SummaryBackgroundResults of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.MethodsFOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.FindingsBetween Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.InterpretationFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.FundingUK Stroke Association and NIHR Health Technology Assessment Programme.

Summary Background Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. Funding British Heart Foundation.

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy. Methods RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.

Obj ftcr/llfJ: To a s se s s whethe r selective sc reening lor ge stational diabe tes mellitus (GOM) on the bas is 01 risk-factor a s se ssment is a pra cticable alternative 10 universal sc reening.06slgn: Case-control study. Setting: A z tz-bed regiona l spectaust hospital in Melbourne, providing services in cbstevlcs an d gyna ecology, pa ed iatrics, gerialrics a nd rehabihtaticn.SUbJects : 6032 women who gave birth a t the hosp ital. Ma y 199610 August 1997 an d Novemb er 1997 to August 199B; all we re s creened for GDM, and 3 13 were diagnosed with the condition.Main outcome measures: Odds ratios (OAs) for rIs k tactore (age, obesity. fa mily history of dia betes rneunu s an d high· risk racia l he rita ge ) in women with GDM compa red to thos e wencut GOM; prcp crn cn 01women with GDM whose diagnosis would have been miss ed by selective sc ree ning.Results: ORs we re 1.9 for ag e ;;' 25 years {95 % Cl. 1.3-2.7). 2.3 lor body mass index ｾ 27 kglm 1 (95% Cl, 1.6-3.3). 2.5 for high.risk racial he ritage (95% Ct. 2.0-3.2), and 7.1 lor family history 01diab ete s mellitus (95% CI. 5.6-8.9). Othe r prop osed crite ria [p revsous GDM and glycosuria) a dded no further d iagn os tic power. Selective sc ree ning using me ab ove four c rite ria would have miss ed two 01 313 ca ses (0.6%) a nd cou ld have sa ved sc ree ning up to 1025 women ｷ ｩ ｴ ｨ ｯ ｵ ｾ GOM (17% 01all women), Conc lusions :Selective screening lor GOM ba sed on prior risk as s es sment ca n reduce the need lor lesting , with neg ligible loss 0 1 diagnostic efficiency.Wellt e rn HOJipital, Me lbou rn e , VIC.

Background The misnamed 'vitamin' D is actually the hormone calcitriol (1,25 dihydroxyhydroxyvitamin D). It has a central regulatory role in calcium metabolism, and more widely in the immune system. The prohormone calcifediol (25 hydroxyvitamin D) is more easily measured in the laboratory and is the analyte used in reference interval formulation. Being highly lipid soluble, both calcifediol and calcitriol travel in the bloodstream on carriage proteins, principally on vitamin D-binding protein. Summary This review reports our current understanding of vitamin D-binding protein. Its genetic determinants and their effect on it and secondarily on calcifediol concentrations and assays are described. Its complex interplay with parathyroid hormone is considered. The analytical state of the art is translated into the challenge it imposes clinically, in the formulation of reference intervals and in their use in advising and managing patients. Several recent challenges thrown up to laboratories by percipient clinicians highlight the dilemma vitamin D-binding protein poses. A way forward is suggested.