Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Highly Mesoporous Hybrid Transition Metal Oxide Nanowires for Enhanced Adsorption of Rare Earth Elements from Wastewater.

Removal of rare earth elements (REEs) from industrial wastewater is a continual challenge. To date, several approaches to the synthesis of nanoadsorbants for this application have been reported, although these are characterized by insufficient adsorption capacity and limitations in cycling stability. The present work reports the fabrication and performance of hierarchical hybrid transition metal oxide (TMO) nanowires deposited on carbon fibers. An ordered assembly of hybrid TMO nanowires exhibits an outstanding adsorbance of 1000 mg·g-1 of REEs with 93% recyclability. This superior performance is attributed to the unique mesoporous architecture of the nanowires, which exhibits a high surface area of 122 cm3·g-1. Further, rapid adsorption/desorption of the REEs reveals minimal morphological alteration and hence high structural stability of these hybrid TMO nanowires after multiple cycles. The ready accessibility of the adsorption sites at crystallite boundaries and the surfaces as well as rapid adsorption of the REEs on the mesoporous nanostructure facilitate considerable adsorption capacity, improved structural stability, and extended cyclability, all of which suggest the potential for this material in REE extraction.

Research and application of in-situ control technology for sediment rehabilitation in eutrophic water bodies.

Phosphorus (P) is often the limiting nutrient for algal growth, and P in sediments can be released under suitable conditions. To control P release, in-situ control technology with lanthanum (La) modified bentonite clay (Phoslock(®)) was proposed and its effectiveness was tested and evaluated both in laboratory and field trials. The results of static and dynamic simulation experiments under different environmental conditions showed that with the application rate of Phoslock(®) at 0.5 kg/m(2), the orthophosphate (PO(4)-P) concentration of the overlying water decreased to a low level (≤0.02 mg/L) within 10 days. Even under anaerobic and high pH (pH = 9.0) conditions, the phosphate release suppression efficiency reached 98.3%, and the P-release rate was -8.20 mg/m(2) d (negative value indicates P adsorption by Phoslock(®)). The monitoring data of the field sediments rehabilitation project were consistent with the results achieved in laboratory experiments, thus showing that the application of Phoslock(®) could inhibit the internal P release effectively.

Assessment of concentration and distribution of total mercury and polychlorinated biphenyls in Green Bay, Wisconsin, USA.

Under the 1987 Great Lakes Water Quality Agreement, the lower Green Bay and Fox River estuary have been labeled as areas of concern due to the contamination of mercury and polychlorinated biphenyls (PCBs) from industrialization. These pollutants pose substantial health and environmental hazards for the Green Bay region. The PCBs reported in this region, including Aroclor 1242, are known to trigger carcinogenic responses in animals and mercury targets the central nervous system and vital organs. Furthermore, these compounds are extremely difficult to remove from the environment once introduced. Extensive remedial actions have been implemented including dredging sediments in the Lower Fox River from DePere to Green Bay. The purpose of this study is to assess the concentration and distribution of Aroclor 1242 and total mercury in the Green Bay region sediments and pore waters and to assess the impact of interventions and the natural rates of change previously found.

Obstetrical unit closures and racial and ethnic differences in severe maternal morbidity in the state of New Jersey.

BACKGROUND: In the United States, racial disparities in maternal morbidity and mortality are pronounced and persistent. Although the maternal mortality ratio and the severe maternal morbidity rates have increased over the past 30 years, the number of obstetrical units in the country has simultaneously diminished. Black women are 3 times more likely to die during childbirth than White women and twice as likely to suffer severe maternal morbidity (or a near miss). Between 2003 and 2013, 366 (10%) obstetrical units closed, and rural obstetrical unit closures were more likely in the Black communities. The state of New Jersey has the highest Black maternal mortality rate (131.8/100,000 live births) of all states reporting these data. Very few studies have examined the role that urban obstetrical unit closures play in racial and ethnic disparities in maternal health outcomes. OBJECTIVE: To analyze racial differences in severe maternal morbidity in New Jersey hospitals among women experiencing the loss of their nearest obstetrical unit during the years 2006-2015. STUDY DESIGN: This study used data on all births in New Jersey hospitals (2006-2015) by women living in ZIP code tabulation areas that lost their nearest obstetrical unit during that period. Severe maternal morbidity was measured using a composite variable for severe illness during hospitalizations (eg, acute heart failure, acute renal disease, disseminated intravascular coagulation, sepsis) identified using the International Classification of Diseases, Ninth Revision. Logistic regression models were used to analyze the associations between race and ethnicity on the individual likelihood of severe maternal morbidity, adjusting for annual trends, individual socioeconomic characteristics, age, preexisting conditions, and delivery hospital characteristics (ie, percentage of Black patients >25% [Black-serving hospital] and percentage of Medicaid discharges in the delivery obstetrical unit). RESULTS: There were 227,412 delivery hospitalizations among women who lived in the 124 New Jersey ZIP code tabulation areas that lost the nearest obstetrical unit from 2006 to 2015. Black women had the highest severe maternal morbidity rates, increasing from 1.2% in 2006 to 2.3% in 2015. The Black-White gap remained similar in magnitude over the period, as White women's severe maternal morbidity rates increased from 0.7% to 1.4%. However, for Hispanic women, the severe maternal morbidity increased dramatically from 0.7% in 2006 to 2.4% in 2013, followed by a decreasing trend during 2013-2015. When adjusting for individual factors, the odds of severe maternal morbidity among all women was greater if they delivered after the loss of the nearest obstetrical unit (adjusted odds ratio, 1.55; 95% confidence interval, 1.30-1.86). Hispanic women experienced the greatest increase in severe maternal morbidity, regardless of whether they delivered before or after the closure of their nearest obstetrical unit. For all women, delivering in a Black-serving obstetrical unit was associated with a greater likelihood of individual severe maternal morbidity (adjusted odds ratio, 1.36; 95% confidence interval, 1.19-1.56). CONCLUSION: Racial and ethnic disparities in severe maternal morbidity persist and might be exacerbated by nearby obstetrical unit closures. In New Jersey ZIP codes with obstetrical unit loss, the Hispanic-White gap in the severe maternal morbidity widened substantially, and the rates were also higher among women who delivered in Black-serving hospitals. Policymakers should take steps to prevent obstetrical unit closures and to ensure that the resources available at Black-serving obstetrical units are at least on par with those of other institutions.

PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors.

In neuronal synapses, PDZ domains [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] of PSD-95 proteins interact with C termini of NMDA receptor [NMDAR (NR)] subunits, linking them to downstream neurotoxic signaling molecules. Perturbing NMDAR/PSD-95 interactions with a Tat peptide comprising the nine C-terminal residues of the NR2B subunit (Tat-NR2B9c) reduces neurons' vulnerability to excitotoxicity and ischemia. However, NR subunit C termini may bind many of >240 cellular PDZs, any of which could mediate neurotoxic signaling independently of PSD-95. Here, we performed a proteomic and biochemical analysis of the interactions of all known human PDZs with synaptic signaling proteins including NR1, NR2A-NR2D, and neuronal nitric oxide synthase (nNOS). Tat-NR2B9c, whose interactions define PDZs involved in neurotoxic signaling, was also used. NR2A-NR2D subunits and Tat-NR2B9c had similar, highly specific, PDZ protein interactions, of which the strongest were with the PSD-95 family members (PSD-95, PSD-93, SAP97, and SAP102) and Tax interaction protein 1 (TIP1). The PSD-95 PDZ2 domain bound NR2A-NR2C subunits most strongly (EC50, approximately 1 microM), and fusing the NR2B C terminus to Tat enhanced its affinity for PSD-95 PDZ2 by >100-fold (EC50, approximately 7 nM). IC50 values for Tat-NR2B9c inhibiting NR2A-NR2C/PSD-95 interactions (approximately 1-10 microM) and nNOS/PSD-95 interactions (200 nM) confirmed the feasibility of such inhibition. To determine which of the PDZ interactions of Tat-NR2B9c mediate neuroprotection, one of PSD-95, PSD-93, SAP97, SAP102, TIP1, or nNOS expression was inhibited in cortical neurons exposed to NMDA toxicity. Only neurons lacking PSD-95 or nNOS but not PSD-93, SAP97, SAP102, or TIP1 exhibited reduced excitotoxic vulnerability. Thus, despite the ubiquitousness of PDZ domain-containing proteins, PSD-95 and nNOS above any other PDZ proteins are keys in effecting NMDAR-dependent excitotoxicity. Consequently, PSD-95 inhibition may constitute a highly specific strategy for treating excitotoxic disorders.

Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS: For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS: Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION: Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING: NoNO Inc and Arbor Vita Corp.