that control of cholesterol levels improved and coincided with increased use of statins. The percentage of people with BP > 140/90 mmHg was higher in 2015 than in 2006. Hypertension treatment shifted from using angiotensin-converting enzyme inhibitors to angiotensin II receptor blockers. Despite the potentially greater tolerability of angiotensin II receptor blockers, there was no associated improvement in BP levels., (© 2018 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Modern epidemiological studies collect data on time-varying individual-specific characteristics, such as body mass index and blood pressure. Incorporation of such time-dependent covariates in time-to-event models is of great interest, but raises some challenges. Of specific concern are measurement error, and the non-synchronous updating of covariates across individuals, due for example to missing data. It is well known that in the presence of either of these issues the last observation carried forward (LOCF) approach traditionally used leads to bias. Joint models of longitudinal and time-to-event outcomes, developed recently, address these complexities by specifying a model for the joint distribution of all processes and are commonly fitted by maximum likelihood or Bayesian approaches. However, the adequate specification of the full joint distribution can be a challenging modeling task, especially with multiple longitudinal markers. In fact, most available software packages are unable to handle more than one marker and offer a restricted choice of survival models. We propose a two-stage approach, Multiple Imputation for Joint Modeling (MIJM), to incorporate multiple time-dependent continuous covariates in the semi-parametric Cox and additive hazard models. Assuming a primary focus on the time-to-event model, the MIJM approach handles the joint distribution of the markers using multiple imputation by chained equations, a computationally convenient procedure that is widely available in mainstream statistical software. We developed an R package "survtd" that allows MIJM and other approaches in this manuscript to be applied easily, with just one call to its main function. A simulation study showed that MIJM performs well across a wide range of scenarios in terms of bias and coverage probability, particularly compared with LOCF, simpler two-stage approaches, and a Bayesian joint model. The Framingham Heart Study is used to illustrate the approach.

Introduction: Little is known about the association of urine metabolites with structural lesions in persons with diabetes., Objectives: We examined the relationship between 12 urine metabolites and kidney structure in American Indians with type 2 diabetes., Methods: Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan, and included a kidney biopsy at the end of the treatment period. Metabolites were measured in urine samples collected within a median of 6.5 months before the research biopsy. Associations of the creatinine-adjusted urine metabolites with kidney structural variables were examined by Pearson's correlations and multivariable linear regression after adjustment for age, sex, diabetes duration, hemoglobin A 1c , mean arterial pressure, glomerular filtration rate (iothalamate), and losartan treatment., Results: Participants (n = 62, mean age 45 ± 10 years) had mean ± standard deviation glomerular filtration rate of 137 ± 50 ml/min and median (interquartile range) urine albumin:creatinine ratio of 34 (14-85) mg/g near the time of the biopsy. Urine aconitic and glycolic acids correlated positively with glomerular filtration surface density (partial r = 0.29, P = 0.030 and r = 0.50, P < 0.001) and total filtration surface per glomerulus (partial r = 0.32, P = 0.019 and r = 0.43, P = 0.001). 2-ethyl 3-OH propionate correlated positively with the percentage of fenestrated endothelium (partial r = 0.32, P = 0.019). Citric acid correlated negatively with mesangial fractional volume (partial r=-0.36, P = 0.007), and homovanillic acid correlated negatively with podocyte foot process width (partial r=-0.31, P = 0.022)., Conclusions: Alterations of urine metabolites may associate with early glomerular lesions in diabetic kidney disease.

Population monitoring of obesity is most commonly conducted using body mass index (BMI). We test the hypothesis that because of increases in waist circumference (WC) independent of increases in weight, BMI alone detects an increasingly smaller proportion of the population with obesity., Methods: Australian adults with measured height, weight, and WC were selected from three nationally representative cross-sectional surveys (1989, 1999-2000, 2011-12; n=8313, 5903 & 3904). Participants were defined as having obesity using classifications for an obese BMI (≥30kg·m -2 ) and substantially-increased-risk WC (≥88cm [women], ≥102cm [men]). Age-standardised prevalence of obesity according to BMI and/or WC, and the proportion of these detected by BMI and by WC were compared across surveys., Findings: Between 1989 and 2011-12, weight and WC increased by 5.4kg and 10.7cm (women), and by 7.0kg and 7.3cm (men). For women and men, 63% and 38% of increases in WC were independent of increases in weight. Over this period, the prevalence of obesity according to BMI and/or WC increased by 25.3 percentage-points for women (18.9% to 44.3%) and 21.1 percentage-points for men (17.1% to 38.2%). The proportion of these detected by BMI decreased for women by 20 percentage-points (77% to 57%) with no change for men. The proportion of these detected by WC increased for women and men by 10 percentage-points (87% to 97%) and 6 percentage-points (85% to 91%) respectively., Conclusion: BMI alone is detecting a decreasing proportion of those considered obese by BMI and/or WC. Renewed discussion regarding how we monitor obesity at the population level is required., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Inflammation linked to diabetic kidney disease (DKD) may affect white blood cell (WBC) counts and differentials. We examined the cross-sectional associations of total WBC count and WBC fractions with structural lesions of DKD in 108 Pima Indians with Type 2 diabetes who underwent research kidney biopsies. We also examined the longitudinal association of these WBC variables with renal function loss (RFL) in 941 Europeans with Type 2 diabetes from the SURDIAGENE study., Methods: Associations of WBC variables with morphometric parameters were assessed by linear regression. RFL was defined as≥40% loss of estimated glomerular filtration rate from baseline. Associations with RFL were evaluated by Cox regression. Hazard ratios (HRs) were reported per standard deviation increment of each WBC variable., Results: After multivariable adjustment, lymphocyte (r  = -0.20, P = 0.043) and eosinophil (r = 0.21, P = 0.032) fractions in the Pima Indians correlated with glomerular basement membrane width. Eosinophil fraction also correlated with glomerular filtration surface density (r  = -0.21, P = 0.031). Lymphocyte fraction (r = 0.25, P = 0.013), neutrophil fraction (r  = -0.23, P = 0.021) and the neutrophil:lymphocyte ratio (r  = -0.22, P = 0.024) correlated with percentage of normally fenestrated endothelial cells. During median follow-up of 4.5 years, 321 SURDIAGENE participants developed RFL. Lower lymphocyte fraction [HR = 0.67, 95% confidence interval (95% CI) 0.60-0.76] and higher neutrophil fraction (HR = 1.35, 95% CI 1.20-1.52), total WBC count (HR = 1.20, 95% CI 1.08-1.35) and neutrophil:lymphocyte ratio (HR = 1.44, 95% CI 1.28-1.62) each predicted RFL in this cohort., Conclusions: WBC fractions associate with morphometric lesions of DKD and predict RFL in individuals with Type 2 diabetes.

Objectives: The risk of early-onset type 2 diabetes associated with the severity of obesity in youth is not well understood. This study aims to determine metabolic alterations and type 2 diabetes risk among American Indian children who are obese or severely obese., Methods: Incidence rates of diabetes before 20 years (youth-onset) and 45 years were computed in 2728 children who were from 5 to <10 years and 4317 adolescents who were from 10 to <18 years without diabetes examined between 1965 and 2007. Obesity was defined as age-sex-adjusted body mass index (BMI) ≥95th percentile, and its severity was quantified as the percentage of the 95th percentile (%BMI p95 )., Results: In the younger cohort, 0.9% of those non-obese and 2.9% of those with 100% to <120%BMI p95 had impaired glucose tolerance (IGT) compared to 8.6% of those with ≥140%BMI p95 . In the older cohort, 2.9% of those non-obese and 9.8% of those with 100% to <120%BMI p95 had IGT compared to 13.3% of those with ≥160%BMI p95 . The incidence of youth-onset diabetes was 3.8 and 4.9/1000 person-years in the child and adolescent cohorts, respectively, and before the age of 45 was 12.3 and 16.8/1000 person-years, respectively. Incidence rates of youth-onset diabetes in those with the most severe obesity (≥140%BMI p95 ) were 2.3 to 5.1 times as high as in those with the least severe obesity (100 to <120%BMI p95 ), and for onset of diabetes before the age of 45 were 1.6 to 2.2 times as high., Conclusions: Severe obesity in an American Indian population is a major driver of type 2 diabetes developing in adolescents and young adults., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Background: In Caucasians, lower triglycerides (TG), total or LDL cholesterol and high HDL cholesterol are generally associated with lower mortality. However, low cholesterol is associated with higher mortality in some Asian populations. This study examines the relationship between serum lipids and mortality in American Indians., Methods: 2125 American Indians aged ≥40years were examined biennially between 1993 and 2007. Vital status was determined through 2011. Mortality rates, adjusted for age, sex and diabetes, were calculated using Poisson regression., Results: The median baseline age was 46years and 61% were women. Over a median follow-up of 10.1years, 522 deaths occurred. Relationships between baseline lipids, except for HDL cholesterol, and all-cause mortality were negative and linear in persons without diabetes and U-shaped in persons with diabetes. For HDL cholesterol, the relationship was U-shaped in the total cohort. Cardiovascular mortality was positively associated with total, LDL and non-HDL cholesterol whereas lower lipid concentrations were adversely associated with mortality from liver disease or external causes, except for HDL cholesterol, where associations were positive., Conclusion: The common belief that low cholesterol and TG are beneficial for health is not universally observed; evidence suggests increased mortality at both ends of the cholesterol and TG distributions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To illustrate the difficulties in optimal growth monitoring of children with severe obesity or underweight by using the Centers for Disease Control and Prevention (CDC) 2000 age- and sex-specific BMI percentile growth charts. We also aimed to examine the utility of a new modified CDC BMI z score chart to monitor growth in children with normal and extreme BMI percentiles by using real-life clinical scenarios., Methods: Modified BMI z score charts were created by using the 2000 CDC algorithm. Three cases of children with extreme BMI values and abnormal growth patterns were plotted by using the standard CDC 2000 clinical growth chart, the modified BMI z score chart, and the CDC BMI percentile chart, modified to include the percentage of the 95th percentile (%BMI p95 ) curves., Results: Children with severe obesity could not be plotted on the standard CDC BMI percentile chart because their BMI points lay above the chart cutoff. Children with a low BMI (<3%) were also difficult to track on the standard BMI percentile chart. The addition of the %BMI p95 scale to the standard BMI percentile chart allowed tracking of severely obese children; however, it did not address severely underweight children and required a change of units within the chart when transitioning from normal to obese BMIs. The modified BMI z score chart allowed uniform tracking., Conclusions: The modified CDC z score chart is suitable for growth tracking of children with normal and extreme growth patterns; the measures correlate well with the %BMI p95, and the chart can be incorporated easily into existing electronic health record systems for clinical use., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Background: Underlying blood pressure is that observed in the absence of antihypertensive treatment or, among those treated, the estimate of that which would be observed without treatment. This study aims to examine the relationships between diabetes or obesity and underlying systolic blood pressure adjusted for antihypertensive treatment by several methods., Methods: Data from two population studies were analyzed-an American Indian community in Arizona and the National Health and Nutrition Examination Surveys. Antihypertensive treatment was accounted for using: no adjustment; antihypertensive use as a covariate; blood pressure dichotomized into normotension and hypertension; addition of a fixed treatment effect; non-parametric algorithm; and censored normal regression., Results: The magnitude of association at each time point differed by adjustment method particularly where there was a difference in prevalence of antihypertensive use between people with and without diabetes or obesity. The common methods of ignoring antihypertensive treatment or including it as a covariate in a regression model underestimated the effects of diabetes and obesity on underlying blood pressure, compared to the recommended method of the censored normal regression., Conclusion: Proper accounting for antihypertensive treatment is needed in interpreting variables that affect blood pressure., (Published by Elsevier Inc.)

Aims: Uncertainties about the role of cystatin C-based estimated glomerular filtration rate (eGFR) in the prediction of cardiovascular disease (CVD) beyond traditional CVD risk factors remain. We assessed contributions of eGFR to CVD and mortality in the general population., Methods: Using 14 year follow-up data on 9353 adults without a reported history of CVD from the Australian Diabetes, Obesity and Lifestyle study, we assessed the contributions of eGFR (assessed by cystatin C (eGFR cysC ) and serum creatinine (eGFR cr ) and albuminuria (uACR) to total and CVD mortality., Results: After adjusting for age, sex, CVD risk factors and uACR, compared with an eGFR cysC >90 mL/min per 1.73 m 2 , eGFR cysC <60 mL/min per 1.73 m 2 was associated with 56% and 73% increases in the risks for all-cause and CVD mortality, respectively. The respective changes for the c-statistic when eGFR cysC was added to a risk prediction model were 0.003 (95% confidence interval: 0.001 to 0.005) and 0.002 (95% confidence interval: -0.001 to 0.006). The net proportion of non-events assigned a lower-risk category significantly improved with the addition of eGFR (non-event net reclassification index eGFR cr : 1.0% and eGFR cysC : 1.5%) for all-cause mortality, but for CVD mortality, improvements were only significant when eGFR was combined with uACR. The net proportion of events assigned a higher-risk category was not significantly improved., Conclusion: In our community-based cohort, reduced eGFR cysC was associated with all-cause and CVD mortality. The addition of chronic kidney disease measures to risk prediction models improved overall risk stratification among those at low risk as opposed to those at high baseline risk of mortality., (© 2016 Asian Pacific Society of Nephrology.)

Background: Serum amyloid A (SAA) induces inflammation and apoptosis in kidney cells and is found to be causing the pathologic changes that are associated with diabetic kidney disease (DKD). Higher serum SAA concentrations were previously associated with increased risk of end-stage renal disease (ESRD) and death in persons with type 2 diabetes and advanced DKD. We explored the prognostic value of SAA in American Indians with type 2 diabetes without DKD or with early DKD., Methods: SAA concentration was measured in serum samples obtained at the start of follow-up. Multivariate proportional hazards models were employed to examine the magnitude of the risk of ESRD or death across tertiles of SAA concentration after adjustment for traditional risk factors. The C statistic was used to assess the additional predictive value of SAA relative to traditional risk factors., Results: Of 256 participants (mean ± SD glomerular filtration rate [iothalamate] = 148 ± 45 mL/min, and median [interquartile range] urine albumin/creatinine = 39 [14-221] mg/g), 76 developed ESRD and 125 died during a median follow-up period of 15.2 and 15.7 years, respectively. After multivariable proportional hazards regression, participants in the 2 highest SAA tertiles together exhibited a 53% lower risk of ESRD (hazard ratio [HR] 0.47, 95% CI 0.29-0.78), and a 30% lower risk of death (HR 0.70, 95% CI 0.48-1.02), compared with participants in the lowest SAA tertile, although the lower risk of death was not statistically significant. Addition of SAA to the ESRD model increased the C statistic from 0.814 to 0.815 (p = 0.005)., Conclusions: Higher circulating SAA concentration is associated with a reduced risk of ESRD in American Indians with type 2 diabetes., (© 2017 S. Karger AG, Basel.)

We examined associations of advanced glycation end products (AGEs) with renal function loss (RFL) and its structural determinants in American Indians with type 2 diabetes. Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan. Participants remained under observation after the trial concluded. Glomerular filtration rate (GFR) was measured annually. Kidney biopsies were performed at the end of the trial. Five AGEs were measured in serum collected at enrollment and at kidney biopsy. RFL was defined as ≥40% decline of measured GFR from baseline. Of 168 participants (mean baseline age 41 years, HbA 1c 9.2%, GFR 164 mL/min, and albumin-to-creatinine ratio 31 mg/g), 104 reached the RFL end point during median follow-up of 8.0 years. After multivariable adjustment, each doubling of carboxyethyl lysine (hazard ratio [HR] 1.60 [95% CI 1.08-2.37]) or methylglyoxal hydroimidazolone (HR 1.30 [95% CI 1.02-1.65]) concentration was associated with RFL. Carboxyethyl lysine, carboxymethyl lysine, and methylglyoxal hydroimidazolone correlated positively with cortical interstitial fractional volume (partial r = 0.23, P = 0.03; partial r = 0.25, P = 0.02; and partial r = 0.31, P = 0.003, respectively). Glyoxyl hydroimidazolone and methylglyoxal hydroimidazolone correlated negatively with total filtration surface per glomerulus (partial r = -0.26, P = 0.01; and partial r = -0.21, P = 0.046, respectively). AGEs improve prediction of RFL and its major structural correlates., (© 2016 by the American Diabetes Association.)

Objective: To compare a simple measure - age of onset of obesity - to an obese-years construct (a product of duration and magnitude of obesity) as risk factors for type 2 diabetes., Method: Participants from the Framingham Heart Study who were not obese and did not have diabetes at baseline were included (n=4,320). The Akaike Information Criterion (AIC) was computed to compare four Cox proportional hazards models with incident diabetes as the outcome and: (i) obese-years; (ii) age of onset of obesity; (iii) body mass index (BMI); and (iv) age of onset of obesity plus magnitude of BMI combined, as exposures., Results: AIC indicated that the model with obese-years provided a more effective explanation of incidence of type 2 diabetes compared to the remaining three models. Models including age of onset of obesity plus BMI were not appreciably different from the model with BMI alone, except in those aged ≥60., Conclusions: While obese-years was the optimal obesity construct to explain risk of type 2 diabetes, age of onset may be a useful, practical addition to current BMI in the elderly., Implications: Where computation of obese-years is not possible or impractical, age of onset of obesity combined with BMI may provide a useful alternative., (© 2016 Public Health Association of Australia.)

Objective: To determine whether early administration of losartan slows progression of diabetic kidney disease over an extended period., Research Design and Methods: We conducted a 6-year clinical trial in 169 American Indians with type 2 diabetes and urine albumin/creatinine ratio <300 mg/g; 84 participants were randomly assigned to receive losartan and 85 to placebo. Primary outcome was a decline in glomerular filtration rate (GFR; iothalamate) to ≤60 mL/min or to half the baseline value in persons who entered with GFR <120 mL/min. At enrollment, GFR averaged 165 mL/min (interquartile range 49-313 mL/min). During the trial, nine persons reached the primary outcome with a hazard ratio (HR; losartan vs. placebo) of 0.50 (95% CI 0.12-1.99). Participants were then followed posttrial for up to 12 years, with treatment managed outside the study. The effect of losartan on the primary GFR outcome was then reanalyzed for the entire study period, including the clinical trial and posttrial follow-up., Results: After completion of the clinical trial, treatment with renin-angiotensin system inhibitors was equivalent in both groups. During a median of 13.5 years following randomization, 29 participants originally assigned to losartan and 35 to placebo reached the primary GFR outcome with an HR of 0.72 (95% CI 0.44-1.18)., Conclusions: Long-term risk of GFR decline was not significantly different between persons randomized to early treatment with losartan and those randomized to placebo. Accordingly, we found no evidence of an extended benefit of early losartan treatment on slowing GFR decline in persons with type 2 diabetes., (© 2016 by the American Diabetes Association.)

With the obesity epidemic, and the effects of aging populations, human phenotypes have changed over two generations, possibly more dramatically than in other species previously. As obesity is an important and growing hazard for population health, we recommend a systematic evaluation of the optimal measure(s) for population-level excess body fat. Ideal measure(s) for monitoring body composition and obesity should be simple, as accurate and sensitive as possible, and provide good categorization of related health risks. Combinations of anthropometric markers or predictive equations may facilitate better use of anthropometric data than single measures to estimate body composition for populations. Here, we provide new evidence that increasing proportions of aging populations are at high health-risk according to waist circumference, but not body mass index (BMI), so continued use of BMI as the principal population-level measure substantially underestimates the health-burden from excess adiposity., (© The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To determine the risk of mortality associated with and quantify the deaths attributable to combinations of body mass index (BMI) and waist circumference (WC)., Methods: This study included 41,439 participants. For the hazard ratio (HR) calculation, adiposity categories were defined as: BMI(N) /WC(N) , BMI(N) /WC(O) , BMI(O) /WC(N) , and BMI(O) /WC(O) (N = non-obese, O = obese). For the population attributable fraction analysis, obesity was classified as: (i) obese by BMI and/or WC; (ii) obese by BMI; and (iii) obese by WC. Mortality data was complete to the end of 2012., Results: The prevalence of BMI(N) /WC(N) , BMI(N) /WC(O) , BMI(O) /WC(N) , and BMI(O) /WC(O) was 73%, 6%, 6%, and 15%, respectively. There was an increased risk of all-cause and cardiovascular disease (CVD) mortality in those with BMI(N) /WC(O) (HR (95% CI) 1.2 (1.2, 1.3) and 1.3 (1.1, 1.6)) and BMI(O) /WC(O) (1.3 (1.3, 1.4) and 1.7 (1.5, 1.9)) compared to those with BMI(N) /WC(N) . The estimated proportion of all-cause and CVD mortality attributable to obesity defined using WC or using BMI and/or WC was higher compared to obesity defined using BMI., Conclusions: Current population obesity monitoring misses those with BMI(N) /WC(O) who are at increased risk of mortality. By targeting reductions in population WC, the potential exists to prevent more deaths in the population than if we continue to target reductions in BMI alone., (© 2016 The Obesity Society.)

Objective: To examine associations of time spent sitting in cars with markers of cardio-metabolic risk in Australian adults., Method: Data were from 2800 participants (age range: 34-65) in the 2011-12 Australian Diabetes, Obesity and Lifestyle Study. Self-reported time spent in cars was categorized into four groups: ≤15min/day; >15 to ≤30min/day; >30 to ≤60min/day; and >60min/day. Markers of cardio-metabolic risk were body mass index (BMI), waist circumference, systolic and diastolic blood pressure, triglycerides, HDL (high-density lipoprotein)-cholesterol, fasting plasma glucose, 2-h plasma glucose, a clustered cardio-metabolic risk score, and having the metabolic syndrome or not. Multilevel linear and logistic regression analyses examined associations of car time with each cardio-metabolic risk outcome, adjusting for socio-demographic and behavioral variables and medication use for blood pressure and cholesterol/triglycerides., Results: Compared to spending 15min/day or less in cars, spending more than 1h/day in cars was significantly associated with higher BMI, waist circumference, fasting plasma glucose, and clustered cardio-metabolic risk, after adjusting for socio-demographic attributes and potentially relevant behaviors including leisure-time physical activity and dietary intake. Gender interactions showed car time to be associated with higher BMI in men only., Conclusions: Prolonged time spent sitting in cars, in particular over 1h/day, was associated with higher total and central adiposity and a more-adverse cardio-metabolic risk profile. Further studies, ideally using objective measures of sitting time in cars and prospective designs, are needed to confirm the impact of car use on cardio-metabolic disease risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Recent evidence suggests that a substantial subgroup of the population who have a high-risk waist circumference (WC) do not have an obese body mass index (BMI). This study aimed to explore whether including those with a non-obese BMI but high risk WC as 'obese' improves prediction of adiposity-related metabolic outcomes., Methods: Eleven thousand, two hundred forty-seven participants were recruited. Height, weight and WC were measured. Ten thousand, six hundred fifty-nine participants with complete data were included. Adiposity categories were defined as: BMI(N)/WC(N), BMI(N)/WC(O), BMI(O)/WC(N), and BMI(O)/WC(O) (N = non-obese and O = obese). Population attributable fraction, area under the receiver operating characteristic curve (AUC), and odds ratios (OR) were calculated., Results: Participants were on average 48 years old and 50 % were men. The proportions of BMI(N)/WC(N), BMI(N)/WC(O), BMI(O)/WC(N) and BMI(O)/WC(O) were 68, 12, 2 and 18 %, respectively. A lower proportion of diabetes was attributable to obesity defined using BMI alone compared to BMI and WC combined (32 % vs 47 %). AUC for diabetes was also lower when obesity was defined using BMI alone (0.62 vs 0.66). Similar results were observed for all outcomes. The odds for hypertension, dyslipidaemia, diabetes and CVD were increased for those with BMI(N)/WC(O) (OR range 1.8-2.7) and BMI(O)/WC(O) (OR 1.9-4.9) compared to those with BMI(N)/WC(N)., Conclusions: Current population monitoring, assessing obesity by BMI only, misses a proportion of the population who are at increased health risk through excess adiposity. Improved identification of those at increased health risk needs to be considered for better prioritisation of policy and resources.

Introduction: There is a paucity of data examining the effects of weight change on knee joint structures and symptoms. This study examined the effect of weight change on change in knee cartilage volume and symptoms in an obese cohort., Methods: 112 obese subjects (Body Mass Index ≥30 kg/m(2)) were recruited from various community sources to examine the effect of obesity on musculoskeletal health. Tibial cartilage volume, determined by MRI, and knee symptoms, determined by the Western Ontario and McMaster Osteoarthritis Index (WOMAC) were collected at baseline and an average of 2.3 years later., Results: Percentage weight change was associated with change in medial tibial cartilage volume (β -1.2 mm(3), 95% CI -2.3 to -0.1 mm(3), p=0.03) that was consistent throughout the spectrum of weight loss through to mild weight gain. Percentage weight change was not associated with change in the lateral tibial (p=0.93) or patella (p=0.32) cartilage volumes. Percentage weight change was associated with change in all WOMAC subscales (all p≤0.01): pain (β -1.8 mm, 95% CI -3.2 to -0.4 mm), stiffness (β -1.6 mm, 95% CI -2.5 to -0.7 mm) and function (β -6.9 mm, 95% CI -11.6 to -2.1 mm)., Conclusions: The linearity of effect implies that weight loss is associated with reduced medial cartilage volume loss and improved knee symptoms, while weight gain is associated with increased medial cartilage volume loss and worse knee symptoms. These results suggest that in obese people, small amounts of weight change may have the potential for a disease modifying effect on both knee joint structure and symptoms. While weight loss is an important primary management strategy in obese individuals, avoidance of further weight gain should also be a clinical goal., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: Environmental initiatives to support walking are keys to noncommunicable disease prevention, but the relevant evidence comes mainly from cross-sectional studies. We examined neighborhood environmental attributes associated cross-sectionally with walking and those associated prospectively with walking maintenance., Methods: Data were from the Australian Diabetes, Obesity and Lifestyle study collected in 2004-2005 (baseline) and in 2011-2012 (follow-up). Participants who did not move residence during the study period (n = 2684, age range: 30-77 yr at baseline) were categorized as regular walkers (walked five times per week or more) or not at baseline. Regular walkers were divided into those who stopped and those who maintained regular walking at follow-up. Regression analyses examined relationships of regular walking and walking maintenance with perceived attributes of neighborhood destinations and pedestrian environments., Results: Regular walking at baseline was significantly associated with availability of shops (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.04-1.22), many alternative routes (OR = 1.12, 95% CI = 1.01-1.23), park or nature reserve (OR = 1.13, 95% CI = 1.02-1.26), bicycle or walking tracks (OR = 1.08, 95% CI = 1.00-1.17), and feeling safe to walk (OR = 1.18, 95% CI = 1.01-1.38). Maintenance of regular walking was associated with the availability of multiple alternative routes (OR = 1.19, 95% CI = 1.03-1.38). Having many alternative routes and walking tracks was associated with walking maintenance among those who were not or had stopped working., Conclusions: Neighborhood destinations (shops and parks) and pedestrian environments (alternative routes, walking trails, and safety from crime) were found to be associated with regular walking, but only pedestrian environment attributes were found to be related to the maintenance of regular walking. Further evidence from prospective studies is required to identify other neighborhood environmental attributes that might support walking maintenance.

Background: Previous studies exploring the association between obesity and hypertension generally used a single baseline measurement of obesity. The effect of accumulating excess adiposity over time on the risk of hypertension is uncertain. This study aimed to examine the relationship between duration of obesity and incident hypertension using the Framingham Heart Study., Methods: Two thousand, nine hundred and fifty-three participants aged 30-62 years without baseline hypertension were included. Blood pressure, height and weight were measured biennially. Duration of obesity was calculated. Time to incident hypertension was analysed using time-varying Cox proportional hazards regression with age as the time scale and censoring at time of death or end of follow-up., Results: Eighty percent of participants developed hypertension (median follow-up 15.9 years). A positive association between obesity duration and incident hypertension was observed in women. There was no longer an association when time-varying BMI was adjusted for (hazard ratio 0.95; (95% confidence interval 0.85-1.05))., Conclusion: These findings suggest that the mechanism by which excess adiposity may increase blood pressure is primarily immediate and that long-term exposure to obesity does not further increase the risk of developing hypertension beyond the level of BMI attained.

Objective: To relate measured obesity duration in mid-life with subsequent incidence of physical disability over and above body mass index (BMI) attained., Methods: Framingham Offspring Study is a longitudinal study that began in 1971. Examination 5 (1991-1995; "baseline") and disability onset ascertained from examinations 6-8 (2008) were used. About 2,095 disability-free participants aged 45-65 years at baseline were included. Obesity (BMI ≥ 30 kg/m(2) ) duration was calculated between examination 1 and examination 5. Cox regression was used to analyze time to disability., Results: 204 participants developed disability (incidence rate=7.9 per 1,000 person-years). Obesity duration ranged from 0 to 22 years (mean of 2.0 years overall, 8.3 years for those with baseline obesity). Obesity duration increased risk of new disability (hazard ratio [HR] 1.07 per year of obesity; 95% confidence interval [CI] 1.05-1.09). This association was attenuated on further adjustment for baseline BMI (HR 1.03; 95% CI 1.00-1.06)., Conclusions: Being obese for longer during mid-life increases the risk of later-life disability over and above attained BMI. These results support the need for prevention of weight gain in young adults to avoid an increasing burden of physical disability in later life., (© 2014 The Obesity Society.)

It is believed that diabetes risk scores need to be ethnic specific. However, this prerequisite has not been tested. We examined the performance of several risk models, developed in various populations, in a Europid and a South Asian population. The performance of 14 published risk prediction models were tested in two prospective studies: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study and the Mauritius non-communicable diseases survey. Eight models were developed in Europid populations; the remainder in various non-Europid populations. Model performance was assessed using area under the receiver operating characteristic curves (discrimination), Hosmer-Lemeshow tests (goodness-of-fit) and Brier scores (accuracy). In both AusDiab and Mauritius, discrimination was highest for a model developed in a mixed population (non-Hispanic white and African American) and lowest for a model developed in a Europid population. Discrimination for all scores was higher in AusDiab than in Mauritius. For almost all models, goodness-of-fit was poor irrespective of the ethnicity of the development cohort, and accuracy was higher in AusDiab compared to Mauritius. Our results suggest that similarity of ethnicity or similarity of diabetes risk may not be the best way of identifying models that will perform well in another population. Differences in study methodology likely account for much of the difference in the performance. Thus, identifying models which use measurements that are clearly described and easily reproducible for both research and clinical settings may be more important.

Objective: To examine the association between obese-years and the risk of cardiovascular disease (CVD)., Study Design: Prospective cohort study., Setting: Boston, USA., Participants: 5036 participants of the Framingham Heart Study were examined., Methods: Obese-years was calculated by multiplying for each participant the number of body mass index (BMI) units above 29 kg/m(2) by the number of years lived at that BMI during approximately 50 years of follow-up. The association between obese-years and CVD was analysed using time-dependent Cox regression adjusted for potential confounders and compared with other models using the Akaike information criterion (AIC). The lowest AIC indicated better fit., Primary Outcome Cvd Results: The median cumulative obese-years was 24 (range 2-556 obese-years). During 138,918 person-years of follow-up, 2753 (55%) participants were diagnosed with CVD. The incidence rates and adjusted HR (AHR) for CVD increased with an increase in the number of obese-years. AHR for the categories 1-24.9, 25-49.9, 50-74.9 and ≥75 obese-years were, respectively, 1.31 (95% CI 1.15 to 1.48), 1.37 (95% CI 1.14 to 1.65), 1.62 (95% CI 1.32 to 1.99) and 1.80 (95% CI 1.54 to 2.10) compared with those who were never obese (ie, had zero obese-years). The effect of obese-years was stronger in males than females. For every 10 unit increase in obese-years, the AHR of CVD increased by 6% (95% CI 4% to 8%) for males and 3% (95% CI 2% to 4%) for females. The AIC was lowest for the model containing obese-years compared with models containing either the level of BMI or the duration of obesity alone., Conclusions: This study demonstrates that obese-years metric conceptually captures the cumulative damage of obesity on body systems, and is found to provide slightly more precise estimation of the risk of CVD than the level or duration of obesity alone., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: This study aimed to describe the changes in weight and waist circumference (WC), examine the incidence of obesity as defined by body mass index (BMI) and WC, and describe the changes in the prevalence of obesity over 12 years., Methods: In 1999/2000, 11,247 adults aged ≥25 years were recruited from 42 randomly selected areas across Australia. In total, 44.6% of eligible participants completed follow-up in 2011/12. Height, weight, and WC were measured at both surveys., Results: People who were 25-34 years of age at baseline gained an average of 6.7 kg weight and 6.6 cm WC, whereas those aged ≥75 years lost an average of 4.5 kg and gained an average of 0.8 cm. Women had a greater increase in WC than men, but did not differ in terms of weight gain. The 12-year incidence of obesity was 15.0% when defined by BMI and 31.8% when defined by WC. According to BMI and WC combined, the percentage of the cohort that was normal weight decreased from 33 to 21% and the percentage that was obese increased from 32 to 49% between baseline and 2012., Conclusions: In addition to BMI, assessment of WC should be incorporated more frequently when assessing population trends of obesity and the burden of disease associated with excess adiposity., (Copyright © 2014 The Obesity Society.)

Aims: A very limited number of prospective studies have reported conflicting data on the relation between heart rate and diabetes risk. Our aim therefore was to determine in a large, national, population-based cohort if heart rate predicts the development of diabetes., Methods: The Australian Diabetes Obesity and Lifestyle study followed up 6537 people over 5 years. Baseline measurements included questionnaires, anthropometrics and blood and urine collection. Heart rate was recorded in beats per min (Dinamap). An oral glucose tolerance test was performed at baseline and follow-up, and diabetes was defined using World Health Organization criteria., Results: A total of 5817 participants were eligible for analysis, 221 of whom developed diabetes. Compared with participants with a heart rate < 60 b min(-1), those with a heart rate ≥ 80 b min(-1) were more likely to develop diabetes (odds ratio 1.89, 95% CI 1.07-3.35) over 5 years, independent of traditional risk factors. This relationship was highly significant, particularly in non-obese men (odds ratio 5.61, 95% CI 1.75-17.98), but not in their obese counterparts or in women., Conclusions: Resting heart rate is associated with an increased risk of diabetes over a 5-year period, particularly among non-obese men. This suggests that sympathetic overactivity may be a contributing factor to the development of diabetes, and that resting heart rate may be useful in predicting risk of Type 2 diabetes in non-obese men., (© 2012 Baker IDI Heart and Diabetes Institute. Diabetic Medicine © 2012 Diabetes UK.)

Objective: To examine the longitudinal association between significant weight change and change in knee symptoms (pain, stiffness, and function), and to determine whether the effects differ in those who are obese and those with osteoarthritis (OA)., Methods: Two hundred fifty subjects ranging from normal weight to obese (body mass index range 16.9-59.1 kg/m(2) ) and no significant musculoskeletal disease were recruited from the general community and weight loss clinics and organizations. Seventy-eight percent were followed at ~2 years. Weight, height, and knee symptoms (using the Western Ontario and McMaster Universities Osteoarthritis Index) were assessed at baseline and followup. Any weight loss methods were recorded., Results: Thirty percent of subjects lost ≥5% of baseline weight, 56% of subjects' weight remained stable (loss or gain of <5% of baseline weight), and 14% of subjects gained ≥5% of baseline weight. Using estimated marginal means, weight gain was associated with worsening pain (mean 27.1 mm; 95% confidence interval [95% CI] -1.1, 55.2), stiffness (mean 18.4 mm; 95% CI 1.5, 35.3), and function (mean 99.3 mm; 95% CI 4.0, 194.6) compared to stable weight. Weight loss was associated with reduced pain (mean -22.4 mm; 95% CI -44.4, -0.3), stiffness (mean -15.3 mm; 95% CI -28.50, -2.0), and function (mean -73.2 mm; 95% CI -147.9, 1.3) compared to stable weight., Conclusion: Weight gain was associated with adverse effects on knee symptoms, particularly in those who are obese and who have OA. Although losing weight is potentially beneficial for symptom improvement, the effects were more modest. Avoiding weight gain is important in managing knee symptoms., (Copyright © 2013 by the American College of Rheumatology.)

Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure (BP) in patients with resistant hypertension. The effect of renal denervation on health-related quality of life (QoL) has not been evaluated. Using the Medical Outcomes Study 36-Item Short-Form Health Survey and Beck Depression Inventory-II, we examined QoL before and 3 months after renal denervation in patients with uncontrolled BP. For baseline comparisons, matched data were extracted from the Australian Diabetes, Obesity, and Lifestyle database. Before renal denervation, patients with resistant hypertension (n = 62) scored significantly worse in 5 of the eight 36-Item Short-Form Health Survey domains and the Mental Component Summary score. Three months after denervation (n = 40), clinic BP was reduced (change in systolic and diastolic BP, -16 ± 4 and -6 ± 2 mm Hg, respectively; P<0.01). The Mental Component Summary score improved (47.6 ± 1.1 versus 52 ± 1; P = 0.001) as a result of increases in the vitality, social function, role emotion, and mental health domains. Beck Depression Inventory scores were also improved, particularly with regard to symptoms of sadness (P = 0.01), tiredness (P<0.001), and libido (P<0.01). The magnitude of BP reduction or BP level achieved at 3 months bore no association to the change in QoL. Renal denervation was without a detrimental effect on any elements of the 36-Item Short-Form Health Survey. These results indicate that patients with severe hypertension resistant to therapy present with a marked reduction in subjective QoL. In this pre- and post-hypothesis generating study, several aspects of QoL were improved after renal denervation; however, this was not directly associated with the magnitude of BP reduction.