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A new mixed-methods approach to knowing trajectories involving mentoring romantic relationship development.

power (hazard ratio 1·060, 95% credible interval 1·053-1·066). These associations persisted over the duration of mechanical ventilation.

Cumulative exposure to higher intensities of mechanical ventilation was harmful, even for short durations. Limiting exposure to driving pressure or mechanical power should be evaluated in further studies as promising ventilation strategies to reduce mortality in patients with acute respiratory failure.

Canadian Institutes of Health Research.

Canadian Institutes of Health Research.Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. Bexotegrast chemical structure The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.Burkitt lymphoma is a rare and aggressive non-Hodgkin lymphoma with three classifications endemic, sporadic, and immunodeficiency-related. High-intensity chemotherapeutic regimens have considerably improved overall survival for patients with Burkitt lymphoma. In this Review of HIV-associated Burkitt lymphoma, we summarise expert opinion and provide general recommendations for the treatment of Burkitt lymphoma in patients with HIV on the basis of retrospective and prospective studies, taking into consideration immune status, CD4 cell counts, the presence of systemic disease, and the risk of CNS involvement or relapse. Bexotegrast chemical structure We also discuss the role of rituximab and antiretroviral therapy. We highlight the reasons behind the possible different mechanisms of lymphomagenesis in HIV-associated Burkitt lymphoma and endemic Burkitt lymphoma, which indicate that HIV might have either a direct or indirect oncogenic role in Burkitt lymphoma. We discuss the possible mechanisms by which HIV and HIV proteins could directly contribute to lymphomagenesis. Identifying these mechanisms might lead to the development of therapies that have fewer toxic effects than high-intensity chemotherapeutic regimens.

Venous thromboembolism is associated with increased mortality risk in some populations, but how frequently it is a direct cause of death is unclear. We used data from venous thromboembolism prevention trials to evaluate the causal effect of venous thromboembolism reduction on mortality.

We did a systematic review and meta-analysis of randomised controlled trials (RCTs) evaluating venous thromboembolism prevention. We searched MEDLINE, Embase, PubMed, and Web of Science starting from Jan 1, 1993, to March 19, 2018. We included studies of patients who were at elevated risk of venous thromboembolism and were randomly assigned to either anticoagulant or antiplatelet therapy versus placebo or no treatment. We excluded studies with an active control agent (which might mitigate the lethality of venous thromboembolism) and those for which mortality data were unavailable. We modelled heterogeneity in a Bayesian framework, taking overall mortality as a primary endpoint, and pulmonary embolism, fatal pulmonary embolsm (RR 2·22, 95% CrI 1·78-2·89, p<0·0001) and fatal pulmonary embolism (1·58, 1·14-2·19, p=0·01), but less major bleeding (0·60, 0·47-0·75, p<0·0001) than those in treatment groups. A meta-analysis with the additional 34 negative studies yielded similar results for all endpoints except fatal pulmonary embolism, where evidence of an effect was weaker (1·42, 1·05-1·91, p=0·02).

The perception that venous thromboembolism is a common cause of mortality should be revised considering the null effect of venous thromboembolism prevention on mortality. Our findings call into question the use of composite endpoints in venous thromboembolism-prevention trials and provide rationale for de-escalation trials.

None.

None.

The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents.

We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week lon achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths.

Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment.

Karyopharm Therapeutics.

Karyopharm Therapeutics.