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Background: \ud Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT).\ud \ud Methods: \ud COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130.\ud \ud Findings: \ud Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273. The results were similar between those aged 30–69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.\ud \ud Interpretation: \ud All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination.\ud \ud Funding: \ud UK Vaccine Taskforce and National Institute for Health Research.

AimTo study the association of caregiver factors and stroke patient factors with rehospitalizations over the first 3 months and subsequent 3–12 months post-stroke in Singapore.MethodsPatients with stroke and their caregivers were recruited in the Singapore Stroke Study, a prospective yearlong cohort. While caregiver and patient variables were taken from this study, hospitalization data were extracted from the national claims database. We used Poisson modelling to perform bivariate and multivariable analysis with counts of hospitalization as the outcome.ResultsTwo hundred and fifty-six patient with stroke and caregiver dyads (N = 512) were analysed, with patients having spouse (60%), child (29%), sibling (4%) and other (7%) as their caregivers. Among all participants, 89% of index strokes were ischemic, 57% were mild in severity and more than half (59%) of the patients had moderate or severe disability post-stroke as measured on the Modified Rankin Scale. Having social support in the form of a foreign domestic worker for general help of caregiver reduced the hospitalization rate over 3 months post-stroke by 66% (IRR: 0.342; 95% CI: 0.180, 0.651). Compared to having a spousal caregiver, those with a child caregiver had an almost three times greater rate of hospitalizations over 3–12 months post-stroke (IRR: 2.896; 95% CI: 1.399, 5.992). Higher reported caregiving burden at the 3-month point was associated with the higher subsequent rate of hospitalization.ConclusionRecommendations include the adoption of a dyadic or holistic approach to post-stroke care provision by healthcare practitioners, giving due importance to both patients with stroke and their caregivers, integrating caregivers in the healthcare system to extend the care continuum to include informal care in the community and provision of timely support for caregivers.

Background Health-related quality of life (HRQoL) is a key metric to understand the impact of stroke from patients’ perspective. Yet HRQoL is not readily measured in clinical practice. This study aims to investigate the extent to which clinical outcomes during admission predict HRQoL at 3 months and 1 year post-stroke. Methods Stroke patients admitted to five tertiary hospitals in Singapore were assessed with Shah-modified Barthel Index (Shah-mBI), National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), and Frontal Assessment Battery (FAB) before discharge, and the EQ-5D questionnaire at 3 months and 12 months post-stroke. Association of clinical measures with the EQ index at both time points was examined using multiple linear regression models. Forward stepwise selection was applied and consistently significant clinical measures were analyzed for their association with individual dimensions of EQ-5D in multiple logistic regressions. Results All five clinical measures at baseline were significant predictors of the EQ index at 3 months and 12 months, except that MMSE was not significantly associated with the EQ index at 12 months. NIHSS (3-month standardized β = − 0.111; 12-month standardized β = − 0.109) and mRS (3-month standardized β = − 0.122; 12-month standardized β = − 0.080) were shown to have a larger effect size than other measures. The contribution of NIHSS and mRS as significant predictors of HRQoL was mostly explained by their association with the mobility, self-care, and usual activities dimensions of EQ-5D. Conclusions HRQoL at 3 months and 12 months post-stroke can be predicted by clinical outcomes in the acute phase. NIHSS and mRS are better predictors than BI, MMSE, and FAB.

Background Health services research aimed at understanding service use and improving resource allocation often relies on collecting subjectively reported or proxy-reported healthcare service utilization (HSU) data. It is important to know the discrepancies in such self or proxy reports, as they have significant financial and policy implications. In high-dependency populations, such as stroke survivors, with varying levels of cognitive impairment and dysphasia, caregivers are often potential sources of stroke survivors’ HSU information. Most of the work conducted on agreement analysis to date has focused on validating different sources of self-reported data, with few studies exploring the validity of caregiver-reported data. Addressing this gap, our study aimed to quantify the agreement across the caregiver-reported and national claims-based HSU of stroke patients. Methods A prospective study comprising multi-ethnic stroke patient and caregiver dyads (N = 485) in Singapore was the basis of the current analysis, which used linked national claims records. Caregiver-reported health services data were collected via face-to-face and telephone interviews, and similar health services data were extracted from the national claims records. The main outcome variable was the modified intraclass correlation coefficient (ICC), which provided the level of agreement across both data sources. We further identified the amount of over- or under-reporting by caregivers across different service types. Results We observed variations in agreement for different health services, with agreement across caregiver reports and national claims records being the highest for outpatient visits (specialist and primary care), followed by hospitalizations and emergency department visits. Interestingly, caregivers over-reported hospitalizations by approximately 49% and under-reported specialist and primary care visits by approximately 20 to 30%. Conclusions The accuracy of the caregiver-reported HSU of stroke patients varies across different service types. Relatively more objective data sources, such as national claims records, should be considered as a first choice for quantifying health care usage before considering caregiver-reported usage. Caregiver-reported outpatient service use was relatively more accurate than inpatient service use over shorter recall periods. Therefore, in situations where objective data sources are limited, caregiver-reported outpatient information can be considered for low volumes of healthcare consumption, using an appropriate correction to account for potential under-reporting. Electronic supplementary material The online version of this article (10.1186/s12913-018-3634-4) contains supplementary material, which is available to authorized users.

We describe a rare neurological presentation of internal jugular vein thrombosis induced by central venous catheter placement in a patient with cancer. A 71-year-old man gave a 3-week history of dysphagia and dysarthria with left-sided neck pain and headache. He was receiving chemotherapy for appendiceal adenocarcinoma. On examination, he had left 9th-12th cranial neuropathies, manifesting as voice hoarseness, decreased palatal movement, absent gag reflex, weakness of scapular elevation and left-sided tongue wasting. CT scan of neck showed the left subclavian central venous catheter tip was in the left internal jugular vein. Skull base MRI showed thrombus within the left jugular foramen extending intracranially. We diagnosed Collet-Sicard syndrome secondary to thrombosis in the sigmoid-jugular venous complex. His headache and neck pain resolved 2 days after removing the catheter and starting anticoagulation. Collet-Sicard syndrome is an unusual syndrome of lower cranial nerve palsies, often signifying disease at the skull base, including malignancy, trauma or vascular causes.

There has been resurgence in the attention placed on pharmacotherapy in atrial fibrillation (AF) recently as specialists in international conferences discuss the utility of novel anticoagulants with caution owing to limited knowledge of the side effect profile in this nascent stage. AF is a well-known risk factor for stroke and has been for more than 20 years, since warfarin was demonstrated to reduce the risk of stroke, with aspirin doing so to a lesser degree.1 Today, there is international variation in the use of warfarin to prevent stroke despite well-established data.2 Singapore finds itself in a peculiar geographical and clinical position.

To report the serial magnetic resonance (MR) imaging findings of the Nipah virus.Twelve patients underwent serial MR imaging. Eight patients were examined at the outbreak; 11, at 1 month; and seven, at 6 months. Contrast material-enhanced MR images, diffusion-weighted images, and single-voxel proton MR spectroscopic images were reviewed. Clinical and neurologic assessment, as well as analysis of the size, location, and appearance of brain lesions on MR images, were performed.During the outbreak, all eight patients had multiple small foci of high signal intensity within the white matter on T2-weighted images. In six patients, cortical and brain stem lesions were also detected, and five patients had diffusion-weighted MR imaging-depicted hyperintensities. One month after the outbreak, five patients had widespread tiny foci of high signal intensity on T1-weighted images, particularly in the cerebral cortex. Diffusion-weighted images showed decreased prominence or disappearance of lesions over time. There was no evidence of progression or relapse of the lesions at 6-month follow-up. MR spectroscopy depicted reduction in N-acetylaspartate-to-creatine ratio and elevation of choline-to-creatine ratios.The Nipah virus has findings unlike other viral encephalitides: small lesions that are primarily within the white matter, with transient punctate cortical hyperintensities on T1-weighted images.

Editors' Note: In response to the article “The quest to prevent stroke in atrial fibrillation: Fighting the fluttering heart in Singapore,” Dr. Sethi comments on the challenges faced by neurologists in countries where traditional and Western medicines are used in parallel. Authors Goh et al. outline efforts made in Singapore to integrate the 2 spheres. Dr. Svenningsson et al. question several aspects of the article “MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study” on ethical grounds, specifically the …

Summary Background In March 1999, an outbreak of encephalitis and pneumonia occurred in workers at an abattoir in Singapore. We describe the clinical presentation and the results of investigations in these patients. Methods Clinical and laboratory data were collected by systemic review of the case records. Serum and cerebrospinal fluid (CSF) samples were tested for IgM antibodies to Nipah virus with an IgM capture ELISA. Reverse-transcriptase PCR was done on the CSF and tissue samples from one patient who died. Findings Eleven patients were confirmed to have acute Npah-virus infection based on raised IgM in serum. Mpah virus was identified by reverse-transcriptase PCR in the CSF and tissue of the patient who died. The patients were all men, with a median age of 44 years. The commonest presenting symptoms were fever, headache, and drowsiness. Eght patients presented with signs of encephalitis (decreased level of consciousness or focal neurological signs). Three patients presented with atypical pneumonia, but one later developed hallucinations and had evidence of encephalitis on CSF examination Abnormal laboratory findings included a bw lymphocyte count (nine patients), low platelet count, low serum sodium, and high aspartate aminostransferase concentration (each observed in five patients). The CSF protein was high in eight patients and white-blood-cell count was high in seven Chest radiography showed mild interstitial shadowing in eight patients. Magnetic resonance imaging (MRI) showed focal areas of increased signal intensity in the cortical white marker in all eight patients who were scanned. The nine patients with encephalitis received empirical treatment with intravenous aciclovir and eight survived. Interpretation Infection with Nipah virus caused an encephalitis illness with characteristic focal areas of increased intensity seen on MRI Lung involvement was also common, and the disease may present as an atypical pneumonia.

A novel Hendra-like paramyxovirus named Nipah virus (NiV) was the cause of an outbreak among workers from one abattoir who had contact with pigs. Two patients had only respiratory symptoms, while 9 patients had encephalitis, 7 of whom are described in this report. Neurological involvement was diverse and multifocal, including aseptic meningitis, diffuse encephalitis, and focal brainstem involvement. Cerebellar signs were relatively common. Magnetic resonance imaging scans of the brain showed scattered lesions. IgM antibodies against Hendra virus (HeV) were present in the serum of all patients. Two patients recovered completely. Five had residual deficits 8 weeks later.

Background Safe Implementation of Thrombolysis in Stroke-Non-European Union World was a multinational, prospective, open, monitored, observational study of intravenous alteplase as thrombolytic therapy in clinical practice. Safe Implementation of Thrombolysis in Stroke-Non-European Union World was required to assess the safety of alteplase in an Asian population by comparison with results from the European Safe Implementation of Thrombolysis in Stroke-Monitoring Study and pooled results from randomized controlled trials. Aims and/or hypothesis To evaluate the efficacy and safety of intravenous alteplase (0·9 mg/kg) as thrombolytic therapy within three-hours of onset of acute ischaemic stroke in an Asian population. Methods The 591 patients included were treated at 48 centers in four countries (South Korea, China, India, and Singapore) between 2006 and 2008. Primary outcomes were symptomatic (deterioration in National Institutes of Health Stroke Scale score ≥4 or death within the first 24 h) intracerebral haemorrhage type 2 22–36 h after the thrombolysis and mortality at three-month follow-up. The secondary outcome was functional independence (modified Rankin Scale score 0–2) at three-months. Results were compared with those from Safe Implementation of Thrombolysis in Stroke-Monitoring Study ( n = 6483) and pooled results of patients ( n = 415) who received intravenous alteplase (0·9 mg/kg) zero- to three-hours from onset of stroke symptoms in four randomized controlled trials (National Institute of Neurological Disorders and Stroke A and B, Altephase Thrombolysis for Acute Noninterventional Therapy in Ischaemic Stroke, and European Cooperative Acute Stroke Study II). Results Results are presented as Safe Implementation of Thrombolysis in Stroke-Non-European Union World vs. Safe Implementation of Thrombolysis in Stroke-Monitoring Study vs. pooled randomized controlled trials. Median age was 64 vs. 68 vs. 70 years, National Institutes of Health Stroke Scale score at baseline was 12 vs. 12 vs. 13, time from stroke onset to treatment was 130 vs. 140 vs. 135 mins, and females were 36·4% vs. 39·8% vs. 41·2%. Main outcomes (proportion of patients and 95% confidence intervals) were symptomatic intracerebral haemorrhage: 1·9% (1·1–3·3) vs. 1·7% (1·4–2·0) vs. 3·1% (1·8–5·3); mortality: 10·2% (8·0–12·9) vs. 11·3% (10·5–12·1) vs. 16·4% (13·1–20·3); and functional independence: 62·5% (58·5–66·4) vs. 54·8% (53·5–56·0) vs. 50·1% (45·3–54·9) at three-months. Adjusted odds ratio (95% confidence intervals) between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and Safe Implementation of Thrombolysis in Stroke-Monitoring Study, and between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and the pooled trials were 1·83 (0·89–3·77; P = 0·1156) and 0·63 (0·19–2·07; P = 0·4470) for symptomatic intracerebral haemorrhage, 0·90 (0·64–1·25; P = 0·5092) and 0·93 (0·52–1·64; P = 0·7915) for mortality at three-months, and 1·57 (1·25–1·96; P < 0·0001) and 1·35 (0·91–2·00; P = 0·1325) for functional independence. Conclusions These data demonstrate the safety and efficacy of the standard dose of intravenous alteplase (0·9 mg/kg) in an Asian population, as previously observed in the European population studied in Safe Implementation of Thrombolysis in Stroke-Monitoring Study and the populations in pooled randomized controlled trials, when used in routine clinical practice within three-hours of stroke onset. The findings should encourage wider use of thrombolytic therapy in Asian countries for suitable patients treated in stroke centers.

Introduction: Inconsistencies in the recommendation of prophylactic antibiotics for patients with intracranial pressure monitors compelled us to assess the effect of our standard regimen of continuous antibiotic prophylaxis on cerebrospinal fluid infection. We examined the rate, possible risk factors, causative organisms, and characteristics of infection. Methods: Three hundred eleven patients admitted between September 1998 and February 2001 with an intracranial pressure monitoring device in place were included. Two hundred eleven patients received a ventriculostomy, 95 an intraparenchymal fiber optic intracranial pressure monitor (ICPM), and 5 both an ICPM and a ventriculostomy. Results: The overall infection rate was 5.5% (17/311). No patient with an ICPM developed CSF infection. The infection rate among ventriculostomy patients was 8.1% (17/211). The majority of infections (82%) were caused by Gram-positive species. Younger age (OR=1.04 for each year, 95% CI=1.01–1.08, p=0.03) and increasing duration of ventriculostomy insertion (OR=1.2 for each day of catheter insertion, 95% CI=1.1–1.3, p