Showing papers by "Texas Medical Center published in 2021"

Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer.

Abstract: Rationale: Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. Methods: We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. Results: We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, β-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Conclusions: Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.

Spatiotemporal dynamics of orthographic and lexical processing in the ventral visual pathway.

Abstract: Reading is a rapid, distributed process that engages multiple components of the ventral visual stream. To understand the neural constituents and their interactions that allow us to identify written words, we performed direct intra-cranial recordings in a large cohort of humans. This allowed us to isolate the spatiotemporal dynamics of visual word recognition across the entire left ventral occipitotemporal cortex. We found that mid-fusiform cortex is the first brain region sensitive to lexicality, preceding the traditional visual word form area. The magnitude and duration of its activation are driven by the statistics of natural language. Information regarding lexicality and word frequency propagates posteriorly from this region to visual word form regions and to earlier visual cortex, which, while active earlier, show sensitivity to words later. Further, direct electrical stimulation of this region results in reading arrest, further illustrating its crucial role in reading. This unique sensitivity of mid-fusiform cortex to sub-lexical and lexical characteristics points to its central role as the orthographic lexicon-the long-term memory representations of visual word forms.

Standardized Nomenclature for Modified Rankin Scale Global Disability Outcomes: Consensus Recommendations From Stroke Therapy Academic Industry Roundtable XI.

Abstract: The modified Rankin Scale (mRS), a 7-level, clinician-reported, measure of global disability, is the most widely employed outcome scale in acute stroke trials. The scale's original development preceded the advent of modern clinimetrics, but substantial subsequent work has been performed to enable the mRS to meet robust contemporary scale standards. Prior research and consensus recommendations have focused on modernizing 2 aspects of the mRS: operationalized assignment of scale scores and statistical analysis of scale distributions. Another important characteristic of the mRS still requiring elaboration and specification to contemporary clinimetric standards is the Naming of scale outcomes. Recent clinical trials have used a bewildering variety, often mutually contradictory, of rubrics to describe scale states. Understanding of the meaning of mRS outcomes by clinicians, patients, and other clinical trial stakeholders would be greatly enhanced by use of a harmonized, uniform set of labels for the distinctive mRS outcomes that would be used consistently across trials. This statement advances such recommended rubrics, developed by the Stroke Therapy Academic Industry Roundtable collaboration using an iterative, mixed-methods process. Specific guidance is provided for health state terms (eg, Symptomatic but Nondisabled for mRS score 1; requires constant care for mRS score 5) and valence terms (eg, excellent for mRS score 1; very poor for mRS score 5) to employ for 23 distinct numeric mRS outcomes, including: all individual 7 mRS levels; all 12 positive and negative dichotomized mRS ranges, positive and negative sliding dichotomies; and utility-weighted analysis of the mRS.

Utilization and Availability of Advanced Imaging in Patients With Acute Ischemic Stroke.

Abstract: Background: Recent clinical trials have established the efficacy of endovascular stroke therapy and intravenous thrombolysis using advanced imaging, particularly computed tomography perfusion (CTP)...

Endomembrane targeting of human OAS1 p46 augments antiviral activity.

Abstract: Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.

Prospective Evaluation of TMVR for Failed Surgical Annuloplasty Rings: MITRAL Trial Valve-in-Ring Arm 1-Year Outcomes.

Abstract: Objectives The authors report 1-year outcomes of high-risk patients with failed surgical annuloplasty rings undergoing transseptal mitral valve–in–ring (MViR) with the SAPIEN 3 aortic transcatheter heart valve (THV). Background The MITRAL (Mitral Implantation of Transcatheter Valves) trial is the first prospective study evaluating transseptal MViR with the SAPIEN 3 aortic THV in high-risk patients with failed surgical annuloplasty rings. Methods Prospective enrollment of high-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis and failed annuloplasty rings at 13 U.S. sites. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year). Results Thirty patients were enrolled between January 2016 and October 2017 (median age 71.5 years [interquartile range: 67.0 to 76.8 years], 36.7% women, median Society of Thoracic Surgeons score 7.6% [interquartile range: 5.1% to 11.8%], 76.7% in New York Heart Association functional class III or IV). Technical success was 66.7% (driven primarily by need for a second valve in 6 patients). There was no intraprocedural mortality or conversion to surgery. The primary performance endpoint was achieved in 85.7% of survivors at 30 days (24 of 28) and 89.5% of patients alive at 1 year with echocardiographic data available (17 of 19). All-cause mortality at 30 days was 6.7% and at 1 year was 23.3%. Among survivors at 1-year follow-up, 84.2% were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.0 mm Hg (interquartile range: 4.7 to 7.3 mm Hg), and all had ≤1+ MR. Conclusions Transseptal MViR was associated with a 30-day mortality rate lower than predicted by the Society of Thoracic Surgeons score. At 1 year, transseptal MViR was associated with symptom improvement and stable THV performance.

The Story of Intracerebral Hemorrhage: From Recalcitrant to Treatable Disease.

Abstract: This invited special report is based on an award presentation at the World Stroke Organization/European Stroke Organization Conference in November of 2020 outlining progress in the acute management...

RNA Modification of N6-Methyladenosine Predicts Immune Phenotypes and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma.

Abstract: RNA modification of N6-methyladenosine (m6A) plays critical roles in various biological processes, such as cancer development, inflammation, and the anticancer immune response. However, the role played by a comprehensive m6A modification pattern in regulating anticancer immunity in kidney renal clear cell carcinoma (KIRC) has not been fully elucidated. In this study, we identified two independent m6A modification patterns with distinct biological functions, immunological characteristics, and prognoses in KIRC. Next, we developed an m6A score algorithm to quantify an individual's m6A modification pattern, which was independently validated in external cohorts. The m6A cluster 1 and low m6A score groups were characterized by a hot tumor microenvironment with an increased infiltration level of cytotoxic immune cells, higher tumor mutation burden, higher immune checkpoint expression, and decreased stroma-associated signature enrichment. In general, the m6A cluster 1 and low m6A score groups reflected an inflammatory phenotype, which may be more sensitive to anticancer immunotherapy. The m6A cluster 2 and high m6A score groups indicated a non-inflammatory phenotype, which may not be sensitive to immunotherapy but rather to targeted therapy. In this study, we first identified m6A clusters and m6A scores to elucidate immune phenotypes and to predict the prognosis and immunotherapy response in KIRC, which can guide urologists for making more precise clinical decisions.

Endomembrane targeting of human OAS1 p46 augments antiviral activity

Abstract: Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from host cell innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense viral RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flavivirus, picornavirus, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform strongly associates with COVID-19 severity. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.

5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer.

Abstract: Background Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. Methods In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. Results Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways. Conclusions The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.

Gene therapy for diabetic peripheral neuropathy: A randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor.

Abstract: VM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3-1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3-1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3-1 was change from baseline in the mean 24-h Numerical Rating Scale (NRS) pain score. In DPN 3-1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well-tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3-1. In DPN 3-1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3-1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3-1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long-lasting pain-relieving effects of VM202 observed in DPN 3-1b warrant another rigorous phase III study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN. WHAT QUESTION DID THIS STUDY ADDRESS? Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Nonviral gene therapy can be used safely and practically to treat DPN. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.

The multiarm optimization of stroke thrombolysis phase 3 acute stroke randomized clinical trial: Rationale and methods.

Abstract: BackgroundIntravenous recombinant tissue plasminogen activator is the only proven effective medication for the treatment of acute ischemic stroke. Two approaches that may augment recombinant tissue...

Inter-hospital COVID ECMO air transportation.

Abstract: The Coronavirus Disease 2019 (COVID-19) pandemic has required rapid and effective protocol adjustments at every level of healthcare. The use of extracorporeal membrane oxygenation (ECMO) is pivotal to COVID-19 treatment in cases of refractory hypoxemic hypercapnic respiratory failure. As such, our large, metropolitan air ambulance system in conjunction with our experts in advanced cardiopulmonary therapies modified protocols to assist peripheral hospitals in evaluation, cannulation and initiation of ECMO for rescue and air transportation of patients with COVID-19 to our quaternary center. The detailed protocol is described alongside initial data of its use. To date, 14 patients have been placed on ECMO support at an outside facility and successfully transported via helicopter to our hub hospital using this protocol.

Risk of intracranial hemorrhage associated with pregnancy in women with cerebral arteriovenous malformations.

Abstract: Background Prior studies on rupture risk of brain arteriovenous malformations (AVMs) in women undergoing pregnancy and delivery have reported conflicting findings, but also have not accounted for AVM morphology and heterogeneity. Here, we assess the association between pregnancy and the risk of intracranial hemorrhage (ICH) in women with AVMs using a cohort-crossover design in which each woman serves as her own control. Methods Women who underwent pregnancy and delivery were identified using DRG codes from the Healthcare Cost and Utilization Project State Inpatient Databases for California (2005–2011), Florida (2005–2014), and New York (2005–2014). The presence of AVM and ICH was determined using ICD 9 codes. Pregnancy was defined as the 40 weeks prior to delivery, and postpartum as 12 weeks after. We defined a non-exposure control period as a 52-week period prior to pregnancy. The relative risks of ICH during pregnancy were compared against the non-exposure period using conditional Poisson regression. Results Among 4 022 811 women identified with an eligible delivery hospitalization (median age, 28 years; 7.3% with gestational diabetes; 4.5% with preeclampsia/eclampsia), 568 (0.014%) had an AVM. The rates of ICH during pregnancy and puerperium were 6355.4 (95% CI 4279.4 to 8431.5) and 14.4 (95% CI 13.3 to 15.6) per 100 000 person-years for women with and without AVM, respectively. In cohort-crossover analysis, in women with AVMs the risk of ICH increased 3.27-fold (RR, 95% CI 1.67 to 6.43) during pregnancy and puerperium compared with a non-pregnant period. Conclusions Among women with AVM, pregnancy and puerperium were associated with a greater than 3-fold risk of ICH.

First in Man Pilot Feasibility Study in Extracranial Carotid Robotic-Assisted Endovascular Intervention

Abstract: Background Robotic-assistance in endovascular intervention represents a nascent yet promising innovation. Objective To present the first human experience utilizing robotic-assisted angiography in the extracranial carotid circulation. Methods Between March 2019 and September 2019, patients with extracranial carotid circulation pathology presenting to Houston Methodist Hospital were enrolled. Results A total of 6 patients met inclusion criteria: 5 underwent diagnostic angiography only with robotic-assisted catheter manipulation, while 1 underwent both diagnostic followed by delayed therapeutic intervention. Mean age was 51 +/- 17.5 yr. Mean anesthesia time was 158.7 +/- 37.9 min, mean fluoroscopic time was 22.0 +/- 7.3 min, and mean radiation dose was 815.0 +/- 517.0 mGy. There were no technical complications and no clinical deficits postprocedure. None of the cases required conversion to manual neurovascular intervention (NVI). Conclusion Incorporating robotic technology in NVI can enhance procedural technique and diminish occupational hazards. Its application in the coronary and peripheral vascular settings has established safety and efficacy, but in the neurovascular setting, this has yet to be demonstrated. This study presents the first in human feasibility experience of robotic-assisted NVI in the extracranial carotid circulation.

Ultrasound for the diagnosis of malrotation and volvulus in children and adolescents: a systematic review and meta-analysis.

Abstract: Context Despite the advantages of ultrasound (US), upper gastrointestinal contrast series (UGI) remains the first-line diagnostic modality in the diagnosis of midgut malrotation and volvulus in children. Objective Evaluate the diagnostic accuracy of US in the diagnosis of malrotation with or without volvulus in children and adolescents aged 0–21 years, compared with the reference standard (diagnosis by surgery, UGI, CT, MRI, and clinical follow-up individually or as a composite). Data sources We searched the electronic databases Ovid-MEDLINE, Embase, Scopus, CINAHL, and the Cochrane library in October 2019 and updated on 18 August 2020. Study selection Studies evaluating the diagnostic performance of US for diagnosis of midgut malrotation with or without volvulus in children (0–21 years). Data extraction and synthesis The data were extracted independently by two authors and a bivariate model was used for synthesis. Results Meta-analysis of 17 cohort or cross-sectional studies and 2257 participants estimated a summary sensitivity of 94% (95% CI 89% to 97%) and summary specificity of 100% (95% CI 97% to 100%) (moderate certainty evidence) for the use of US for the diagnosis of malrotation with or without midgut volvulus compared with the reference standard. Subgroup analysis and meta-regression revealed better diagnostic accuracy in malrotation not complicated by volvulus, in the neonatal population and enteric fluid administration before US. Conclusions Moderate certainty evidence suggests excellent diagnostic accuracy and coupled with the advantages, a strong case exists for the use of abdominal US as the first-line diagnostic test for suspected midgut malrotation with or without volvulus in children and adolescents.

Fifty Years of Acute Ischemic Stroke Treatment: A Personal History.

Abstract: Background It has been 50 years since the first explorations of the physiology of cerebral ischemia by measuring cerebral blood flow (CBF), and 25 years since the approval of tissue plasminogen activator for treating acute ischemic stroke. My personal career began and matured during those eras. Here, I provide my perspective on the evolution of acute stroke research and treatment from 1971 to the present, with some in-depth discussion of the National Institutes of Neurologic Disease and Stroke (NINDS) tissue-type plasminogen activator (tPA) stroke trial and development of mobile stroke units. Summary Studies of CBF and metabolism in acute stroke patients revealed graded tissue injury that was dependent on the duration of ischemia. Subsequent animal research unraveled the biochemical cascade of events occurring at the cellular level after cerebral ischemia. After a decade of failed translation, the development of a relatively safe thrombolytic allowed us to achieve reperfusion and apply the lessons from earlier research to achieve positive clinical results. The successful conduct of the NINDS tPA stroke study coupled with positive outcomes from companion tPA studies around the world created the specialty of vascular neurology. This was followed by an avalanche of research in imaging, a focus on enhancing reperfusion through thrombectomy, and improving delivery of faster treatment culminating in mobile stroke units. Key Messages: The last half century has seen the birth and evolution of successful acute stroke treatment. More research is needed in developing new drugs and catheters to build on the advances we have already made with reperfusion and also in evolving our systems of care to get more patients treated more quickly in the prehospital setting. The history of stroke treatment over the last 50 years exemplifies that medical "science" is an evolving discipline worth an entire career's dedication. What was impossible 50 years ago is today's standard of care, what we claim as dogma today will be laughed at a decade from now, and what appears currently impossible will be tomorrow's realities.

Habitual Sleep Duration and the Colonic Mucosa-Associated Gut Microbiota in Humans-A Pilot Study.

Abstract: We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the V4 region. The sequence reads were processed using UPARSE and DADA2, respectively. Lifestyle factors, including sleep habits, were obtained using an interviewer-administered questionnaire. We categorized the participants into short sleepers (<6 h per night; n = 16) and normal sleepers (6–8 h per night; n = 47) based on self-reported data. Differences in bacterial biodiversity and the taxonomic relative abundance were compared between short vs. normal sleepers, followed by multivariable analysis. A false discovery rate-adjusted p value (q value) < 0.05 indicated statistical significance. The bacterial community composition differed in short and normal sleepers. The relative abundance of Sutterella was significantly lower (0.38% vs. 1.25%) and that of Pseudomonas was significantly higher (0.14% vs. 0.08%) in short sleepers than in normal sleepers (q values < 0.01). The difference was confirmed in the multivariable analysis. Nocturnal sleep duration was associated with the bacterial community composition and structure in the colonic gut microbiota in adults.

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

Abstract: Objective To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). Methods We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. Results The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53). Conclusion BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

A meta-analysis of the global impact of the COVID-19 pandemic on stroke care & the Houston Experience.

Abstract: Objective To review the global impact of the COVID-19 pandemic on stroke care-metrics and report data from a health system in Houston. Methods We performed a meta-analysis of the published literature reporting stroke admissions, intracerebral hemorrhage (ICH) cases, number of thrombolysis (tPA) and thrombectomy (MT) cases, and time metrics (door to needle, DTN; and door to groin time, DTG) during the pandemic compared to prepandemic period. Within our hospital system, between January-June 2019 and January-June 2020, we compared the proportion of stroke admissions and door to tPA and MT times. Results A total of 32,640 stroke admissions from 29 studies were assessed. Compared to prepandemic period, the mean ratio of stroke admissions during the pandemic was 70.78% [95% CI, 65.02%, 76.54%], ICH cases was 83.10% [95% CI, 71.01%, 95.17%], tPA cases was 81.74% [95% CI, 72.33%, 91.16%], and MT cases was 88.63% [95% CI, 74.12%, 103.13%], whereas DTN time was 104.48% [95% CI, 95.52%, 113.44%] and DTG was 104.30% [95% CI, 81.99%, 126.61%]. In Houston, a total of 4808 cases were assessed. There was an initial drop of ~30% in cases at the pandemic onset. Compared to 2019, there was a significant reduction in mild strokes (NIHSS 1-5) [N (%), 891 (43) vs 635 (40), P = 0.02]. There were similar mean (SD) (mins) DTN [44 (17) vs 42 (17), P = 0.14] but significantly prolonged DTG times [94 (15) vs 85 (20), P = 0.005] in 2020. Interpretation The COVID-19 pandemic led to a global reduction in stroke admissions and treatment interventions and prolonged treatment time metrics.

Spatial Characteristics of Colonic Mucosa-Associated Gut Microbiota in Humans.

Abstract: Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray–Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.

Demon: Momentum Decay for Improved Neural Network Training

Abstract: Momentum is a popular technique in deep learning for gradient-based optimizers. We propose a decaying momentum (Demon) rule, motivated by decaying the total contribution of a gradient to all future updates. Applying Demon to Adam leads to significantly improved training, notably competitive to momentum SGD with learning rate decay, even in settings in which adaptive methods are typically non-competitive. Similarly, applying Demon to momentum SGD improves over momentum SGD with learning rate decay in most cases. Notably, Demon momentum SGD is observed to be significantly less sensitive to parameter tuning than momentum SGD with learning rate decay schedule, critical to training neural networks in practice. Results are demonstrated across a variety of settings and architectures, including image classification, generative models, and language models. Demon is easy to implement and tune, and incurs limited extra computational overhead, compared to the vanilla counterparts. Code is readily available.