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Traumatic brain injury (TBI) is associated with cerebral edema, blood brain barrier breakdown, and neuroinflammation that contribute to the degree of injury severity and functional recovery. Unfortunately, there are no effective proactive treatments for limiting immediate or long-term consequences of TBI. Therefore, the objective of this study was to determine the efficacy of methylene blue (MB), an antioxidant agent, in reducing inflammation and behavioral complications associated with a diffuse brain injury. Here we show that immediate MB infusion (intravenous; 15–30 minutes after TBI) reduced cerebral edema, attenuated microglial activation and reduced neuroinflammation, and improved behavioral recovery after midline fluid percussion injury in mice. Specifically, TBI-associated edema and inflammatory gene expression in the hippocampus were significantly reduced by MB at 1 d post injury. Moreover, MB intervention attenuated TBI-induced inflammatory gene expression (interleukin [IL]-1β, tumor necrosis factor α) in enriched microglia/macrophages 1 d post injury. Cell culture experiments with lipopolysaccharide-activated BV2 microglia confirmed that MB treatment directly reduced IL-1β and increased IL-10 messenger ribonucleic acid in microglia. Last, functional recovery and depressive-like behavior were assessed up to one week after TBI. MB intervention did not prevent TBI-induced reductions in body weight or motor coordination 1–7 d post injury. Nonetheless, MB attenuated the development of acute depressive-like behavior at 7 d post injury. Taken together, immediate intervention with MB was effective in reducing neuroinflammation and improving behavioral recovery after diffuse brain injury. Thus, MB intervention may reduce life-threatening complications of TBI, including edema and neuroinflammation, and protect against the development of neuropsychiatric complications.

Current fetal alcohol spectrum disorders (FASD) studies primarily focus on alcohol’s actions on the fetal brain although respiratory infections are a leading cause of morbidity/mortality in newborns. The limited studies examining the pulmonary adaptations in FASD demonstrate decreased surfactant protein A and alveolar macrophage phagocytosis, impaired differentiation, and increased risk of Group B streptococcal pneumonia with no study examining sexual dimorphism in adaptations. We hypothesized that developmental alcohol exposure in pregnancy will lead to sexually dimorphic fetal lung morphological and immune adaptations. Pregnant rats were orogastrically treated once daily with alcohol (4.5 g/kg, gestational day [GD] 4 to 10, peak BAC, 216 mg/dl; 6.0 g/kg, GD 11 to 20, peak BAC, 289 mg/dl) or 50% maltose dextrin (isocalorically matched pair-fed controls) to control for calories derived from ethanol. Male and female fetal lung RNA from a total of 20 dams were assessed using the TapeStation (Agilent) and Qubit RNA broad-range assay. Samples with RNA Integrity Numbers (RINs) > 8 were prepared using the NEBNext Poly(A) mRNA Magnetic Isolation Module (NEB), xGen Broad-range RNA Library Prep (IDT), and xGen Normalase UDI Primer Plate 2 (IDT). Final libraries were checked for quality and quantity by Qubit hsDNA and LabChip. The samples were sequenced on the Illumina NovaSeq S4 Paired-end 150 bp. Fetal lung tissue were analyzed for histopathological assessments. Mean fetal weight, crown-rump length and placental efficiency of the alcohol-administered rats were significantly lower ( P  < 0.05) than the pair-fed control pups. Differentially expressed genes indicated a sex-linked gene regulation dichotomy with a significantly higher number of genes altered in the female fetal lungs compared to the male. Network analysis plot of downregulated genes in the females exposed to alcohol in utero showed a negative impact on T cell activation and regulation, T cell differentiation, decrease in CD8 + T cell number etc. The most altered genes were Cd8b, Ccl25, Cd3e, Cd27, Cd247, Cd3d, Ccr9, Cd2, Cd8a and were decreased by a log2fold change of > 2 ( P  < 0.05) in the female fetal lungs. KEGG analyses showed that male and female fetal lungs had downregulated genes associated with development and mitosis, whereas the females alone showed dysregulation of T cell genes. Comparison of gross appearance and histopathologic morphology showed that the developing lungs of both male and female fetal pups, displayed stunted differentiation, were relatively hypoplastic, and displayed a diminution of alveolar size and air spaces. Similarly, in both sexes, decreased alveolar capillarization was also evident in the alcohol-exposed fetal lungs. These data provide novel information in a growing area focused on alcohol effects on the offspring lung and its influence on appropriate fetal/neonatal immune responses and highlights the importance of examining sexual dimorphism in developmental adaptations.

BackgroundAdherence to oral endocrine therapy (OET) is crucial in ensuring its maximum benefit in the prevention and treatment of hormone receptor-positive (HR +) breast cancer (BC). Medication use behavior is suboptimal especially in racial/ethnic minorities with lower socioeconomic status (SES).AimWe aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on OET adherence and identify demographic and/or clinical characteristics associated with nonadherence in racial/ethnic minorities with lower SES.MethodA retrospective study was conducted at the Harris Health System in Houston, Texas. Data were collected during the 6 months before and 6 months after the start of the pandemic. The adherence was assessed using the prescription refill data using the proportion of days covered. A multivariable logistic regression model was used to identify demographic/clinical characteristics associated with nonadherence. Eighteen years or older patients on appropriate doses of OET for prevention or treatment of BC were included.ResultsIn 258 patients, adherence was significantly lower during the pandemic (44%) compared to before the pandemic (57%). The demographic/clinical characteristics associated with OET nonadherence before the pandemic were Black/African American, obesity/extreme obesity, prevention setting, tamoxifen therapy, and 4 or more years on OET. During the pandemic, prevention setting and those not using home delivery were more likely to be nonadherent.ConclusionOET adherence was significantly reduced during the COVID-19 pandemic in racial/ethnic minority patients with low SES. Patient-centered interventions are necessary to improve OET adherence in these patients.

Venous thromboembolism (VTE) is a common complication in hospitalized patients. Pharmacologic prophylaxis is used in order to reduce the risk of VTE events. The main purpose of this study is to compare the prevalence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients admitted to the intensive care unit (ICU) who received unfractionated heparin (UFH) versus enoxaparin as VTE prophylaxis. Mortality was evaluated as a secondary outcome. This was a Propensity Score Adjusted Analysis. Patients admitted to neurology, surgical, or medical ICUs and screened with venous doppler ultrasonography or computed tomography angiography for detection of VTE were included in the analysis. We identified 2228 patients in the cohort, 1836 (82.4%) patients received UFH and 392 (17.6%) patients received enoxaparin. Propensity score matching yielded a well-balanced cohort of 950 (74% UFH, 26% enoxaparin) patients. After matching, there was no difference in prevalence of DVT (RR 1.05; 95% CI 0.67–1.64, p = 0.85) and PE (RR 0.76; 95% CI, 0.44–1.30, p = 0.31). No significant differences in location and severity of DVT and PE between the two groups were detected. Hospital and intensive care unit stay was similar between the two groups. Unfractionated heparin was associated with a higher rate of mortality, (HR 2.04; 95% CI, 1.13–3.70; p = 0.019). The use of UFH as VTE prophylaxis in ICU patients was associated with a similar prevalence of DVT and PE compared with enoxaparin, and the site and degree of occlusion were similar. However, a higher mortality rate was seen in the UFH group.

In March 2014, an outbreak of Ebola virus disease associated with a high fatality rate was identified in Guinea, with evidence of ongoing person-to-person transmission. In this update to the preliminary report, the virus is found to be a new strain related to Zaire ebolavirus . Outbreaks caused by viruses of the genera ebolavirus and marburgvirus represent a major public health issue in sub-Saharan Africa. Ebola virus disease is associated with a case fatality rate of 30 to 90%, depending on the virus species. Specific conditions in hospitals and communities in Africa facilitate the spread of the disease from human to human. Three ebolavirus species have caused large outbreaks in sub-Saharan Africa: EBOV, Sudan ebolavirus, and the recently described Bundibugyo ebolavirus . 1 , 2 Epidemics have occurred in the Democratic Republic of Congo, Sudan, Gabon, Republic of Congo, and Uganda. Reston ebolavirus circulates in the Philippines. It . . .

Background Chad with 7,698 confirmed cases of infection and 194 deaths since the beginning of the COVID-19 pandemic, is one of the African countries with the lowest reported case numbers. However, this figure likely underestimates the true spread of the virus due to the low rate of diagnosis. The high rate of asymptomatic infections reflects the reality of SARS-CoV-2 transmission in Chad. In this study, we estimated the seroprevalence and identified factors associated with SARS-CoV-2 infection. Methods A cross-sectional study was conducted between September 2022 and February 2023. A total of 1,290 plasma samples were collected from outpatient attendees at Health Facilities located in 11 provinces of Chad and tested by ELISA method, for the presence of IgG antibodies to SARS-CoV2 nucleocapsid (N) protein. KoboToolbox was used to gather data from the participants and data were analyzed using STATA 16. Results The overall seroprevalence was 83.0% [95% CI = 81.6%—85.5%], with variations between provinces, ranging from 99.2% [95% CI = 94.0%—100%] in Moundou (Southern Chad) to 46.8% [95% CI = 36.0% -57.1%] in Biltine (Eastern Chad). Factors associated with the seroprevalence included military occupation (OR = 0.37 CI [0.80–1.77] p  = 0.025) and age group between 55–64 years (OR = 0.33 CI [0.15–0.72] p  = 0.005). While, other factors, such as gender and age were not significantly associated with seroprevalence. Conclusion Our results indicated that, the seroprevalence of COVID-19 in Chad is among the highest in Sub-Saharan Africa. These estimates could guide the response and public health policy decisions, enhancing the management of future outbreaks involving respiratory pathogens.

PurposeThe relation between driving pressure (plateau pressure-positive end-expiratory pressure) and mortality has never been studied in obese ARDS patients. The main objective of this study was to evaluate the relationship between 90-day mortality and driving pressure in an ARDS population ventilated in the intensive care unit (ICU) according to obesity status.MethodsWe conducted a retrospective single-center study of prospectively collected data of all ARDS patients admitted consecutively to a mixed medical-surgical adult ICU from January 2009 to May 2017. Plateau pressure, compliance of the respiratory system (Crs) and driving pressure of the respiratory system within 24 h of ARDS diagnosis were compared between survivors and non-survivors at day 90 and between obese (body mass index ≥ 30 kg/m2) and non-obese patients. Cox proportional hazard modeling was used for mortality at day 90.ResultsThree hundred sixty-two ARDS patients were included, 262 (72%) non-obese and 100 (28%) obese patients. Mortality rate at day 90 was respectively 47% (95% CI, 40–53) in the non-obese and 46% (95% CI, 36–56) in the obese patients. Driving pressure at day 1 in the non-obese patients was significantly lower in survivors at day 90 (11.9 ± 4.2 cmH2O) than in non-survivors (15.2 ± 5.2 cmH2O, p < 0.001). Contrarily, in obese patients, driving pressure at day 1 was not significantly different between survivors (13.7 ± 4.5 cmH2O) and non-survivors (13.2 ± 5.1 cmH2O, p = 0.41) at day 90. After three multivariate Cox analyses, plateau pressure [HR = 1.04 (95% CI 1.01–1.07) for each point of increase], Crs [HR = 0.97 (95% CI 0.96–0.99) for each point of increase] and driving pressure [HR = 1.07 (95% CI 1.04–1.10) for each point of increase], respectively, were independently associated with 90-day mortality in non-obese patients, but not in obese patients.ConclusionsContrary to non-obese ARDS patients, driving pressure was not associated with mortality in obese ARDS patients.

Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional gene silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. Additionally, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we found that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of a subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not linked to loss of Polycomb chromatin domains. Instead, PDS5A removal causes aberrant cohesin activity leading to ectopic insulation sites, which disrupt the formation of ultra-long Polycomb loops. We show that these loops are important for robust silencing at a subset of PRC1/PRC2 target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation. Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.

BackgroundSelective dorsal rhizotomy (SDR) has been established as an effective surgical treatment for spastic diplegia. The applicability of SDR to the full spectrum of spastic cerebral palsy and the durability of its therapeutic effects remain under investigation. There are currently limited data in the literature regarding efficacy and outcomes following SDR in Gross Motor Function Classification System (GMFCS) IV and V patients. Intrathecal baclofen has traditionally been the surgical treatment of choice for these patients. When utilised primarily as a treatment for the relief of spasticity, it is proposed that SDR represents a rational and effective treatment option for this patient group. We report our outcomes of SDR performed on children with severe cerebral palsy (GMFCS grade IV and V). The commensurate improvement in upper as well as lower limb spasticity is highlighted. Apparent benefit to urological function following SDR in this patient group is also discussed.MethodA retrospective review of prospectively collected data for 54 paediatric patients with severe cerebral palsy (GMFCS IV-V) who received SDR plus specialised physiotherapy. Mean age was 10.2 years (range, 3.0–19.5). SDR guided by electrophysiological monitoring was performed by a single experienced neurosurgeon. All subjects received equivalent physiotherapy. The primary outcome measure was change to the degree of spasticity following SDR. Spasticity of upper and lower limb muscle groups were quantified and standardised using the Ashworth score. Measures were collected at baseline and at 2-, 8- and 14-month postoperative intervals. In addition, baseline and 6-month postoperative urological function was also evaluated as a secondary outcome measure.ResultsThe mean lower limb Ashworth score at baseline was 3.2 (range, 0–4). Following SDR, significant reduction in lower limb spasticity scores was observed at 2 months and maintained at 8 and 14 months postoperatively (Wilcoxon rank, p < 0.001). The mean reduction at 2, 8 and 14 months was 3.0, 3.2 and 3.2 points respectively (range, 1–4), confirming a sustained improvement of spasticity over a 1-year period of follow-up. Significant reduction in upper limb spasticity scores following SDR was also observed (mean, 2.9; Wilcoxon rank, p < 0.001). Overall, the improvement to upper and lower limb tone following SDR—generally to post-treatment Ashworth scores of 0—was clinically and statistically significant in GMFCS IV and V patients. Urological assessment identified pre-existing bladder dysfunction in 70% and 90% of GMFCS IV and V patients respectively. Following SDR, improvement in urinary continence was observed in 71% of affected GMFCS IV and 42.8% of GMFCS V patients. No serious postoperative complications were identified.ConclusionsWe conclude that SDR is safe and—in combination with physiotherapy—effectively reduces spasticity in GMFCS grade IV and V patients. Our series suggests that spastic quadriplegia is effectively managed with significant improvements in upper limb spasticity that are commensurate with those observed in lower limb muscle groups. These gains are furthermore sustained more than a year postoperatively. In light of these findings, we propose that SDR constitutes an effective treatment option for GMFCS IV and V patients and a rational alternative to intrathecal baclofen.

We study the large time behavior of Fujita–Kato type solutions to the Vlasov–Navier–Stokes system set on T3×R3. Under the assumption that the initial so-called modulated energy is small enough, we prove that the distribution function converges to a Dirac mass in velocity, with exponential rate. The proof is based on the fine structure of the system and on a bootstrap analysis allowing us to get global bounds on moments.