Adaptation of sea turtles to climate warming: Will phenological responses be sufficient to counteract changes in reproductive output?

Sea turtles are vulnerable to climate change since their reproductive output is influenced by incubating temperatures, with warmer temperatures causing lower hatching success and increased feminization of embryos. Their ability to cope with projected increases in ambient temperatures will depend on their capacity to adapt to shifts in climatic regimes. Here, we assessed the extent to which phenological shifts could mitigate impacts from increases in ambient temperatures (from 1.5 to 3°C in air temperatures and from 1.4 to 2.3°C in sea surface temperatures by 2100 at our sites) on four species of sea turtles, under a "middle of the road" scenario (SSP2-4.5). Sand temperatures at sea turtle nesting sites are projected to increase from 0.58 to 4.17°C by 2100 and expected shifts in nesting of 26-43 days earlier will not be sufficient to maintain current incubation temperatures at 7 (29%) of our sites, hatching success rates at 10 (42%) of our sites, with current trends in hatchling sex ratio being able to be maintained at half of the sites. We also calculated the phenological shifts that would be required (both backward for an earlier shift in nesting and forward for a later shift) to keep up with present-day incubation temperatures, hatching success rates, and sex ratios. The required shifts backward in nesting for incubation temperatures ranged from -20 to -191 days, whereas the required shifts forward ranged from +54 to +180 days. However, for half of the sites, no matter the shift the median incubation temperature will always be warmer than the 75th percentile of current ranges. Given that phenological shifts will not be able to ameliorate predicted changes in temperature, hatching success and sex ratio at most sites, turtles may need to use other adaptive responses and/or there is the need to enhance sea turtle resilience to climate warming.

Marrow Adipocyte Senescence in the Pathogenesis of Bone Loss.

PURPOSE OF REVIEW: Beyond aging, senescent cells accumulate during multiple pathological conditions, including chemotherapy, radiation, glucocorticoids, obesity, and diabetes, even earlier in life. Therefore, cellular senescence represents a unifying pathogenic mechanism driving skeletal and metabolic disorders. However, whether senescent bone marrow adipocytes (BMAds) are causal in mediating skeletal dysfunction has only recently been evaluated. RECENT FINDINGS: Despite evidence of BMAd senescence following glucocorticoid therapy, additional evidence for BMAd senescence in other conditions has thus far been limited. Because the study of BMAds presents unique challenges making these cells difficult to isolate and image, here we review issues and approaches to overcome such challenges, and present advancements in isolation and histological techniques that may help with the future study of senescent BMAds. Further insights into the roles of BMAd senescence in the pathogenesis of skeletal dysfunction may have important basic science and clinical implications for human physiology and disease.

Implementation of large, multi-site hospital interventions: a realist evaluation of strategies for developing capability.

BACKGROUND: This study presents guidelines for implementation distilled from the findings of a realist evaluation. The setting was local health districts in New South Wales, Australia that implemented three clinical improvement initiatives as part of a state-wide program. We focussed on implementation strategies designed to develop health professionals' capability to deliver value-based care initiatives for multisite programs. Capability, which increases implementers' ability to cope with unexpected scenarios is key to managing change. METHODS: We used a mixed methods realist evaluation which tested and refined program theories elucidating the complex dynamic between context (C), mechanism (M) and outcome (O) to determine what works, for whom, under what circumstances. Data was drawn from program documents, a realist synthesis, informal discussions with implementation designers, and interviews with 10 key informants (out of 37 identified) from seven sites. Data analysis employed a retroductive approach to interrogate the causal factors identified as contributors to outcomes. RESULTS: CMO statements were refined for four initial program theories: Making it Relevant- where participation in activities was increased when targeted to the needs of the staff; Investment in Quality Improvement- where engagement in capability development was enhanced when it was valued by all levels of the organisation; Turnover and Capability Loss- where the effects of staff turnover were mitigated; and Community-Wide Priority- where there was a strategy of spanning sites. From these data five guiding principles for implementers were distilled: (1) Involve all levels of the health system to effectively implement large-scale capability development, (2) Design capability development activities in a way that supports a learning culture, (3) Plan capability development activities with staff turnover in mind, (4) Increased capability should be distributed across teams to avoid bottlenecks in workflows and the risk of losing key staff, (5) Foster cross-site collaboration to focus effort, reduce variation in practice and promote greater cohesion in patient care. CONCLUSIONS: A key implementation strategy for interventions to standardise high quality practice is development of clinical capability. We illustrate how leadership support, attention to staff turnover patterns, and making activities relevant to current issues, can lead to an emergent learning culture.

Influenza Vaccination Uptake and Associated Factors Among Adults With and Without Human Immunodeficiency Virus in a Large, Integrated Healthcare System.

BACKGROUND: Influenza vaccination is recommended for adults regardless of human immunodeficiency virus (HIV) status. There may be facilitators or barriers to vaccinating people with HIV (PWH) that differ from people without HIV (PWoH). We sought to describe the uptake of influenza vaccination by HIV status and identify factors associated with vaccination. METHODS: We abstracted data from the electronic health records of PWH and PWoH in Kaiser Permanente Northern California during 6 influenza seasons (2013-2018). We determined vaccination uptake and used Poisson regression models to evaluate factors associated with vaccination in PWH and PWoH. RESULTS: 9272 PWH and 194 393 PWoH matched by age, sex, and race/ethnicity were included (mean age: 48 vs 49 years; men: 91% vs 90%; White race: 53% for both groups). PWH were more likely to receive the influenza vaccine (65-69% across years for PWH and 37-41% for PWoH) with an adjusted risk ratio for all years of 1.48 (95% CI: 1.46-1.50). For PWH, lower vaccination uptake was associated with several factors that suggested more complex health needs, such as lower CD4 cell counts, higher HIV viral loads, prior depression diagnoses, having Medicare insurance, and having a higher number of comorbidities. Associations with vaccination uptake were attenuated in PWH, compared with PWoH, for smoking, alcohol, and demographic factors. CONCLUSIONS: PWH had an almost 50% higher uptake of influenza vaccination than PWoH, possibly reflecting greater engagement with the healthcare system. We also found that PWH with more complex health needs had reduced vaccination uptake. Findings may inform outreach strategies to increase influenza vaccination in PWH.

Characterizing Unhealthy Alcohol Use Patterns and Their Association with Alcohol Use Reduction and Alcohol Use Disorder During Follow-Up in HIV Care.

Outcomes of PWH with unhealthy alcohol use, such as alcohol use reduction or progression to AUD, are not well-known and may differ by baseline patterns of unhealthy alcohol use. Among 1299 PWH screening positive for NIAAA-defined unhealthy alcohol use in Kaiser Permanente Northern California, 2013-2017, we compared 2-year probabilities of reduction to low-risk/no alcohol use and rates of new AUD diagnoses by baseline use patterns, categorized as exceeding: only daily limits (72% of included PWH), only weekly limits (17%), or both (11%), based on NIAAA recommendations. Overall, 73.2% (95% CI 70.5-75.9%) of re-screened PWH reduced to low-risk/no alcohol use over 2 years, and there were 3.1 (95% CI 2.5-3.8%) new AUD diagnoses per 100 person-years. Compared with PWH only exceeding daily limits at baseline, those only exceeding weekly limits and those exceeding both limits were less likely to reduce and likelier to be diagnosed with AUD during follow-up. PWH exceeding weekly drinking limits, with or without exceeding daily limits, may have a potential need for targeted interventions to address unhealthy alcohol use.

Cutting Edge: Subunit Booster Vaccination Confers Sterilizing Immunity against Liver-Stage Malaria in Mice Initially Primed with a Weight-Normalized Dose of Radiation-Attenuated Sporozoites.

Radiation-attenuated sporozoite (RAS) vaccination offers hope for global malaria control through induction of protective liver-stage-specific memory CD8 T cells. Effective RAS vaccination regimens exist; however, widespread implementation remains unfeasible. A key difficulty resides in the need to administer three or more doses i.v. to achieve sufficient immunity. Strategies to reduce the number of RAS doses are therefore desirable. Here we used mice to model human immune responses to a single, suboptimal weight-normalized RAS dose administered i.v. followed by subunit vaccination to amplify liver-stage-specific memory CD8 T cells. RAS+subunit prime-boost regimens increased the numbers of liver-stage-specific memory CD8 T cells to a level greater than is present after one RAS vaccination. Both i.v. and i.m. subunit vaccine delivery induced immunity in mice, and many vaccinated mice completely cleared liver infection. These findings are particularly relevant to human vaccine development because RAS+subunit prime-boost vaccination would reduce the logistical challenges of multiple RAS-only immunizations.

Perioperative interventions to improve early mobilisation and physical function after hip fracture: a systematic review and meta-analysis.

BACKGROUND: Perioperative interventions could enhance early mobilisation and physical function after hip fracture surgery. OBJECTIVE: Determine the effectiveness of perioperative interventions on early mobilisation and physical function after hip fracture. METHODS: Ovid MEDLINE, CINAHL, Embase, Scopus and Web of Science were searched from January 2000 to March 2022. English language experimental and quasi-experimental studies were included if patients were hospitalised for a fractured proximal femur with a mean age 65 years or older and reported measures of early mobilisation and physical function during the acute hospital admission. Data were pooled using a random effect meta-analysis. RESULTS: Twenty-eight studies were included from 1,327 citations. Studies were conducted in 26 countries on 8,192 participants with a mean age of 80 years. Pathways and models of care may provide a small increase in early mobilisation (standardised mean difference [SMD]: 0.20, 95% confidence interval [CI]: 0.01-0.39, I2 = 73%) and physical function (SMD: 0.07, 95% CI 0.00 to 0.15, I2 = 0%) and transcutaneous electrical nerve stimulation analgesia may provide a moderate improvement in function (SMD: 0.65, 95% CI: 0.24-1.05, I2 = 96%). The benefit of pre-operative mobilisation, multidisciplinary rehabilitation, recumbent cycling and clinical supervision on mobilisation and function remains uncertain. Evidence of no effect on mobilisation or function was identified for pre-emptive analgesia, intraoperative periarticular injections, continuous postoperative epidural infusion analgesia, occupational therapy training or nutritional supplements. CONCLUSIONS: Perioperative interventions may improve early mobilisation and physical function after hip fracture surgery. Future studies are needed to model the causal mechanisms of perioperative interventions on mobilisation and function after hip fracture.

Transition models of care for type 1 diabetes: a systematic review.

BACKGROUND: Managing the care regimen for Type 1 Diabetes is challenging for emerging adults, as they take on greater responsibility for self-management. A diverse range of models of care have been implemented to improve safety and quality of care during transition between paediatric and adult services. However, evidence about acceptability and effectiveness of these is limited. Our aim was to synthesise the evidence for transition models and their components, examine the health related and psychosocial outcomes, and to identify determinants associated with the implementation of person-centred models of transition care. METHOD: We searched Medline, CINAHL, EMBASE and Scopus. Peer reviewed empirical studies that focused on T1D models of care published from 2010 to 2021 in English, reporting experimental, qualitative, mixed methods, and observational studies were included. RESULTS: Fourteen studies reported on health and psychosocial outcomes, and engagement with healthcare. Three key models of care emerged: structured transition education programs (6 studies), multidisciplinary team transition support (5 studies) and telehealth/virtual care (3 studies). Compared with usual practice, three of the six structured transition education programs led to improvements in maintenance of glycaemic control, psychological well-being, and engagement with health services. Four MDT transition care models reported improved health outcomes, and improved engagement with health services, however, three studies reported no benefit. Reduced diabetes related stress and increased patient satisfaction were reported by two studies, but three reported no benefit. Telehealth and virtual group appointments improved adherence to self-management and reduced diabetes distress but did not change health outcomes. CONCLUSIONS: Although some health and psychosocial benefits are reported, the results were mixed. No studies reported on T1D transition model implementation outcomes such as acceptability, adoption, and appropriateness among clinicians or managers implementing these models. This gap needs to be addressed to support future adoption of successful models.

International approaches for implementing accreditation programmes in different healthcare facilities: a comparative case study in Australia, Botswana, Denmark, and Jordan.

Healthcare accreditation programmes have been adopted internationally to maintain the quality and safety of services. Accreditation assesses the compliance of organizations to a series of standards. The evidence base supporting the benefits of accreditation is mixed, potentially influenced by differences in local implementation and operationalization of standards. Successful implementation is associated with optimizing regulation, funding, and government commitment. Implementation of accreditation is a complex intervention that needs to be tailored to meet contextual differences across settings. Comparing why and how accreditation is implemented across countries supports the effective implementation of new programmes and refinements to existing systems. This article presents four case studies from Australia, Botswana, Denmark, and Jordan to consider a geographic spread and mix of high- and upper-middle-income countries. The data were derived from a review of accreditation programme documents and follow-up discussions with directors of the accrediting bodies in the countries of interest. Each case study was summarized according to a standardized framework for comparison: (i) goals (why), (ii) programme implementation (how), (iii) outcomes based on pre-post measures (what), and (iv) lessons learned (enablers and barriers). The accreditation programmes were all introduced in the 2000s to improve quality and safety. Documents from each country outlined motivations for introducing an accreditation programme, which was predominantly initiated by the government. The programmes were adopted in demarcated healthcare sectors (e.g. primary care and hospital settings), with a mix of mandatory and voluntary approaches. Implementation support centred on the interpretation and operationalization of standards and follow-up on variation in compliance with standards, after announced surveys. Most standards focused on patient safety, patient centredness, and governance but differed between using standard sets on quality management or supportive processes for patient care. Methods for evaluation of programme success and outcomes measured varied. Frequently reported enablers of successful implementation included strong leadership and ownership of the process. A lack of awareness of quality and safety, insufficient training in quality improvement methods, and transfer of staff represented the most common challenges. This case analysis of accreditation programmes in a variety of countries highlights consistent strategies utilized, key enabling factors, barriers, and the influence of contextual differences. Our framework for describing why, how, what, and lessons learned demonstrates innovation and experimentation in approaches used across high- and upper-middle-income countries, hospital and primary care, and specialist clinics.

Barriers to and Facilitators of Implementing Guidelines for Detecting Familial Hypercholesterolaemia in Australia.

BACKGROUND: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any approach across Australian health settings. The aim of this study was to identify the implementation barriers to and facilitators of the detection of FH in Australia. METHODS: Four, 2-hour virtual focus groups were facilitated by implementation scientists and a clinicians as part of the 2021 Australasian FH Summit. Template analysis was used to identify themes. RESULTS: There were 28 workshop attendees across four groups (n=6-8 each), yielding 13 barriers and 10 facilitators across three themes: (1) patient related, (2) provider related, and (3) system related. A "lack of care pathways" and "upskilling clinicians in identifying and diagnosing FH" were the most interconnected barriers and facilitators for the detection of FH. CONCLUSIONS: The relationships between barriers and facilitators across the patient, provider, and system themes indicates that a comprehensive implementation strategy is needed to address these different levels. Future research is underway to develop a model for implementing the Australian FH guidelines into practice.

Making implementation science more real.

Implementation science in healthcare aims to understand how to get evidence into practice. Once this is achieved in one setting, it becomes increasingly difficult to replicate elsewhere. The problem is often attributed to differences in context that influence how and whether implementation strategies work. We argue that realist research paradigms provide a useful framework to express the effect of contextual factors within implementation strategy causal processes. Realist studies are theory-driven evaluations that focus on understanding how and why interventions work under different circumstances. They consider the interaction between contextual circumstances, theoretical mechanisms of change and the outcomes they produce, to arrive at explanations of conditional causality (i.e., what tends to work, for whom, under what circumstances). This Commentary provides example applications using preliminary findings from a large realist implementation study of system-wide value-based healthcare initiatives in New South Wales, Australia. If applied judiciously, realist implementation studies may represent a sound approach to help optimise delivery of the right care in the right setting and at the right time.

Effectiveness of knowledge brokering and recommendation dissemination for influencing healthcare resource allocation decisions: A cluster randomised controlled implementation trial.

BACKGROUND: Implementing evidence into clinical practice is a key focus of healthcare improvements to reduce unwarranted variation. Dissemination of evidence-based recommendations and knowledge brokering have emerged as potential strategies to achieve evidence implementation by influencing resource allocation decisions. The aim of this study was to determine the effectiveness of these two research implementation strategies to facilitate evidence-informed healthcare management decisions for the provision of inpatient weekend allied health services. METHODS AND FINDINGS: This multicentre, single-blinded (data collection and analysis), three-group parallel cluster randomised controlled trial with concealed allocation was conducted in Australian and New Zealand hospitals between February 2018 and January 2020. Clustering and randomisation took place at the organisation level where weekend allied health staffing decisions were made (e.g., network of hospitals or single hospital). Hospital wards were nested within these decision-making structures. Three conditions were compared over a 12-month period: (1) usual practice waitlist control; (2) dissemination of written evidence-based practice recommendations; and (3) access to a webinar-based knowledge broker in addition to the recommendations. The primary outcome was the alignment of weekend allied health provision with practice recommendations at the cluster and ward levels, addressing the adoption, penetration, and fidelity to the recommendations. The secondary outcome was mean hospital length of stay at the ward level. Outcomes were collected at baseline and 12 months later. A total of 45 clusters (n = 833 wards) were randomised to either control (n = 15), recommendation (n = 16), or knowledge broker (n = 14) conditions. Four (9%) did not provide follow-up data, and no adverse events were recorded. No significant effect was found with either implementation strategy for the primary outcome at the cluster level (recommendation versus control ß 18.11 [95% CI -8,721.81 to 8,758.02] p = 0.997; knowledge broker versus control ß 1.24 [95% CI -6,992.60 to 6,995.07] p = 1.000; recommendation versus knowledge broker ß -9.12 [95% CI -3,878.39 to 3,860.16] p = 0.996) or ward level (recommendation versus control ß 0.01 [95% CI 0.74 to 0.75] p = 0.983; knowledge broker versus control ß -0.12 [95% CI -0.54 to 0.30] p = 0.581; recommendation versus knowledge broker ß -0.19 [-1.04 to 0.65] p = 0.651). There was no significant effect between strategies for the secondary outcome at ward level (recommendation versus control ß 2.19 [95% CI -1.36 to 5.74] p = 0.219; knowledge broker versus control ß -0.55 [95% CI -1.16 to 0.06] p = 0.075; recommendation versus knowledge broker ß -3.75 [95% CI -8.33 to 0.82] p = 0.102). None of the control or knowledge broker clusters transitioned to partial or full alignment with the recommendations. Three (20%) of the clusters who only received the written recommendations transitioned from nonalignment to partial alignment. Limitations include underpowering at the cluster level sample due to the grouping of multiple geographically distinct hospitals to avoid contamination. CONCLUSIONS: Owing to a lack of power at the cluster level, this trial was unable to identify a difference between the knowledge broker strategy and dissemination of recommendations compared with usual practice for the promotion of evidence-informed resource allocation to inpatient weekend allied health services. Future research is needed to determine the interactions between different implementation strategies and healthcare contexts when translating evidence into healthcare practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000029291.

Applying a framework to assess the impact of cardiovascular outcomes improvement research.

BACKGROUND: Health and medical research funding agencies are increasingly interested in measuring the impact of funded research. We present a research impact case study for the first four years of an Australian National Health and Medical Research Council funded Centre of Research Excellence in Cardiovascular Outcomes Improvement (2016-2020). The primary aim of this paper was to explore the application of a research impact matrix to assess the impact of cardiovascular outcomes improvement research. METHODS: We applied a research impact matrix developed from a systematic review of existing methodological frameworks used to measure research impact. This impact matrix was used as a bespoke tool to identify and understand various research impacts over different time frames. Data sources included a review of existing internal documentation from the research centre and publicly available information sources, informal iterative discussions with 10 centre investigators, and confirmation of information from centre grant and scholarship recipients. RESULTS: By July 2019, the impact on the short-term research domain category included over 41 direct publications, which were cited over 87 times (median journal impact factor of 2.84). There were over 61 conference presentations, seven PhD candidacies, five new academic collaborations, and six new database linkages conducted. The impact on the mid-term research domain category involved contributions towards the development of a national cardiac registry, cardiovascular guidelines, application for a Medicare Benefits Schedule reimbursement item number, introduction of patient-reported outcome measures into several databases, and the establishment of nine new industry collaborations. Evidence of long-term impacts were described as the development and use of contemporary management for aortic stenosis, a cardiovascular risk prediction model and prevention targets in several data registries, and the establishment of cost-effectiveness for stenting compared to surgery. CONCLUSIONS: We considered the research impact matrix a feasible tool to identify evidence of academic and policy impact in the short- to midterm; however, we experienced challenges in capturing long-term impacts. Cost containment and broader economic impacts represented another difficult area of impact to measure.

Synergistic Interactions of Cannabidiol with Chemotherapeutic Drugs in MCF7 Cells: Mode of Interaction and Proteomics Analysis of Mechanisms.

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN-38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN-38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II ß and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN-38 (CSN-38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN-38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of CBD and its synergistic combination with SN-38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer.

Impact of the Method of Delivering Electronic Health Behavior Change Interventions in Survivors of Cancer on Engagement, Health Behaviors, and Health Outcomes: Systematic Review and Meta-Analysis.

BACKGROUND: Increased accessibility to the internet and mobile devices has seen a rapid expansion in electronic health (eHealth) behavior change interventions delivered to patients with cancer and survivors using synchronous, asynchronous, and combined delivery methods. Characterizing effective delivery methods of eHealth interventions is required to enable improved design and implementation of evidence-based health behavior change interventions. OBJECTIVE: This study aims to systematically review the literature and synthesize evidence on the success of eHealth behavior change interventions in patients with cancer and survivors delivered by synchronous, asynchronous, or combined methods compared with a control group. Engagement with the intervention, behavior change, and health outcomes, including quality of life, fatigue, depression, and anxiety, were examined. METHODS: A search of Scopus, Ovid MEDLINE, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature Plus, PsycINFO, Cochrane CENTRAL, and PubMed was conducted for studies published between March 2007 and March 2019. We looked for randomized controlled trials (RCTs) examining interventions delivered to adult cancer survivors via eHealth methods with a measure of health behavior change. Random-effects meta-analysis was performed to examine whether the method of eHealth delivery impacted the level of engagement, behavior change, and health outcomes. RESULTS: A total of 24 RCTs were included predominantly examining dietary and physical activity behavior change interventions. There were 11 studies that used a synchronous approach and 11 studies that used an asynchronous approach, whereas 2 studies used a combined delivery method. Use of eHealth interventions improved exercise behavior (standardized mean difference [SMD] 0.34, 95% CI 0.21-0.48), diet behavior (SMD 0.44, 95% CI 0.18-0.70), fatigue (SMD 0.21, 95% CI -0.08 to 0.50; SMD change 0.22, 95% CI 0.09-0.35), anxiety (SMD 1.21, 95% CI: 0.36-2.07; SMD change 0.15, 95% CI -0.09 to 0.40), depression (SMD 0.15, 95% CI 0.00-0.30), and quality of life (SMD 0.12, 95% CI -0.10 to 0.34; SMD change 0.14, 95% CI 0.04-0.24). The mode of delivery did not influence the amount of dietary and physical activity behavior change observed. CONCLUSIONS: Physical activity and dietary behavior change eHealth interventions delivered to patients with cancer or survivors have a small to moderate impact on behavior change and a small to very small benefit to quality of life, fatigue, depression, and anxiety. There is insufficient evidence to determine whether asynchronous or synchronous delivery modes yield superior results. Three-arm RCTs comparing delivery modes with a control with robust engagement reporting are required to determine the most successful delivery method for promoting behavior change and ultimately favorable health outcomes.

Deferred treatment with a fixed-dose combination of sofosbuvir-velpatasvir for chronic hepatitis C virus genotype 1, 2, 4 and 6 infection.

Sofosbuvir-velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single-arm, open-label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir-velpatasvir among patients randomized to the placebo group in the ASTRAL-1 study. Patients received sofosbuvir-velpatasvir (400/100 mg) once daily for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12 weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%-99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%-100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%-100%) with genotype 2, 19/19 (100%; 95%CI, 82%-100%) with genotype 4 and 8/9 (89%; 95% CI, 52%-100%) with genotype 6. All (19/19; 95%CI, 82-100) patients with cirrhosis and all (31/31, 95%CI, 89-100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir-velpatasvir for 12 weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721).

Ablation using 3D maps adjusted for spatial displacement of premature ventricular complexes relative to sinus beats: Improving precision by correcting for the shift.

INTRODUCTION: Point-by-point 3-dimensional (3D) electroanatomic mapping (EAM) is used to guide catheter ablation of premature ventricular complexes (PVCs). Due to the differences in the spatial excursion of the cardiac chambers during cardiac cycles in PVCs vs sinus rhythm, the 3D location registration during PVCs is shifted relative to sinus rhythm. In this study, we describe our strategy to adjust for this displacement in real-time during PVC mapping. METHODS AND RESULTS: We report 21 patients who underwent catheter ablation of 23 unique PVCs using Carto 3. After mapping the earliest site for each PVC, we reregistered its 3D location to a sinus rhythm beat in real-time, and used this to guide ablation lesion delivery. The PVC earliest location was spatially displaced from the successful ablation lesion in sinus rhythm by average 6.7 (range 3.3-13.0) mm. Offline, we subsequently analyzed 25 unique chamber maps and 606 PVC points. For each point, we reregistered the 3D location to a preceding sinus beat. The PVC points were displaced from sinus rhythm location by average 4.4 (0.3-13.7) mm. The maximally displaced point for each chamber was 7.7 (4.7-13.7) mm. The general direction of shift during PVC was leftward and inferior relative to sinus rhythm. CONCLUSIONS: During electroanatomic mapping of PVCs using the Carto 3 system, points mapped during PVCs are spatially displaced relative to their location in sinus rhythm. Electrophysiologists should recognize this phenomenon and account for the shift to guide accurate delivery of ablation lesions.

Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen.

The optimal retreatment strategy for patients chronically infected with hepatitis C virus who experience virologic failure after treatment with direct-acting antiviral-based therapies remains unclear. In this multicenter, open-label, phase 2 study, we evaluated the efficacy and safety of a fixed-dose combination of sofosbuvir-velpatasvir (400 mg/100 mg) plus weight-adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response after prior treatment with direct-acting antiviral regimens that included the nucleotide analogue nonstructural protein 5B inhibitor sofosbuvir plus the nonstructural protein 5A inhibitor velpatasvir with or without the nonstructural protein 3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval, 82%-97%) patients achieved sustained virologic response at 12 weeks, including 36 of 37 (97%; 95% confidence interval, 86%-100%) patients with hepatitis C virus genotype 1 infection, 13 of 14 (93%; 95% confidence interval, 66%-100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% confidence interval, 52%-94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all study drugs due to an adverse event (irritability). CONCLUSION: Retreatment of patients who previously failed direct-acting antiviral-based therapies with sofosbuvir-velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with hepatitis C virus genotype 1 or 2 infection. (Hepatology 2017;66:1083-1089).