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Lori M Minasian,1 Ann O’Mara,2,3 Sandra A Mitchell4 1Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA; 2Consultant, ICF, Fairfax, VA, USA; 3Consultant to Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA; 4Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USACorrespondence: Lori M Minasian, Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Drive, 5E-342, MSC-9784, Bethesda, MD, 20892-9784, USA, Tel +11 240 276 7053, Fax +11 240 276 7846, Email minasilo@mail.nih.govAbstract: Inclusion of the patient perspective in the reporting of symptomatic adverse events provides different and complementary information to clinician reporting using the Common Terminology Criteria for Adverse Events (CTCAE). The National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) is designed for patients to self-report their symptomatic adverse events in a manner that complements CTCAE reporting. Using CTCAE and PRO-CTCAE together offers the potential to refine our understanding of the prevalence and trajectory of lower grade AEs that can lead to elective discontinuation of therapy and diminished quality of life. This review addresses the development of PRO-CTCAE with an emphasis on the differences between PRO-CTCAE scores and CTCAE severity grades. This distinction is important when evaluating, grading and reporting toxicity and tolerability in cancer clinical trials.Keywords: Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, PRO-CTCAE, patient-reported outcomes, cancer therapy, toxicity, tolerability

Sarah Batson,1 Stephen A Mitchell,1 Ricarda Windisch,2 Elisabetta Damonte,2 Veronica C Munk,2 Noemi Reguart3,4 1DRG Abacus, Bicester, Oxfordshire, UK; 2F Hoffmann-La Roche Ltd, Basel, Switzerland; 3Medical Oncology, Hospital Clinic, 4Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Introduction: The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) is ~12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC.Methods: Literature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan–Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy.Results: Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval [CrI] 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for erlotinib. There was no evidence for differences between EGFR-TKI monotherapies, as all 95% CrIs included the null value.Conclusion: Although data for erlotinib plus bevacizumab came from a single Phase 2 study, the results of the NMA suggest that adding bevacizumab to erlotinib may be a promising approach to improving the outcomes achieved with EGFR-TKI monotherapy in patients with advanced EGFR+ NSCLC. Keywords: bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitor, network meta-analysis, non-small-cell lung cancer, non-squamous, progression-free survival

Roxanne Ferdinand,1 Stephen A Mitchell,2 Sarah Batson,2 Indra Tumur11Pfizer, Tadworth, UK; 2Abacus International, Bicester, UKBackground: Chronic myeloid leukemia (CML) is a myeloproliferative disorder of blood stem cells. The tyrosine kinase inhibitor (TKI) imatinib was the first targeted therapy licensed for patients with chronic-phase CML, and its introduction was associated with substantial improvements in response and survival compared with previous therapies. Clinical trial data are now available for the second-generation TKIs (nilotinib, dasatinib, and bosutinib) in the first-, second-, and third-line settings. A qualitative systematic review was conducted to qualitatively compare the clinical effectiveness, safety, and effect on quality of life of TKIs for the management of chronic-, accelerated-, or blast-phase CML patients.Methods: Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature.Results: In the first-line setting, the long-term efficacy (up to 8 years) of imatinib has been confirmed in a single randomized controlled trial (International Randomized Study of Interferon [IRIS]). All second-generation TKIs reported lower rates of transformation, and comparable or superior complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response rates compared with imatinib by 2-year follow-up. Each of the second-generation TKIs was associated with a distinct adverse-event profile. Bosutinib was the only second-generation TKI to report quality-of-life data (no significant difference compared with imatinib treatment). Data in the second- and third-line setting confirmed the efficacy of the second-generation TKIs in either imatinib-resistant or -intolerant patients, as measured by CCyR and MMR rates.Conclusion: Data from first-line randomized controlled trials reporting up to 2-year follow-up indicate superior response rates of the second-generation TKIs compared with imatinib. Current evidence from single-arm studies in the second-line setting confirm that nilotinib, dasatinib, and bosutinib are valuable treatment options for the significant subgroup of patients who are intolerant or resistant to imatinib treatment.Keywords: chronic myeloid leukemia, imatinib, nilotinib, dasatinib, bosutinib

In this work, we introduced k-d darts as a particular type of higherdimensional sampling. We described a k-d dart framework for hyperplanes of general dimension k, and then demonstrated efficiency and accuracy over three applications using k = 1, and accuracy for one application using k = 1. In particular, darts produce accurate estimates of the volume of an object regardless of the dimension, orientation, and aspect ratio of the object. Axis-aligned darts are universally preferable to unaligned ones for sampling square domains, and we expect this to extend to hyperrectangles, such as bounding boxes. Darts also produce accurate mean estimates for function integration. © 2014 ACM 0730-0301/2014/01-ART3 15.00.

We provide a simple algorithm and data structures for d-dimensional unbiased maximal Poisson-disk sampling. We use an order of magnitude less memory and time than the alternatives. Our results become more favorable as the dimension increases. This allows us to produce bigger samplings. Domains may be non-convex with holes. The generated point cloud is maximal up to round-off error. The serial algorithm is provably bias-free. For an output sampling of size n in fixed dimension d, we use a linear memory budget and empirical Θ(n) runtime. No known methods scale well with dimension, due to the "curse of dimensionality." The serial algorithm is practical in dimensions up to 5, and has been demonstrated in 6d. We have efficient GPU implementations in 2d and 3d. The algorithm proceeds through a finite sequence of uniform grids. The grids guide the dart throwing and track the remaining disk-free area. The top-level grid provides an efficient way to test if a candidate dart is disk-free. Our uniform grids are like quadtrees, except we delay splits and refine all leaves at once. Since the quadtree is flat it can be represented using very little memory: we just need the indices of the active leaves and a global level. Also it is very simple to sample from leaves with uniform probability. © 2012 The Author(s).

Acute leukemia is a rapidly progressive cancer of the blood and bone marrow that requires a high degree of complex, specialized, resource-intensive clinical and supportive care. The aging Canadian population has introduced an unprecedented demand on the health care system for a variety of illnesses, including acute leukemia. The purpose of this work was to develop organizational requirements for service providers delivering care for patients aged 18 years and older with acute leukemia within a single-payer health care system in Ontario. This initiative was intended to support streamlining high-quality health care across Ontario. We worked collaboratively with an expert panel to conduct a review of the literature to synthesize the organizational requirements for delivering acute leukemia care. A total of 229 requirements were developed. The requirements were categorized into themes including (1) facility requirements, including infrastructure, data management, safety, policies and procedures; (2) availability of clinical services and service complexity; (3) personnel, including roles, responsibilities, and ongoing education; (4) patient care; (5) quality management; (6) clinical research; and (7) laboratory services. These requirements will act as a framework for the provision of service, complexity of care, safety, accessibility, and quality care across all levels from the patient, organization, and system perspectives. This framework will help support person-centred care, emphasizing providing care close to home, while optimizing the use of specialized resources. Moving forward, Ontario Health (Cancer Care Ontario) will continue to work with acute leukemia service providers in the province to determine compliance and focus improvement efforts in priority areas.

Abstract Background and aim The evidence about the acceptability and effectiveness of innovative paediatric models of care for Type 1 diabetes is limited. To address this gap, we synthesised literature on implemented models of care, model components, outcomes, and determinants of implementation and sustainability. Methods A systematic review was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Database searches of Medline, CINAHL, EMBASE and Scopus were conducted. Empirical studies focused on Type 1 diabetes paediatric models of care, published from 2010 to 2022 in English were included. Results Nineteen extant studies reported on models and their associations with health and psychosocial outcomes, patient engagement with healthcare, and healthcare costs. Thirteen studies described multidisciplinary teamwork, education and capacity building that supported self-care. Four studies involved shared decision making between providers and patients, and two discussed outreach support where technology was an enabler. Fourteen studies reported improvements in health outcomes (e.g. glycaemic control), mostly for models that included multidisciplinary teams, education, and capacity building (11 studies), outreach support or shared care (3 studies). Four studies reported improvements in quality of life, three reported increased satisfaction for patients and carers and, and one reported improved communication. Four of five studies describing shared care and decision-making reported improvements in quality of life, support and motivation. Outreach models reported no negative outcomes, however, accessing some models was limited by technological and cost barriers. Eight studies reported on model sustainability, but only half reported implementation determinants; none reported applying a theoretical framework to guide their research. Conclusion Some health and psychosocial benefits were associated with newer models. To address knowledge gaps about implementation determinants and model sustainability, longitudinal studies are needed to inform future adoption of innovative models of care for children with Type 1 diabetes.

Abstract Purpose To determine the relationship between three postoperative physiotherapy activities (time to first postoperative walk, activity on the day after surgery, and physiotherapy frequency), and the outcomes of hospital length of stay (LOS) and discharge destination after hip fracture. Methods A cohort study was conducted on 437 hip fracture surgery patients aged ≥ 50 years across 36 participating hospitals from the Australian and New Zealand Hip Fracture Registry Acute Rehabilitation Sprint Audit during June 2022. Study outcomes included hospital LOS and discharge destination. Generalised linear and logistic regressions were used respectively, adjusted for potential confounders. Results Of 437 patients, 62% were female, 56% were aged ≥ 85 years, 23% were previously living in a residential aged care facility, 48% usually walked with a gait aid, and 38% were cognitively impaired prior to their injury. The median acute and total LOS were 8 (IQR 5–13) and 20 (IQR 8–38) days. Approximately 71% (n = 179/251) of patients originally living in private residence returned home and 29% (n = 72/251) were discharged to a residential aged care facility. Previously mobile patients had a higher total LOS if they walked day 2–3 (10.3 days; 95% CI 3.2, 17.4) or transferred with a mechanical lifter or did not get out of bed day 1 (7.6 days; 95% CI 0.6, 14.6) compared to those who walked day 1 postoperatively. Previously mobile patients from private residence had a reduced odds of return to private residence if they walked day 2–3 (OR 0.38; 95% CI 0.17, 0.87), day 4 + (OR 0.38; 95% CI 0.15, 0.96), or if they only sat, stood or stepped on the spot day 1 (OR 0.29; 95% CI 0.13, 0.62) when compared to those who walked day 1 postoperatively. Among patients from private residence, each additional physiotherapy session per day was associated with a -2.2 (95% CI -3.3, -1.0) day shorter acute LOS, and an increased log odds of return to private residence (OR 1.76; 95% CI 1.02, 3.02). Conclusion Hip fracture patients who walked earlier, were more active day 1 postoperatively, and/or received a higher number of physiotherapy sessions were more likely to return home after a shorter LOS.

ABSTRACT Introduction It is now widely recognised that engaging consumers in research activities can enhance the quality, equity and relevance of the research. Much of the commentary about consumer engagement in research focuses on research processes and implementation, rather than dissemination in conference settings. This article offers reflections and learnings from consumers, researchers and conference organisers on the 12th Health Services Research Conference, a biennial conference hosted by the Health Services Research Association of Australia and New Zealand (HSRAANZ). Method We were awarded funds via a competitive application process by Bellberry Limited, a national not‐for‐profit agency with a focus on improving research quality, to incorporate consumer engagement strategies in conference processes and evaluate their impact. Findings Strategies included consumer scholarships, a buddy system, designated quiet space and consumer session co‐chairs; the reflections explored in this paper were collected in the funded, independent evaluation. Our insights suggest a need for more structured consumer involvement in conference planning and design, as well as the development of specific engagement strategies. Conclusion To move toward active partnership in scientific conference settings, our experience reinforces the need to engage consumers as members in designing and conducting research and in presenting research and planning conference content and processes. Public Contribution Consumer engagement in research dissemination at conferences is the focus of this viewpoint article. Consumers were involved in the conception of this article and have contributed to authorship at all stages of revisions and edits.

Objective: This study examined the extent of disaster preparedness in Australian hospitals, seeking to identify opportunities for improvement. Insufficient preparation can lead to mortality/morbidity in post-disaster scenarios. Early identification of resolvable shortcomings in preparing for events is an important goal. Materials and methods: A purpose-designed anonymous survey was distributed to all Local-Hospital-Networks, organizations responsible for managing public hospitals and their disaster preparedness, across Australia's six states and two territories. Participant recruitment targeted disaster-managers, emergency-preparedness-managers, and business-continuity-managers. Results: Survey responses were received from 53/130 (40.8 %) of Australia's Local-Hospital-Networks with representation from six states and one territory. Most risk reduction measures were widely adopted. However, for 17/39 (43.6 %) measures, one-fifth of the respondents had either never heard of the measure or were not implementing it. Underutilized measures related to post-disaster-triage, emergency-evacuation, water-backup, secondary-electricity-feed, point-of-care-testing, alternative-decontamination-sites, and waste-management-systems. Local-Hospital-Networks' region-type, catchment-population and number-of-healthcare-facilities were associated with adoption of underutilized measures. Conclusion: Although 22/39 (56.4 %) of carefully chosen measures were widely implemented, the state of Australia's disaster preparedness is variable. There remains room for improvement, particularly against an “all-hazards” standard. Limited implementation of disaster-triage, evacuation-measures, and procedural issues, suggests that Australian Local-Hospital-Networks, particularly those managing fewer facilities are not sufficiently prepared for catastrophes.

Abstract Background Unwarranted clinical variation in hospital care includes the underuse, overuse, or misuse of services. Audit and feedback is a common strategy to reduce unwarranted variation, but its effectiveness varies widely across contexts. We aimed to identify implementation strategies, mechanisms, and contextual circumstances contributing to the impact of audit and feedback on unwarranted clinical variation. Methods Realist study examining a state-wide value-based healthcare program implemented between 2017 and 2021 in New South Wales, Australia. Three initiatives within the program included audit and feedback to reduce unwarranted variation in inpatient care for different conditions. Multiple data sources were used to formulate the initial audit and feedback program theory: a systematic review, realist review, program document review, and informal discussions with key program stakeholders. Semi-structured interviews were then conducted with 56 participants to refute, refine, or confirm the initial program theories. Data were analysed retroductively using a context-mechanism-outcome framework for 11 transcripts which were coded into the audit and feedback program theory. The program theory was validated with three expert panels: senior health leaders (n = 19), Agency for Clinical Innovation (n = 11), and Ministry of Health (n = 21) staff. Results The program’s audit and feedback implementation strategy operated through eight mechanistic processes. The strategy worked well when clinicians (1) felt ownership and buy-in, (2) could make sense of the information provided, (3) were motivated by social influence, and (4) accepted responsibility and accountability for proposed changes. The success of the strategy was constrained when the audit process led to (5) rationalising current practice instead of creating a learning opportunity, (6) perceptions of unfairness and concerns about data integrity, 7) development of improvement plans that were not followed, and (8) perceived intrusions on professional autonomy. Conclusions Audit and feedback strategies may help reduce unwarranted clinical variation in care where there is engagement between auditors and local clinicians, meaningful audit indicators, clear improvement plans, and respect for clinical expertise. We contribute theoretical development for audit and feedback by proposing a Model for Audit and Feedback Implementation at Scale. Recommendations include limiting the number of audit indicators, involving clinical staff and local leaders in feedback, and providing opportunities for reflection.

Objective. This study is aimed at exploring whether the mode of nutrition intervention delivery affected participant goal achievement in a three-arm randomised controlled trial of early and intensive nutrition intervention delivered to upper gastrointestinal cancer patients. Methods. Newly diagnosed upper gastrointestinal cancer patients were recruited from four tertiary hospitals in Melbourne, Australia. Participants in the intervention groups received a regular nutrition intervention for 18 weeks from an experienced dietitian via telephone or mobile application (app) using behaviour change techniques to assist in goal achievement. Univariate and multiple regression models using STATA determined goal achievement, dose, and frequency of contact between groups. A p value

[This corrects the article DOI: 10.1371/journal.pone.0271910.].

Abstract Background Resilience, the capacity to adapt and respond to challenges and disturbances, is now considered fundamental to understanding how healthcare systems maintain required levels of performance across varying conditions. Limited research has examined healthcare resilience in the context of implementing healthcare improvement programs across multiple system levels, particularly within community-based mental health settings or systems. In this study, we explored resilient characteristics across varying system levels (individual, team, management) during the implementation of a large-scale community-based suicide prevention intervention. Methods Semi-structured interviews (n=53) were conducted with coordinating teams from the four intervention regions and the central implementation management team. Data were audio-recorded, transcribed, and imported into NVivo for analysis. A thematic analysis of eight transcripts involving thirteen key personnel was conducted using a deductive approach to identify characteristics of resilience across multiple system levels and an inductive approach to uncover both impediments to, and strategies that supported, resilient performance during the implementation of the suicide prevention intervention. Results Numerous impediments to resilient performance were identified (e.g., complexity of the intervention, and incompatible goals and priorities between system levels). Consistent with the adopted theoretical framework, indicators of resilient performance relating to anticipation, sensemaking, adaptation and tradeoffs were identified at multiple system levels. At each of the system levels, distinctive strategies were identified that promoted resilience. At the individual and team levels, several key strategies were used by the project coordinators to promote resilience, such as building relationships and networks and carefully prioritising available resources. At the management level, strategies included teambuilding, collaborative learning, building relationships with external stakeholders, monitoring progress and providing feedback. The results also suggested that resilience at one level can shape resilience at other levels in complex ways; most notably we identified that there can be a downside to resilience, with negative consequences including stress and burnout, among individuals enacting resilience. Conclusions The importance of considering resilience from a multilevel systems perspective, as well as implications for theory and future research, are discussed.

Abstract Background A broad-based international shift to virtual care models over recent years has accelerated following COVID-19. Although there are increasing numbers of studies and reviews, less is known about clinicians’ and consumers’ perspectives concerning virtual modes in contrast to inpatient modes of delivery. Methods We conducted a mixed-methods study in late 2021 examining consumers’ and providers’ expectations of and perspectives on virtual care in the context of a new facility planned for the north-western suburbs of Sydney, Australia. Data were collected via a series of workshops, and a demographic survey. Recorded qualitative text data were analysed thematically, and surveys were analysed using SPSS v22. Results Across 12 workshops, 33 consumers and 49 providers from varied backgrounds, ethnicities, language groups, age ranges and professions participated. Four advantages, strengths or benefits of virtual care reported were: patient factors and wellbeing, accessibility, better care and health outcomes, and additional health system benefits, while four disadvantages, weaknesses or risks of virtual care were: patient factors and wellbeing, accessibility, resources and infrastructure, and quality and safety of care. Conclusions Virtual care was widely supported but the model is not suitable for all patients. Health and digital literacy and appropriate patient selection were key success criteria, as was patient choice. Key concerns included technology failures or limitations and that virtual models may be no more efficient than inpatient care models. Considering consumer and provider views and expectations prior to introducing virtual models of care may facilitate greater acceptance and uptake.

Abstract Background Integrated care is a model recognised internationally, however, there is limited evidence about its usability in the community. This study aimed to elicit community and provider views about integrated care and how implementation could meet their healthcare needs in a new hospital. Methods Using a qualitative approach, consumer and provider views on the strengths, barriers and enablers for integrated care were collected via a series of online workshops and supplementary interviews. Results A total of 22 consumers and 49 providers participated in 11 focus groups; all perceived integrated care to be an accessible and efficient model that offers a high level of care which enhanced staff and patient well-being. Providers expressed concerns about longer waiting times and safety risks associated with communication gaps and insufficient staff. Enablers include supporting consumers in navigating the integrated care process, co-ordinating and integrating primary care into the model as well as centralising patient electronic medical records. Discussion Primary, tertiary and community linkages are key for integrated care. Successful interoperability of services and networks requires an investment in resources and infrastructure to build the capability for providers to seamlessly access information at all points along the patient pathway. Conclusion Integrated care is perceived by consumers and providers to be a flexible and patient-focused model of healthcare that offers benefits for a hospital of the future.

Background: Social media platforms are frequently used by the general public to access health information, including information relating to complementary and alternative medicine (CAM). The aim of this study was to measure how often naturopathic influencers make evidence-informed recommendations on Instagram, and to examine associations between the level of evidence available or presented, and user engagement. Methods: A retrospective observational study using quantitative content analysis on health-related claims made by naturopathic influencers with 30000 or more followers on Instagram was conducted. Linear regression was used to measure the association between health-related posts and the number of Likes, and Comments. Results: A total of 494 health claims were extracted from eight Instagram accounts, of which 242 (49.0%) were supported by evidence and 34 (6.9%) included a link to evidence supporting the claim. Three naturopathic influencers did not provide any evidence to support the health claims they made on Instagram. Posts with links to evidence had fewer Likes (B=-1343.9, 95% CI=-2424.4 to -263.4, X=-0.1, P=0.02) and fewer Comments (B=-82.0, 95% CI=-145.9 to -18.2, X=-0.2, P=0.01), compared to posts without links to evidence. The most common areas of health were claims relating to ‘women’s health’ (n=94; 19.0%), and ‘hair, nail and skin’ (n=74; 15.0%). Conclusion: This study is one of the first to look at the evidence available to support health-related claims by naturopathic influencers on Instagram. Our findings indicate that around half of Instagram posts from popular naturopathic influencers with health claims are supported by high-quality evidence.

Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (80%), (≤500 μg/L, 501-800 μg/L, >800 μg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 μg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.

Abstract Background Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. Methods We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months’ standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox’s regression was performed to identify risk factors for virological failure. Results We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0–39.1) and a median observation time of 5.4 years (IQR 3.7–7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20–1.89; p

Abstract Background Health policy and management decisions rarely reflect research evidence. As part of a broader randomized controlled study exploring implementation science strategies we examined how allied health managers respond to two distinct recommendations and the evidence that supports them. Methods A qualitative study nested in a larger randomized controlled trial. Allied health managers across Australia and New Zealand who were responsible for weekend allied health resource allocation decisions towards the provision of inpatient service to acute general medical and surgical wards, and subacute rehabilitation wards were eligible for inclusion. Consenting participants were randomized to (1) control group or (2) implementation group 1, which received an evidence-based policy recommendation document guiding weekend allied health resource allocation decisions, or (3) implementation group 2, which received the same policy recommendation document guiding weekend allied health resource allocation decisions with support from a knowledge broker. As part of the trial, serial focus groups were conducted with a sample of over 80 allied health managers recruited to implementation group 2 only. A total 17 health services participated in serial focus groups according to their allocated randomization wave, over a 12-month study period. The primary outcome was participant perceptions and data were analysed using an inductive thematic approach with constant comparison. Thematic saturation was achieved. Results Five key themes emerged: (1) Local data is more influential than external evidence; (2) How good is the evidence and does it apply to us? (3) It is difficult to change things; (4) Historically that is how we have done things; and (5) What if we get complaints? Conclusions This study explored implementation of strategies to bridge gaps in evidence-informed decision-making. Results provide insight into barriers, which prevent the implementation of evidence-based practice from fully and successfully occurring, such as attitudes towards evidence, limited skills in critical appraisal, and lack of authority to promote change. In addition, strategies are needed to manage the risk of confirmation biases in decision-making processes. Trial registration This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12618000029291). Universal Trial Number (UTN): U1111-1205-2621.

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.

Abstract Background Studies of clinical effectiveness have demonstrated the many benefits of programmes that avoid unnecessary hospitalisations. Therefore, it is imperative to examine the factors influencing implementation of these programmes to ensure these benefits are realised across different healthcare contexts and settings. Numerous factors may act as determinants of implementation success or failure (facilitators and barriers), by either obstructing or enabling changes in healthcare delivery. Understanding the relationships between these determinants is needed to design and tailor strategies that integrate effective programmes into routine practice. Our aims were to describe the implementation determinants for hospital avoidance programmes for people with chronic conditions and the relationships between these determinants. Methods An electronic search of four databases was conducted from inception to October 2019, supplemented by snowballing for additional articles. Data were extracted using a structured data extraction tool and risk of bias assessed using the Hawker Tool. Thematic synthesis was undertaken to identify determinants of implementation success or failure for hospital avoidance programmes for people with chronic conditions, which were categorised according to the Consolidated Framework for Implementation Research (CFIR). The relationships between these determinants were also mapped. Results The initial search returned 3537 articles after duplicates were removed. After title and abstract screening, 123 articles underwent full-text review. Thirteen articles (14 studies) met the inclusion criteria. Thematic synthesis yielded 23 determinants of implementation across the five CFIR domains. ‘Availability of resources’, ‘compatibility and fit’, and ‘engagement of interprofessional team’ emerged as the most prominent determinants across the included studies. The most interconnected implementation determinants were the ‘compatibility and fit’ of interventions and ‘leadership influence’ factors. Conclusions Evidence is emerging for how chronic condition hospital avoidance programmes can be successfully implemented and scaled across different settings and contexts. This review provides a summary of key implementation determinants and their relationships. We propose a hypothesised causal loop diagram to represent the relationship between determinants within a complex adaptive system. Trial registration PROSPERO 162812

BackgroundThe development and adoption of a learning health system (LHS) has been proposed as a means to address key challenges facing current and future health care systems. The first review of the LHS literature was conducted 5 years ago, identifying only a small number of published papers that had empirically examined the implementation or testing of an LHS. It is timely to look more closely at the published empirical research and to ask the question, Where are we now? 5 years on from that early LHS review. ObjectiveThis study performed a scoping review of empirical research within the LHS domain. Taking an “implementation science” lens, the review aims to map out the empirical research that has been conducted to date, identify limitations, and identify future directions for the field. MethodsTwo academic databases (PubMed and Scopus) were searched using the terms “learning health* system*” for papers published between January 1, 2016, to January 31, 2021, that had an explicit empirical focus on LHSs. Study information was extracted relevant to the review objective, including each study’s publication details; primary concern or focus; context; design; data type; implementation framework, model, or theory used; and implementation determinants or outcomes examined. ResultsA total of 76 studies were included in this review. Over two-thirds of the studies were concerned with implementing a particular program, system, or platform (53/76, 69.7%) designed to contribute to achieving an LHS. Most of these studies focused on a particular clinical context or patient population (37/53, 69.8%), with far fewer studies focusing on whole hospital systems (4/53, 7.5%) or on other broad health care systems encompassing multiple facilities (12/53, 22.6%). Over two-thirds of the program-specific studies utilized quantitative methods (37/53, 69.8%), with a smaller number utilizing qualitative methods (10/53, 18.9%) or mixed-methods designs (6/53, 11.3%). The remaining 23 studies were classified into 1 of 3 key areas: ethics, policies, and governance (10/76, 13.2%); stakeholder perspectives of LHSs (5/76, 6.6%); or LHS-specific research strategies and tools (8/76, 10.5%). Overall, relatively few studies were identified that incorporated an implementation science framework. ConclusionsAlthough there has been considerable growth in empirical applications of LHSs within the past 5 years, paralleling the recent emergence of LHS-specific research strategies and tools, there are few high-quality studies. Comprehensive reporting of implementation and evaluation efforts is an important step to moving the LHS field forward. In particular, the routine use of implementation determinant and outcome frameworks will improve the assessment and reporting of barriers, enablers, and implementation outcomes in this field and will enable comparison and identification of trends across studies.

IntroductionDespite HIV viral load (VL) monitoring being serial, most studies use a cross-sectional design to evaluate the virological status of a cohort. The objective of our study was to use a simplified approach to calculate viraemic-time: the proportion of follow-up time with unsuppressed VL above the limit of detection. We estimated risk factors for higher viraemic-time and whether viraemic-time predicted mortality in a second-line antiretroviral treatment (ART) cohort in Myanmar.MethodsWe conducted a retrospective cohort analysis of people living with HIV (PLHIV) who received second-line ART for a period >6 months and who had at least two HIV VL test results between 01 January 2014 and 30 April 2018. Fractional logistic regression assessed risk factors for having higher viraemic-time and Cox proportional hazards regression assessed the association between viraemic-time and mortality. Kaplan-Meier curves were plotted to illustrate survival probability for different viraemic-time categories.ResultsAmong 1,352 participants, 815 (60.3%) never experienced viraemia, and 172 (12.7%), 214 (15.8%), and 80 (5.9%) participants were viraemic ConclusionsKey populations were at risk for having a higher viraemic-time on second-line ART. Viraemic-time predicts clinical outcomes. Differentiated services should target subgroups at risk for a higher viraemic-time to control both HIV transmission and mortality.

To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5’ splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical records of 3 ASD patients with TNRC6C variant revealed respiratory issues consistent with phenotypes observed in TNRC6 depleted mice. Overall, this study highlights the need for splicing analysis in determining variant pathogenicity, especially as it relates to ASD. Author summary Autism Spectrum Disorders (ASD) is the most common neurodevelopmental disorder that presents with both phenotypic and genetic heterogeneity. Before genetically defined therapeutic approaches can be applied to the treatment of ASD, it is crucial to understand the genetic basis of the disorder. Tremendous effort by consortiums, such as the Simon Foundation for Autism Research Initiative, has led to the identification of variants and, in turn, genes associated with ASD. However, the effect of ASD variants have on the process of splicing is often not fully considered when assessing ASD risk genes. Using a high-throughput splicing assay, MaPSy, ~6.3% of ASD-associated variants affected splicing, highlighting a substantial contribution of defective splicing to ASD. This analysis led to identification of genes, such as TNRC6C, that warrant further investigation with respect to ASD risk.

The purpose of this study was to examine sex-specific differences in the blood glucose (BG) response to recurrent aerobic exercise in type 1 diabetes rats. Specifically, we examined the role of peak estrogen (E2) concentrations during proestrus on BG response to prolonged repetitive aerobic exercise. To do so, nineteen Sprague-Dawley rats were assigned to four exercised groups: control female (CXF; n = 5), control male (CXM; n = 5), diabetic female (DXF, n = 5) and diabetic male (DXM, n = 4). Diabetes was induced in DX groups via subcutaneous multiple injections of low dose streptozotocin (20mg/day for 7 days). After four days of exercise, muscle and liver glycogen content, liver gluconeogenic enzyme content, muscle Beta oxidation activity and BG responses to exercise were compared. The final bout of exercise took place during proestrus when E2 concentrations were at their highest in the female rats. During days 1–3 DXM had significantly lower BG concentrations during exercise than DXF. While both T1DM and non-T1DM females demonstrated higher hepatic G6Pase expression and muscle beta oxidation activity levels on day 4 exercise, no differences in BG response between the male and female T1DM rats were evident. Further, no differences in liver and muscle glycogen content following day 4 of exercise were seen between the sexes. These results would suggest that heightened E2 levels during proestrus may not be an important factor governing glucose counter regulatory response to exercise in female T1DM rats. Rather, the pre-exercise blood glucose levels are likely to be a large determinant of the blood glucose response to exercise in both male and female rats.