A Core Outcome Set for the Benefits and Adverse Events of Bariatric and Metabolic Surgery:the BARIACT project

BackgroundBariatric and metabolic surgery is used as a treatment for patients with severe and complex obesity. However, there is a need to improve outcome selection and reporting in bariatric surgery trials. A Core Outcome Set (COS), an agreed minimum set of outcomes reported in all studies of a specific condition, may achieve this. Here, we present the development of a COS for BARIAtric and metabolic surgery Clinical Trials-the BARIACT Study.Methods and findingsOutcomes identified from systematic reviews and patient interviews informed a questionnaire survey. Patients and health professionals were surveyed three times and asked to rate the importance of each item on a 1-9 scale. Delphi methods provided anonymised feedback to participants. Items not meeting predefined criteria were discarded between rounds. Remaining items were discussed at consensus meetings, held separately with patients and professionals, where the COS was agreed. Data sources identified 2,990 outcomes, which were used to develop a 130-item questionnaire. Round 1 response rates were moderate but subsequently improved to above 75% for other rounds. After rounds 2 and 3, 81 and 14 items were discarded, respectively, leaving 35 items for discussion at consensus meetings. The final COS included nine items: "weight," "diabetes status," "cardiovascular risk," "overall quality of life (QOL)," "mortality," "technical complications of the specific operation," "any re-operation/re-intervention," "dysphagia/regurgitation," and "micronutrient status." The main limitation of this study was that it was based in the United Kingdom only.ConclusionsThe COS is recommended to be used as a minimum in all trials of bariatric and metabolic surgery. Adoption of the COS will improve data synthesis and the value of research data. Future work will establish methods for the measurement of the outcomes in the COS

Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylationa

Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80% : A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT)

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS scorePeer reviewe

Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m(2) (FluMel) and fludarabine/treosulfan 42 g/m(2) (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.Peer reviewe

Identifying and addressing psychosocial determinants of adherence to physical distancing guidance during the COVID-19 pandemic – project protocol

Optimising public health physical distancing measures has been a critical part of the global response to the spread of COVID-19. Evidence collected during the current pandemic shows that the transmission rate of the virus is significantly reduced following implementation of intensive physical distancing measures. Adherence to these recommendations has been poorer than adherence to other key transmission reduction behaviours such as handwashing. There are a complex range of reasons that are likely to predict why people do not or only partially adhere to physical distancing recommendations. In the current project we aim to address the following research questions: (1) What are the psychosocial determinants of physical distancing for the general public and for key socio-demographic sub-groups (e.g., young adults, older adults, etc.)?; (2) Do current Government of Ireland COVID-19 physical distancing communications address the determinants of physical distancing?; and (3) How can communications be optimised and tailored to sub-groups to ensure maximum adherence to guidelines? These will be addressed by conducting three work packages (WPs). In WP1, we will work closely with the iCARE international study, which includes a large online survey of public responses to measures established to reduce and slow the spread of COVID-19, including physical distancing. We will analyse Irish data, comparing it to data from other countries, to identify the key psychosocial determinants of physical distancing behaviour. This will be followed by a qualitative study to explore in depth the barriers and facilitators of physical distancing behaviour among the Irish public (WP2). In WP3, we will conduct a content analysis and evidence mapping of current government messaging around physical distancing, to ensure the findings from this research feed into the development of ongoing communication and future messaging about physical distancing

Investigating and evaluating evidence of the behavioural determinants of adherence to social distancing measures – A protocol for a scoping review of COVID-19 research

Background: The WHO has declared the outbreak of coronavirus disease 2019 (COVID-19) as a pandemic. With no vaccine currently available, using behavioural measures to reduce the spread of the virus within the population is an important tool in mitigating the effects of this pandemic. As such, social distancing measures are being implemented globally and have proven an effective tool in slowing the large-scale spread of the virus. Aim: This scoping review will focus on answering key questions about the state of the evidence on the behavioural determinants of adherence to social distancing measures in research on COVID-19. Methods: A scoping review will be conducted in accordance with guidelines for best practice. Literature searches will be conducted using online databases and grey literature sources. Databases will include Medline, Web of Science, Embase and PsycInfo, alongside relevant pre-print servers. Grey literature will be searched on Google Scholar. Screening, data extraction and quality appraisal will be conducted by members of the research team, with any discrepancies resolved by consensus discussion. Quality appraisal will be conducted using the Cochrane’s ROBINS-I tool, the Cochrane Risk of Bias tool, and the JBI Critical Appraisal Checklist where appropriate. Results will be analysed by mapping findings onto the Theoretical Domains Framework and visualising characteristics of the included studies using EviAtlas. This scoping review is pre-registered with Open Science Framework. Conclusions: The results of this study may facilitate the systematic development of behavioural interventions to increase adherence to social distancing measures

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

BACKGROUND: Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia (CML) with deep molecular responses, defined as stable MR4 (BCR-ABL1/ABL1 ratio 0.1%) on two consecutive samples. The study endpoint is the proportion of patients who lose their MMR on de-escalation and regain MMR on TKI resumption. The trial was registered at https://clinicaltrials.gov/ as NCT 01804985.FINDINGS: During the 12 months of half-dose therapy, 12 patients had molecular recurrence, all of whom regained MMR within 4 months of full dose TKI resumption. Recurrence was lower in the MR4 cohort (3 of 121 evaluable patients; 2.5%, 90% CI: 0.2-4.8%) than in the MMR cohort (9 of 48 evaluable patients; 18.8%, 90% CI: 9.5-28%) (p = 0.0007), but was unrelated to prior TKI or TKI therapy duration. Many adverse events improved during the first 3 months of de-escalation, though not thereafter. Overall, de-escalation saved 46.7% from an expected TKI budget (without de-escalation) of £4,156,969.INTERPRETATION: TKI de-escalation is safe for the vast majority of patients with excellent responses to TKI therapy, and is associated with improvement in symptoms and significant financial savings. The data imply that lower TKI doses may maintain responses in these patients

Exploring barriers and facilitators of physical distancing in the context of the COVID-19 pandemic: a qualitative interview study [version 2; peer review: 2 approved]

Background: Physical distancing measures (e.g., keeping a distance of two metres from others, avoiding crowded areas, and reducing the number of close physical contacts) continue to be among the most important preventative measures used to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Therefore, it is important to understand barriers and facilitators of physical distancing to help inform future public health campaigns. Methods: The current study aimed to qualitatively explore barriers and facilitators of physical distancing in the context of the COVID-19 pandemic using a qualitative interpretative design. Semi-structured one-to-one phone interviews were conducted with 25 participants aged 18+ years and living in the Republic of Ireland between September and October 2020. A purposive sampling strategy was used to maximise diversity in terms of age, gender, and socioeconomic status. Interviews were analysed using inductive thematic analysis. Results: Analysis resulted in the development of six main themes related to barriers and facilitators of physical distancing: (1) Maintaining and negotiating close relationships; (2) Public environments support or discourage physical distancing; (3) Habituation to threat; (4) Taking risks to protect well-being; (5) Personal responsibility to control the “controllables”; and (6) Confusion and uncertainty around government guidelines. Conclusions: Physical distancing measures were judged to be more or less difficult based on a number of internal and external psychosocial factors. Barriers to distancing included difficulties maintaining and negotiating close relationships, habituation to COVID-19-related threat, risk compensation, and confusion and uncertainty around government guidelines. Having a sense of personal responsibility to prevent COVID-19 transmission through distancing was an important facilitator. The structure of public environments was viewed as both barrier and facilitator. Barriers and facilitators may vary depending on context and life stage, which should be considered in the design of interventions to target physical distancing behaviour

Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation

Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were ‘low-risk’, 31% ‘intermediate-risk’ and 24% ‘high-risk’. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates