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OBJECTIVES: We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury. DESIGN: Retrospective cohort study. SETTING: ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. PATIENTS: Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of

INTRODUCTION: Early circulatory shock following traumatic brain injury (TBI) is a multifactorial process; however, the impact of brain injury biomarkers on the risk of shock has not been evaluated. We examined the association between neuronal injury biomarker levels and the development of circulatory shock following moderate-severe TBI. METHODS: In this retrospective cohort study, we examined adults with moderate-severe TBI (Glasgow Coma Scale score

Abstract There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.

Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor β (TGFβ) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance.

Abstract The COVID-19 pandemic caused by the SARS-CoV-2 virus has greatly affected global health. Emerging evidence suggests a complex interplay between Alzheimer’s disease (AD), diabetes (DM), and COVID-19. Given COVID-19’s involvement in the increased risk of other diseases, there is an urgent need to identify novel targets and drugs to combat these interconnected health challenges. Lysophosphatidic acid receptors (LPARs), belonging to the G protein-coupled receptor family, have been implicated in various pathological conditions, including inflammation. In this regard, the study aimed to investigate the involvement of LPARs (specifically LPAR1, 3, 6) in the tri-directional relationship between AD, DM, and COVID-19 through network analysis, as well as explore the therapeutic potential of selected anti-AD, anti-DM drugs as LPAR, SPIKE antagonists. We used the Coremine Medical database to identify genes related to DM, AD, and COVID-19. Furthermore, STRING analysis was used to identify the interacting partners of LPAR1, LPAR3, and LPAR6. Additionally, a literature search revealed 78 drugs on the market or in clinical studies that were used for treating either AD or DM. We carried out docking analysis of these drugs against the LPAR1, LPAR3, and LPAR6. Furthermore, we modeled the LPAR1, LPAR3, and LPAR6 in a complex with the COVID-19 spike protein and performed a docking study of selected drugs with the LPAR-Spike complex. The analysis revealed 177 common genes implicated in AD, DM, and COVID-19. Protein–protein docking analysis demonstrated that LPAR (1,3 & 6) efficiently binds with the viral SPIKE protein, suggesting them as targets for viral infection. Furthermore, docking analysis of the anti-AD and anti-DM drugs against LPARs, SPIKE protein, and the LPARs-SPIKE complex revealed promising candidates, including lupron, neflamapimod, and nilotinib, stating the importance of drug repurposing in the drug discovery process. These drugs exhibited the ability to bind and inhibit the LPAR receptor activity and the SPIKE protein and interfere with LPAR-SPIKE protein interaction. Through a combined network and targeted-based therapeutic intervention approach, this study has identified several drugs that could be repurposed for treating COVID-19 due to their expected interference with LPAR(1, 3, and 6) and spike protein complexes. In addition, it can also be hypothesized that the co-administration of these identified drugs during COVID-19 infection may not only help mitigate the impact of the virus but also potentially contribute to the prevention or management of post-COVID complications related to AD and DM.

Char is any accretion in a river course that extends or establishes new land. A well-planned integrated land-use system combining woody perennials (agroforestry) can ensure sustainable, environmentally friendly climate resilience land-use systems and livelihood options on charland. To date, no systemic investigation of charland land agroforestry has been undertaken. A comprehensive study of the potential of agroforestry systems in charland areas was conducted using qualitative and quantitative methodologies. Two methods were employed: structured questionnaire interviews and botanical surveys. Findings revealed that considerable variation exists in both charland and mainland areas in terms of socio-demographic characteristics. Both tree and agroforestry knowledge of mainland farmers is greater than that of charland farmers. Charland dwellers sell almost all their farm products, while most mainland farmers consume their products. Agroforestry-related communication between extension workers and farmers is limited in both ecosystems. However, farmer interaction with extension workers is far less common in charland areas. Mainland farmers are satisfied with their homestead production systems, whereas cha land farmers face huge problems with the free grazing of cattle and goats. Mainland farmers think quality planting materials and fencing systems are key issues. Leafy short-rotation vegetables and climbing vegetables are more common in charlands. Other common marketable vegetables are tomato, brinjal, carrot, cauliflower, and cabbage. All fruit trees common on charland are more frequently found in the mainland areas. In the case of timber, eucalyptus (Eucalyptus camaldulensis) is more common on charland, whereas mahogany (Swietenia macrophylla) frequency is higher in the mainland. Medicinal trees are uncommon in both ecosystems except for neem (Azadirachta indica). Through proper training and motivation of farmers, there is a vast scope to increase tree and vegetable diversity in charland farms.

The sigma-1 receptor (σ-1R), a chaperone protein located at the mitochondria-associated membrane (MAM) of the endoplasmic reticulum, can interact with and modify the signaling pathways of various proteins, thereby modulating many disease pathologies, including Alzheimer's disease (AD). The σ-1R ligand dipentylammonium (DPA) was analyzed for its anti-AD properties using PC12 cells (in vitro) and Caenorhabditis elegans (in vivo) models along with molecular docking (in silico) analysis. DPA at 1 and 10 µM concentrations was able to significantly potentiate NGF-induced neurite growth length by 137.7 ± 12.0 and 187.8 ± 16.4, respectively, when compared to the control 76.9 ± 7.4. DPA also regulated neurite damage caused by Aβ(25−35) treatment in differentiated PC12 cells by improving cell viability and neurite length. In C. elegans, DPA could significantly extend the median and maximum lifespan of Aβ transgenic strain CL2006 without impacting wild-type nematodes. Additionally, it could significantly reduce the paralysis phenotype of another Aβ transgenic strain, CL4176, thereby improving the overall health in AD pathogenesis. This effect depended on σ-1R, as DPA could not modulate the lifespan of σ-1R mutant TM3443. This was further confirmed using agonist PRE084 and antagonist BD1047, wherein the agonist alone could extend the lifespan of CL2006, while the antagonist suppressed the effect of DPA in CL2006. Interestingly, neither had an TM3443. Further, molecular docking analysis showed that DPA had a similar binding affinity as that of PRE084, BD1047 and pentazocine against the σ-1R receptor in humans and C. elegans, which collectively suggests the anti-AD properties of DPA.

Summary: Background: Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries. Methods: We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381). Findings: Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p

BACKGROUND: Extracranial multisystem organ failure is a common sequela of severe traumatic brain injury (TBI). Risk factors for developing circulatory shock and long-term functional outcomes of this patient subset are poorly understood. OBJECTIVE: To identify emergency department predictors of circulatory shock after moderate-severe TBI and examine long-term functional outcomes in patients with moderate-severe TBI who developed circulatory shock. METHODS: We conducted a retrospective cohort study using the Transforming Clinical Research and Knowledge in TBI database for adult patients with moderate-severe TBI, defined as a Glasgow Coma Scale (GCS) score of

The University of Alabama at Birmingham (UAB) and the McWane Science Center have partnered for over 20 years to provide secondary students in Alabama opportunities to conduct inquiry-based, standards-aligned science labs. LabWorks (middle school) and GENEius (high school) programs offer multiple research laboratory experiences in which students explore molecular biology, physical science, genetics, engineering, anatomy, and forensic science, with associated summer professional development for teachers: BioTeach and GeoTeach. These programs each attract 3,000-4,000 participants annually. This partnership has been synergistic, allowing the science center to offer high-level secondary science programming, while giving the university a conduit into the K-12 world. Originally, these programs were developed through Howard Hughes Medical Institute funding, and then expanded through support from the National Institutes of Health, the National Science Foundation, and the US Department of Education. These programs have excited secondary students and teachers about science education and careers, provided authentic science experiences, and given teachers the opportunity to experience a model of learning that engages students in "real science" closely linked to their curriculum. For over 20 years, this unique, evolving partnership has increased the understanding of over 90,000 students and teachers relative to the opportunities that science and STEM careers hold.

BackgroundTraumatic brain injury (TBI) is a major global health problem. Little research has addressed extracranial organ dysfunction following TBI, particularly myocardial injury. Using a sensitive marker of myocardial injury-high sensitivity troponin (hsTn)-we examined the incidence of early myocardial injury following TBI and explored its association with neurological outcomes following moderate-severe TBI.MethodsWe conducted a pilot cohort study of 133 adult (age above 17 y) subjects enrolled in the TRACK-TBI 18-center prospective cohort study. Descriptive statistics were used to examine the incidence of myocardial injury (defined as hsTn >99th percentile for a standardized reference population) across TBI severities, and to explore the association of myocardial injury with a 6-month extended Glasgow Outcome Score among patients with moderate-severe TBI.ResultsThe mean (SD) age of the participants was 44 (17) years, and 87 (65%) were male. Twenty-six patients (20%) developed myocardial injury following TBI; myocardial injury was present in 15% of mild TBI patients and 29% of moderate-severe TBI patients (P=0.13). Median (interquartile range) hsTn values were 3.8 ng/L (2.1, 9.0), 5.8 ng/L (4.5, 34.6), and 10.2 ng/L (3.0, 34.0) in mild, moderate, and severe TBI participants, respectively (P=0.04). Overall, 11% of participants with moderate-severe TBI and myocardial injury experienced a good outcome (6-mo extended Glasgow Outcome Score≥5) at 6 months, compared with 65% in the group that did not experience myocardial injury (P=0.01).ConclusionsMyocardial injury is common following TBI, with a likely dose-response relationship with TBI severity. Early myocardial injury was associated with poor 6-month clinical outcomes following moderate-severe TBI.

BackgroundEarly hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury.MethodsWe conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score

Abstract Brain–computer interface (BCI), an emerging technology that facilitates communication between brain and computer, has attracted a great deal of research in recent years. Researchers provide experimental results demonstrating that BCI can restore the capabilities of physically challenged people, hence improving the quality of their lives. BCI has revolutionized and positively impacted several industries, including entertainment and gaming, automation and control, education, neuromarketing, and neuroergonomics. Notwithstanding its broad range of applications, the global trend of BCI remains lightly discussed in the literature. Understanding the trend may inform researchers and practitioners on the direction of the field, and on where they should invest their efforts more. Noting this significance, we have analyzed 25,336 metadata of BCI publications from Scopus to determine advancement of the field. The analysis shows an exponential growth of BCI publications in China from 2019 onwards, exceeding those from the United States that started to decline during the same period. Implications and reasons for this trend are discussed. Furthermore, we have extensively discussed challenges and threats limiting exploitation of BCI capabilities. A typical BCI architecture is hypothesized to address two prominent BCI threats, privacy and security, as an attempt to make the technology commercially viable to the society.

ObjectivesTraumatic brain injury is a leading cause of death and disability in the United States. While the impact of early multiple organ dysfunction syndrome has been studied in many critical care paradigms, the clinical impact of early multiple organ dysfunction syndrome in traumatic brain injury is poorly understood. We examined the incidence and impact of early multiple organ dysfunction syndrome on clinical, functional, and disability outcomes over the year following traumatic brain injury.DesignRetrospective cohort study.SettingPatients enrolled in the Transforming Clinical Research and Knowledge in Traumatic Brain Injury study, an 18-center prospective cohort study of traumatic brain injury patients evaluated in participating level 1 trauma centers.SubjectsAdult (age > 17 yr) patients with moderate-severe traumatic brain injury (Glasgow Coma Scale < 13). We excluded patients with major extracranial injury (Abbreviated Injury Scale score ≥ 3).InterventionsDevelopment of early multiple organ dysfunction syndrome, defined as a maximum modified Sequential Organ Failure Assessment score greater than 7 during the initial 72 hours following admission.Measurements and main resultsThe main outcomes were: hospital mortality, length of stay, 6-month functional and disability domains (Glasgow Outcome Scale-Extended and Disability Rating Scale), and 1-year mortality. Secondary outcomes included: ICU length of stay, 3-month Glasgow Outcome Scale-Extended, 3-month Disability Rating Scale, 1-year Glasgow Outcome Scale-Extended, and 1-year Disability Rating Scale. We examined 373 subjects with moderate-severe traumatic brain injury. The mean (sd) Glasgow Coma Scale in the emergency department was 5.8 (3.2), with 280 subjects (75%) classified as severe traumatic brain injury (Glasgow Coma Scale 3-8). Among subjects with moderate-severe traumatic brain injury, 252 (68%) developed early multiple organ dysfunction syndrome. Subjects that developed early multiple organ dysfunction syndrome had a 75% decreased odds of a favorable outcome (Glasgow Outcome Scale-Extended 5-8) at 6 months (adjusted odds ratio, 0.25; 95% CI, 0.12-0.51) and increased disability (higher Disability Rating Scale score) at 6 months (adjusted mean difference, 2.04; 95% CI, 0.92-3.17). Subjects that developed early multiple organ dysfunction syndrome experienced an increased hospital length of stay (adjusted mean difference, 11.4 d; 95% CI, 7.1-15.8), with a nonsignificantly decreased survival to hospital discharge (odds ratio, 0.47; 95% CI, 0.18-1.2).ConclusionsEarly multiple organ dysfunction following moderate-severe traumatic brain injury is common and independently impacts multiple domains (mortality, function, and disability) over the year following injury. Further research is necessary to understand underlying mechanisms, improve early recognition, and optimize management strategies.

Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.