Strokes Averted by Intravenous Thrombolysis: A Secondary Analysis of a Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

OBJECTIVE: This study was undertaken to examine averted stroke in optimized stroke systems. METHODS: This secondary analysis of a multicenter trial from 2014 to 2020 compared patients treated by mobile stroke unit (MSU) versus standard management. The analytical cohort consisted of participants with suspected stroke treated with intravenous thrombolysis. The main outcome was a tissue-defined averted stroke, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis and no acute infarction/hemorrhage on imaging. An additional outcome was stroke with early symptom resolution, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis. RESULTS: Among 1,009 patients with a median last known well to thrombolysis time of 87 minutes, 159 (16%) had tissue-defined averted stroke and 276 (27%) had stroke with early symptom resolution. Compared with standard management, MSU care was associated with more tissue-defined averted stroke (18% vs 11%, adjusted odds ratio [aOR] = 1.82, 95% confidence interval [CI] = 1.13-2.98) and stroke with early symptom resolution (31% vs 21%, aOR = 1.74, 95% CI = 1.12-2.61). The relationships between thrombolysis treatment time and averted/early recovered stroke appeared nonlinear. Most models indicated increased odds for stroke with early symptom resolution but not tissue-defined averted stroke with earlier treatment. Additionally, younger age, female gender, hyperlipidemia, lower National Institutes of Health Stroke Scale, lower blood pressure, and no large vessel occlusion were associated with both tissue-defined averted stroke and stroke with early symptom resolution. INTERPRETATION: In optimized stroke systems, 1 in 4 patients treated with thrombolysis recovered within 24 hours and 1 in 6 had no demonstrable brain injury on imaging. ANN NEUROL 2024;95:347-361.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

Evolutionary drivers of sex-specific parasite prevalence in wild birds.

Males and females often differ in ecology, behaviour and lifestyle, and these differences are expected to lead to sex differences in parasite susceptibility. However, neither the sex differences in parasite prevalence, nor their ecological and evolutionary drivers have been investigated across a broad range of taxa using phylogenetically corrected analyses. Using the most extensive dataset yet that includes 755 prevalence estimates from 151 wild bird species in a meta-analytic framework, here we compare sex differences in blood and gastrointestinal parasites. We show that despite sex differences in parasite infection being frequently reported in the literature, only Haemoproteus infections were more prevalent in females than in males. Notably, only seasonality was strongly associated with the sex-specific parasite prevalence of both Leucocytozoon and Haemoproteus, where birds showed greater female bias in prevalence during breeding periods compared to the non-breeding period. No other ecological or sexual selection variables were associated with sex-specific prevalence of parasite prevalence. We suggest that much of the variation in sex-biased prevalence could be idiosyncratic, and driven by local ecology and behavioural differences of the parasite and the host. Therefore, breeding ecology and sexual selection may only have a modest influence on sex-different parasite prevalence across wild birds.

Rapid Synthesis of Highly Substituted 1,6-Naphthyridines Via Heteroaryl Ditriflates.

We report the discovery of a convenient and efficient method for the synthesis of highly substituted 1,6-naphthyridines. A tandem nitrile hydration/cyclization procedure was developed to access 1,6-naphthyridine-5,7-diones under mild conditions. Subsequently, we have found that ditriflation of these intermediates provides 1,6-naphthyridine-5,7-ditriflates which are bench-stable but highly reactive intermediates that can be engaged in one-pot difunctionalization reactions leading to diverse drug-like products in rapid fashion.

A DFT Comparison of C-C Reductive Coupling from Terminal Cyanido and Cyaphido Complexes of Nickel.

The density functional theory study of the thermal C-C reductive coupling from terminal cyanido and hypothetical cyaphido complexes of [Ni(dmpe)] (dmpe = 1,2-bis(dimethylphosphino)ethane) revealed the key reaction intermediate in the reductive C-CP coupling being a σ-CC complex unlike an η2-aryl complex in the Ni C-CN system, as already observed in our previous studies. The reaction in THF is endothermic by 4.9 kcal/mol for cyanido with a 32.0 kcal/mol activation barrier and exothermic by 28.5 kcal/mol for cyaphido with an 11.3 kcal/mol activation barrier. To compare our results with the existing experimental data, we chose mesityl as the aryl group and also studied the CP reaction with [Pt(dmpe)] and [Pt(dmpm)] (dmpe = 1,2-bis(dimethylphosphino)methane) fragments. Our findings are consistent with the thermodynamically uphill photolytic C-CP bond activation in phosphaalkynes with Pt and a faster thermal back-reaction with [Pt(dmpe)] compared to that of [Pt(dmpm)]. Based on the natural population analysis, when the polarity of the C-C bond is inverted, the sign of ΔG° is also inverted.

Development and Validation of a Natural Language Processing Model to Identify Low-Risk Pulmonary Embolism in Real Time to Facilitate Safe Outpatient Management.

STUDY OBJECTIVE: This study aimed to (1) develop and validate a natural language processing model to identify the presence of pulmonary embolism (PE) based on real-time radiology reports and (2) identify low-risk PE patients based on previously validated risk stratification scores using variables extracted from the electronic health record at the time of diagnosis. The combination of these approaches yielded an natural language processing-based clinical decision support tool that can identify patients presenting to the emergency department (ED) with low-risk PE as candidates for outpatient management. METHODS: Data were curated from all patients who received a PE-protocol computed tomography pulmonary angiogram (PE-CTPA) imaging study in the ED of a 3-hospital academic health system between June 1, 2018 and December 31, 2020 (n=12,183). The "preliminary" radiology reports from these imaging studies made available to ED clinicians at the time of diagnosis were adjudicated as positive or negative for PE by the clinical team. The reports were then divided into development, internal validation, and temporal validation cohorts in order to train, test, and validate an natural language processing model that could identify the presence of PE based on unstructured text. For risk stratification, patient- and encounter-level data elements were curated from the electronic health record and used to compute a real-time simplified pulmonary embolism severity (sPESI) score at the time of diagnosis. Chart abstraction was performed on all low-risk PE patients admitted for inpatient management. RESULTS: When applied to the internal validation and temporal validation cohorts, the natural language processing model identified the presence of PE from radiology reports with an area under the receiver operating characteristic curve of 0.99, sensitivity of 0.86 to 0.87, and specificity of 0.99. Across cohorts, 10.5% of PE-CTPA studies were positive for PE, of which 22.2% were classified as low-risk by the sPESI score. Of all low-risk PE patients, 74.3% were admitted for inpatient management. CONCLUSION: This study demonstrates that a natural language processing-based model utilizing real-time radiology reports can accurately identify patients with PE. Further, this model, used in combination with a validated risk stratification score (sPESI), provides a clinical decision support tool that accurately identifies patients in the ED with low-risk PE as candidates for outpatient management.

Location and timing of infection drives a sex-bias in Haemoproteus prevalence in a hole-nesting bird.

Sex biases in prevalence of disease are often attributed to intrinsic factors, such as physiological differences while a proximate role of extrinsic factors such as behavioural or ecological differences may be more difficult to establish. We combined large-scale screening for the presence and lineage identity of avian malaria (haemosporidian) parasites, in 1234 collared flycatchers (Ficedula albicollis) with life-history information from each bird to establish the location and timing of infection. We found an overall infection rate of 36.2% ± 0.03 (95% CI) with 25 distinct malaria lineages. Interestingly, first-year breeding males and females had similar infection prevalence while females accrued a significantly higher infection rate than males later in life. The sex difference in infection rate was driven by the most abundant Haemoproteus, lineage, hPHSIB1, while the infection rate of Plasmodium lineages was similar in males and females. Furthermore, when infections were assigned to an apparent transmission location, we found that the sex difference in infection rate trend was driven by lineages transmitted in Europe, more specifically by one lineage (the hPHSIB1), while no similar pattern was found in African lineages. We deduce that the observed infection patterns are likely to be caused by differences in breeding behaviour, with incubating females (and nestling individuals of both sexes) being easy targets for the biting insects that are the vectors of avian malaria parasites. Overall, our results are most consistent with ecological factors rather than intrinsic factors underlying the observed sex-biased infection rate of avian malaria in collared flycatchers.

Association between psoas major muscle mass and CPET performance and long-term survival following major colorectal surgery: A retrospective cohort study.

OBJECTIVES: To evaluate whether computed tomography (CT)-derived psoas major muscle measurements could predict preoperative cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery and to compare predictive performance of psoas muscle measurements using 2D approach and 3D approach. METHODS: A retrospective cohort study compliant with STROCSS standards was conducted. Consecutive patients undergoing major colorectal surgery between January 2011 and January 2017 following CPET as part of their preoperative assessment were included. Regression analyses were modelled to investigate association between the CT-derived psoas major muscle mass variables [total psoas muscle area (TPMA), total psoas muscle volume (TPMV) and psoas muscle index (PMI)] and CPET performance and mortality (1-year and 5-year). Discriminative performances of the variables were evaluated using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: A total of 457 eligible patients were included. The median TPMA and TPMV were 21 â€‹cm2 (IQR: 15-27) and 274 â€‹cm3 (IQR: 201-362), respectively. The median PMI measured via 2D and 3D approaches were 7 â€‹cm2/m2 (IQR: 6-9) and 99 â€‹cm3/m2 (IQR: 76-120), respectively. The risks of 1-year and 5-year mortality were 7.4% and 27.1%, respectively. Regression analyses showed TPMA, TPMV, and PMI can predict preoperative CPET performance and long-term mortality. However, ROC curve analyses showed no significant difference in predictive performance amongst TPMA, TPMV, and PMI. CONCLUSION: Radiologically-measured psoas muscle mass variables may predict preoperative CPET performance and may be helpful with informing more objective selection of patients for preoperative CPET and prehabilitation.

Meiosis in allopolyploid Arabidopsis suecica.

Polyploidy is a major force shaping eukaryote evolution but poses challenges for meiotic chromosome segregation. As a result, first-generation polyploids often suffer from more meiotic errors and lower fertility than established wild polyploid populations. How established polyploids adapt their meiotic behaviour to ensure genome stability and accurate chromosome segregation remains an active research question. We present here a cytological description of meiosis in the model allopolyploid species Arabidopsis suecica (2n = 4x = 26). In large part meiosis in A. suecica is diploid-like, with normal synaptic progression and no evidence of synaptic partner exchanges. Some abnormalities were seen at low frequency, including univalents at metaphase I, anaphase bridges and aneuploidy at metaphase II; however, we saw no evidence of crossover formation occurring between non-homologous chromosomes. The crossover number in A. suecica is similar to the combined number reported from its diploid parents Arabidopsis thaliana (2n = 2x = 10) and Arabidopsis arenosa (2n = 2x = 16), with an average of approximately 1.75 crossovers per chromosome pair. This contrasts with naturally evolved autotetraploid A. arenosa, where accurate chromosome segregation is achieved by restricting crossovers to approximately 1 per chromosome pair. Although an autotetraploid donor is hypothesized to have contributed the A. arenosa subgenome to A. suecica, A. suecica harbours diploid A. arenosa variants of key meiotic genes. These multiple lines of evidence suggest that meiosis in the recently evolved allopolyploid A. suecica is essentially diploid like, with meiotic adaptation following a very different trajectory to that described for autotetraploid A. arenosa.

2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. Structure: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

Golden Hour Treatment With tPA (Tissue-Type Plasminogen Activator) in the BEST-MSU Study.

BACKGROUND: Treatment of patients with acute ischemic stroke on mobile stroke units (MSUs) improves outcomes compared with management by standard emergency medical services ambulances and is associated with more patients treated with intravenous tPA (tissue-type plasminogen activator) in the first golden hour after last known normal. We explored the predictors and outcomes of first-hour treatment (FHT) compared with later treatment in an alternating-week cluster-controlled trial of MSUs. METHODS: We analyzed all patients treated with intravenous tPA in the BEST-MSU Study (Benefits of Stroke Treatment Delivered by a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services). After stratifying by treatment timeframe, we identified factors associated with FHT. We performed adjusted analyses of the association between FHT and clinical outcome and modeled the shape of the relationship between last known normal-to-treatment time and excellent outcome. RESULTS: Among 941 tPA-treated patients, 206 (21.8%) had lytic started within 60 minutes. Treatment on the MSU, older age, male sex, alert by 911, faster arrival on-scene and imaging, more severe stroke, atrial fibrillation, and absence of heart failure and pretreatment antihypertensive treatment were associated with FHT. Compared with later treatment, FHT was associated with higher adjusted odds ratio for 90-day modified Rankin Scale score of 0 to 1 (odds ratio, 1.87 [95% CI, 1.25-2.84]; P=0.003). Among FHT patients, 68% achieved a 90-day modified Rankin Scale of 0 or 1 or returned to their baseline status. FHT was not associated with higher risk of hemorrhage and was associated with reduced risk of treating neurovascular mimics. CONCLUSIONS: FHT almost doubles the odds of excellent clinical outcome without increased risk compared with later treatment, which supports the use of MSUs.

Rapid Activation of Neuroinflammation in Stroke: Plasma and Extracellular Vesicles Obtained on a Mobile Stroke Unit.

BACKGROUND: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We sought to identify the onset of the neuroinflammatory cascade using a mobile stroke unit. METHODS: The study is a proof-of-concept, cohort investigation of ultra-early blood- and extracellular vesicle-derived markers of neuroinflammation and outcome in acute stroke. Blood was obtained, prehospital, on an mobile stroke unit. Outcomes were biomarker concentrations, modified Rankin Scale score, and National Institutes of Health Stroke Scale score. RESULTS: Forty-one adults were analyzed, including 15 patients treated on the mobile stroke unit between August 2021 and April 2022, and 26 healthy controls to establish biomarker reference levels. Median patient age was 74 (range, 36-97) years, 60% were female, and 80% White. Ten (67%) were diagnosed as stroke, with 8 (53%) confirmed and 2 likely transient ischemic attack or stroke averted by thrombolysis; 5 were stroke mimics. For strokes, median initial National Institutes of Health Stroke Scale score was 11 (range, 4-19) and 6 (75%) received tPA (tissue-type plasminogen activator). Blood was obtained a median of 58 (range, 36-133) minutes after symptom onset. Within 36 minutes after stroke, plasma IL-6 (interleukin-6), neurofilament light chain, UCH-L1 (ubiquitin C-terminal hydrolase L1), and GFAP (glial fibrillary acidic protein) were elevated by as much as 10 times normal. In EVs, MMP-9 (matrix metalloproteinase-9), CXCL4 (chemokine (C-X-C motif) ligand 4), CRP (C-reactive protein), IL-6, OPN (osteopontin), and PECAM1 (platelet and endothelial cell adhesion molecule 1) were elevated. Inflammatory markers increased rapidly in the first 2 hours and continued rising for 24 hours. CONCLUSIONS: The neuroinflammatory cascade was found to be activated within 36 to 133 minutes after stroke and progresses rapidly. This is earlier than observed previously in humans and suggests injury from neuroinflammation occurs faster than had been surmised. These findings could inform development of acute immunomodulatory stroke therapies and lead to new diagnostic tools and improved outcomes.

Shooting the messenger: a systematic review investigating extracellular vesicle isolation and characterisation methods and their influence on understanding extracellular vesicles-radiotherapy interactions in glioblastoma.

BACKGROUND: Extracellular vesicles (EVs) hold promise for improving our understanding of radiotherapy response in glioblastoma due to their role in intercellular communication within the tumour microenvironment (TME). However, methodologies to study EVs are evolving with significant variation within the EV research community. METHODS: We conducted a systematic review to critically appraise EV isolation and characterisation methodologies and how this influences our understanding of the findings from studies investigating radiotherapy and EV interactions in glioblastoma. 246 articles published up to 24/07/2023 from PubMed and Web of Science were identified using search parameters related to radiotherapy, EVs, and glioblastoma. Two reviewers evaluated study eligibility and abstracted data. RESULTS: In 26 articles eligible for inclusion (16 investigating the effects of radiotherapy on EVs, five investigating the effect of EVs on radiation response, and five clinical studies), significant heterogeneity and frequent omission of key characterisation steps was identified, reducing confidence that the results are related to EVs and their cargo as opposed to co-isolated bioactive molecules. However, the results are able to clearly identify interactions between EVs and radiotherapy bi-directionally within different cell types within the glioblastoma TME. These interactions facilitate transferable radioresistance and oncogenic signalling, highlighting that EVs are an important component in the variability of glioblastoma radiotherapy response. CONCLUSIONS: Future multi-directional investigations interrogating the whole TME are required to improve subsequent clinical translation, and all studies should incorporate up to date controls and reporting requirements to increase the validity of their findings. This would be facilitated by increased collaboration between less experienced and more experienced EV research groups.

Evaluation of weight change and cardiometabolic risk factors in a real-world population of US adults with overweight or obesity.

Whether individuals in real-world settings are able to lose weight and improve cardiometabolic risk factors over time is unclear. We aimed to determine the management of and degree of body weight change over 2 years among individuals with overweight or obesity, and to assess associated changes in cardiometabolic risk factors and clinical outcomes. Using data from 11 large health systems within the Patient-Centered Outcomes Research Network in the U.S., we collected the following data on adults with a recorded BMI ≥25 kg/m2 between January 1, 2016 and December 31, 2016: body-mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), triglycerides and glycated hemoglobin (HbA1c). We found that among 882,712 individuals with BMI ≥25 kg/m2 (median age 59 years; 56% female), 52% maintained stable weight over 2 years and 1.3% utilized weight loss pharmacotherapy. Weight loss of 10% was associated with small but significant lowering of mean SBP (-2.69 mmHg [95% CI -2.88, -2.50]), DBP (-1.26 mmHg [95% CI -1.35, -1.18]), LDL-C (-2.60 mg/dL [95% CI -3.14, -2.05]), and HbA1c (-0.27% [95% CI -0.35, -0.19]) in the same 12 months. However, these changes were not sustained over the following year. In this study of adults with BMI ≥25 kg/m2, the majority had stable weight over 2 years, pharmacotherapies for weight loss were under-used, and small changes in cardiometabolic risk factors with weight loss were not sustained, possibly due to failure to maintain weight loss.

Evaluation of Cerebrovascular Reactivity and Vessel Wall Imaging in Patients With Prior COVID-19: A Prospective Case-Control MRI Study.

BACKGROUND. SARS-CoV-2 infection is associated with acute stroke, possibly caused by viral tropism to the vascular endothelium. Whether cerebrovascular endothelial dysfunction and inflammation persist after acute infection is poorly understood. OBJECTIVE. The purposes of this study were to assess the association between prior SARS-CoV-2 infection and cerebrovascular reactivity (CVR) and vessel wall imaging (VWI) abnormalities and to explore the association between CVR impairment and post-COVID neurologic conditions. METHODS. This prospective study included 15 participants with prior SARS-CoV-2 infection (11 women, four men; mean age, 43 years; mean time since infection, 238 days; three with prior critical illness, 12 with prior mild illness; seven with post-COVID neurologic conditions) and 10 control participants who had never had SARS-CoV-2 infection (two women, two men; mean age, 44 years) from July 1, 2021, to February 9, 2022. Participants underwent research MRI that included arterial spin labeling perfusion imaging with acetazolamide stimulus to measure cerebral blood flow (CBF) and calculate CVR. Examinations also included VWI, performed with a contrast-enhanced black-blood 3D T1-weighted sequence. An age- and sex-adjusted linear model was used to assess associations between CVR and prior infection. A t test was used to assess associations between CVR and post-COVID neurologic conditions in participants with previous infection. A difference of proportions test was used to assess associations between VWI abnormalities and infection status. RESULTS. Mean whole-cortex CBF after acetazolamide administration was greater in participants without previous infection than in participants with previous infection (73.8 ± 13.2 [SD] vs 60.5 ± 15.8 mL/100 gm/min; p = .04). Whole-brain CVR was lower in participants with previous infection than those without previous infection (difference, -8.9 mL/100 g/min; p < .001); significantly lower CVR was also observed in participants with previous infection after exclusion of those with prior critical illness. Among participants with previous infection, CVR was lower in those with than those without post-COVID neurologic conditions, although this difference was not significant (16.9 vs 21.0 mL/100 g/min; p = .22). Six of 15 (40%) participants with previous infection versus 1 of 10 (10%) participants without previous infection had at least one VWI abnormality (p = .18). All VWI abnormalities were consistent with atherosclerosis. CONCLUSION. SARS-CoV-2 infection is associated with chronic impairment of CVR. The mechanism is unknown from this study. CLINICAL IMPACT. Future studies are needed to determine the clinical implications of SARS-CoV-2-associated CVR impairment.

ortho-Fluoro or ortho Effect? Oxidative Addition of Zerovalent Nickel into the C-CN Bond of Substituted Benzonitriles.

A recent study of the oxidative addition of zerovalent Ni to the C-CN bond of F-substituted benzonitriles showed significantly increased stabilization of the C-CN oxidative addition products with o-F groups (-6.6 kcal/mol per o-F) compared to m-F groups (-1.8 kcal/mol per m-F). To answer the question of whether this is an o-F effect or an ortho effect, in this study the effect of CF3 and CH3 groups on the oxidative addition of the [Ni(dmpe)] fragment [dmpe = 1,2-bis(dimethylphosphino)ethane] to the C-CN bond of benzonitriles has been studied. A density functional theory study of the reaction pathway between η2-CN complexes and the C-CN oxidative addition products shows stabilization of the C-CN oxidative addition product with the electron-withdrawing CF3 group and destabilization with the electron-donating CH3 group in both tetrahydrofuran and toluene. There is a slightly larger ortho effect with CF3 (-7.4 kcal/mol) than with F. However, due to steric crowding, two o-CF3 groups did not show considerably more stabilization than one o-CF3 group. There is a linear relationship between ΔG° and the number of meta groups (2.0 kcal/mol stabilization per m-CF3 and 0.8 kcal/mol destabilization per m-CH3). On the basis of natural population analysis, as the C-CN bond becomes more polarized, the stability of the C-CN oxidative addition products with respect to the η2-CN complexes increases.

Effect of intraoperative botulinum toxin injection on delayed gastric emptying and need for endoscopic pyloric intervention following esophagectomy: a systematic review, meta-analysis, and meta-regression analysis.

The aim of this study was to evaluate the effect of intraoperative botulinum toxin (BT) injection on delayed gastric emptying (DGE) and need for endoscopic pyloric intervention (NEPI) following esophagectomy. In compliance with Preferred Reporting Items for Systematic reviews and Meta-Analyses statement standards, a systematic review of studies reporting the outcomes of intraoperative BT injection in patients undergoing esophagectomy for esophageal cancer was conducted. Proportion meta-analysis model was constructed to quantify the risk of the outcomes and direct comparison meta-analysis model was constructed to compare the outcomes between BT injection and no BT injection or surgical pyloroplasty. Meta-regression was modeled to evaluate the effect of variations in different covariates among the individual studies on overall summary proportions. Nine studies enrolling 1070 patients were included. Pooled analyses showed that the risks of DGE and NEPI following intraoperative BT injection were 13.3% (95% confidence interval [CI]: 7.9-18.6%) and 15.2% (95% CI: 7.9-22.5%), respectively. There was no difference between BT injection and no BT injection in terms of DGE (odds ratio [OR]: 0.57, 95% CI: 0.20-1.61, P = 0.29) and NEPI (OR: 1.73, 95% CI: 0.42-7.12, P = 0.45). Moreover, BT injection was comparable to pyloroplasty in terms of DGE (OR: 0.85, 95% CI: 0.35-2.08, P = 0.73) and NEPI (OR: 8.20, 95% CI: 0.63-105.90, P = 0.11). Meta-regression suggested that male gender was negatively associated with the risk of DGE (coefficient: -0.007, P = 0.003). In conclusion, level 2 evidence suggests that intraoperative BT injection may not improve the risk of DGE and NEPI in patients undergoing esophagectomy. The risk of DGE seems to be higher in females and in early postoperative period. High quality randomized controlled trials with robust statistical power are required for definite conclusions. The results of the current study can be used for hypothesis synthesis and power analysis in future prospective trials.

Aerosols enhance cloud lifetime and brightness along the stratus-to-cumulus transition.

Anthropogenic aerosols are hypothesized to enhance planetary albedo and offset some of the warming due to the buildup of greenhouse gases in Earth's atmosphere. Aerosols can enhance the coverage, reflectance, and lifetime of warm low-level clouds. However, the relationship between cloud lifetime and aerosol concentration has been challenging to measure from polar orbiting satellites. We estimate two timescales relating to the formation and persistence of low-level clouds over [Formula: see text] spatial domains using multiple years of geostationary satellite observations provided by the Clouds and Earth's Radiant Energy System (CERES) Synoptic (SYN) product. Lagrangian trajectories spanning several days along the classic stratus-to-cumulus transition zone are stratified by aerosol optical depth and meteorology. Clouds forming in relatively polluted trajectories tend to have lighter precipitation rates, longer average lifetime, and higher cloud albedo and cloud fraction compared with unpolluted trajectories. While liquid water path differences are found to be negligible, we find direct evidence of increased planetary albedo primarily through increased drop concentration ([Formula: see text]) and cloud fraction, with the caveat that the aerosol influence on cloud fraction is positive only for stable atmospheric conditions. While the increase in cloud fraction can be large typically in the beginning of trajectories, the Twomey effect accounts for the bulk (roughly 3/4) of the total aerosol indirect radiative forcing estimate.

Clinical events classification (CEC) in clinical trials: Report on the current landscape and future directions - proceedings from the CEC Summit 2018.

IMPORTANCE: Clinical events adjudication is pivotal for generating consistent and comparable evidence in clinical trials. The methodology of event adjudication is evolving, but research is needed to develop best practices and spur innovation. OBSERVATIONS: A meeting of stakeholders from regulatory agencies, academic and contract research organizations, pharmaceutical and device companies, and clinical trialists convened in Chicago, IL, for Clinical Events Classification (CEC) Summit 2018 to discuss key topics and future directions. Formal studies are lacking on strategies to optimize CEC conduct, improve efficiency, minimize cost, and generally increase the speed and accuracy of the event adjudication process. Major challenges to CEC discussed included ensuring rigorous quality of the process, identifying safety events, standardizing event definitions, using uniform strategies for missing information, facilitating interactions between CEC members and other trial leadership, and determining the CEC's role in pragmatic trials or trials using real-world data. Consensus recommendations from the meeting include the following: (1) ensure an adequate adjudication infrastructure; (2) use negatively adjudicated events to identify important safety events reported only outside the scope of the primary endpoint; (3) conduct further research in the use of artificial intelligence and digital/mobile technologies to streamline adjudication processes; and (4) emphasize the importance of standardizing event definitions and quality metrics of CEC programs. CONCLUSIONS AND RELEVANCE: As novel strategies for clinical trials emerge to generate evidence for regulatory approval and to guide clinical practice, a greater understanding of the role of the CEC process will be critical to optimize trial conduct and increase confidence in the data generated.

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism.

IκB kinase ε (IKKε) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NFκB and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKKε remodels cellular metabolism is currently unknown. Here, we used metabolic tracer analysis to show that IKKε orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKKε upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose-derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces activating transcription factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKKε-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKKε and PSAT1 are both overexpressed, corroborating the link between IKKε and the SBP in the clinical context.