Results of a reevaluation of cardiovascular outcomes in the RECORD trial

Background The US Food and Drug Administration (FDA) required a reevaluation of cardiovascular (CV) outcomes in the RECORD trial. This provided an opportunity to assess the implications of event adjudication by 2 groups and quantify the differences as well as to use new FDA end point definitions in development.<p></p> Methods Original data were used to systematically identify all potential deaths, myocardial infarctions (MIs), and strokes. Site investigators were approached for additional source documents and information about participants lost to follow-up. Suspected events were adjudicated using standard procedures, and the results were compared with the original trial outcomes.<p></p> Results Follow-up for mortality was 25,833 person-years, including an additional 328 person-years identified during the reevaluation effort. A total of 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 participants with an MI (68 rosiglitazone, 60 metformin/sulfonylurea), and 113 participants with a stroke (50 rosiglitazone, 63 metformin/sulfonylurea) were included. The hazard ratio (HR) for rosiglitazone versus metformin/sulfonylurea for the end point of CV (or unknown cause) death, MI, or stroke was 0.95 (95% CI 0.78-1.17) compared with 0.93 (95% CI 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR 1.13, 95% CI 0.80-1.59) and mortality (HR 0.86, 95% CI 0.68-1.08) were also the same compared with the original RECORD results. Sensitivity analyses were also consistent with the original RECORD results. Analyses using the FDA definitions showed similar results.<p></p> Conclusions Only a modest number of additional person-years of follow-up were ascertained from this reevaluation of CV end points in RECORD. Observed HRs and CIs from these analyses using the original RECORD or new FDA end point definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results.<p></p&gt

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

Acknowledgments: We thank Dr. Robert Barkley and Charis Uhlson for mass spectrometry analysis. Funding: This work was supported by grants from the National Institutes of Health HL34303 (to C.C.L., R.C.M. and D.L.B), DK54741 (to J.V.B.), GM5322 (to D.L.W.) and the Wellcome Trust (to N.A.R.G. and G.D.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Current Understanding of the Impact of Childhood Obesity on the Foot and Lower Limb

Childhood obesity has emerged in recent years as a major public health problem. As this continues to concern across local, national and international populations, and as our understanding of obesity advances, access to multi-disciplinary care and understanding of the complications is warranted. Recent findings have suggested that the musculoskeletal system is one of the multiple body systems compromised by obesity and that aberrant biomechanical function may be a precursor to the onset of musculoskeletal symptoms. This review will consider childhood obesity and its impact on the paediatric foot and lower limb through examination of literature on foot structure and biomechanics of gait. An overview of evidence-based management is out with the context of this review, however some recommendations for clinical practice will be proposed

Long-Term Outcomes in Children with Acute Flaccid Myelitis

The purpose of our critically appraised topic is to combine the best evidence regarding the long-term outcomes in children with acute flaccid myelitis (AFM) regarding posture and movement, gross and fine motor control, and activities of daily living (ADL) performance. The final portfolio contains eight articles. The study designs of these articles include a retrospective cohort study, two retrospective non-randomized studies without a control group, a retrospective review, a nationwide follow-up questionnaire analysis study, a case report, a case series, and a multiple quantitative case study. All studies related directly to our evidence-based PICO question and were used to determine the best evidence of the long-term outcomes in children with AFM. Overall, our findings showed that functional improvements were seen in most individuals, however, this varied from complete to incomplete recovery along with some persistent motor and functional deficits. Every case is different depending on when they were diagnosed, and how quickly they were able to implement a rehabilitation program into their everyday routine

Temporal variability of nitrogen fixation and particulate nitrogen export at Station ALOHA

We present nearly 9 yrs (June 2005–December 2013) of measurements of upper‐ocean (0 m to 125 m) dinitrogen (N2) fixation rates, coupled with particulate nitrogen (PN) export at 150 m, from Station ALOHA (22° 45′N, 158°W) in the North Pacific Subtropical Gyre. Between June 2005 and June 2012, N2 fixation rates were measured based on adding the 15N2 tracer as a gas bubble. Beginning in August 2012, 15N2 was first dissolved into filtered seawater and the 15N2‐enriched water was subsequently added to N2 fixation incubations. Direct comparisons between methodologies revealed a robust relationship, with the addition of 15N2‐enriched seawater resulting in twofold greater depth‐integrated rates than those derived from adding a 15N2 gas bubble. Based on this relationship, we corrected the initial period of measurements, and the resulting rates of N2 fixation averaged 230 ± 136 μmol N m−2 d−1 for the full time series (n = 71). Analysis of the 15N isotopic composition of sinking PN, together with an isotope mass balance model, revealed that N2 fixation supported 26–47% of PN export during calendar years 2006–2013. The N export derived from these fractional contributions and measured N2 fixation rates ranged between 502 and 919 μmol N m−2 d−1, which are equivalent to rates of net community production (NCP) of 1.5 to 2.7 mol C m−2 yr−1, consistent with previous independent estimates of NCP at this site

Glider observations of enhanced deep water upwelling at a shelf break canyon: a mechanism for cross-slope carbon and nutrient exchange

Using underwater gliders we have identified canyon driven upwelling across the Celtic Sea shelf-break, in the vicinity of Whittard Canyon. The presence of this upwelling appears to be tied to the direction and strength of the local slope current, which is in itself highly variable. During typical summer time equatorward flow, an unbalanced pressure gradient force and the resulting disruption of geostrophic flow can lead to upwelling along the main axis of two small shelf break canyons. As the slope current reverts to poleward flow, the upwelling stops and the remnants of the upwelled features are mixed into the local shelf water or advected away from the region. The upwelled features are identified by the presence of sub-pycnocline high salinity water on the shelf, and are upwelled from a depth of 300 m on the slope, thus providing a mechanism for the transport of nutrients across the shelf break onto the shelf

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

IntroductionPatient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.MethodsROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).ResultsA total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.ConclusionsStudy drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.FundingThe ROCKET AF trial was funded by Johnson & Johnson and Bayer

Movements and spatial use of odontocetes in the western main Hawaiian Islands: results from satellite-tagging and photo-identification off Kaua‘i and Ni‘ihau in July/August 2011

Although considerable information is available on residency patterns and spatial use of odontocetes in the eastern half of the Hawai‘i Range Complex (HRC), much less is known about odontocetes in the western half of the HRC. In the second year of a three-year effort in the western main Hawaiian Islands we undertook surveys off Kaua‘i and Ni‘ihau in July/August 2011, to examine spatial use and residency patterns using satellite tags, to provide visual verification of acoustically-detected odontocetes on the Pacific Missile Range Facility (PMRF), and to obtain individual identification photographs and biopsy samples for assessment of population identity and structure. During 18 days of field effort we covered 1,972 km of trackline and had 65 encounters with five species of odontocetes. Twenty-four of the encounters, of three species, were cued by acoustic detections from the Marine Mammal Monitoring on Navy Ranges (M3R) system, thus providing species verifications for future use of the M3R system on the PMRF range. During the 65 encounters we obtained 22,645 photos for individual and species identification, and collected 48 biopsy samples for genetic analyses. One encounter with a group of four killer whales was only the second encounter with this species in 12 years of directed field surveys in Hawaiian waters. Photos from that encounter were compared to our photo-identification catalog but no matches were found, further suggesting that there is no population of this species resident to the Hawaiian Islands. There were three encounters with a lone pantropical spotted dolphin, each time in association with a group of spinner dolphins. Photos of this individual matched to a spotted dolphin identified off Kaua‘i in 2004 and in 2005, both times with spinner dolphins, suggesting this individual may be part of a long-term association with spinner dolphins. Four satellite tags were deployed; three on rough-toothed dolphins and one on a bottlenose dolphin. These are the first tag deployments on either species in Hawaiian waters and the first deployments of satellite tags on free-ranging rough-toothed dolphins anywhere in the world. Rough-toothed dolphin tag data were obtained over periods from 7.6 to 18.5 days. Over these periods the three rough-toothed dolphins moved cumulative horizontal distances ranging from 573 to 1,295 km, yet remained an average distance from the tagging locations of from 10.4 to 13.9 km. Median depths used by the three rough-toothed dolphins ranged from 816 to 1,107 m, with median distance from shore ranging from 11.6 to 12.2 km. Two of the three individuals had been previously photo-identified off Kaua‘i (in 2007 or 2008), and all link by association with the resident population from Kaua‘i and Ni‘ihau. Movement and habitat use data were obtained over a 34-day period for the satellite-tagged bottlenose dolphin. During this time the individual remained associated with the island of Kaua‘i using waters with a median depth of 82 m. Although this individual had not been previously photo-identified, others from the group it was in had been previously documented off Kaua‘i and/or Ni‘ihau in 2003-2005, suggesting it is part of the island-resident population. Overall these efforts provide the first unbiased movement and habitat use data for both species in Hawaiian waters.Grant No. N00244-10-1-004

Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes: results from the CANVAS Program

Patients with type 2 diabetes mellitus are at high risk of developing heart failure (HF).1 Sodium glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated, in large scale trials, to reduce the risk of HF events in patients with type 2 diabetes deemed to be at high risk based on established cardiovascular disease or multiple risk factors.2-4 However, it is unclear whether benefits are experienced across the broad spectrum of HF patients that includes those with preserved (HFpEF) as well as reduced ejection fraction (HFrEF)