Early versus Later Anticoagulation for Stroke with Atrial Fibrillation.

BACKGROUND: The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear. METHODS: We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days. RESULTS: Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days. CONCLUSIONS: In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).

High-Resolution Plasma Metabolomics Identifies Alterations in Fatty Acid, Energy, and Micronutrient Metabolism in Adults Across the Leprosy Spectrum.

BACKGROUND: High-resolution metabolomics (HRM) is an innovative tool to study challenging infectious diseases like leprosy, where the pathogen cannot be grown with standard methods. Here, we use HRM to better understand associations between disease manifestations, nutrition, and host metabolism. METHODS: From 2018 to 2019, adults with leprosy and controls were recruited in Minas Gerais, Brazil. Plasma metabolites were detected using an established HRM workflow and characterized by accurate mass, mass to charge ratio m/z and retention time. The mummichog informatics package compared metabolic pathways between cases and controls and between multibacillary (MB) and paucibacillary (PB) leprosy. Additionally, select individual metabolites were quantified and compared. RESULTS: Thirty-nine cases (62% MB and 38% PB) and 25 controls were enrolled. We found differences (P < .05) in several metabolic pathways, including fatty acid metabolism, carnitine shuttle, retinol, vitamin D3, and C-21 steroid metabolism, between cases and controls with lower retinol and associated metabolites in cases. Between MB and PB, leukotrienes, prostaglandins, tryptophan, and cortisol were all found to be lower in MB (P < .05). DISCUSSION: Metabolites associated with several nutrient-related metabolic pathways appeared differentially regulated in leprosy, especially MB versus PB. This pilot study demonstrates the metabolic interdependency of these pathways, which may play a role in the pathophysiology of disease.

Açaí (Euterpe oleracea Mart.) Seed Oil and Its Nanoemulsion: Chemical Characterisation, Toxicity Evaluation, Antioxidant and Anticancer Activities.

This study explores a nanoemulsion formulated with açaí seed oil, known for its rich fatty acid composition and diverse biological activities. This study aimed to characterise a nanoemulsion formulated with açaí seed oil and explore its cytotoxic effects on HeLa and SiHa cervical cancer cell lines, alongside assessing its antioxidant and toxicity properties both in vitro and in vivo. Extracted from fruits sourced in Brazil, the oil underwent thorough chemical characterization using gas chromatography-mass spectrometry. The resulting nanoemulsion was prepared and evaluated for stability, particle size, and antioxidant properties. The nanoemulsion exhibited translucency, fluidity, and stability post centrifugation and temperature tests, with a droplet size of 238.37, PDI -9.59, pH 7, and turbidity 0.267. In vitro assessments on cervical cancer cell lines revealed antitumour effects, including inhibition of cell proliferation, migration, and colony formation. Toxicity tests conducted in cell cultures and female Swiss mice demonstrated no adverse effects of both açaí seed oil and nanoemulsion. Overall, açaí seed oil, particularly when formulated into a nanoemulsion, presents potential for cancer treatment due to its bioactive properties and safety profile.

Homozygosity for a Rare FASTKD2 Variant Resulting in an Adult Onset Autosomal Recessive Mitochondrial Podocytopathy.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy-which might be, instead, pathogenically related to adenosine triphosphate deficiency.

Fe(III)-Based Phenylsilsesquioxane/Acetylacetonate Complexes: Synthesis, Cage-like Structure, and High Catalytic Activity.

Unprecedented iron-based silsesquioxane/acetylacetonate complexes were synthesized. The intriguing cage-like structure of compounds is alkaline metal-dependent: the Fe2Li2 complex includes condensed Si6-silsesquioxane and four acetylacetonate ligands; the Fe4Na4 complex exhibits two cyclic Si4-silsesquioxane and eight acetylacetonate ligands, while the Fe3K3 complex features two cyclic Si3-silsesquioxane and six acetylacetonate ligands. The latter case is the very first observation of small trimeric silsesquioxane ligands in the composition of cage-like metallasilsesquioxanes. The Fe4Na4-based complex exhibits a record high activity in the oxidation of inert alkanes with peroxides (55% yield of oxygenates in cyclohexane oxidation). It also acts as a catalyst in the cycloaddition of CO2 with epoxides, leading to cyclic carbonates in good yields (58-96%).

Using the IUCN Environmental Impact Classification for Alien Taxa to inform decision-making.

The Environmental Impact Classification for Alien Taxa (EICAT) is an important tool for biological invasion policy and management and has been adopted as an International Union for Conservation of Nature (IUCN) standard to measure the severity of environmental impacts caused by organisms living outside their native ranges. EICAT has already been incorporated into some national and local decision-making procedures, making it a particularly relevant resource for addressing the impact of non-native species. Recently, some of the underlying conceptual principles of EICAT, particularly those related to the use of the precautionary approach, have been challenged. Although still relatively new, guidelines for the application and interpretation of EICAT will be periodically revisited by the IUCN community, based on scientific evidence, to improve the process. Some of the criticisms recently raised are based on subjectively selected assumptions that cannot be generalized and may harm global efforts to manage biological invasions. EICAT adopts a precautionary principle by considering a species' impact history elsewhere because some taxa have traits that can make them inherently more harmful. Furthermore, non-native species are often important drivers of biodiversity loss even in the presence of other pressures. Ignoring the precautionary principle when tackling the impacts of non-native species has led to devastating consequences for human well-being, biodiversity, and ecosystems, as well as poor management outcomes, and thus to significant economic costs. EICAT is a relevant tool because it supports prioritization and management of non-native species and meeting and monitoring progress toward the Kunming-Montreal Global Biodiversity Framework (GBF) Target 6.

Uso de la Clasificación de Impacto Ambiental de los Taxones Exóticos de la UICN para la toma de decisiones Resumen La Clasificación de Impacto Ambiental de los Taxones Exóticos (EICAT, en inglés) es una herramienta importante para las políticas y manejo de las invasiones biológicas y ha sido adoptada como un estándar de la Unión Internacional para la Conservación de la Naturaleza (UICN) para medir la seriedad del impacto ambiental causado por los organismos que viven fuera de su extensión nativa. La EICAT ya ha sido incorporada a algunos procedimientos locales y nacionales de toma de decisiones, lo que la vuelve un recurso particularmente relevante para abordar el impacto de las especies no nativas. Algunos principios conceptuales subyacentes de la EICAT han sido cuestionados recientemente, en particular aquellos relacionados con el uso del principio de precaución. Aunque todavía son relativamente nuevas, las directrices para la aplicación e interpretación de la EICAT tendrán una revisión periódica, basada en evidencia científica, por parte de la comunidad de la UICN para mejorar el proceso. Algunas de las críticas recientes están basadas en suposiciones seleccionadas subjetivamente que no pueden generalizarse y podrían perjudicar los esfuerzos globales para manejar las invasiones biológicas. La EICAT adopta un principio de precaución cuando considera el historial de impacto de una especie en cualquier otro lugar ya que algunos taxones tienen características que podrían volverlos más dañinos. Además, las especies no nativas suelen ser factores de pérdida de bidiversidad, incluso bajo otras presiones. Cuando ignoramos el principio de precaución al abordar el impacto de las especies no nativas, hay consecuencias devastadoras para el bienestar humano, la biodiversidad y los ecosistemas, así como resultados pobres de conservación, y por lo tanto con costos económicos importantes. La EICAT es una herramienta relevante porque respalda la priorización y el manejo de las especies no nativas y ayuda con el cumplimiento y monitoreo del progreso para llegar al objetivo 6 del Marco Mundial de Biodiversidad Kunming­Montreal.

Resilience: conceptualisations and challenges for effective heatwave public health planning.

OBJECTIVES: This article examines diverse perspectives on heatwave resilience in public health planning, interviewing stakeholders from various sectors. It identifies challenges, including operational, political, economic, and cultural aspects, hindering effective strategies. The study advocates for a holistic approach to heatwave resilience, emphasising interdisciplinary research and collaboration for targeted interventions. Enhancing resilience is crucial to mitigating adverse health impacts and safeguarding vulnerable populations during heatwaves. Conceptualisations of resilience related to heatwave public health planning and heatwave resilience vary significantly. There is a need to unveil the multifaceted nature of resilience in the context of heatwaves and identify key challenges that hinder effective public health planning efforts. STUDY DESIGN: Qualitative study to explore key stakeholders' conceptualisations of resilience and highlight challenges and opportunities needed for greater heatwave resilience and public health planning. METHODS: Interviews were conducted with a diverse group of key stakeholders involved in local, regional, and national heatwave planning, academics, civil sector and private sector representatives. RESULTS: The findings of this study highlight diverse conceptualisations of resilience. Conceptualisations of resilience mainly differ on the following: 'whom'; 'what'; 'how'; 'when'; and 'why'. This analysis shows that the concept of resilience is well understood but has different functions. The analysis of challenges revealed several key problems, such as operational and technical; political and governance; organisational and institutional; economic; linguistic; cultural, social, and behavioural; and communication, information, and awareness. These significantly hinder effective heatwave public health planning strategies. CONCLUSIONS: The study emphasises the need for a holistic and integrated approach to heatwave resilience. Addressing these challenges is crucial for enhancing heatwave public health planning. This study provides valuable insights into the complexities of heatwave resilience, offering guidance for different sectors of society to develop targeted interventions and strategies. The development of new resilience interdisciplinary and intersectoral research, practice, and governance will prove crucial to ongoing efforts to strengthen national heatwave resilience public health planning. By fostering resilience, societies can mitigate the adverse impacts of heatwaves and safeguard the health and well-being of vulnerable populations.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.

Surface Basicity and Hydrophilic Character of Coal Ash-Derived Zeolite NaP1 Modified by Fatty Acids.

Zeolite NaP1 was found to display the highest affinity for CO2 in preliminary modifications of coal fly ash-derived zeolites (4A, Y, NaP1 and X) by four amines (1,3-diaminopropane, N,N,N',N'-tetramethylethylenediamine, Tris(2-aminoethyl)amine and ethylenediamine). In the second step, different fatty acid loaded NaP1 samples were prepared using palmitic, oleic and lauric acids. CO2 and H2O thermal programmed desorption (TPD) revealed changes in intrinsic basicity and hydrophilic character, expressed in terms of CO2 and H2O retention capacity (CRC and WRC, respectively). Infrared spectroscopy (IR), N2 adsorption-desorption isotherms and scanning electron microscopy allowed for correlating these changes with the type of interactions between the incorporated species and the zeolite surface. The highest CRC values and the lowest CO2 desorption temperatures were registered for NaP1 with the optimum content in palmitic acid (PA) and were explained in terms of the shading effect of surface acidity by the rise of basic Na+-palmitate salt upon cation exchange. The amine/fatty acid combination was found to paradoxically mitigate this beneficial effect of PA incorporation. These results are of great interest because they demonstrate that fatty acid incorporation is an interesting strategy for reversible CO2 capture.

Hydroxytyrosol recovery from olive pomace: a simple process using olive mill industrial equipment and membrane technology.

In this work, pilot-scale nanofiltration was used to obtain aqueous solutions rich in hydroxytyrosol and tyrosol from olive oil by-products. A large-scale simple process involving olive mill standard machinery (blender and decanter) was used for the olive pomace pre-treatment with water. The aqueous extract was then directly fed to a nanofiltration unit and concentrated by reverse osmosis. Final concentration factors ranged between 7 and 9 for hydroxytyrosol and between 4 and 7 for tyrosol. The final aqueous solution, obtained as retentate stream of reverse osmosis, was highly concentrated in hydroxytyrosol and tyrosol and their concentrations remained stable over at least 14 months.

Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

Detection of Plasmodium simium gametocytes in non-human primates from the Brazilian Atlantic Forest.

BACKGROUND: Plasmodium species of non-human primates (NHP) are of great interest because they can naturally infect humans. Plasmodium simium, a parasite restricted to the Brazilian Atlantic Forest, was recently shown to cause a zoonotic outbreak in the state of Rio de Janeiro. The potential of NHP to act as reservoirs of Plasmodium infection presents a challenge for malaria elimination, as NHP will contribute to the persistence of the parasite. The aim of the current study was to identify and quantify gametocytes in NHP naturally-infected by P. simium. METHODS: Whole blood samples from 35 NHP were used in quantitative reverse transcription PCR (RT-qPCR) assays targeting 18S rRNA, Pss25 and Pss48/45 malaria parasite transcripts. Absolute quantification was performed in positive samples for 18S rRNA and Pss25 targets. Linear regression was used to compare the quantification cycle (Cq) and the Spearman's rank correlation coefficient was used to assess the correlation between the copy numbers of 18S rRNA and Pss25 transcripts. The number of gametocytes/µL was calculated by applying a conversion factor of 4.17 Pss25 transcript copies per gametocyte. RESULTS: Overall, 87.5% of the 26 samples, previously diagnosed as P. simium, were positive for 18S rRNA transcript amplification, of which 13 samples (62%) were positive for Pss25 transcript amplification and 7 samples (54%) were also positive for Pss48/45 transcript. A strong positive correlation was identified between the Cq of the 18S rRNA and Pss25 and between the Pss25 and Pss48/45 transcripts. The 18S rRNA and Pss25 transcripts had an average of 1665.88 and 3.07 copies/µL, respectively. A positive correlation was observed between the copy number of Pss25 and 18S rRNA transcripts. Almost all gametocyte carriers exhibited low numbers of gametocytes (< 1/µL), with only one howler monkey having 5.8 gametocytes/µL. CONCLUSIONS: For the first time, a molecular detection of P. simium gametocytes in the blood of naturally-infected brown howler monkeys (Alouatta guariba clamitans) was reported here, providing evidence that they are likely to be infectious and transmit P. simium infection, and, therefore, may act as a reservoir of malaria infection for humans in the Brazilian Atlantic Forest.

Predictors of functional outcome after symptomatic intracranial hemorrhage complicating intravenous thrombolysis: results from the SITS-ISTR.

BACKGROUND AND PURPOSE: Several risk factors of symptomatic intracerebral hemorrhage (SICH) following intravenous thrombolysis for acute ischaemic stroke have been established. However, potential predictors of good functional outcome post-SICH have been less studied. METHODS: Patient data registered in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) from 2005 to 2021 were used. Acute ischaemic stroke patients who developed post intravenous thrombolysis SICH according to the SITS Monitoring Study definition were analyzed to identify predictors of functional outcomes. RESULTS: A total of 1679 patients with reported SICH were included, out of which only 2.8% achieved good functional outcome (modified Rankin Scale scores of 0-2), whilst 80.9% died at 3 months. Higher baseline National Institutes of Health Stroke Scale (NIHSS) score and 24-h ΔNIHSS score were independently associated with a lower likelihood of achieving both good and excellent functional outcomes at 3 months. Baseline NIHSS and hematoma location (presence of both SICHs, defined as remote and local SICH concurrently; n = 478) were predictors of early mortality within 24 h. Independent predictors of 3-month mortality were age, baseline NIHSS, 24-h ΔNIHSS, admission serum glucose values and hematoma location (both SICHs). Age, baseline NIHSS score, 24-h ΔNIHSS, hyperlipidemia, prior stroke/transient ischaemic attack, antiplatelet treatment, diastolic blood pressure at admission, glucose values on admission and SICH location (both SICHs) were associated with reduced disability at 3 months (≥1-point reduction across all modified Rankin Scale scores). Patients with remote SICH (n = 219) and local SICH (n = 964) had comparable clinical outcomes, both before and after propensity score matching. CONCLUSIONS: Symptomatic intracerebral hemorrhage presents an alarmingly high prevalence of adverse clinical outcomes, with no difference in clinical outcomes between remote and local SICH.

Intravenous thrombolysis + endovascular thrombectomy versus thrombolysis alone in large vessel occlusion mild stroke: a propensity score matched analysis.

BACKGROUND AND PURPOSE: The best reperfusion treatment for patients with mild acute ischaemic stroke harbouring proximal anterior circulation large vessel occlusion (LVO) is unknown. The aim was to compare the safety and efficacy of intravenous thrombolysis (IVT) plus endovascular thrombectomy (EVT) versus IVT alone in LVO patients with mild symptoms. METHODS: From the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis and Thrombectomy Register (SITS-ISTR), were included: (i) consecutive acute ischaemic stroke patients, (ii) treated within 4.5 h from symptoms onset, (iii) baseline National Institutes of Health Stroke Scale (NIHSS) score ≤5 and (iv) intracranial internal carotid artery [ICA], M1 or T occlusion [defined as occlusion of ICA terminal bifurcation]. After propensity score matching, 3-month functional outcomes (modified Rankin Scale [mRS] 0-1 and 0-2) and safety outcomes (symptomatic intracerebral haemorrhage and death) were compared (via univariable and multivariable logistic [and ordinal] regression analyses) in patients treated with IVT + EVT versus IVT alone. RESULTS: In all, 1037 patients were included. After propensity score matching (n = 312 per group), IVT + EVT was independently associated with poor functional outcomes (adjusted odds ratio [aOR] 0.46 for mRS 0-1, 95% confidence interval [CI] 0.30-0.72, p = 0.001; aOR 0.52 for mRS 0-2, 95% CI 0.32-0.84, p = 0.007; aOR 1.61 for 1-point shift in mRS score, 95% CI 1.12-2.32, p = 0.011), with no significant differences in safety outcomes compared to IVT alone, despite numerically higher rates of symptomatic intracerebral haemorrhage (3.3% vs. 1.1%; p = 0.082), a higher rate of any haemorrhagic transformation (17.6% vs. 7.3%; p < 0.001) and subarachnoid haemorrhage (7.9% vs. 1.5%; p = 0.002) in the IVT + EVT group. DISCUSSION: In anterior circulation LVO patients presenting with NIHSS score ≤5, IVT + EVT (vs. IVT alone) was associated with poorer 3-month functional outcome. Randomized controlled trials are needed to elucidate the best treatments in mild LVO patients.

Boroxine benzaldehyde complex for pharmaceutical applications probed by electron interactions.

RATIONALE: 2,4,6-Tris(4-formylphenyl)boroxine (TFPB) is a substituted boroxine containing a benzaldehyde molecule bonded to each boron atom. Boroxine cages are an emerging class of functional nanostructures used in host-guest chemistry, and benzaldehyde is a potential radiosensitizer. Reactions initiated by low-energy electrons with such complexes may dictate and bring new fundamental knowledge for biomedical and pharmaceutical applications. METHODS: The electron ionization properties of TFPB are investigated using a gas-phase electron-molecule crossed beam apparatus coupled with a reflectron time-of-flight mass spectrometer in an orthogonal geometry. Ionization and threshold energies are experimentally determined by mass spectra acquisition as a function of the electron energy. RESULTS: The abundance of the molecular precursor cation in the mass spectrum at 70 eV is significantly lower than that of the most abundant fragment C7 H5 O+ . Twenty-nine cationic fragments with relative intensities >2% are detected and identified. The appearance energies of six fragment cations are reported, and the experimental first ionization potential is found at 9.46 ± 0.11  eV. Moreover, eight double cations are identified. The present results are supported by quantum chemical calculations based on bound state techniques, electron ionization models and thermodynamic thresholds. CONCLUSIONS: According to these results, the TPFB properties may combine the potential radiosensitizer effect of benzaldehyde with the stability of the boroxine ring.

A Family of Cagelike Mn-Silsesquioxane/Bathophenanthroline Complexes: Synthesis, Structure, and Catalytic and Antifungal Activity.

This study reports a novel family of cage manganesesilsesquioxanes prepared via complexation with bathophenanthroline (4,7-diphenyl-1,10-phenanthroline). The resulting Mn4-, Mn6Li2-, and Mn4Na-compounds exhibit several unprecedented cage metallasilsesquioxane structural features, including intriguing self-assembly of silsesquioxane ligands. Complexes were tested in vitro for fungicidal activity against seven classes of phytopathogenic fungi. The representative Mn4Na-complex acts as a catalyst in the cycloaddition of CO2 to epoxides under solvent-free conditions to form cyclic carbonates in good yields.

Evidence for an association of prenatal exposure to particulate matter with clinical severity of Autism Spectrum Disorder.

Early-life exposure to air pollutants, including ozone (O3), particulate matter (PM2.5 or PM10, depending on diameter of particles), nitrogen dioxide (NO2) and sulfur dioxide (SO2) has been suggested to contribute to the etiology of Autism Spectrum Disorder (ASD). In this study, we used air quality monitoring data to examine whether mothers of children with ASD were exposed to high levels of air pollutants during critical periods of pregnancy, and if higher exposure levels may lead to a higher clinical severity in their offspring. We used public data from the Portuguese Environment Agency to estimate exposure to these pollutants during the first, second and third trimesters of pregnancy, full pregnancy and first year of life of the child, for 217 subjects with ASD born between 2003 and 2016. These subjects were stratified in two subgroups according to clinical severity, as defined by the Autism Diagnostic Observational Schedule (ADOS). For all time periods, the average levels of PM2.5, PM10 and NO2 to which the subjects were exposed were within the admissible levels defined by the European Union. However, a fraction of these subjects showed exposure to levels of PM2.5 and PM10 above the admissible threshold. A higher clinical severity was associated with higher exposure to PM2.5 (p = 0.001), NO2 (p = 0.011) and PM10 (p = 0.041) during the first trimester of pregnancy, when compared with milder clinical severity. After logistic regression, associations with higher clinical severity were identified for PM2.5 exposure during the first trimester (p = 0.002; OR = 1.14, 95%CI: 1.05-1.23) and full pregnancy (p = 0.04; OR = 1.07, 95%CI: 1.00-1.15) and for PM10 (p = 0.02; OR = 1.07, 95%CI: 1.01-1.14) exposure during the third trimester. Exposure to PM is known to elicit neuropathological mechanisms associated with ASD, including neuroinflammation, mitochondrial disruptions, oxidative stress and epigenetic changes. These results offer new insights on the impact of early-life exposure to PM in ASD clinical severity.

Opportunistic sightings of manta rays on Brazil's Amazon Coast.

Little is known about the ecology and distribution of mobulid rays along Brazil's extensive coastline. Here we report opportunistic sightings of manta rays (Mobula cf. birostris) in the Brazilian Amazon estuaries and the Great Amazon Reef System. These sightings consist of manta ray individuals stranded in tide pools, caught in artisanal fisheries, and footage obtained with a submersible. Future investigations on the spatial, temporal, and environmental drivers of manta rays' distribution on the northern Brazilian coast and the threats posed by fishing gear are warranted.

Developmental Effects of Oxytocin Neurons on Social Affiliation and Processing of Social Information.

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders (ASDs); however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naive state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely, to shape forebrain neuroarchitecture during development and to acquire an affiliative response toward conspecifics.SIGNIFICANCE STATEMENT Social behavior is developed over the lifetime of an organism and the neuropeptide oxytocin (OXT) modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether OXT plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by OXT neurons. Animals whose OXT system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the social brain. We provide a window into the mechanisms underlying OXT-dependent developmental processes that implement adult sociality.

Esketamine for Unipolar Major Depression With Psychotic Features: A Retrospective Chart Review and Comparison With Nonpsychotic Depression.

PURPOSES/BACKGROUND: The aims of the study were to assess subanesthetic esketamine as an antidepressant for major depressive disorder with psychotic features (PMDD) and to compare posttreatment symptoms among those with PMDD to a sample of nonpsychotic depression (major depressive disorder [MDD]). METHODS/PROCEDURES: This study is a retrospective chart review of patients with major depression and current psychotic symptoms, treated with a single parenteral 0.5-mg/kg dose of esketamine. Depression symptoms were assessed at baseline and 24-hour posttreatment with the Montgomery-Åsberg Depression Rating Scale. Individuals with PMDD were matched in a 1:2 ratio to nonpsychotic MDD patients from a randomized, noninferiority clinical trial of esketamine. FINDINGS/RESULTS: A total of 15 individuals with PMDD were included, which had higher baseline depression scores (PMDD = 40.9, MDD = 33.6, P = 0.004). A statistically significant change in depressive symptoms was found for the PMDD sample (ß = -16.20 [95% confidence interval, -23.30 to -9.10], P < 0.001), and no difference between PMDD and MDD groups was observed in the matched-sample analysis (ß = -2.2 [95% confidence interval, -9.32 to 4.58], P = 0.537). Treatment-induced dissociative symptoms were present for both groups, self-contained to within 2 hours after treatment, and no exacerbation of psychotic symptoms was found in clinical assessments. IMPLICATIONS/CONCLUSIONS: Results suggest a single 0.5-mg/kg dose of esketamine may benefit individuals with PMDD, and the symptom reduction may be comparable with esketamine's effects for MDD. Furthermore, esketamine may induce an antidepressant response in those with PMDD without complication of psychotic symptoms. Future research with controlled designs is warranted.