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Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenstrom macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ++1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P 5 .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ++3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.Copyright © 2020 American Society of Hematology. All rights reserved.

Objectives: This study sought to determine the long-term outcomes of restoring sinus rhythm with catheter ablation (CA). Background(s): The CAMERA-MRI (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Heart Failure-An MRI-Guided Multicenter Randomized Controlled Trial) study demonstrated that restoration of sinus rhythm with CA significantly improved left ventricular ejection fraction (LVEF) compared with medical rate control (MRC) at 6 months in persistent atrial fibrillation and otherwise unexplained systolic heart failure. However, the long-term outcomes have not been reported. Method(s): Patients enrolled in the CAMERA-MRI study were followed for 4 years with echocardiogram and cardiac magnetic resonance. CA involved pulmonary vein isolation and posterior left atrial wall isolation in 94%. Patients crossed over to CA after 6-month study duration. Arrhythmia burden was determined with implanted cardiac monitors or cardiac devices. Result(s): Sixty-six patients (age 62 +/- 10 years, atrial fibrillation duration of 22 +/- 16 months, and LVEF 33 +/- 9%) were randomized 1:1 to CA versus MRC. Eighteen of 33 patients crossed over from MRC group to CA group. At 4.0 +/- 0.9 years, atrial fibrillation recurred in 27 patients (57%) in the CA group with a mean burden of 10.6 +/- 21.2% after 1.4 +/- 0.6 procedures. There was an absolute increase in LVEF with CA of 16.4 +/- 13.3% compared with 8.6 +/- 7.6% in MRC (p = 0.001). In the CA group, the absence of ventricular late gadolinium enhancement was associated with a greater improvement in absolute LVEF (19 +/- 13% vs. 10 +/- 11% in the late gadolinium enhancement-positive group; p = 0.04) and LVEF normalization in 19 patients (58%) versus 4 patients (18%) in the late gadolinium enhancement-positive group (p = 0.008) at 4.0 +/- 0.9 years follow-up. Conclusion(s): CA is superior to MRC in improving LVEF in the long term in patients with atrial fibrillation and systolic heart failure. The greatest recov

OBJECTIVES: In children, intravenous therapy (IVT) is generally administered via peripheral intravenous catheters (PIVCs) (2-6 cm in length). There is evidence that PIVCs are unreliable after 2 days. Long peripheral catheters (LPCs) (6-15 cm in length) could improve the delivery of IVT. The aim of this trial was to determine if LPCs could decrease catheter failure and the number of catheters in children receiving multiday IVT. METHOD(S): This was an open-label randomized controlled trial conducted at Monash Children's Hospital in Melbourne, Australia. Participants were from the ages of 1 to 17 years, undergoing surgery and requiring.48 hours of postoperative IVT. Participants were randomly assigned to a 2.5-cm 22G PIVC or an 8-cm 22G LPC. RESULT(S): Seventy-two children were randomly assigned, 36 received PIVCs, and 36 received LPCs. The median duration of IVT was 5.1 days and was similar between groups (P =.9). Catheter failure was higher for PIVCs than LPCs (66.7% vs 19.4%; relative risk [RR]: 3.4; P =.0001 or 187.9 vs 41.0 failures per 1000 catheter-days). Infiltration was the most common reason for PIVC failure (33.3% vs 2.8%; RR: 12.0; P =.001). LPCs exhibited superior life span (4.7 vs 3.5 days [median]; P =.01). Children with LPCs were twice as likely to complete therapy with a single catheter (80.6% vs 38.9%; RR: 2.1; P =.0006). CONCLUSION(S): LPCs reduce catheter failure and total catheters in children. They should be considered as the first-line device for peripheral access in any child receiving prolonged IVT.Copyright © 2021 by the American Academy of Pediatrics

OBJECTIVES: We sought to compare the effects of conventional wire cerclage with that of the band and plate fixation of the sternum. METHOD(S): A parallel randomized open-label trial with 1:1 allocation ratio compared healing after adult cardiac surgery using 'figure-of-8' stainless steel wire cerclage or a band and plate system (plates). The primary end point was maximal sternal edge displacement during active coughing of >_2 mm in >_2 of 4 sites measured with ultrasound by 2 assessors blinded to the other at 6 weeks postoperatively. Secondary end points at 12 weeks included ultrasound assessment, computed tomography (CT) scan and multidimensional assessment of quality of recovery using the Postoperative Quality of Recovery Scale. RESULT(S): Of 50 patients, 26 received plates and 24 wires. Two patients died and 1 withdrew consent leaving 25 plates and 22 wires for primary end point analysis. Operations included 37 coronary, 5 valve and 8 combined coronary and valve procedures. At 6 weeks, less sternal movement was observed in patients with plates than those with wires, 4% (1/25) vs 32% (7/22), P = 0.018. Agreement between observers was high, kappa = 0.850. At 12 weeks, less ultrasound motion was seen in patients with plates, 0% (0/23) than those with wires, 25% (5/20), P = 0.014. Recovery from pain was higher for patients with plates 92% (22/24) than those with wires 67% (14/21), P = 0.004. CT bone edge separation was less for plates 38% (9/24) than wires 71% (15/21), P = 0.036. CT mild bone synthesis or greater was similar between patients with plates 21% (5/24) and wires 14% (3/21), P = 0.71. CONCLUSION(S): Patients receiving the band and plate system had significantly less sternal edge motion than those receiving wires, 6 and 12 weeks after cardiac surgery and experienced less pain.Copyright © The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Aims: International data demonstrate strong correlation between clinical trial participation and improved cancer survival. Adolescents and young adults (AYA) have low enrolment rates onto clinical trials and considerable international effort has worked to understand barriers to AYA trial access. In 2018, the Victorian Comprehensive Cancer Centre (VCCC) established a programof work to understand local barriers to AYA trial access, with the aim of developing targeted solutions that lead to greater AYA trial participation. Method(s): A steering committee (SC) was assembled, including expertise in adult and paediatric oncology, research ethics and governance, and consumer representation. The SC mapped Victorian barriers related to AYA trial access, and establishedWorking Groups (WG) around three themes: Ethics and Governance, Access, and Availability. EachWGwas tasked with identifying solutions to their assigned barriers. Result(s): Identified ethics barriers for AYA trials in Victoria were found to be perceived. A guideline document was produced to raise awareness of current processes that support the approval of protocols with age eligibility less than or equal to 18 years. The AccessWGidentified the most significant barrier was young adult (18-25 years) access to a paediatric hospital to enrol in a paediatric trial. A procedure has been written to streamline applications to Hospital Executive for young adult access (pending Executive approval). The availability WG identified a lack of reciprocal relationships between paediatric and adult oncology as a key barrier to awareness of open trials, and to future research collaboration. An 'AYA Craft Group' Framework has been established to support growth of such relationships within relevant tumour streams across institutions. Conclusion(s): A multi-pronged approach to improving AYA cancer clinical trial accrual has been developed. Although our program of work is Victorian based, the AYA trial equity issue should be on the

Background: After decades of ubiquitous oxygen therapy in all patients with acute myocardial infarction (MI), recent guidelines are more restrictive based on lack of efficacy in contemporary trials evaluating hard clinical outcomes in patients without hypoxemia at baseline. However, no evidence regarding treatment effects on health-related quality of life (HRQoL) exists. In this study, we investigated the impact of routine oxygen supplementation on HRQoL 6–8 weeks after hospitalization with acute MI. Secondary objectives included analyses of MI subtypes, further adjustment for infarct size, and oxygen saturation at baseline and 1-year follow-up. Methods: In the DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial, 6,629 normoxemic patients with suspected MI were randomized to oxygen at 6 L/min for 6–12 h or ambient air. In this prespecified analysis, patients younger than 75 years of age with confirmed MI who had available HRQoL data by European Quality of Life Five Dimensions questionnaire (EQ-5D) in the national registry were included. Primary endpoint was the EQ-5D index assessed by multivariate linear regression at 6–10 weeks after MI occurrence. Results: A total of 3,086 patients (median age 64, 22% female) were eligible, 1,518 allocated to oxygen and 1,568 to ambient air. We found no statistically significant effect of oxygen therapy on EQ-5D index (−0.01; 95% CI: −0.03–0.01; p = 0.23) or EQ-VAS score (−0.57; 95% CI: −1.88–0.75; p = 0.40) compared to ambient air after 6–10 weeks. Furthermore, no significant difference was observed between the treatment groups in EQ-5D dimensions. Results remained consistent across MI subtypes and at 1-year follow-up, including further adjustment for infarct size or oxygen saturation at baseline. Conclusions: Routine oxygen therapy provided to normoxemic patients with acute MI did not improve HRQoL up to 1 year after MI occurrence. Clinical Trial Registration: ClinicalTrials.gov number

Rationale: The comparative efficacy and cost-effectiveness of constraint-induced and multi-modality aphasia therapy in chronic stroke are unknown. Aims and hypotheses: In the COMPARE trial, we aim to determine whether Multi-Modal Aphasia Treatment (M-MAT) and Constraint-Induced Aphasia Therapy Plus (CIAT-Plus) are superior to usual care (UC) for chronic post-stroke aphasia. Primary hypothesis: CIAT-Plus and M-MAT will reduce aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient (WAB-R-AQ)) compared with UC: CIAT-Plus superior for moderate aphasia; M-MAT superior for mild and severe aphasia. Sample size estimates: A total of 216 participants (72 per arm) will provide 90% power to detect a 5-point difference on the WAB-R-AQ between CIAT-Plus or M-MAT and UC at alpha = 0.05. Methods and design: Prospective, randomized, parallel group, open-label, assessor blinded trial. Participant(s): Stroke >6 months; aphasia severity categorized using WAB-R-AQ. Computer-generated blocked and stratified randomization by aphasia severity (mild, moderate, and severe), to 3 arms: CIAT-Plus, M-MAT (both 30 h therapy over two weeks); UC (self-reported usual community care). Study outcomes: WAB-R-AQ immediately post-intervention. Secondary Outcomes: WAB-R-AQ at 12-week follow-up; naming scores, discourse measures, Communicative Effectiveness Index, Scenario Test, and Stroke and Aphasia Quality of Life Scale-39 g immediately and at 12 weeks post-intervention; incremental cost-effectiveness ratios compared with UC at 12 weeks. Discussion(s): This trial will determine whether CIAT-Plus and M-MAT are superior and more cost-effective than UC in chronic aphasia. Participant subgroups with the greatest response to CIAT-Plus and M-MAT will be described.Copyright © 2019 World Stroke Organization.

Background: Despite significant therapeutic advances in ITP over the past 15 years, a subset of patients is refractory to existing options and durable remission remains elusive. PRN1008 (rilzabrutinib) is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase targeting underlying disease mechanisms of platelet destruction. Initial phase I/II dose-escalation results support the 400 mg BID dose as optimal for clinical activity and safety (Kuter. ASH 2019). Aim(s): Subset efficacy/safety analysis of rilzabrutinib at optimal 400 mg BID dose. Method(s): This ongoing, open-label study examines rilzabrutinib in heavily-pretreated ITP adults with baseline platelet counts < 30,000/muL, including patients on stable doses of concomitant corticosteroids/thrombopoietin-receptor agonists who had inadequate response. Primary endpoint: >=2 consecutive platelet counts >=50,000/muL and increase of >=20,000/muL from baseline without requiring rescue medication. Result(s): As of 13Nov2019, 16 patients initiated rilzabrutinib 400 mg BID (14/16 ongoing). Median baseline age: 44.5 years (range, 21-74); all primary ITP for a median of 7.2 years (range, 0.8-40.3) and median of 6 prior therapies (range, 1-41; 25% prior splenectomy). Median baseline platelet count was 12,050/muL (range, 3500-27,670/ muL). Related treatment-emergent AEs (all grade 1/2) were similar to the overall study population; most frequent were nausea, diarrhea, and abdominal distension. With a median of 12.1 weeks (range, 1.3-28.9) of rilzabrutinib, 6/16 patients (38%) achieved the primary endpoint (Table 1); none required rescue medication. In 10 patients treated >=12 weeks, 5 (50%) achieved the primary endpoint. Platelet counts increased to >=30,000/muL by day 8 for 100% of responders (n=6/16; Figure 1) and this increase is predictive of achieving the primary endpoint and durable response. Conclusion(s): Rilzabrutinib 400 mg BID showed rapid, durable clinical activity, and a positive day 8 predictive value

Background In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed. Methods An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS. Results Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus <= 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus <= 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group. Conclusions Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR.Copyright © 2020 Clarke et al. Thi

Background: Electronic communication is used in various populations to achieve health goals, but evidence in stroke is lacking. We pilot tested the feasibility and potential effectiveness of a novel personalised electronic self-management intervention to support person-centred goal attainment and secondary prevention after stroke. Method(s): A phase I, prospective, randomised controlled pilot trial (1:1 allocation) with assessor blinding, intention-to-treat analysis, and a process evaluation. Community-based survivors of stroke were recruited from participants in the Australian Stroke Clinical Registry (AuSCR) who had indicated their willingness to be contacted for research studies. Inclusion criteria include 1-2 years following hospital admission for stroke and living within 50 km of Monash University (Melbourne). Person-centred goals were set with facilitation by a clinician using a standardised template. The intervention group received electronic support messages aligned to their goals over 4 weeks. The control group received only 2-3 electronic administrative messages. Primary outcomes were study retention, goal attainment (assessed using Goal Attainment Scaling method) and satisfaction. Secondary outcomes were self-management (Health Education Impact Questionnaire: 8 domains), quality of life, mood and acceptability. Result(s): Of 340 invitations sent from AuSCR, 73 responded, 68 were eligible and 57 (84%) completed the baseline assessment. At the goal-setting stage, 54/68 (79%) were randomised (median 16 months after stroke): 25 to intervention (median age 69 years; 40% female) and 29 to control (median age 68 years; 38% female). Forty-five (83%) participants completed the outcome follow-up assessment. At follow-up, goal attainment (mean GAS-T score >= 50) in the intervention group was achieved for goals related to function, participation and environment (control: environment only). Most intervention participants provided positive feedback and reported that th

Background Bronchiolitis is the most common reason for hospital admission in infants. High-flow oxygen therapy has emerged as a new treatment; however, the cost-effectiveness of using it as first-line therapy is unknown. Objective To compare the cost of providing high-flow therapy as a first-line therapy compared with rescue therapy after failure of standard oxygen in the management of bronchiolitis. Methods A within-trial economic evaluation from the health service perspective using data from a multicentre randomised controlled trial for hypoxic infants (<=12 months) admitted to hospital with bronchiolitis in Australia and New Zealand. Intervention costs, length of hospital and intensive care stay and associated costs were compared for infants who received first-line treatment with high-flow therapy (early high-flow, n=739) or for infants who received standard oxygen and optional rescue high-flow (rescue high-flow, n=733). Costs were applied using Australian costing sources and are reported in 2016-2017 AU$. Results The incremental cost to avoid one treatment failure was AU$1778 (95% credible interval (CrI) 207 to 7096). Mean cost of bronchiolitis treatment including intervention costs and costs associated with length of stay was AU$420 (95% CrI -176 to 1002) higher per infant in the early high-flow group compared with the rescue high-flow group. There was an 8% (95% CrI 7.5 to 8.6) likelihood of the early high-flow oxygen therapy being cost saving. Conclusions The use of high-flow oxygen as initial therapy for respiratory failure in infants with bronchiolitis is unlikely to be cost saving to the health system, compared with standard oxygen therapy with rescue high-flow.Copyright © 2020 BMJ Publishing Group. All rights reserved.

Aim: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. Method(s): Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 mug/L) were administered variable-dose tocilizumab. Result(s): At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. Conclusion(s): Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.Copyright © 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd

Importance: It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. Objective(s): To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. Design, Setting, and Participant(s): Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. Intervention(s): Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. Main Outcomes and Measures: The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. Result(s): Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was-0.6 hours (95% CI,-8.3 to 7.2 hours; P =.83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI

Background: AK112 is a humanized IgG1 bispecific anti-PD-1/VEGF antibody. VEGF blockade potentiates PD-1 inhibition by, inter alia, opposing the immunosuppressive effects of VEGF-A, which include suppression of dendritic cell activity and enhancement of checkpoint molecule expression on CD8+ T cells and proliferation of regulatory T cells. Combination therapies involving PD-(L)1 and VEGF inhibitors have been approved for the treatment of selected patients with metastatic non-small cell lung carcinoma, advanced renal cell carcinoma and advanced endometrial carcinoma. A supplemental Biologics License Application has been submitted for an anti-PD-L1 + anti-VEGF combination for the firstline treatment of unresectable hepatocellular carcinoma. Given the strong correlation between VEGF and PD-1 expression in the tumor microenvironment, the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificities and synergistically produce enhanced antitumor activity compared to co-administration of anti-PD-(L)1 and anti-VEGF therapies. Method(s): This is a Phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced or metastatic solid tumor that is refractory/relapsed to standard therapies. The primary objective is to assess safety, tolerability and DLTs; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose of AK112. Antitumor activity, PK and immunogenicity of AK112 will be studied as secondary objectives. As exploratory endpoints, tumor tissue samples may be evaluated for PD-L1 expression, mRNA expression profile and biomarkers (e.g. CD8+, FoxP3, Granzyme B, apelin and EPHB4). PD-1 receptor occupancy on circulating T-cells and serum VEGF level may also be measured as indications of target engagement. The dose-escalation phase will evaluate 5 dose levels of AK112 (up to 20 mg/kg Q2W IV) using a 3+3+3 study design. Additional subjects (up to 18 subjects) may be enrolled at any

Background: Prophylactic intra-aortic balloon counterpulsation (IABC) is commonly used in selected patients undergoing coronary artery bypass graft (CABG) surgery, but definitive evidence is lacking. The aim of the multicentre PINBALL Pilot randomised controlled trial (RCT) was to assess the feasibility of performing a definitive trial to address this question. Method(s): Patients listed for CABG surgery with impaired left ventricular function and at least one additional risk factor for postoperative low cardiac output syndrome were eligible for inclusion if the treating surgical team was uncertain as to the benefit of prophylactic IABC. The primary outcome of feasibility was based on exceeding a pre-specified recruitment rate, protocol compliance and follow-up. Result(s): The recruitment rate of 0.5 participants per site per month did not meet the feasibility threshold of two participants per site per month and the study was stopped early after enrolment of 24 out of the planned sample size of 40 participants. For 20/24 (83%) participants, preoperative IABC use occurred according to study assignment. Six (6)-month follow-up was available for all enrolled participants, [IABC 1 death (8%) vs. control 1 death (9%), p = 0.95]. Conclusion(s): The PINBALL Pilot recruitment rate was insufficient to demonstrate feasibility of a multicentre RCT of prophylactic IABC in high risk patients undergoing CABG surgery.Copyright © 2019

Background: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. Method(s): CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0.5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. Finding(s): Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to

Background: Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown. Method(s): In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks. Result(s): A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservativemanagement group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurren

BACKGROUND Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear. METHODS We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week "blanking period") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up. RESULTS Of 140 patients who underwent randomization (85% men; mean [+/-SD] age, 62+/-9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8+/-7.7 to 2.1+/-3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4+/-6.9 to 13.2+/-6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01). CONCLUSIONS Abstinence from alcohol reduced a

Introduction Acute hypoxaemic respiratory failure (AHRF) in children is the most frequent reason for non-elective hospital admission. During the initial phase, AHRF is a clinical syndrome defined for the purpose of this study by an oxygen requirement and caused by pneumonia, lower respiratory tract infections, asthma or bronchiolitis. Up to 20% of these children with AHRF can rapidly deteriorate requiring non-invasive or invasive ventilation. Nasal high-flow (NHF) therapy has been used by clinicians for oxygen therapy outside intensive care settings to prevent escalation of care. A recent randomised trial in infants with bronchiolitis has shown that NHF therapy reduces the need to escalate therapy. No similar data is available in the older children presenting with AHRF. In this study we aim to investigate in children aged 1 to 4 years presenting with AHRF if early NHF therapy compared with standard-oxygen therapy reduces hospital length of stay and if this is cost-effective compared with standard treatment. Methods and analysis The study design is an open-labelled randomised multicentre trial comparing early NHF and standard-oxygen therapy and will be stratified by sites and into obstructive and non-obstructive groups. Children aged 1 to 4 years (n=1512) presenting with AHRF to one of the participating emergency departments will be randomly allocated to NHF or standard-oxygen therapy once the eligibility criteria have been met (oxygen requirement with transcutaneous saturation <92%/90% (dependant on hospital standard threshold), diagnosis of AHRF, admission to hospital and tachypnoea >=35 breaths/min). Children in the standard-oxygen group can receive rescue NHF therapy if escalation is required. The primary outcome is hospital length of stay. Secondary outcomes will include length of oxygen therapy, proportion of intensive care admissions, healthcare resource utilisation and associated costs. Analyses will be conducted on an intention-to-treat basis. Ethics and dis

PURPOSE To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naive advanced anal cancer to establish the optimal regimen. PATIENTS AND METHODS Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m2 (day 1) plus FU 1,000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner. RESULTS We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; P 5 .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; P 5 .014). CONCLUSION This is the first international randomized trial to our knowledge conducted in chemotherapy-naive advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus pacli

Background: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. Methods: In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. Findings: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved eff

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 1 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P 5 .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities.Copyright © 2019 by The American Society of Hematology

Cognitive-behavioral therapy (CBT) is an evidence-based treatment for school refusal. However, some youth do not respond to CBT. The serious risks associated with school nonattendance call for novel approaches to help those who do not respond to CBT. Because school refusal is commonly associated with anxiety disorders, and the combination of CBT and antidepressant medication enhances outcomes in the treatment of anxiety disorders, combined treatment may be effective for school refusal. This narrative review evaluates the current evidence base for adding antidepressant treatment to CBT for school refusal. Six randomized controlled trials (RCTs), two open trials, six case studies/series, and one observational study were identified and reviewed. There is support for combined CBT and imipramine, but this medication is not typically used due to the risk of concerning side effects. Two recent RCTs failed to provide evidence for the superiority of combined CBT and fluoxetine. Further research in this area is required because the extant studies have a number of methodological limitations. Recommendations are provided for clinicians who consider prescribing antidepressant medication or referring for adjunctive antidepressant treatment for school refusal.Copyright © 2018

Introduction: KEYNOTE-155 (NCT02684617) evaluated the antitumor activity of pembrolizumab (pembro) plus dinaciclib in patients (pts) with relapsed/refractory (rr) CLL, MM, and DLBCL. Here we present data from an interim analysis of safety and efficacy in pts with rrDLBCL. Method(s): In this phase 1b, two-part, non-randomized, open-label study, pts with rrDLBCL who received >=2 prior therapies were enrolled into a dose-evaluation phase (two 21-day [d] cycles of pembro 200 mg [d1] and dinaciclib 7 mg/m2 [d1], 10 mg/m2 [d8] in cycle 1 and 14 mg/m2 [d1, d8] from cycle 2 onwards). The DLBCL expansion cohort was opened for the signal-detection phase (>=30 patients) if <=4 pts had dose-limiting toxicities (DLTs) during dose-evaluation. Treatment continued up to 35 cycles or until progression (PD) or unacceptable toxicity. Response was assessed every 3 cycles for DLBCL (Revised Response Criteria for Malignant Lymphoma 2007). Pts who discontinued before PD were followed Q12W until PD, new anticancer treatment, or death. The primary endpoint was safety and tolerability. Secondary endpoints included ORR by investigator, DOR, PFS, and OS. Efficacy and safety were assessed in all pts who received >=1 dose of pembrolizumab or dinaciclib. Result(s): As of Apr 25, 2018, 38 pts with rrDLBCL were enrolled and treated. Median age was 64.5 years (range, 39-85), 22 (58%) pts had ECOG PS 1, and 22 (58%) had >=3 prior therapies. After median follow-up of 2.79 mo (range, 1.5-6.8), 36 (95%) pts discontinued treatment: 21 (55%) PD, 12 (32%) by physician decision (10 [26%] clinical progression, 1[3%] logistics, 1 [3%] new therapy), 2 (5%) pt decision, and 1 (3%) AE. Median time on treatment was 51d (range, 1-471). Among 12 pts in all disease cohorts enrolled in the dose-evaluation phase, DLTs occurred in 1 of 6 (17%) evaluable pts (grade 4 thrombocytopenia) with rrDLBCL. Of 38 pts with rrDLBCL, 24 (63%) had a treatment-related AE. Common treatment-related AEs were decreased platelets (21%), l

Background: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). Method(s): KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. Finding(s): Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On Jul

Introduction Intracytoplasmic sperm injection (ICSI), originally introduced as add-on to in vitro fertilisation (IVF) for couples with severe male infertility, is in current clinical practice also used in couples with mild male or even unexplained infertility. However, ICSI has involved unresolved concerns regarding the selection and damage to gametes and the health conditions of the offspring, and it is also labour intensive and therefore more expensive than conventional IVF. High-quality well-powered randomised clinical trials (RCTs) comparing ICSI and IVF are lacking. Methods and analysis We propose a multicentre, open-label RCT in 10 reproductive medical centres across China. We will study couples with non-severe male infertility (defined as a semen concentrate 5-15x10 6/mL or sperm with a progressive motility 10%-32%) scheduled for their first or second ICSI or IVF cycle, as low fertility rate after fertilisation are more frequent in this population, which could lead to controversy about ICSI or conventional IVF for fertilisation. On the day of oocyte retrieval, eligible participants are after informed consent be randomised to undergo either ICSI or conventional IVF in a 1:1 treatment ratio. Other standard assisted reproductive treatments are similar and parallel between two groups. Our primary outcome is ongoing pregnancy leading to live birth after the first cycle with embryo transfer. To demonstrate or refute a difference of 7% between ICSI and conventional IVF, we need to include 2346 women (1173 in each intervention arm). In addition, we will follow-up neonatal outcomes after delivery to identify the influence of ICSI on offspring. Ethics and dissemination Ethical approval was obtained from Peking University Third Hospital medical science research ethics committee. The findings will be disseminated to the public through conference presentations and peer-reviewed scientific journals.Copyright © 2019 Author(s).

Background: Programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Tislelizumab is a humanized IgG4 monoclonal antibody against PD-1. A first-inhuman, phase 1A/1B study (NCT02407990) demonstrated that single-agent tislelizumab was generally well tolerated and showed evidence of antitumor activity in patients with advanced solid tumors at the recommended dose of 200 mg administered every 3 weeks (Q3W). BGB-A333 is a humanized IgG1 monoclonal antibody against PD-L1 which increased functional activities of human T cells in in vitro studies, and showed antitumor activity in various cancer xenograft models. BGB-A333 blocks the interaction between PD-L1 and CD80 (B7-1), which in turn release the inhibitory signals to Tcells, enhances T-cell expansion, and prevents T-cell energy induction. Therefore, a combination of anti-PD-1 and anti-PD-L1 can potentially elicit stronger antitumor immunity through blockade of multiple complementary immune-suppressive signals in tumor microenvironments. Method(s): This open-label study (NCT03379259) consists of two phases, each phase consisting of two parts. Phase 1 is designed to investigate the safety and tolerability of the BGB-A333 RP2D alone and in combination with tislelizumab. Phase 1A (BGB-A333 dose escalation) will follow a 3+3 design to establish the RP2D of BGB-A333. Phase 1B (combination dose confirmation) explores safety and tolerability of IV BGB-A333 (determined from dose escalation) in combination with IV tislelizumab (200 mg Q3W). Phase 2 is designed to evaluate the antitumor activity of BGB-A333 alone and in combination with tislelizumab. Phase 2A (BGB-A333 dose expansion) will enroll patients into two cohorts: non-small cell lung cancer and urothelial carcinoma. Phase 2B (combination dose expansion) will enroll patients with specific tumor types, which will be chosen based on data from phase 2A and other studies. The primary en

Background: Nivo (antiPD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3-4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti-PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)naive advBC cohort are reported. Method(s): Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1. 1 (includes unconfirmed responses). Result(s): As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had >=2 prior regimens. TRAEs occurred in 57% of pts (grade 3-4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-Onaive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 >1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusion(s): BMS-986205 + nivo was well tolerated in hea

BACKGROUND: Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied. METHOD(S): In an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from -5 [unresponsive] to +4 [combative]) was -2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days. RESULT(S): We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, -2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group. CONCLUSION(S): Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that

Background: Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus. Method(s): ConSEPT was an open-label, multicentre, randomised controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus that failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes 2 and 4) randomisation sequence, stratified by site and age (<=5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 min). The primary outcome was clinical cessation of seizure activity 5 min after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. Finding(s): Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed, and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 min after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (ris