Explore the vast range of titles available.

Atraumatic convexity subarachnoid haemorrhage describes spontaneous bleeding into the convexities of the brain sulci without parenchymal involvement. Its many causes include reversible cerebral vasoconstriction syndrome, cerebral sinus venous thrombosis, posterior reversible encephalopathy syndrome and (in older people) cerebral amyloid angiopathy. We describe the clinical and radiological features of non-traumatic convexity subarachnoid haemorrhage with its various presentations, causes, treatments and prognoses, and use clinical vignettes to highlight important clinical points and pitfalls.

BackgroundPatients with chronic kidney disease are at increased risk of stroke and frequently have cerebral microbleeds. Whether such patients also encounter an increased risk of recurrent stroke has not been firmly established. We aimed to determine whether impaired kidney function is associated with the risk of recurrent stroke, and microbleed presence, distribution and severity.MethodsWe used pooled data from the Microbleeds International Collaborate Network to investigate associations of impaired kidney function, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Our primary outcome was a composite of recurrent ischaemic stroke (IS) and intracranial haemorrhage (ICrH). Secondary outcomes included: (1) individual components of the primary outcome; (2) modification of the primary outcome by microbleed presence or anticoagulant use and (3) microbleed presence, distribution and severity.Results11 175 patients (mean age 70.7±12.6, 42% female) were included, of which 2815 (25.2%) had impaired kidney function. Compared with eGFR ≥60, eGFR <60 was associated with a higher risk of the primary outcome (adjusted HR, aHR 1.33 (95% CI 1.14 to 1.56), p<0.001) and higher rates of the recurrent IS (aHR 1.33 (95% CI 1.12 to 1.58)). Reduced eGFR was not associated with ICrH risk (aHR 1.07 (95% CI 0.70 to 1.60)). eGFR was also associated with microbleed presence (adjusted OR, aOR 1.14 (95% CI 1.03 to 1.26)) and severity (aOR 1.17 (95% CI 1.06 to 1.29)). Compared with having no microbleeds, eGFR was lower in those with strictly lobar microbleeds (adjusted mean difference (aMD) −2.10 mL/min/1.73 cm2 (95% CI −3.39 to −0.81)) and mixed microbleeds (aMD −2.42 (95% CI −3.70 to −1.15)), but not strictly deep microbleeds (aMD −0.67 (95% CI −1.85 to 0.51)).ConclusionsIn patients with IS or transient ischaemic attack, impaired kidney function was associated with a higher risk of recurrent stroke and higher microbleeds burden, compared with those with normal kidney function. Further research is needed to investigate potential additional measures for secondary prevention in this high-risk group.

Abstract Introduction Glomerular hyperfiltration has previously been associated with cardiovascular events and mortality but has scarcely been investigated in patients with stroke. Patients and methods We used pooled data from an individual patient data meta-analysis of prospective, cohort studies of stroke or TIA populations. For this analysis, we included participants from study sites that collected estimated glomerular filtration rate (eGFR) at stroke presentation. Using Cox proportional hazards regression, we investigated the risk of death, any stroke and vascular death according to glomerular hyperfiltration, defined as having an eGFR greater than the age- and sex-adjusted 95th percentile. We also investigated these outcomes according to eGFR as a continuous variable, modelled using fractional polynomials. Results A total of 11,175 patients (mean age 70.7 years, 42% female) were included in the analysis, 554 (4.9%) with hyperfiltration. Compared to the normofiltration group (absence of hyperfiltration and eGFR ≥ 60 mL/min/1.73 m2), the hyperfiltration group had a higher rate of all-cause death, 147 per 1000 person-years (95% CI, 119–180) vs 61 (95% CI, 57–66). Compared to normofiltration, hyperfiltration was independently associated with the risk of death from any cause (adjusted hazard ratio [HR] 1.76; 95% CI, 1.46–2.11; P < .001) and the risk of vascular death (adjusted HR 1.68; 95% CI, 1.29–2.17; P < .001). There were non-linear associations of eGFR with risk of death and vascular death, with increasing risk at both low and high eGFR (Pnon-linearity < .001 for both). Discussion and conclusion Glomerular hyperfiltration was associated with a 76% increased risk of death and a 68% increased risk of vascular death in multivariable models adjusted for age, sex and comorbidities. Glomerular hyperfiltration may be associated with adverse health outcomes, specifically in patients with ischaemic stroke. Further research is needed to confirm these findings. Graphical Abstract Graphical Abstract

Introduction Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018-2019 had an impact on fluoroquinolone prescribing rates. Methods A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC). Results The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC - 33.3%, 95% confidence interval [CI] - 35.9 to - 30.7; Germany: February/May 2019, MPC - 12.6%, 95% CI - 13.7 to - 11.6]; UK: January/April 2016, MPC - 4.9%, 95% CI - 6.2 to - 3.6). Conclusion The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care.

Whole-exome sequencing of circulating tumor cells enables accurate and powered calling of somatic point mutations. Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

Reoperation rates are high after surgery for hip fractures. We investigated the effect of a sliding hip screw versus cancellous screws on the risk of reoperation and other key outcomes. For this international, multicentre, allocation concealed randomised controlled trial, we enrolled patients aged 50 years or older with a low-energy hip fracture requiring fracture fixation from 81 clinical centres in eight countries. Patients were assigned by minimisation with a centralised computer system to receive a single large-diameter screw with a side-plate (sliding hip screw) or the present standard of care, multiple small-diameter cancellous screws. Surgeons and patients were not blinded but the data analyst, while doing the analyses, remained blinded to treatment groups. The primary outcome was hip reoperation within 24 months after initial surgery to promote fracture healing, relieve pain, treat infection, or improve function. Analyses followed the intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT00761813. Between March 3, 2008, and March 31, 2014, we randomly assigned 1108 patients to receive a sliding hip screw (n=557) or cancellous screws (n=551). Reoperations within 24 months did not differ by type of surgical fixation in those included in the primary analysis: 107 (20%) of 542 patients in the sliding hip screw group versus 117 (22%) of 537 patients in the cancellous screws group (hazard ratio [HR] 0·83, 95% CI 0·63–1·09; p=0·18). Avascular necrosis was more common in the sliding hip screw group than in the cancellous screws group (50 patients [9%] vs 28 patients [5%]; HR 1·91, 1·06–3·44; p=0·0319). However, no significant difference was found between the number of medically related adverse events between groups (p=0·82; appendix); these events included pulmonary embolism (two patients [<1%] vs four [1%] patients; p=0·41) and sepsis (seven [1%] vs six [1%]; p=0·79). In terms of reoperation rates the sliding hip screw shows no advantage, but some groups of patients (smokers and those with displaced or base of neck fractures) might do better with a sliding hip screw than with cancellous screws. National Institutes of Health, Canadian Institutes of Health Research, Stichting NutsOhra, Netherlands Organisation for Health Research and Development, Physicians' Services Incorporated.

Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years). In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. British Heart Foundation and UK Stroke Association.

Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69–0·77) with a calibration slope of 0·94 (0·81–1·06) for the intracranial haemorrhage model and 0·63 (0·62–0·65) with a calibration slope of 0·97 (0·87–1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. British Heart Foundation and Stroke Association.

Hormone receptors HER2/neu and Ki-67 are markers of residual risk in early breast cancer. An algorithm (IHC4) combining these markers may provide additional information on residual risk of recurrence in patients treated with hormone therapy. To independently validate the IHC4 algorithm in the multinational Tamoxifen Versus Exemestane Adjuvant Multicenter Trial (TEAM) cohort, originally developed on the trans-ATAC (Arimidex, Tamoxifen, Alone or in Combination Trial) cohort, by comparing 2 methodologies. The IHC4 biomarker expression was quantified on TEAM cohort samples (n = 2919) by using 2 independent methodologies (conventional 3,3'-diaminobezidine [DAB] immunohistochemistry with image analysis and standardized quantitative immunofluorescence [QIF] by AQUA technology). The IHC4 scores were calculated by using the same previously established coefficients and then compared with recurrence-free and distant recurrence-free survival, using multivariate Cox proportional hazards modeling. The QIF model was highly significant for prediction of residual risk (P < .001), with continuous model scores showing a hazard ratio (HR) of 1.012 (95% confidence interval [95% CI]: 1.010-1.014), which was significantly higher than that for the DAB model (HR: 1.008, 95% CI: 1.006-1.009); P < .001). Each model added significant prognostic value in addition to recognized clinical prognostic factors, including nodal status, in multivariate analyses. Quantitative immunofluorescence, however, showed more accuracy with respect to overall residual risk assessment than the DAB model. The use of the IHC4 algorithm was validated on the TEAM trial for predicting residual risk in patients with breast cancer. These data support the use of the IHC4 algorithm clinically, but quantitative and standardized approaches need to be used.

Abstract Talaromyces marneffei causes fatal invasive mycosis in Southeast Asia. Diagnosis by culture has limited sensitivity and can result in treatment delay. We describe the use of a novel Mp1p enzyme immunoassay (EIA) to identify blood culture–negative talaromycosis, subsequently confirmed by bone marrow cultures. This EIA has the potential to speed diagnosis, enabling early therapy initiation.