SummaryBackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

When movements of individuals with stroke (iwS) are elicited by startling acoustic stimulus (SAS), reaching movements are faster, further, and directed away from the body. However, these startle-evoked movements also elicit task-inappropriate flexor activity, raising concerns that chronic exposure to startle might also induce heightened flexor activity during voluntarily elicited movement. The objective of this study is to evaluate the impact of startle exposure on voluntary movements during point-to-point reaching in individuals with moderate and severe stroke. We hypothesize that startle exposure will increase task-inappropriate activity in flexor muscles, which will be associated with worse voluntarily initiated reaching performance (e.g. decreased distance, displacement, and final accuracy). Eleven individuals with moderate-to-severe stroke (UEFM = 8–41/66 and MAS = 0–4/4) performed voluntary point-to-point reaching with 1/3 of trials elicited by an SAS. We used electromyography to measure activity in brachioradialis (BR), biceps (BIC), triceps lateral head (TRI), pectoralis (PEC), anterior deltoid (AD), and posterior deltoid (PD). Conversely to our hypothesis, exposure to startle did not increase abnormal flexion but rather antagonist activity in the elbow flexors and shoulder horizontal adductors decreased, suggesting that abnormal flexor/extensor co-contraction was reduced. This reduction of flexion led to increased reaching distance (18.2% farther), movement onset (8.6% faster), and final accuracy (16.1% more accurate) by the end of the session. This study offers the first evidence that exposure to startle in iwS does not negatively impact voluntary movement; moreover, exposure may improve volitionally activated reaching movements by decreasing abnormal flexion activity.

Purpose: The StartReact effect, whereby movements are elicited by loud, startling acoustic stimuli (SAS), allows the evaluation of movements when initiated through involuntary circuitry, before auditory feedback. When StartReact is applied during poststroke upper extremity movements, individuals exhibit increased muscle recruitment, reaction times, and reaching distances. StartReact releases unimpaired speech with similar increases in muscle recruitment and reaction time. However, as poststroke communication disorders have divergent neural circuitry from upper extremity tasks, it is unclear if StartReact will enhance speech poststroke. Our objective is to determine if (a) StartReact is present in individuals with poststroke aphasia and apraxia and (b) SAS exposure enhances speech intelligibility. Method: We remotely delivered startling, 105-dB white noise bursts (SAS) and quiet, non-SAS cues to 15 individuals with poststroke aphasia and apraxia during repetition of six words. We evaluated average word intensity, pitch, pitch trajectories, vowel formants F1 and F2 (first and second formants), phonemic error rate, and percent incidence of each SAS versus non–SAS-elicited phoneme produced under each cue type. Results: For SAS trials compared to non-SAS, speech intensity increased (∆ + 0.6 dB), speech pitch increased (∆ + 22.7 Hz), and formants (F1 and F2) changed, resulting in a smaller vowel space after SAS. SAS affected pitch trajectories for some, but not all, words. Non-SAS trials had more stops (∆ + 4.7 utterances) while SAS trials had more sustained phonemes (fricatives, glides, affricates, liquids; ∆ + 5.4 utterances). SAS trials had fewer distortion errors but no change in substitution errors or overall error rate compared to non-SAS trials. Conclusions: We show that stroke-impaired speech is susceptible to StartReact, evidenced by decreased intelligibility due to altered formants, pitch trajectories, and articulation, including increased incidence of sounds that could not be produced without SAS. Future studies should examine the impact of SAS on voluntary speech intelligibility and clinical measures of aphasia and apraxia.