Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0–2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30–0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69–0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81–0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Funding: Medtronic

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

Cryopreservation of rainbow trout

Cryopreservation of sperm is an important component of genetic conservation programs for fish. However, since fish eggs or embryos cannot be successfully cryopreserved and since the mitochondrial DNA is maternally inherited, the mitochondrial genomes of fish populations are presently not being preserved in these programs. One method of obtaining eggs from stored materials would be to cryopreserve embryonic cells that could later be transplanted into female recipient embryos, forming chimeras; a proportion of these transplanted cells would be expected to enter the germ line and subscquently develop into eggs. The hypothesis of this study is that isolated blastomeres of rainbow trout can be successfully cryopreserved and thawed. The objective of this investigation was to determine if the rate of cooling or the type of container alters cryopreservation success. Isolated blastomeres in a freezing solution containing 8.7% DMSO were subjected to one of two different cooling rates in either 0.5 ml French semen straws or cryovials. Thawed samples were examined using phase contrat microscopy, wkh cells scored as being either intact or non-intact. In the nonfrozen control group, 85.4%f 7.6 ($\bar{x}$ ± S.D.) of the blastomeres were intact. There was no significant difference between the cooling rates used in this investigation based on the proportion of intact cells, but there was a significant (p < 0.002) difference in the proportion of intact cells between samples frozen in French straws (35.9% ± 16.5) and those frozen in cryovials (19.4% ± 4.9)

Variation Among Rainbow Trout (Oncorhynchus mykiss) Estrogen Receptor Isoform 3′ Untranslated Regions and the Effect of 17β-Estradiol on mRNA Stability in Hepatocyte Culture

Adenine and uridine (AU)–rich elements in the 3′ untranslated region (3′UTR) have been implicated in the 17β-estradiol (E2) stabilization of vertebrate estrogen receptor (ER) mRNAs. To date, fishes have the most complex arrangement of nuclear ERs with up to two isoforms of each of the two genes in some species (i.e., four different ERs). The objective of this study was to analyze the sequence variation of 3′UTRs among the four ER isoforms in the rainbow trout and determine to what degree it is responsible for the estrogen-induced increase of ER mRNAs in the liver of this fish. This was done by comparing the 3′UTR DNA sequence length and composition, and by measuring expression of ER isoform 3′UTR luciferase reporter constructs in primary cultures of trout hepatocytes treated with E2. There were large differences both in overall length and in sequence composition among the four ER isoform 3′UTRs. The ERα1 sequence was the longest and the only one of the four that contained multiple copies of the canonical AU-rich elements (AUUUA) as well as the stability sequence (GCUGAU). E2 treatment significantly increased the luciferase activity in cells transiently transfected with the ERα1 reporter construct, relative to cells transfected with reporter vectors containing the other three ER isoform 3′UTRs or the parental vector control. These results support the hypothesis that the E2-induced increase in hepatic ERα1 mRNA in rainbow trout is due in part to sequence variability among ER isoform 3′UTRs. We conclude that posttranscriptional stabilization of ER mRNA by E2 appears to be conserved among vertebrates

Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial

Background Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. Methods In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [= 15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials. gov, number NCT00818441, and is no longer accruing patients. Findings Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76.8% (95% CI 66.4-84.4) in the as-enrolled population, and was 95.5% (95% CI 83.2-98.9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. Interpretation Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.

Behavioral determinants of arsenic-safe water use among Great Plains Indian Nation private well users: results from the Community-Led Strong Heart Water Study Arsenic Mitigation Program

Abstract Background The objective of this study was to evaluate the behavioral determinants associated with exclusive use of arsenic-safe water in the community-led Strong Heart Water Study (SHWS) arsenic mitigation program. Methods The SHWS is a randomized controlled trial of a community-led arsenic mitigation program designed to reduce arsenic exposure among private well users in American Indian Great Plains communities. All households received point-of-use (POU) arsenic filters installed at baseline and were followed for 2 years. Behavioral determinants selected were those targeted during the development of the SHWS program, and were assessed at baseline and follow-up. Results Among participants, exclusive use of arsenic-safe water for drinking and cooking at follow-up was associated with higher self-efficacy for accessing local resources to learn about arsenic (OR: 5.19, 95% CI: 1.48–18.21) and higher self-efficacy to resolve challenges related to arsenic in water using local resources (OR: 3.11, 95% CI: 1.11–8.71). Higher commitment to use the POU arsenic filter faucet at baseline was also a significant predictor of exclusive arsenic-safe water use for drinking (OR: 32.57, 95% CI: 1.42–746.70) and cooking (OR: 15.90, 95% CI: 1.33–189.52) at follow-up. From baseline to follow-up, the SHWS program significantly increased perceived vulnerability to arsenic exposure, self-efficacy, descriptive norms, and injunctive norms. Changing one’s arsenic filter cartridge after installation was associated with higher self-efficacy to obtain arsenic-safe water for drinking (OR: 6.22, 95% CI: 1.33–29.07) and cooking (OR: 10.65, 95% CI: 2.48–45.68) and higher perceived vulnerability of personal health effects (OR: 7.79, 95% CI: 1.17–51.98) from drinking arsenic-unsafe water. Conclusions The community-led SHWS program conducted a theory-driven approach for intervention development and evaluation that allowed for behavioral determinants to be identified that were associated with the use of arsenic safe water and changing one’s arsenic filter cartridge. These results demonstrate that theory-driven, context-specific formative research can influence behavior change interventions to reduce water arsenic exposure. The SHWS can serve as a model for the design of theory-driven intervention approaches that engage communities to reduce arsenic exposure. Trial registration The SHWS is registered with ClinicalTrials.gov (Identifier: NCT03725592)