Use of thromboprophylaxis guidelines and risk stratification tools in atrial fibrillation : A survey of general practitioners in Australia

Mr. Eyob A. Gebreyohannes is a PhD student and a recipient of the University of Western Australia International Fee Scholarship and University Postgraduate Award. Mr. Gebreyohannes would like to acknowledge the University of Western Australia for supporting his studies. This study was funded by the University of Western Australia HDR (Higher Degree by Research) grant (PG 10402154). Also, the research team would like to thank Prof. Luke Bereznicki for his guidance during the initial stages of this study. Open access publishing facilitated by The University of Western Australia, as part of the Wiley - The University of Western Australia agreement via the Council of Australian University Librarians.Peer reviewedPublisher PD

Patients’ Perspectives on Commencing Oral Anticoagulants in Atrial Fibrillation: An Exploratory Qualitative Descriptive Study

Background: Oral anticoagulants (OACs) are prescribed to patients with atrial fibrillation (AF) in order to lower stroke risk. However, patient refusal to commence OACs hinders effective anticoagulation. This study aimed to explore barriers and facilitators to patient agreement to commence OACs from the perspectives of patients with AF attending Australian general practices. // Methods: A qualitative descriptive study utilising semi-structured individual interviews was conducted from March to July 2022. Results: Ten patients (60% male, median age = 78.5 years) completed interviews. Patients’ passive roles in decision-making were identified as a facilitator. Other prominent facilitators included doctors explaining adequately and aligning their recommendations with patients’ overall health goals, including the prevention of stroke and associated disabilities, and a clear understanding of the pros and cons of taking OACs. Reportedly insufficient explanation from doctors and the inconvenience associated with taking warfarin were identified as potential barriers. // Conclusion: Addressing factors that influence patient agreement to commence OACs should be an essential aspect of quality improvement interventions. Subsequent studies should also delve into the perspectives of eligible patients with AF who choose not to commence OACs as well as the perspectives of both patients and doctors regarding the decision to continue OAC treatment

Effectiveness of Quality Incentive Payments in General Practice (EQuIP-GP) cluster randomized trial: impact on patient-reported experience

Background: Relational continuity, ‘a therapeutic relationship between a patient and provider/s that spans health care events’, has been associated with improved patient outcomes.Objectives: To evaluate whether an intervention incorporating patient enrolment and a funding model for higher-risk patients influenced patient-reported experience measures, particularly relational continuity.Methods: Cluster-randomized controlled trial over 12 months (1 August 2018–31 July 2019). Participating patients within intervention practiceswere offered enrolment with a preferred general practitioner, a minimum of 3 longer appointments, and review within 7 days of hospital admission or emergency department attendance. Intervention practices received incentives for longer consultations (dependent on reducing unnecessary prescriptions and tests), early post-hospital follow-up, and hospitalization reductions. The primary outcome was patient-reported relationalcontinuity, measured by the Primary Care Assessment Tool Short Form.Results: A total of 774 patients, aged 18–65 years with a chronic illness or aged over 65 years, from 34 general practices in metropolitan, regional, and rural Australia across 3 states participated. Response rates for questionnaires were >90%. From a maximum of 4.0, mean baselinescores for relational continuity were 3.38 (SE 0.05) and 3.42 (SE 0.05) in control and intervention arms, respectively, with no significant between-group differences in changes pre-post trial. There were no significant changes in other patient-focussed measures.Conclusion: Patient-reported relational continuity was high at baseline and not influenced by the intervention, signalling the need for cautionwith policies incorporating patient enrolment and financial incentives. Further research is required targeting at-risk patient groups with low baseline engagement with primary care

Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety

PurposeThe GALLIUM study (ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101;G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P;CHOP);CVP;or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety.Patients and Methods: A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m(2) on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression.Results: Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68;95% CI, 0.54 to 0.87;P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63;95% CI, 0.46 to 0.88;CHOP: HR, 0.72;95% CI, 0.48 to 1.10;CVP: HR, 0.79;95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles.Conclusion: Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: a prespecified subgroup analysis of high-risk patients from the ECHELON-1 study

Approximately one‐third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high‐risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON‐1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first‐line therapy after a median follow‐up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD‐treated versus ABVD‐treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high‐risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON‐1 shows a favorable benefit‐risk balance in high‐risk patients

Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study

<p>Abstract</p> <p>Background</p> <p>A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near <it>MS4A4A, CD2AP, EPHA1 </it>and <it>CD33</it>. Meta-analyses of this and a previously published GWAS revealed significant association at <it>ABCA7 </it>and <it>MS4A</it>, independent evidence for association of <it>CD2AP, CD33 </it>and <it>EPHA1 </it>and an opposing yet significant association of a variant near <it>ARID5B</it>. In this study, we genotyped five variants (in or near <it>CD2AP, EPHA1, ARID5B</it>, and <it>CD33</it>) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and <it>APOE ε4 </it>dosage.</p> <p>Results</p> <p>We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for <it>EPHA1 </it>(rs11767557; OR = 0.87, p = 5 × 10^-4) and <it>CD33 </it>(rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two <it>ARID5B </it>variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the <it>CD2AP </it>variant (rs9349407, p = 0.56).</p> <p>Conclusions</p> <p>Our data overwhelmingly support the association of <it>EPHA1 </it>and <it>CD33 </it>variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10^-15(<it>EPHA1</it>) and 1.8 × 10^-13(<it>CD33</it>).</p

T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex

Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma

Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer’s pathophysiology and susceptibility

Background Alzheimer’s disease is a neurodegenerative disorder in which extracellular deposition of β-amyloid (Aβ) oligomers causes synaptic injury resulting in early memory loss, altered homeostasis, accumulation of hyperphosphorylated tau and cell death. Since proteins in the SNAP (Soluble N-ethylmaleimide-sensitive factor Attachment Protein) REceptors (SNARE) complex are essential for neuronal Aβ release at pre-synaptic terminals, we hypothesized that genetically controlled SNARE expression could alter neuronal Aß release at the synapse and hence play an early role in Alzheimer’s pathophysiology. Results Here we report 5 polymorphisms in Vesicle-Associated Membrane Protein 1 (VAMP1), a gene encoding a member of the SNARE complex, associated with bidirectionally altered cerebellar VAMP1 transcript levels (all p < 0.05). At the functional level, we demonstrated that control of VAMP1 expression by heterogeneous knockdown in mice resulted in up to 74% reduction in neuronal Aβ exocytosis (p < 0.001). We performed a case-control association study of the 5 VAMP1 expression regulating polymorphisms in 4,667 Alzheimer’s disease patients and 6,175 controls to determine their contribution to Alzheimer’s disease risk. We found that polymorphisms associated with increased brain VAMP1 transcript levels conferred higher risk for Alzheimer’s disease than those associated with lower VAMP1 transcript levels (p = 0.03). Moreover, we also report a modest protective association for a common VAMP1 polymorphism with Alzheimer’s disease risk (OR = 0.88, p = 0.03). This polymorphism was associated with decreased VAMP1 transcript levels (p = 0.02) and was functionally active in a dual luciferase reporter gene assay (p < 0.01). Conclusions Genetically regulated VAMP1 expression in the brain may modify both Alzheimer’s disease risk and may contribute to Alzheimer’s pathophysiology