Comparative analysis of kinetic realizations of insulin signaling.

Several studies have developed dynamical models to understand the underlying mechanisms of insulin signaling, a signaling cascade that leads to the translocation of glucose, the human body's main source of energy. Fortunately, reaction network analysis allows us to extract properties of dynamical systems without depending on their model parameter values. This study focuses on the comparison of insulin signaling in healthy state (INSMS or INSulin Metabolic Signaling) and in type 2 diabetes (INRES or INsulin RESistance) using reaction network analysis. The analysis uses network decomposition to identify the different subsystems involved in insulin signaling (e.g., insulin receptor binding and recycling, GLUT4 translocation, and ERK signaling pathway, among others). Furthermore, results show that INSMS and INRES are similar with respect to some network, structo-kinetic, and kinetic properties. Their differences, however, provide insights into what happens when insulin resistance occurs. First, the variation in the number of species involved in INSMS and INRES suggests that when irregularities occur in the insulin signaling pathway, other complexes (and, hence, other processes) get involved, characterizing insulin resistance. Second, the loss of concordance exhibited by INRES suggests less restrictive interplay between the species involved in insulin signaling, leading to unusual activities in the signaling cascade. Lastly, GLUT4 losing its absolute concentration robustness in INRES may signify that the transporter has lost its reliability in shuttling glucose to the cell, inhibiting efficient cellular energy production. This study also suggests possible applications of the equilibria parametrization and network decomposition, resulting from the analysis, to potentially establish absolute concentration robustness in a species.

Epidemiology of norovirus infection in Nigeria: a systematic review and meta-analysis.

Human norovirus (HuNoV) is responsible for most cases of gastroenteritis worldwide, but information about the prevalence and diversity of HuNoV infections in lower-income settings is lacking. In order to provide more information about the burden and distribution of norovirus in Nigeria, we systematically reviewed original published research articles on the prevalence of HuNoV in Nigeria by accessing databases, including PubMed, Web of Science, ScienceDirect, Google Scholar, and African Journals Online (AJOL). The protocol for the review was registered on PROSPERO (registration number CRD42022308857). Thirteen relevant articles were included in the review, and 10 of them were used for meta-analysis. The pooled prevalence of HuNoV-associated gastroenteritis among children below 5 years of age in Nigeria, determined using the random-effects model, was 10.9% (95% CI, 6.7-16.7%). Among children below the age of 5 presenting with HuNoV infections, the highest prevalence was in children ≤2 years old (n = 127, 83%). The prevalence of HuNoV infections was seen to decrease with increasing age. In addition, HuNoV was detected in asymptomatic food handlers, bats, and seafoods. A total of 85 sequences of HuNoV isolates from Nigeria have been determined, and based on those sequences, the most prevalent norovirus genogroup was GII (84%). Genotypes GII.4 and GI.3 were the most frequently identified genotypes, with GII.4 constituting 46% of all of the HuNoVs identified in Nigeria. These results suggest a risk associated with cocirculation of emerging variants with known genotypes because of their recombination potential. Larger molecular epidemiological studies are still needed to fully understand the extent and pattern of circulation of HuNoVs in Nigeria.

Determination of vitamin c in raw fruit and vegetable homogenates: dietary exposure and health effects of excess intake in adults and children.

Objective: The aim of the study was to determine Vitamin C content in some fruits and vegetables (FAV) including apple, banana, orange, pineapple, watermelon, carrot and cucumber, sold in the local markets in Awka, Anambra State, Nigeria as well as Vitamin C content in two-component and three-component homogenates FAV. The work was also designed to investigate the dietary exposure and health effects of excess vitamin C intake in adults and children. Material and methods: Vitamin C as total ascorbic acid (AA) after reduction of dehydroascorbic acid was analyzed using both titrimetric and spectrophotometric methods. The titrimetric method involved iodometric back-titration while the spectrophotometric method was done at an absorbance of 530 nm. The dietary exposure was evaluated as the total FAV intake multiplied by chemical concentration in the FAV whereas the health effect of excess vitamin C intake was conducted using the hazard quotient (HQ). Results: The results revealed that Vitamin C for single fruits ranged from 11.76 - 41.17 mg/L for spectroscopic method and 16.9 - 31.84 mg/L for titrimetric method. Fruit homogenates showed Vitamin C concentrations of 14.70 - 220.58 mg/L and 17.23 - 209.09 mg/L for two-components homogenates: 29.41-132.35 mg/L and 31.05-113.10 mg/L for tri-components homogenates for spectrophotometric and titrimetric methods respectively. The results of dietary exposure and the health effects of excess vitamin C intake showed that children are more susceptible to health issues than adults in illnesses such as nausea, gastrointestinal pains, increased kidney stones and hyperactivity. Conclusion: There is therefore the need for a national recommended dietary allowance for total ascorbic acid (AA) in FAV homogenates from a stakeholder point of view in Nigeria.

Perinatal outcomes in women with lower-range elevated blood pressure and stage 1 hypertension: insights from the Kaya health and demographic surveillance system, Burkina Faso.

BACKGROUND: The impact of lower thresholds for elevated blood pressure (BP) on adverse perinatal outcomes has been poorly explored in sub-Saharan African populations. We aimed to explore the association between lower BP cutoffs (according to the 2017 American College of Cardiology/American Heart Association [ACC/AHA] criteria) and adverse perinatal outcomes in Kaya, Burkina Faso. METHODS: This retrospective cohort study included 2,232 women with singleton pregnancies between February and September 2021. BP was categorized according to the ACC/AHA criteria and applied throughout pregnancy. A multivariable Poisson regression model based on Generalized Estimating Equation with robust standard errors was used to evaluate the association between elevated BP, stage 1 hypertension, and adverse perinatal outcomes, controlling for maternal sociodemographic characteristics, parity, and the number of antenatal consultations, and the results were presented as adjusted risk ratios (aRRs) with corresponding 95% confidence intervals (CIs). RESULTS: Of the 2,232 women, 1000 (44.8%) were normotensive, 334 (14.9%) had elevated BP, 759 (34.0%) had stage 1 hypertension, and 139 (6.2%) had stage 2 hypertension. There was no significant association between elevated BP and adverse pregnancy outcomes. Compared to normotensive women, women with elevated BP had a 2.05-fold increased risk of delivery via caesarean section (aRR;2.05, 95%CI; 1.08-3.92), while those with stage 1 hypertension had a 1.41-fold increased risk of having low birth weight babies (aRR; 1.41, 95%CI; 1.06-1.86), and a 1.32-fold increased risk of having any maternal or neonatal adverse outcome (aRR; 1.32, 95%CI; 1.02-1.69). CONCLUSIONS: Our results suggest that the risk of adverse pregnancy outcomes is not increased with elevated BP. Proactive identification of pregnant women with stage 1 hypertension in Burkina Faso can improve hypertension management through enhanced clinical surveillance.

Iron-Catalyzed Oxidative Rearrangement of Cyclopropanone Hemiaminals: General Access to Pyrroloindolones from Indoles.

A concise synthetic approach to medicinally relevant pyrroloindolones and related fused heterocycles is reported via the diastereoselective N-addition of unprotected indoles to readily accessible cyclopropanone equivalents. The resulting stable hemiaminals are shown to smoothly rearrange to pyrroloindolones in mild conditions using Fe(III) catalysis in the presence of inexpensive ammonium persulfate as a stoichiometric oxidant. Experimental evidence points toward the formation of a ß-carboxylic radical intermediate prone to cyclization and oxidative rearomatization as the operative mechanistic pathway.

Continental scale dietary patterns in a New World raptor using web-sourced photographs.

Dietary studies are essential to better understand raptor ecology and resource requirements through time and space, informing species habitat use, interspecific interactions and demographic rates. Methods used to collect data on raptor diets can constrain how dietary analyses can be interpreted. Traditional approaches to study raptor diets, such as analysis of pellets or prey remains, often provide dietary data at the local population level and tend to be restricted to pairs during the breeding season. The increasing use of citizen science data has the potential to provide dietary inferences at larger spatial, demographic and temporal scales. Using web-sourced photography, we explore continental-scale demographic and latitudinal dietary patterns between adult and non-adult Crested Caracaras (Caracara plancus), throughout the species' range across the Americas. We analysed 1,555 photographs of caracaras feeding and found no age effects on the probabilities of different food groups being included in photographs. The probability of reptiles being included in photographs of caracaras from the northern population was significantly higher than those from the southern population, with the opposite pattern for birds. There were significant latitudinal effects with the probabilities of fishes and invertebrates in the diet of northern caracaras increasing towards the equator. Contrastingly, the probability of mammals in the diet increased away from the equator for both populations. Assuming the focal species is well-sampled, web-sourced photography can improve our understanding of raptor diets at large-scales and complements more traditional approaches. This approach is more accessible to raptor researchers without access to the field or expertise in physical prey identification techniques.

Dissecting the Genetic Diversity of USDA Cowpea Germplasm Collection Using Kompetitive Allele Specific PCR-Single Nucleotide Polymorphism Markers.

Cowpea (Vigna unguiculata L. Walp) is an important grain legume crop of the subtropics, particularly in West Africa, where it contributes to the livelihoods of small-scale farmers. Despite being a drought-resilient crop, cowpea production is hampered by insect pests, diseases, parasitic weeds, and various abiotic stresses. Genetic improvement can help overcome these limitations, and exploring diverse cowpea genetic resources is crucial for cowpea breeding. This study evaluated the genetic diversity of 361 cowpea accessions from the USDA core collection for the species using 102 Kompetitive Allele Specific PCR (KASP) single nucleotide polymorphism (SNP) markers. A total of 102 KASP-SNP was validated in the germplasm panel, and 72 showed polymorphism across the germplasm panel. The polymorphism information content (PIC) of all SNPs ranged from 0.1 to 0.37, with an average of 0.29, while the mean observed heterozygosity was 0.52. The population structure revealed three distinct populations that clustered into two major groups after phylogenetic analysis. Analysis of molecular variance (AMOVA) indicated greater genetic variation within populations than among populations. Although cowpea generally has a narrow genetic diversity, the accessions used in this study exhibited considerable variation across geographical regions, sub-species, and improvement status. These results indicated that the selected KASP genotyping assay can provide robust and accurate genotyping data for application in the selection and management of cowpea germplasm in breeding programs and genebanks.

Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) is a rare type of stroke indicated by the formation of blood clots within the dural venous sinuses. These are large venous conduits that are situated between the 2 layers of the dura mater which are responsible for draining blood from the brain and returning it to the systemic circulation. Cortical venous thrombosis refers to the blockage of veins on the brain's cortical surface. Cerebral venous thrombosis encompasses both dural and cortical vein occlusions.

Rates of operative intervention and in-hospital mortality following subarachnoid hemorrhage in patients with COVID-19.

OBJECTIVE: COVID-19 had massive effects on the healthcare system and multifactorial implications for the management of intensive care unit and cerebrovascular patients. This study aimed to assess the effect of COVID-19 on the outcomes of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS: The National Inpatient Sample (NIS) was used to identify patients with nontraumatic SAH (ICD-10 code I60.x). Patients with nonaneurysmal cerebrovascular malformations or traumatic intracranial injuries were excluded. Only patients managed from April to December 2020 were included in the study given the availability of an ICD-10 code for COVID-19. Data on sociodemographic factors, hospital characteristics, comorbidities, NIS SAH Severity Score (NIS-SSS), surgical treatment, and death were acquired. Multivariable analysis was used to assess predictors of both surgical intervention and in-hospital mortality. RESULTS: In total, 6984 patients met the study criteria, 359 (5.1%) of whom had COVID-19. Those with COVID-19 were more likely to be younger and male and had a higher All Patient Refined Diagnosis-Related Groups illness severity subclass, and NIS-SSS. Moreover, patients with COVID-19 were less likely to undergo surgery (10.0% vs 23.6%, OR 0.35, p < 0.0001) and had significantly higher mortality rates (48.2% vs 22.7%, p < 0.0001). When controlling for other variables, COVID-19 was an independent predictor of death (OR 1.67, p = 0.0002). Aneurysm surgery was performed in 1597 patients (317 open and 1280 endovascular procedures). There was no difference between the cohorts positive and negative for COVID-19 in terms of time to surgery or type of surgery. CONCLUSIONS: COVID-19 had significant impacts on patients with nontraumatic SAH. Specifically, patients with COVID-19 were significantly less likely to undergo surgery and had higher in-hospital mortality rates; however, for patients who did undergo procedural intervention, there was no significant difference in the type of intervention. Multiple factors, from medical acuity to healthcare system limitations, may contribute to these findings. Further retrospective research is needed to identify both specific causes of lower intervention rates and other potential nonaneurysmal causes of SAH in patients with COVID-19.

Distal mechanical thrombectomy using beveled tip aspiration zoom catheters: A preliminary study.

INTRODUCTION: Distal medium vessel occlusion (DVO) thrombectomy has been shown to be efficacious with safety profiles comparable to large vessel occlusion (LVO) thrombectomy. A novel, highly-trackable, bevel-tipped Zoom 35 catheter can be used as an aspiration catheter for DVO thrombectomy. METHODS: This is a retrospective, single-arm, multi-institutional observational study evaluating the efficacy and safety of aspiration thrombectomy for DVO using the Zoom 35 catheter. Patient demographics, presenting and discharge NIHSS, primary and rescue thrombectomy, site of occlusion, TICI score, and intracranial hemorrhage were chart abstracted. Descriptive statistics were used to evaluate the efficacy and safety of thrombectomy. RESULTS: Fourteen patients (mean age 66.64 ± 13.75 years) were included. The mean NIHSS at presentation was 10.79 ± 5.48, and the mean ASPECTS was 9.00 ± 0.89. Nine patients (64.3%) received tPA. Primary occlusion location was M3 in nine cases (64.3%), M2/M3 junction in two cases (14.3%), A2 in one case (7.1%), A3 in one case (7.1%), and P1 in one case (7.1%). TICI scores were 3 in seven cases (50.0%), 2C in three cases (21.4%), and 2B in four cases (28.6%). There was one postoperative SAH (7.1%) and one asymptomatic ICH (7.1%). Mean discharge NIHSS was 3.38 ± 4.44, with a mean decrease of 7.31 from presentation (p < 0.0001, t-test). CONCLUSION: Zoom 35 beveled-tip aspiration microcatheters are highly trackable and associated with improved radiographic and clinical outcomes for the treatment of DVO with a good safety profile.

Leopard subspecies conservation under climate and land-use change.

Predicting the effects of global environmental changes on species distribution is a top conservation priority, particularly for large carnivores, that contribute to regulating and maintaining ecosystems. As the most widespread and adaptable large felid, ranging across Africa and Asia, leopards are crucial to many ecosystems as both keystone and umbrella species, yet they are threatened across their ranges. We used intraspecific species distribution models (SDMs) to predict changes in range suitability for leopards under future climate and land-use change and identify conservation gaps and opportunities. We generated intraspecific SDMs for the three western leopard subspecies, the African, Panthera pardus pardus; Arabian, Panthera pardus nimr; and Persian, Panthera pardus tulliana, leopards, and overlapped predictions with protected areas (PAs) coverage. We show that leopard subspecies differ in their environmental associations and vulnerability to future changes. The African and Arabian leopards are predicted to lose ~25% and ~14% of their currently suitable range, respectively, while the Persian leopard is predicted to experience ~12% range gains. We found that most areas predicted to be suitable were not protected, with only 4%-16% of the subspecies' ranges falling inside PAs, and that these proportions will decrease in the future. The highly variable responses we found between leopard subspecies highlight the importance of considering intraspecific variation when modelling vulnerability to climate and land-use changes. The predicted decrease in proportion of suitable ranges falling inside PAs threatens global capacity to effectively conserve leopards because survival rates are substantially lower outside PAs due to persecution. Hence, it is important to work with local communities to address negative human-wildlife interactions and to restore habitats to retain landscape connectivity where PA coverage is low. On the other hand, the predicted increase in range suitability across southern Europe presents opportunities for expansion outside of their contemporary range, capitalising on European rewilding schemes.

Open Surgical Treatment of Middle Cerebral Artery Aneurysms: A Single-Center Series in the Endovascular Era.

OBJECTIVE: We review the outcomes of open surgical treatment of middle cerebral artery aneurysms (MCAAs) at a single center, focusing on aneurysm obliteration rates and functional outcomes at the most recent follow-up. These findings can be used for future comparisons of surgical outcomes with MCAAs. METHODS: We retrospectively reviewed cases from a prospectively maintained database of patients receiving open surgical treatment for ruptured or unruptured MCAAs between July 2014 and December 2022. We utilized patients' modified Rankin Scale (mRS) score and Glasgow Outcome Scale score as functional outcome measures. Means, standard deviations, medians, and interquartile ranges were calculated, and a student's t test or its nonparametric equivalent was used to compare subgroups. RESULTS: One hundred fifty patients (114 women, 76%; mean age 55.0 ± 14.7 years) with a total of 156 MCAAs comprised 152 cases; 85 (56%) ruptured and 71 (46%) unruptured. Bypass was performed in 34 cases (22.4%); 18 ruptured (51.4%) and 16 unruptured (48.6%). Intraoperative rupture occurred in 5 (5%) ruptured and 1 (2%) unruptured cases. Onwe hundred forty-five patients (95.4%) had aneurysm obliteration with initial surgery, with 98.4% of patients having complete occlusion at 40.2± 65.5 weeks of follow-up. Intrahospital mortality occurred in 7 (6.9%) ruptured versus 1 (2.0%) unruptured case. Fifty-two (51.5%) of the ruptured compared to 43 (86%) unruptured patients were discharged home, with the remaining patients requiring inpatient rehabilitation or long-term hospitalization. The ruptured group had a mean hospital stay of 18.4 ± 10.5 days versus. 5.7 ± 6.0 days for unruptured. Length of stay, discharge mRS/ Glasgow Outcome Scale, and mRS at 4-6 weeks favored unruptured cases (P < 0.0001-0.0336). Mean change in mRS from presentation to last follow-up favored ruptured cases (-0.7 ± 1.2 vs. -0.04 ± 1.2, P = 0.0215). CONCLUSIONS: Open surgery remains a safe and definitive treatment option for MCAAs in the endovascular era.

Combined endovascular embolization and decompressive craniectomy for microsurgical resection of giant ruptured distal anterior cerebral artery aneurysm.

Giant ruptured distal anterior cerebral artery aneurysms are rare, challenging pathologies that may require a combination of microsurgical and endovascular techniques for optimal treatment [1-9]. We describe the case of a female in her 40 s who presented with a Hunt-Hess 4, Fisher 4 subarachnoid hemorrhage from a multiply ruptured, giant distal anterior cerebral artery aneurysm. The patient underwent coil and n-BCA glue embolization of the aneurysm and its feeding A2 anterior cerebral artery. She subsequently underwent decompressive craniectomy, intracerebral hematoma evacuation, and microsurgical trapping and resection of the aneurysm. Postoperative imaging demonstrated no further aneurysm filling, complete hematoma evacuation, and good decompression. The technical considerations and literature for the combined treatment of large and giant ruptured aneurysms are reviewed. The case presentation, operative nuances, and postoperative course with imaging are reviewed with detailed anatomical diagrams to orient the viewer. The patient consented to the procedure and to the publication of her imaging.

Direct V3 Vertebral Artery Access for Embolization of Partially Thrombosed Fusiform Basilar Trunk Aneurysm: Technical Case Instruction.

BACKGROUND AND IMPORTANCE: Fusiform vertebrobasilar aneurysms carry significant morbidity. Endovascular strategies are preferred; however, unsafe or unfeasible access can call for innovative strategies. CLINICAL PRESENTATION: An octogenarian patient with an enlarging fusiform proximal basilar artery aneurysm causing a sixth nerve palsy was found to have multiple anatomic features that precluded a transradial or transfemoral endovascular approach. She was thus treated with direct microsurgical access of the V3 segment of the vertebral artery for subsequent coil embolization and flow diversion. CONCLUSION: This case introduces a novel combined microsurgical and endovascular strategy for treating a complex partially thrombosed fusiform basilar artery aneurysm. This approach should be reserved only for patients where conventional endovascular access is dangerous or unfeasible.

Pro-inflammatory feedback loops define immune responses to pathogenic Lentivirus infection.

BACKGROUND: The Lentivirus human immunodeficiency virus (HIV) causes chronic inflammation and AIDS in humans, with variable rates of disease progression between individuals driven by both host and viral factors. Similarly, simian lentiviruses vary in their pathogenicity based on characteristics of both the host species and the virus strain, yet the immune underpinnings that drive differential Lentivirus pathogenicity remain incompletely understood. METHODS: We profile immune responses in a unique model of differential lentiviral pathogenicity where pig-tailed macaques are infected with highly genetically similar variants of SIV that differ in virulence. We apply longitudinal single-cell transcriptomics to this cohort, along with single-cell resolution cell-cell communication techniques, to understand the immune mechanisms underlying lentiviral pathogenicity. RESULTS: Compared to a minimally pathogenic lentiviral variant, infection with a highly pathogenic variant results in a more delayed, broad, and sustained activation of inflammatory pathways, including an extensive global interferon signature. Conversely, individual cells infected with highly pathogenic Lentivirus upregulated fewer interferon-stimulated genes at a lower magnitude, indicating that highly pathogenic Lentivirus has evolved to partially escape from interferon responses. Further, we identify CXCL10 and CXCL16 as important molecular drivers of inflammatory pathways specifically in response to highly pathogenic Lentivirus infection. Immune responses to highly pathogenic Lentivirus infection are characterized by amplifying regulatory circuits of pro-inflammatory cytokines with dense longitudinal connectivity. CONCLUSIONS: Our work presents a model of lentiviral pathogenicity where failures in early viral control mechanisms lead to delayed, sustained, and amplifying pro-inflammatory circuits, which in turn drives disease progression.

Acute and Long-Term Management of Blunt Cerebrovascular Injury at a Quaternary Referral Level 1 Trauma Center: The Memphis Experience and Comparison of a New Scoring System.

BACKGROUND AND OBJECTIVES: The management of blunt cerebrovascular injuries (BCVIs) remains an important topic within trauma and neurosurgery today. There remains a lack of consensus within the literature and significant variation across institutions. The purpose of this study was to evaluate management of BCVI at a large, tertiary referral trauma center. METHODS: Institutional Review Board approval was obtained to conduct a retrospective review of patients with BCVI at our Level 1 Trauma Center. Computed tomography angiography was used to identify BCVI for each patient. Patient information was collected, and statistical analysis was performed. With the included risk factors for ischemic complications, a novel scoring system based on ischemic risk, the "Memphis Score," was developed and evaluated to grade BCVI. RESULTS: Two hundred seventeen patients with BCVI from July 2020 to August 2022 were identified. The most common mechanism of injury was motor vehicle collision (141, 65.0%). Vertebral arteries were the most common vessel injured (136, 51.1%) with most injuries occurring at a high cervical location (101, 38.0%). Denver Grade 1 injuries (89, 33.5%) and a Memphis Score of 1 were most frequent (172, 64.6%), and initial anticoagulation with heparin drip was initiated 56.7% of the time (123). Endovascular treatment was required in 24 patients (11.1%) and was usually performed in the first 48 hours (15, 62.5%). While Denver Grade (P = .019) and Memphis Score (P < .00001) were significantly higher in those patients undergoing endovascular treatment, only the Memphis Score demonstrated a significant difference between those patients who had stroke or worsening on follow-up imaging and those who did not (P = .0009). CONCLUSION: Although BCVI management has improved since early investigative efforts, institutions must evaluate and share their data to help clarify outcomes. The novel "Memphis Score" presents a standardized framework to communicate ischemic risk and guide management of BCVI.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

An enhanced IL17 and muted type I interferon nasal epithelial cell state characterizes severe COVID-19 with fungal coinfection.

Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation-in part driven by Candida colonization-and blunted interferon signaling represent a common feature of severe COVID-19 infection. IMPORTANCE: In this paper, we present an analysis suggesting that symptomatic and asymptomatic fungal coinfections can impact patient disease progression during COVID-19 hospitalization. By looking into the presence of other pathogens and their effect on the host immune response during COVID-19 hospitalizations, we aim to offer insight into an underestimated scenario, furthering our current knowledge of determinants of severity that could be considered for future diagnostic and intervention strategies.

Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study.

BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

Compilation of an informative microsatellite set for genetic characterisation of East African finger millet (Eleusine coracana)

Background Genetic diversity of finger millet (Eleusine coracana), a nutritious neglected staple cereal in Africa and South Asia is largely uncharacterized. This study analysed 82 published SSR markers for finger millet across 10 diverse accessions to compile an informative set for genetic characterisation. Extensive optimization compared single samples with bulked leaf or bulked DNA samples for capturing within accession genetic diversity. The markers were evaluated to determine (1) how efficiently they amplified target loci during high-throughput genotyping with a generic PCR protocol, (2) ease of scoring PCR products and (3) polymorphism and ability to discern genetic diversity within the tested finger millet germplasm. Results Across 88 samples, the 52 markers that worked well amplified 274 alleles, ranging from 2 to 14 per locus with a mean of 4.89. Major allele frequency ranged from 0.18 to 0.93 with a mean of 0.57. Polymorphic Information Content (PIC) ranged from 0.13 to 0.88 with a mean of 0.5 and availability varied between 64 and 100% with a mean of 92.8%. Heterozygosity ranged from 0 to 1.0, with a mean of 0.26. Discussion Five individual samples from an accession captured the largest number of alleles per locus compared to the four different bulked sampling strategies but this difference was not significant. The identified set comprised 20 markers: UGEP24, UGEP53, UGEP84, UGEP27, UGEP98, UGEP95, UGEP64, UGEP33, UGEP67, UGEP106, UGEP110, UGEP57, UGEP96, UGEP66, UGEP46, UGEP79, UGEP20, UGEP12, UGEP73 and UGEP5 and was since used to assess East African finger millet genetic diversity in two separate studies.