A phase 3b, open-label, single-arm, multicenter, expanded-access study of the safety and clinical outcomes of StrataGraft® treatment in adults with deep partial-thickness thermal burns.

BACKGROUND: A phase 3b, open-label, multicenter, expanded-access study (NCT04123548) evaluated safety and clinical outcomes of StrataGraft treatment in adults with deep partial-thickness thermal burns with intact dermal elements. METHODS: Adult patients with 3 % to < 50 % total body surface area burns were treated with a single application of ≤ 1:1 meshed StrataGraft and followed for 24 weeks. Primary endpoint was count and percentage of patients with treatment-emergent adverse events (TEAEs). Secondary endpoints included confirmed wound closure (WC) at Week 12, durable WC at Week 24, time to WC, scar evaluation, and wound infection-related events. RESULTS: Fifty-two patients with 96 treatment sites were enrolled. Pruritus was the most common TEAE (22 patients [42.3 %]). Twenty serious TEAEs occurred in 10 patients (19.2 %); none were related to StrataGraft. There were 4 (7.7 %) deaths (aspiration, myocardial infarction, self-injury, Gram-negative rod sepsis); none were related to StrataGraft. Confirmed WC was achieved by Week 12 in 33 patients (63.5 %; 95 % CI: 50.4-76.5 %) and 69 treatment sites (71.9 %; 95 % CI: 62.9-80.9 %). Durable WC was achieved by Week 24 in 29 patients (55.8 %; 95 % CI: 42.3-69.3 %) and 58 treatment sites (60.4 %; 95 % CI: 50.6-70.2 %). CONCLUSIONS: StrataGraft demonstrated clinical benefit. Safety data were consistent with previously reported findings.

Changes in neuroinflammatory biomarkers correlate with disease severity and neuroimaging alterations in patients with COVID-19 neurological complications.

COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2's spike protein in patients' CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62-62.23 vs. Mild 3.91 pg/mL CI 1.5-10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4-4.4 vs. Non-Pronounced 2.0, CI 1.4-2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89-123.31 vs Non-Pronounced 6.22, CI 2.9-13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases.

Select gene mutations associated with survival outcomes in ER-positive ERBB2-negative early-stage invasive breast cancer: A single-institutional tissue bank study.

INTRODUCTION: The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative early-stage invasive breast cancer (EBC) in a real-world setting is uncertain. Therefore, we aimed to determine the correlation between a 22-gene mutational profile and long-term survival outcomes in patients with ER+/ERBB2- EBC. PATIENTS AND METHODS: A total of 73 women diagnosed with ER+/ERBB2- EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse-free survival (RFS) and overall survival (OS). The log-rank test derived p-value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. RESULTS: At follow-up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty-three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85-fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60-5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6-fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31-18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32-27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes. CONCLUSIONS: Our single-institution tissue bank study of Taiwanese women with ER+/ERBB2- EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.

Data-driven modeling of equatorial atmospheric waves: The role of moisture and nonlinearity on global-scale instabilities and propagation speeds.

The equatorial region of the Earth's atmosphere serves as both a significant locus for phenomena, including the Madden-Julian Oscillation (MJO), and a source of formidable complexity. This complexity arises from the intricate interplay between nonlinearity and thermodynamic processes, particularly those involving moisture. In this study, we employ a normal mode decomposition of atmospheric reanalysis ERA-5 datasets to investigate the influence of nonlinearity and moisture on amplitude growth, propagation speed, and mode coupling associated with equatorially trapped waves. We focus our analysis on global-scale baroclinic Kelvin and Rossby waves, recognized as crucial components contributing to the variability of the MJO. We examine the dependence of wave amplitudes on the background moisture field in the equatorial region, as measured by total column water vapor. Our analysis demonstrates the crucial role of moisture in exciting these waves. We further investigate the dependence of the propagation speed of the waves on their amplitudes and the background moisture field. Our analysis reveals a robust correlation between the phase speed of the normal modes and their corresponding amplitude, whereas a weaker correlation is found between the eigenmodes' phase speed and the moisture field. Hence, our findings suggest that moisture plays a role in exciting the global-scale Rossby-Kelvin structure of the MJO. In this context, the propagation speed of the eigenmodes is mainly influenced by their amplitudes, underscoring the significant role of nonlinearity in wave propagation.

RETRACTED: Skelton et al. Contribution of Host Immune Responses against Influenza D Virus Infection toward Secondary Bacterial Infection in a Mouse Model. Viruses 2019, 11, 994.

The Viruses Editorial Office retracts the article, "Contribution of Host Immune Responses Against Influenza D Virus Infection Toward Secondary Bacterial Infection in a Mouse Model" [...].

Fault-network geometry influences earthquake frictional behaviour.

Understanding the factors governing the stability of fault slip is a crucial problem in fault mechanics1-3. The importance of fault geometry and roughness on fault-slip behaviour has been highlighted in recent lab experiments4-7 and numerical models8-11, and emerging evidence suggests that large-scale complexities in fault networks have a vital role in the fault-rupture process12-18. Here we present a new perspective on fault creep by investigating the link between fault-network geometry and surface creep rates in California, USA. Our analysis reveals that fault groups exhibiting creeping behaviour show smaller misalignment in their fault-network geometry. The observation indicates that the surface fault traces of creeping regions tend to be simple, whereas locked regions tend to be more complex. We propose that the presence of complex fault-network geometries results in geometric locking that promotes stick-slip behaviour characterized by earthquakes, whereas simpler geometries facilitate smooth fault creep. Our findings challenge traditional hypotheses on the physical origins of fault creep explained primarily in terms of fault friction19-21 and demonstrate the potential for a new framework in which large-scale earthquake frictional behaviour is determined by a combination of geometric factors and rheological yielding properties.

Volatile Profiles and DNA Barcodes of Myrtaceae Species with Occurrence in the Brazilian Amazon.

Myrtaceae family includes many species with taxonomic challenges, making it one of the most complex families to identify. This study used DNA barcoding to find molecular markers for species authentication based on the Myrtaceae family's chemical composition and genetic diversity. Essential oils and genetic material were extracted from the leaves of six different species: Eugenia uniflora, E. patrisii, Myrcia splendens, Psidium guajava, P. guineense, and Psidium sp. The samples were analyzed based on compound classes and grouped into two categories. Group I included samples with high amounts of oxygenated sesquiterpenes (3.69-76.05 %) and fatty acid derivatives (0.04-43.59 %), such as E. uniflora, Myrcia splendens, and E. patrisii. Group II included samples P. guajava, P. guineense, and Psidium sp., which had a significant content of monoterpene hydrocarbons (0.69-72.35 %), oxygenated sesquiterpenes (8.06-68.1 %), phenylpropanoids (0.45-22.59 %), and sesquiterpene hydrocarbons (0.27-21.84 %). The PsbA-trnH gene sequences had a high genetic variability, allowing the species to be distinguished. A phylogenetic analysis showed two main clusters with high Bootstrap values corresponding to the subtribes Eugeniineae, Myrciinae, and Pimentinae. The results suggest a weak correlation between genetic and chemical data in these Myrtaceae species.

Salvage Ablative Radiotherapy for Isolated Local Recurrence of Pancreatic Adenocarcinoma following Definitive Surgery.

Introduction: The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume. Methods: We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan. Results: Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively. Conclusions: Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.

Lower admission stroke severity is associated with good collateral status in distal medium vessel occlusion stroke.

BACKGROUND AND PURPOSE: Distal medium vessel occlusions (DMVOs) are a significant contributor to acute ischemic stroke (AIS), with collateral status (CS) playing a pivotal role in modulating ischemic damage progression. We aimed to explore baseline characteristics associated with CS in AIS-DMVO. METHODS: This retrospective analysis of a prospectively collected database enrolled 130 AIS-DMVO patients from two comprehensive stroke centers. Baseline characteristics, including patient demographics, admission National Institutes of Health Stroke Scale (NIHSS) score, admission Los Angeles Motor Scale (LAMS) score, and co-morbidities, including hypertension, hyperlipidemia, diabetes, coronary artery disease, atrial fibrillation, and history of transient ischemic attack or stroke, were collected. The analysis was dichotomized to good CS, reflected by hypoperfusion index ratio (HIR) <.3, versus poor CS, reflected by HIR ≥.3. RESULTS: Good CS was observed in 34% of the patients. As to the occluded location, 43.8% occurred in proximal M2, 16.9% in mid M2, 35.4% in more distal middle cerebral artery, and 3.8% in distal anterior cerebral artery. In multivariate logistic analysis, a lower NIHSS score and a lower LAMS score were both independently associated with a good CS (odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.82-0.95, p < .001 and OR: 0.77, 95% CI: 0.62-0.96, p = .018, respectively). Patients with poor CS were more likely to manifest as moderate to severe stroke (29.1% vs. 4.5%, p < .001), while patients with good CS had a significantly higher chance of having a minor stroke clinically (40.9% vs. 12.8%, p < .001). CONCLUSIONS: CS remains an important determinant in the severity of AIS-DMVO. Collateral enhancement strategies may be a worthwhile pursuit in AIS-DMVO patients with more severe initial stroke presentation, which can be swiftly identified by the concise LAMS and serves as a proxy for underlying poor CS.

Predictors and Prevalence of Alcohol and Cannabis Co-use Among Filipino Adolescents: Evidence From a School-based Student Health Survey.

OBJECTIVES: This study explored the prevalence and predictors of alcohol and cannabis co-use among 9263 Filipino adolescents, using data from the 2019 Global School-based Student Health Survey (GSHS). METHODS: We conducted a cross-sectional secondary analysis of the GSHS, targeting adolescents aged 13-17 years and excluding cases with incomplete data on alcohol and cannabis use. Our analysis employed the bivariate chi-square test of independence and multivariable logistic regression using Stata version 18 to identify significant predictors of co-use, with a p-value threshold set at 0.05. RESULTS: The weighted prevalence of co-users was 4.2% (95% confidence interval [CI], 3.4 to 5.3). Significant predictors included male sex (adjusted odds ratio [aOR], 4.50; 95% CI, 3.31 to 6.10; p<0.001) and being in a lower academic year, specifically grade 7 (aOR, 4.08; 95% CI, 2.39 to 6.99; p<0.001) and grade 8 (aOR, 2.20; 95% CI, 1.30 to 3.72; p=0.003). Poor sleep quality was also a significant predictor (aOR, 1.77; 95% CI, 1.29 to 2.44; p<0.001), as was a history of attempted suicide (aOR, 5.31; 95% CI, 4.00 to 7.06; p<0.001). Physical inactivity was associated with lower odds of co-use (aOR, 0.45; 95% CI, 0.33 to 0.62; p<0.001). Additionally, non-attendance of physical education classes (aOR, 1.48; 95% CI, 1.06 to 2.05; p=0.021), infrequent unapproved parental checks (aOR, 1.37; 95% CI, 1.04 to 1.80; p=0.024), and lower parental awareness of free-time activities (aOR, 0.63; 95% CI, 0.45 to 0.87; p=0.005) were associated with higher odds of co-use. Factors not significantly linked to co-use included age group, being in grade 9, always feeling lonely, having no close friends, being bullied outside school, and whether a parent or guardian understood the adolescent's worries. CONCLUSIONS: The findings highlight the critical need for comprehensive interventions in the Philippines, addressing not only physical inactivity and parental monitoring but also focusing on sex, academic grade, participation in physical education classes, sleep quality, and suicide attempt history, to effectively reduce alcohol and cannabis co-use among adolescents.

Higher-order structure and proteoforms of co-occurring C4b-binding protein assemblies in human serum.

The complement is a conserved cascade that plays a central role in the innate immune system. To maintain a delicate equilibrium preventing excessive complement activation, complement inhibitors are essential. One of the major fluid-phase complement inhibitors is C4b-binding protein (C4BP). Human C4BP is a macromolecular glycoprotein composed of two distinct subunits, C4BPα and C4BPß. These associate with vitamin K-dependent protein S (ProS) forming an ensemble of co-occurring higher-order structures. Here, we characterize these C4BP assemblies. We resolve and quantify isoforms of purified human serum C4BP using distinct single-particle detection techniques: charge detection mass spectrometry, and mass photometry accompanied by high-speed atomic force microscopy. Combining cross-linking mass spectrometry, glycoproteomics, and structural modeling, we report comprehensive glycoproteoform profiles and full-length structural models of the endogenous C4BP assemblies, expanding knowledge of this key complement inhibitor's structure and composition. Finally, we reveal that an increased C4BPα to C4BPß ratio coincides with elevated C-reactive protein levels in patient plasma samples. This observation highlights C4BP isoform variation and affirms a distinct role of co-occurring C4BP assemblies upon acute phase inflammation.

From apparent pseudoprogression to durable complete remission of expansile destructive sinonasal mucosal melanoma under pembrolizumab after primary endoscopic resection: A case report.

Head and neck mucosal melanoma is a rare but highly aggressive malignant tumor that usually has a poor prognosis. We describe a 53-year-old male patient, having no any medical history, with left maxillary sinus mucosal melanoma causing bilateral lung metastasis. Rapid tumor regrowth was observed on the 49th day after radical tumor resection. Subsequent pembrolizumab immunotherapy initially elicited pseudoprogression, for which add-on radiation therapy was carried out during maintenance pembrolizumab. A gradual decrease in tumor volume and complete remission were observed by a series of magnetic resonance imaging scans and lung windows of a computer tomography scan of chest. At the 29-month follow-up, the patient was rendered disease-free. In conclusion, head and neck mucosal melanoma may regrow rapidly after surgical resection and pseudoprogression could be frightening during immunotherapy. Subsequent single-agent pembrolizumab plus localized radiation therapy aiming to release more tumor antigens may offer the possibility of long-term remission.

In silico analysis of non-structural protein 12 sequences from SARS-COV-2 found in Manaus, Amazonas, Brazil, reveals mutations linked to higher transmissibility.

The disease coronavirus COVID-19 has been the cause of millions of deaths worldwide. Among the proteins of SARS-CoV-2, non-structural protein 12 (NSP12) plays a key role during COVID infection and is part of the RNA-dependent RNA polymerase complex. The monitoring of NSP12 polymorphisms is extremely important for the design of new antiviral drugs and monitoring of viral evolution. This study analyzed the NSP12 mutations detected in circulating SARS-CoV-2 during the years 2020 to 2022 in the population of the city of Manaus, Amazonas, Brazil. The most frequent mutations found were P323L and G671S. Reports in the literature indicate that these mutations are related to transmissibility efficiency, which may have contributed to the extremely high numbers of cases in this location. In addition, two mutations described here (E796D and R914K) are close and have RMSD that is similar to the mutations M794V and N911K, which have been described in the literature as influential on the performance of the NSP12 enzyme. These data demonstrate the need to monitor the emergence of new mutations in NSP12 in order to better understand their consequences for the treatments currently used and in the design of new drugs.

Examining patient-reported late toxicity and its association with quality of life and unmet need for symptom management among nasopharyngeal cancer survivors: a cross-sectional survey.

Introduction: Alongside the improved survival of nasopharyngeal cancer (NPC), late radiation toxicities are alarmingly hampering survivors' quality of life. A patient-reported symptom burden survey is lacking to address the unmet need for symptom management among local NPC survivors. Methods: A single-center cross-sectional survey was conducted on 211 NPC survivors who had completed radiation therapy for three to 120 months. We employed the Chinese version M. D. Anderson Symptom Inventory - Head & Neck Module (MDASI-HN-C), Functional Assessment of Cancer Therapy - Head & Neck (FACT-HN-C), and a question extracted from the Cancer Survivors' Unmet Needs Measure (CaSUN). Results: Two hundred valid responses were collected. Participants suffered from at least four moderate to severe symptoms (mean = 4.84, SD = 4.99). The top five severe symptoms were dry mouth, mucus problems, difficulty swallowing or chewing, teeth or gum problems, and memory problems. MDASI-HN-C subscales were negatively correlated with the physical, emotional, functional, and HN-specific domains of the FACT-HN-C. The unmet need for symptom management was positively associated with symptom burden, either general symptoms (Adjusted odds ratio [ORadj] = 1.566, 95% CI = 1.282 - 1.914, p < 0.001) or top-5 symptoms (ORadj = 1.379, 95% CI = 1.185 - 1.604, p < 0.001), while negatively associated with post-RT time (ORadj = 0.981, 95% CI [0.972, 0.991], p < 0.001). Conclusion: Virtually all NPC survivors suffer from late toxicities, which interplay with survivors' perceptions intricately to affect their unmet needs for symptom management. Personalized supportive care strategies with regular assessments and stratifications are warranted.

Functional selection in SH3-mediated activation of the PI3 kinase.

The phosphoinositide-3 kinase (PI3K), a heterodimeric enzyme, plays a pivotal role in cellular metabolism and survival. Its deregulation is associated with major human diseases, particularly cancer. The p85 regulatory subunit of PI3K binds to the catalytic p110 subunit via its C-terminal domains, stabilising it in an inhibited state. Certain Src homology 3 (SH3) domains can activate p110 by binding to the proline-rich (PR) 1 motif located at the N-terminus of p85. However, the mechanism by which this N-terminal interaction activates the C-terminally bound p110 remains elusive. Moreover, the intrinsically poor ligand selectivity of SH3 domains raises the question of how they can control PI3K. Combining structural, biophysical, and functional methods, we demonstrate that the answers to both these unknown issues are linked: PI3K-activating SH3 domains engage in additional "tertiary" interactions with the C-terminal domains of p85, thereby relieving their inhibition of p110. SH3 domains lacking these tertiary interactions may still bind to p85 but cannot activate PI3K. Thus, p85 uses a functional selection mechanism that precludes nonspecific activation rather than nonspecific binding. This separation of binding and activation may provide a general mechanism for how biological activities can be controlled by promiscuous protein-protein interaction domains.

Endogenous endophthalmitis due to Escherichia coli: a case report.

Endophthalmitis is a severe form of purulent inflammation caused by the infection of the intraocular tissues or fluids. This infection infrequently occurs through endogenous routes, which are often correlated with major risk factors. Escherichia coli, a gram-negative rod, can cause endophthalmitis through hematogenous spread. We here report a 59-year-old man who presented to our service with acute visual impairment in his left eye, preceded by floaters. He was taking sirolimus and azathioprine for a transplanted kidney, had undergone catheterization for bladder atresia, and had a history of recurrent E. coli urinary tract infections. On evaluation, the left eye exhibited visual acuity of hand motion, anterior chamber reaction (3+/4+), and intense vitritis (4+/4+) with white flake clusters, which prevented appropriate retinal evaluation. Pars plana vitrectomy was performed, and the culture yielded E. coli. The present case highlights the importance of identifying the signs and symptoms of infection early so that diagnosis and treatment of endophthalmitis can be promptly initiated.

Follow-up infarct volume on fluid attenuated inversion recovery (FLAIR) imaging in distal medium vessel occlusions: the role of cerebral blood volume index.

BACKGROUND: Distal medium vessel occlusions (DMVOs) contribute substantially to the incidence of acute ischemic strokes (AIS) and pose distinct challenges in clinical management and prognosis. Neuroimaging techniques, such as Fluid Attenuation Inversion Recovery (FLAIR) imaging and cerebral blood volume (CBV) index derived from perfusion imaging, have significantly improved our ability to assess the impact of strokes and predict their outcomes. The primary objective of this study was to investigate relationship between follow-up infarct volume (FIV) as assessed by FLAIR imaging in patients with DMVOs. METHODS: This prospectively collected, retrospective reviewed cohort study included patients from two comprehensive stroke centers within the Johns Hopkins Medical Enterprise, spanning August 2018-October 2022. The cohort consisted of adults with AIS attributable to DMVO. Detailed imaging analyses were conducted, encompassing non-contrast CT, CT angiography (CTA), CT perfusion (CTP), and FLAIR imaging. Univariable and multivariable linear regression models were employed to assess the association between different factors and FIV. RESULTS: The study included 79 patients with DMVO stroke with a median age of 69 years (IQR, 62-77 years), and 57% (n = 45) were female. There was a negative correlation between the CBV index and FIV in a univariable linear regression analysis (Beta = - 16; 95% CI, - 23 to - 8.3; p < 0.001) and a multivariable linear regression model (Beta = - 9.1 per 0.1 change; 95% CI, - 15 to - 2.7; p = 0.006). Diabetes was independently associated with larger FIV (Beta = 46; 95% CI, 16 to 75; p = 0.003). Additionally, a higher baseline ASPECTS was associated with lower FIV (Beta = - 30; 95% CI, - 41 to - 20; p < 0.001). CONCLUSION: Our findings underscore the CBV index as an independent association with FIV in DMVOs, which highlights the critical role of collateral circulation in determining stroke outcomes in this patient population. In addition, our study confirms a negative association of ASPECTS with FLAIR FIV and identifies diabetes as independent factor associated with larger FIV. These insights pave the way for further large-scale, prospective studies to corroborate these findings, thereby refining the strategies for stroke prognostication and management.

Pathophysiology of chikungunya virus infection associated with fatal outcomes.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute, subacute, and chronic human arthritogenic diseases and, in rare instances, can lead to neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomic, proteomic, and genomic analyses to investigate viral and host factors that contribute to chikungunya-associated (CHIK) death. Our results indicate that CHIK deaths are associated with multi-organ infection, central nervous system damage, and elevated serum levels of pro-inflammatory cytokines and chemokines compared with survivors. The histopathologic, metabolite, and proteomic signatures of CHIK deaths reveal hemodynamic disorders and dysregulated immune responses. The CHIKV East-Central-South-African lineage infecting our study population causes both fatal and survival cases. Additionally, CHIKV infection impairs the integrity of the blood-brain barrier, as evidenced by an increase in permeability and altered tight junction protein expression. Overall, our findings improve the understanding of CHIK pathophysiology and the causes of fatal infections.

Oral administration of obeldesivir protects nonhuman primates against Sudan ebolavirus.

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.