Ethnicity and thrombolysis in ischemic stroke: a hospital based study in Amsterdam

<p>Abstract</p> <p>Background</p> <p>Ethnic differences have been reported with regard to several medical therapies. The aim of this study was to investigate the relation between ethnicity and thrombolysis in stroke patients.</p> <p>Methods</p> <p>Retrospective single-centre study. Patients admitted with an ischemic stroke between 2003 and 2008 were included. Ethnicity was determined by self-identification and stratified into white and non-white (all other ethnicities). The main outcome measure was the difference in thrombolysis rate between white and non-white patients. Logistic regression analysis was used to identify potential confounders of the relation between ethnicity and thrombolysis.</p> <p>Results</p> <p>510 patients were included, 392 (77%) white and 118 (23%) non-white. Non-white patients were younger (median 69 vs. 60 years, p < 0.001), had a higher blood pressure at admission (median systolic 150 vs. 160 mmHg, p = 0.02) and a lower stroke severity (median NIHSS 5 vs. 4, p = 0.04). Non-white patients were significantly less often treated with thrombolysis compared to white patients (odds ratio 0.34, 95% CI 0.17-0.71), which was partly explained by a later arrival at the hospital. After adjustment for potential confounders (late arrival, age, blood pressure above upper limit for thrombolysis, and oral anticoagulation use), a trend towards a lower thrombolysis rate in non-whites remained (adjusted odds ratio 0.38, 95% CI 0.13 to 1.16).</p> <p>Conclusions</p> <p>Non-white stroke patients less often received thrombolysis than white patients, partly as a result of a delay in presentation. In this single centre study, potential bias due to hospital differences or insurance status could be ruled out as a cause. The magnitude of the difference is worrisome and requires further investigation. Modifiable causes, such as patient delay, awareness of stroke symptoms, language barriers and treatment of cardiovascular risk factors, should be addressed specifically in these ethnic groups in future stroke campaigns.</p

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia : The CREAM Consortium

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).Peer reviewe

TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes

The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense TMEM218 variants. Via MatchMaker Exchange, we identified biallelic TMEM218 variants in four additional families with ciliopathy phenotypes. Of note, four of the six families carry missense variants affecting the same highly conserved amino acid position 115. Clinical features included the molar tooth sign (N = 2), occipital encephalocele (N = 5, all fetuses), retinal dystrophy (N = 4, all living individuals), polycystic kidneys (N = 2), and polydactyly (N = 2), without liver involvement. Combined with existing functional data linking TMEM218 to ciliary transition zone function, our human genetic data make a strong case for TMEM218 dysfunction as a cause of ciliopathy phenotypes including JBTS with retinal dystrophy and Meckel syndrome. Identifying all genetic causes of the Joubert-Meckel spectrum enables diagnostic testing, prognostic and recurrence risk counseling, and medical monitoring, as well as work to delineate the underlying biological mechanisms and identify targets for future therapies

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial

Background: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. Methods: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0–2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5–8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. Findings: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3–88·5] for the experimental group vs 76·2% [68·0–84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. Interpretation: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. Funding: Organization for Health Research and Development and the Dutch Cancer Society

Simultaneous determination of CKM angle γ\gamma and charm mixing parameters

International audienceA combination of measurements sensitive to the CP violation angle γ of the Cabibbo-Kobayashi-Maskawa unitarity triangle and to the charm mixing parameters that describe oscillations between D$^{0}$ and $\overline{D} ^{0}$ mesons is performed. Results from the charm and beauty sectors, based on data collected with the LHCb detector at CERN’s Large Hadron Collider, are combined for the first time. This method provides an improvement on the precision of the charm mixing parameter y by a factor of two with respect to the current world average. The charm mixing parameters are determined to be $x=\left({0.400}_{-0.053}^{+0.052}\right)\%$ and y = $\left({0.630}_{-0.030}^{+0.033}\right)\%$. The angle γ is found to be γ = $\left({65.4}_{-4.2}^{+3.8}\right){}^{\circ}$ and is the most precise determination from a single experiment.[graphic not available: see fulltext

First measurement of the Z→μ+μ−Z\rightarrow \mu^+ \mu^- angular coefficients in the forward region of pppp collisions at s=13\sqrt{s}=13 TeV

The first study of the angular distribution of $\mu^+ \mu^-$ pairs produced in the forward rapidity region via the Drell-Yan reaction $pp \rightarrow \gamma^{*}/Z +X \rightarrow l^+ l^- + X$ is presented, using data collected with the LHCb detector at a centre-of-mass energy of 13TeV, corresponding to an integrated luminosity of 5.1 $\rm{fb}^{-1}$. The coefficients of the five leading terms in the angular distribution are determined as a function of the dimuon transverse momentum and rapidity. The results are compared to various theoretical predictions of the $Z$-boson production mechanism and can also be used to probe transverse-momentum-dependent parton distributions within the proton