Rice husk biochar - A novel engineered bio-based material for transforming groundwater-mediated fluoride cycling in natural environments.

Biochar, a promising carbon-rich and carbon-negative material, can control water pollution, harness the synergy of sustainable development goals, and achieve circular economy. This study examined the performance feasibility of treating fluoride-contaminated surface and groundwater using raw and modified biochar synthesized from agricultural waste rice husk as problem-fixing renewable carbon-neutral material. Physicochemical characterizations of raw/modified biochars were investigated using FESEM-EDAX, FTIR, XRD, BET, CHSN, VSM, pHpzc, Zeta potential, and particle size analysis were analyzed to identify the surface morphology, functional groups, structural, and electrokinetic behavior. In fluoride (F-) cycling, performance feasibility was tested at various governing factors, contact time (0-120 min), initial F- levels (10-50 mg L-1), biochar dose (0.1-0.5 g L-1), pH (2-9), salt strengths (0-50 mM), temperatures (301-328 K), and various co-occurring ions. Results revealed that activated magnetic biochar (AMB) possessed higher adsorption capacity than raw biochar (RB) and activated biochar (AB) at pH 7. The results indicated that maximum F- removal (98.13%) was achieved using AMB at pH 7 for 10 mg L-1. Electrostatic attraction, ion exchange, pore fillings, and surface complexation govern F- removal mechanisms. Pseudo-second-order and Freundlich were the best fit kinetic and isotherm for F- sorption, respectively. Increased biochar dose drives an increase in active sites due to F- level gradient and mass transfer between biochar-fluoride interactions, which reported maximum mass transfer for AMB than RB and AB. Fluoride adsorption using AMB could be described through chemisorption processes at room temperature (301 K), though endothermic sorption follows the physisorption process. Fluoride removal efficiency reduced, from 67.70% to 53.23%, with increased salt concentrations from 0 to 50 mM NaCl solutions, respectively, due to increased hydrodynamic diameter. Biochar was used to treat natural fluoride-contaminated surface and groundwater in real-world problem-solving measures, showed removal efficiency of 91.20% and 95.61%, respectively, for 10 mg L-1 F- contamination, and has been performed multiple times after systematic adsorption-desorption experiments. Lastly, techno-economic analysis was analyzed for biochar synthesis and F- treatment performance costs. Overall, our results revealed worth output and concluded with recommendations for future research on F- adsorption using biochar.

Cancer and COVID-19: unravelling the immunological interplay with a review of promising therapies against severe SARS-CoV-2 for cancer patients.

Cancer patients, due to their immunocompromised status, are at an increased risk for severe SARS-CoV-2 infection. Since severe SARS-CoV-2 infection causes multiple organ damage through IL-6-mediated inflammation while stimulating hypoxia, and malignancy promotes hypoxia-induced cellular metabolic alterations leading to cell death, we propose a mechanistic interplay between both conditions that results in an upregulation of IL-6 secretion resulting in enhanced cytokine production and systemic injury. Hypoxia mediated by both conditions results in cell necrosis, dysregulation of oxidative phosphorylation, and mitochondrial dysfunction. This produces free radicals and cytokines that result in systemic inflammatory injury. Hypoxia also catalyzes the breakdown of COX-1 and 2 resulting in bronchoconstriction and pulmonary edema, which further exacerbates tissue hypoxia. Given this disease model, therapeutic options are currently being studied against severe SARS-COV-2. In this study, we review several promising therapies against severe disease supported by clinical trial evidence-including Allocetra, monoclonal antibodies (Tixagevimab-Cilgavimab), peginterferon lambda, Baricitinib, Remdesivir, Sarilumab, Tocilizumab, Anakinra, Bevacizumab, exosomes, and mesenchymal stem cells. Due to the virus's rapid adaptive evolution and diverse symptomatic manifestation, the use of combination therapies offers a promising approach to decrease systemic injury. By investing in such targeted interventions, cases of severe SARS-CoV-2 should decrease along with its associated long-term sequelae and thereby allow cancer patients to resume their treatments.

A Novel Therapeutic Approach With Sodium Pyruvate on Vital Signs, Acid-Base, and Metabolic Disturbances in Rats With a Combined Blast and Hemorrhagic Shock.

Background: Blast injuries from improvised explosive devices (IEDs) are known to cause blast traumatic brain injuries (bTBIs), hemorrhagic shock (HS), organ damage, mitochondrial dysfunction, and subsequent free radical production. A pre-citric acid cycle reagent, pyruvate, is suggested to improve mitochondrial ATP production through the activation of the mitochondrial gatekeeper enzyme "pyruvate dehydrogenase complex (PDH)." Our study aimed to investigate the role of physiologic, metabolic, and mitochondrial effects of hypertonic sodium pyruvate resuscitation in rats with a combined blast and HS injury. Methods: A pre-clinical rat model of combined injury with repetitive 20 PSI blast exposure accompanied with HS and fluid resuscitation (sodium pyruvate as metabolic adjuvant or hypertonic saline as control), followed by transfusion of shed blood was used in this study. Control sham animals (instrumental and time-matched) received anesthesia and cannulation, but neither received any injury nor treatment. The mean arterial pressure and heart rate were recorded throughout the experiment by a computerized program. Blood collected at T0 (baseline), T60 (after HS), and T180 (end) was analyzed for blood chemistry and mitochondrial PDH enzyme activity. Results: Sodium pyruvate resuscitation significantly improved the mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), hemodynamic stability (Shock index), and autonomic response (Kerdo index) after the HS and/or blast injury. Compared with the baseline values, plasma lactate and lactate/pyruvate ratios were significantly increased. In contrast, base excess BE/( HCO 3 - ) was low and the pH was also acidotic <7.3, indicating the sign of metabolic acidosis after blast and HS in all animal groups. Sodium pyruvate infusion significantly corrected these parameters at the end of the experiment. The PDH activity also improved after the sodium pyruvate infusion. Conclusion: In our rat model of a combined blast and HS injury, hypertonic sodium pyruvate resuscitation was significantly effective in hemodynamic stabilization by correcting the acid-base status and mitochondrial mechanisms via its pyruvate dehydrogenase enzyme.

Petrographic and Geochemical Controls on Methane Genesis, Pore Fractal Attributes, and Sorption of Lower Gondwana Coal of Jharia Basin, India.

The Barakar coal seams of Jharia Basin have been evaluated for the geochemical and petrographic control of coalbed methane (CBM) reservoir characteristics. The coal core samples are analyzed for the total gas content, gas chromatography, stable isotopes (δ13C1), and geochemical, petrographic and vitrinite reflectance. The significant face (1.6-7.6%) and butt (0.9-5.3%) cleat intensities specify the brittle characteristics of coal seams and also favor the gas flow mechanism. The thermal cracking position of hydrocarbon compounds was evaluated, which signifies the excellent source rock potential of coal for gas genesis. The inputs of type III and IV organic matter illustrated by the van Krevelan diagram signify thermally matured coal seams. The low values of sorption time (τ) between 2.1 and 5.6 days designate excellent diffusion characteristics that is favored by the cleat intensities. The values of total gas content and sorption capacity (V L) reveal that moderate saturation indicates a higher gas content, attributed to the seam thickness and thermal maturity. Similarly, the CH4 concentrations (89.4-96.6 vol %) display that the genesis pattern is a function of thermal maturity; however, some samples fall under the mixed type substantiated by the stable isotope (δ13C1) (-25.40 to -64.90‰), emphasizing bacterial hold by seasonal influx of freshwater. The ternary facies diagram (Vmmf, Immf, Lmmf) also supports notable generation of methane gas and storage in the coal seams of the Jharia Basin. The volume percentage of each maceral determined from petrographic study was used to estimate the fraction of conversion (f) of the organic content (0.19-0.97). The values of "f" indicate that the Barakar coal has undergone maximum conversion, which may be attributed to the older early Permian coal and placed at a greater depth after deposition due to the basin sink. The high fraction of conversion and thermal maturity may also be explained due to the existence of volcanic intrusion (sills and dykes). The uniformity in the distribution of functional groups is shown by Fourier transform infrared spectra representing moderate to stronger peaks of aromatic carbon (CO and C=C) between 1750 and 1450 cm-1, which indicates that the presence of a larger total organic carbon content likely validates the removal of aliphatic compounds during gas genesis. The variations in the BET curve have been categorized as H1 hysteresis following the type II adsorption pattern, suggesting that cylindrical pores and some of the coal samples have a type IV H4 hysteresis pattern, characterized as the slit type of pores. The average values of the pore diameter indicate the dominance of mesopores suitable for gas storage and release and hence a major part of the pore volume is contributed by the mesopores having a width mainly between 2.98 and 4.48 nm. The significant role of the meso-macropore network (D 1 fractals) in methane storage of the coal matrix is represented by a moderate positive relationship of V L with D 1, which accentuated that meso-macropores developed due to devolatilization and dehydration of organic matter and also by geochemical alteration of macerals and minerals formed heterogenetic inner surfaces suitable for gas adsorption. The estimated recoverable resource applying Mavor Pratt methods is 8.78 BCM, which is found to be a more realistic resource value for the studied CBM block.

The World Health Organization Collaborating Center for Emergency and Trauma (WHO-CCET) in South East Asia, The World Academic Council of Emergency Medicine (WACEM), and The American College of Academic International Medicine (ACAIM) 2021 Framework for using Telemedicine Technology at Healthcare Institutions.

The coronavirus disease 2019 crisis has forced the world to integrate telemedicine into health delivery systems in an unprecedented way. To deliver essential care, lawmakers, physicians, patients, payers, and health systems have all adopted telemedicine and redesigned delivery processes with accelerated speed and coordination in a fragmented way without a long-term vision or uniformed standards. There is an opportunity to learn from the experiences gained by this pandemic to help shape a better health-care system that standardizes telemedicine to optimize the overall efficiency of remote health-care delivery. This collaboration focuses on four pillars of telemedicine that will serve as a framework to enable a uniformed, standardized process that allows for remote data capture and quality, aiming to improve ongoing management outside the hospital. In this collaboration, we recommend learning from this experience by proposing a telemedicine framework built on the following four pillars-patient safety and confidentiality; metrics, analytics, and reform; recording of audio-visual data as a health record; and reimbursement and accountability.

Anxiety among Nursing Students towards Clinical Placement during COVID-19 in a Tertiary Hospital of Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: The world is facing the pandemic of COVID-19 caused by the corona virus since December 2019 and has caused millions of death throughout the world. Exposure of nursing students in clinical placement during pandemic is fearful and stressful with high risk of infection which can cause anxiety and different levels of psychological crisis to individuals. The main objective of the study is to find out the prevalence of anxiety among nursing students during clinical placement in the pandemic of COVID-19. METHODS: A descriptive cross-sectional study was conducted among 144 nursing students enrolled in different clinical placement of a tertiary hospital of Nepal from 20th January 2021 to 2nd February 2021. Ethical approval was received from the Institutional Review Committee. Demographic, COVID-19 related and Beck Anxiety Inventory questionnaires was used for assessing anxiety. Whole sampling was done. Descriptive statistics was conducted using Statistical Package for the Social Sciences 2016 version. RESULTS: Out of 144 females enrolled in the study, all the nursing students 144 (100%) having clinical placement had anxiety. Among them, 117 (81%) had mild anxiety and 27 (19%) had moderate level of anxiety. All the students used coping strategies for the anxiety. The most commonly used strategy to cope with anxiety was religion (5.03±1.78). CONCLUSIONS: All the nursing students had anxiety during the clinical placement and all the students used the coping strategies for the anxiety. Majority of the nursing students had mild anxiety. Religion was most common method of strategy to cope with anxiety.

Assessment of hypertension association with arsenic exposure from food and drinking water in Bihar, India.

Epidemiological studies have associated chronic exposure to arsenic (As) from drinking water with increased risk of hypertension. However, evidence of an association between As exposure from food and hypertension risks is sparse. To quantify the association between daily As intake from both food (rice, wheat and potatoes) and drinking water (Aswater) along with total exposure (Astotal) and hypertension risks in a study population in Bihar, India, we conducted an individual level cross-sectional analysis between 2017 and 2019 involving 150 participants. Arsenic intake variables and three indicators of hypertension risks (general hypertension, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)) were derived, and any relationship was quantified using a series of crude and multivariable log-linear or logistic regression models. The prevalence of general hypertension was 40% for the studied population. The median level of HDL was 45 mg/dL while median value of LDL was 114 mg/dL. Apart from a marginally significant positive relationship between As intake from rice and the changes of LDL (p-value = 0.032), no significant positive association between As intake and hypertension risks could be ascertained. In fact, Astotal was found to be associated with lower risks of general hypertension and higher levels of HDL (p-value = 0.020 and 0.010 respectively) whilst general hypertension was marginally associated with lower Aswater (p-value = 0.043). Due to limitations regarding study design and residual confounding, all observed marginal associations should be treated with caution.

Effects of Pyruvate Administration on Mitochondrial Enzymes, Neurological Behaviors, and Neurodegeneration after Traumatic Brain Injury.

Traumatic brain injury (TBI) is known to increase the susceptibility to various age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although the role of damaged mitochondrial electron transport chain (ETC) in the progression of AD and PD has been identified, its relationship with altered expression of neurodegenerative proteins has not been examined before. This study aimed to investigate 1) how TBI could affect mitochondrial ETC and neurodegeneration in rat brain regions related to behavioral alteration, and 2) if administration of the key mitochondrial substrate pyruvate can improve the outcome of mild TBI (mTBI). In a rat lateral fluid percussion injury model of mTBI, sodium pyruvate in sterile distilled water (1 g/kg body weight) was administered orally daily for 7 days. The protein expression of mitochondrial ETC enzymes, and neurodegeneration proteins in the hippocampus and cerebral cortex and was assessed on Day 7. The hippocampal and cortical expressions of ETC complex I, III, IV, V were significantly and variably impaired following mTBI. Pyruvate treatment altered ETC complex expression, reduced the nitrosyl stress and the MBP expression in the injured brain area, but increased the expression of the glial fibrillary acidic protein (GFAP) and Tau proteins. Pyruvate after mTBI augmented the Rotarod performance but decreased the horizontal and vertical open field locomotion activities and worsened neurobehavioural severity score, indicating a debilitating therapeutic effect on the acute phase of mTBI. These results suggest bidirectional neuroprotective and neurodegenerative modulating effects of pyruvate on TBI-induced alteration in mitochondrial activity and motor behavior. Pyruvate could potentially stimulate the proliferation of astrogliosis, and lactate acidosis, and caution should be exercised when used as a therapy in the acute phase of mTBI. More effective interventions targeted at multiple mechanisms are needed for the prevention and treatment of TBI-induced long-term neurodegeneration.

Animal models of traumatic brain injury: a review of pathophysiology to biomarkers and treatments.

Traumatic brain injury (TBI) is one of the main causes of death and disability in both civilian and military population. TBI may occur via a variety of etiologies, all of which involve trauma to the head. However, the neuroprotective drugs which were found to be very effective in animal TBI models failed in phase II or phase III clinical trials, emphasizing a compelling need to review the current status of animal TBI models and therapeutic strategies. No single animal model can adequately mimic all aspects of human TBI owing to the heterogeneity of clinical TBI. However, due to the ethical limitations, it is difficult to precisely emulate the TBI mechanisms that occur in humans. Therefore, many animal models with varying severity and mechanisms of brain injury have been developed, and each model has its own pros and cons in its implementation for TBI research. These challenges pose a need for study of continued TBI mechanisms, brain injury severity, duration, treatment strategies, and optimization of animal models across the neurotrauma research community. The aim of this review is to discuss (1) causes of TBI, (2) its prevalence in military and civilian population, (3) classification and pathophysiology of TBI, (4) biomarkers and detection methods, (5) animal models of TBI, and (6) the advantages and disadvantages of each model and the species used, as well as possible treatments.

Arsenic exposure from food exceeds that from drinking water in endemic area of Bihar, India.

Extensive evidence of elevated arsenic (As) in the food-chain, mainly rice, wheat and vegetables exists. Nevertheless, the importance of exposure from food towards total As exposure and associated health risks in areas with natural occurring As in drinking water is still often neglected, and accordingly mitigations are largely focused on drinking water only. In this study, the contribution of food over drinking water to overall As exposure was estimated for As exposed populations in Bihar, India. Increased lifetime cancer risk was predicted using probabilistic methods with input parameters based on detailed dietary assessment and estimation of As in drinking water, cooked rice, wheat flour and potato collected from 91 households covering 19 villages. Median total exposure was 0.83 µg/kgBW/day (5th and 95th percentiles were 0.21 and 11.1 µg/kgBW/day) and contribution of food (median = 49%) to overall exposure was almost equal to that from drinking water (median = 51%). More importantly and contrary to previous studies, food was found to contribute more than drinking water to As exposure, even when drinking water As was above the WHO provisional guide value of 10 µg/L. Median and 95th percentile excess lifetime cancer risks from food intake were 1.89 × 10-4 and 7.32 × 10-4 respectively when drinking water As was below 10 µg/L and 4.00 × 10-4 and 1.83 × 10-3 respectively when drinking water As was above 10 µg/L. Our results emphasise the importance of food related exposure in As-endemic areas, and, perhaps surprisingly, particularly in areas with high As concentrations in drinking water - this being partly ascribed to increases in food As due to cooking in high As water. These findings are timely to stress the importance of removing As from the food chain and not just drinking water in endemic areas.

Potential Immunotherapeutic Targets for Hypoxia Due to COVI-Flu.

The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome. In few patients, the disease undergoes phenotypic differentiation between 7 and 14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, comorbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1ß, IL-6, IFN-γ, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.

COVID-19 Blind Spots: A Consensus Statement on the Importance of Competent Political Leadership and the Need for Public Health Cognizance.

As the COVID-19 pandemic continues, important discoveries and considerations emerge regarding the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pathogen; its biological and epidemiological characteristics; and the corresponding psychological, societal, and public health (PH) impacts. During the past year, the global community underwent a massive transformation, including the implementation of numerous nonpharmacological interventions; critical diversions or modifications across various spheres of our economic and public domains; and a transition from consumption-driven to conservation-based behaviors. Providing essential necessities such as food, water, health care, financial, and other services has become a formidable challenge, with significant threats to the existing supply chains and the shortage or reduction of workforce across many sectors of the global economy. Food and pharmaceutical supply chains constitute uniquely vulnerable and critically important areas that require high levels of safety and compliance. Many regional health-care systems faced at least one wave of overwhelming COVID-19 case surges, and still face the possibility of a new wave of infections on the horizon, potentially in combination with other endemic diseases such as influenza, dengue, tuberculosis, and malaria. In this context, the need for an effective and scientifically informed leadership to sustain and improve global capacity to ensure international health security is starkly apparent. Public health "blind spotting," promulgation of pseudoscience, and academic dishonesty emerged as significant threats to population health and stability during the pandemic. The goal of this consensus statement is to provide a focused summary of such "blind spots" identified during an expert group intense analysis of "missed opportunities" during the initial wave of the pandemic.

Colchicine, Aspirin, and Montelukast - A Case of Successful Combined Pharmacotherapy for Adult Multisystem Inflammatory Syndrome in COVID-19.

Since the beginning of the COVID-19 pandemic, many therapeutic strategies have been tried, with mixed results, to prevent and treat adult multisystem inflammatory syndrome in COVID-19 (AMIS-COVID-19). The reason behind this may the complex web of highly intertwined pathophysiologic mechanisms involved in the SARS-CoV-2 infection and the corresponding human systemic response, leading to end-organ damage, disability, and death. Colchicine, high-dose aspirin, and montelukast are being investigated currently as potential modulators of AMIS-COVID-19 in patients who fail to improve with traditional therapeutic approaches. Here, we present a patient who presented with high fevers, extreme fatigue and dyspnea, and ongoing deterioration. As part of our clinical approach, we used the simultaneous combination of the three agents listed above, capitalizing on their different respective mechanisms of action against AMIS-COVID-19. Following the initiation of therapy, the patient showed symptomatic improvement within 24 h, with the ability to return to daily activities after 72 h of continued triple-agent approach. Based on this experience, we have reviewed the immunomodulatory basis of this regimen, including potential avenues in which it may prevent the development of cytokine release syndrome (CRS) and its clinical manifestation, AMIS-COVID-19. By blocking the early stages of an inflammatory response, via diverse mechanistic pathways, the regimen in question may prove effective in halting the escalation of CRS and AMIS-COVID-19 in acutely symptomatic, nonimproving COVID-19 patients.

Wheat is an emerging exposure route for arsenic in Bihar, India.

In arsenic (As) endemic areas of south-east Asia, where a subsistence rice-based diet is prevalent, As exposure from food is mainly focused on rice intake. However, consumption of wheat is substantial and increasing. We present a probabilistic assessment of increased cancer risk from wheat-based food intake in a study population of rural Bihar, India where As exposure is endemic. Total As in wheat grains (43.64 ±â€¯48.19 µg/kg, n = 72) collected from 77 households across 19 villages was found to be lower than reported As in wheat grains from other south-east Asian countries but higher than a previous study from Bihar. This is the first study where As concentration in wheat flour was used for risk estimation, bearing in mind that it was the flour obtained after indigenous household processing of the grains that was used for making the home-made bread (chapati) which contributed 95% of wheat intake for the studied population. Interestingly, while 78% of the surveyed participants (n = 154) consumed rice every day, chapati was consumed every day by 99.5% of the participants. In contrast to previous studies, where As concentration in wheat grains was found to be lower than the flour due to the removal of the bran on grinding, we did not find any appreciable lowering of arsenic in the wheat flour (49.80 ±â€¯74.08 µg/kg, n = 58), most likely due to external contamination during processing and grinding. Estimated gender adjusted excess lifetime cancer risk of 1.23 × 10-4 for the studied rural population of Bihar indicated risk higher than the 10-4-10-6 range, typically used by the USEPA as a threshold to guide regulatory values. Hence, our findings suggest As exposure from wheat-based food intake to be of concern not only in As endemic areas of rural Bihar but also in non-endemic areas with similar wheat-based diet due to public distribution of the wheat across India.

A randomized placebo-controlled trial of progesterone with or without hypothermia in patients with acute severe traumatic brain injury.

OBJECTIVE: Among newer neuroprotectant modalities, hypothermia and progesterone have shown a beneficial role in preliminary studies enrolling patients with severe traumatic brain injury (sTBI). The primary objective of this study was to evaluate the efficacy of progesterone with or without prophylactic hypothermia in acute sTBI patients. MATERIALS AND METHODS: This is a prospective, outcome assessor, statistician blinded, randomized, and placebo-controlled phase II trial of progesterone with or without hypothermia (factorial design). All adult patients (18-65 years) with acute sTBI (Glasgow coma score of 4-8) and presenting to trauma center within 8 h after injury were included in the trial. Computer-generated randomization was done after exclusion; sequentially numbered, opaque, sealed envelope technique was used for allocation concealment. The enrollment duration was from January 2012 to October 2014. The primary endpoint was dichotomized Glasgow outcome score (GOS) [poor recovery = GOS 1-3; good recovery = GOS 4-5], and secondary endpoints were functional independence measure (FIM) score and mortality rate at 6 and 12 months follow-up after recruitment. RESULTS: A total of 107 patients were randomized into four groups (placebo [n = 27], progesterone [n = 26], hypothermia alone [n = 27], and progesterone + hypothermia [n = 27]). The study groups were comparable in baseline parameters except for a higher incidence of decompressive craniectomy in the placebo group (P = 0.001). The analysis of GOS at 6 months revealed statistically significant better outcome in the hypothermia group (82%; P = 0.01) and a weaker evidence for progesterone group (74%; P = 0.07) as compared with the placebo group (44%). However, the outcome benefit was marginal at 1-year follow-up for the hypothermia group (82% vs. 58%, P = 0.17). The adjusted odds ratio of poor recovery at 6 months in the hypothermia group was 0.21 (confidence interval = 0.05-0.84, P = 0.03), as compared with the placebo group. Although mean FIM scores at 6 and 12 months respectively were marginally higher in the hypothermia and progesterone groups compared with the placebo group (P = 0.06 and 0.27), the proportion of functionally independent individuals were similar in all the groups (P = 0.79 and 0.51). The mortality rates were similar in all the groups at 6 and 12 months (P = 0.78 and 0.52 respectively). CONCLUSIONS: A strong evidence for prophylactic hypothermia and a weak evidence for progesterone therapy was observed for a better primary outcome at 6 months as compared to the placebo. A similar trend was observed at a 1-year follow-up. Contrary to our hypothesis, prophylactic hypothermia therapy suppressed the beneficial effects of progesterone therapy in sTBI patients. The complex cascades of factors responsible for such interactions are still unknown and need to be further determined.

Blood mitochondrial enzymatic assay as a predictor of long-term outcome in severe traumatic brain injury.

Recent studies have observed the central role of mitochondrial dysfunction in severe traumatic brain injury (sTBI). One hundred and seven sTBI patients (18-65years old, presenting within 8hours of injury) were randomised for a placebo controlled phase II trial of progesterone with or without hypothermia. We serially analysed blood mitochondrial enzymes (Complex I [C1], Complex IV [C4] and pyruvate dehydrogenase complex [PDH]) using a dipstick assay at admission and 7days later for 37 patients, irrespective of assigned group. Favorable Glasgow Outcome Scale (GOS) at 1year was associated with admission C1 levels above 0.19µg, admission C4 levels above 0.19µg and day 7 C1 levels above 0.17µg, all per 25µl of blood. Unfavorable GOS at 1year was associated with admission serum PDH levels above 0.23µg/25µl of blood. Survivors at 1year had significantly higher admission serum C1 levels above 0.19µg/25µl and day 7 C1 levels above 0.17µg/25µl. To our knowledge this is the first clinical trial associating blood mitochondrial enzymes with long-term outcome in sTBI. Serial monitoring and optimisation of blood C1, C4 and PDH levels could aid in prognostication and potentially guide in using mitochondrial targeted therapies. Blood mitochondrial enzymatic assay might suggest global reduction-oxidation status.

Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial.

OBJECTIVE There has been increased interest in the potential importance of biochemical parameters as predictors of outcome in severe traumatic brain injury (sTBI). METHODS Of 107 patients with sTBI (age 18-65 years with a Glasgow Coma Scale score of 4-8 presenting within 8 hours after injury) who were randomized for a placebo-controlled Phase II trial of progesterone with or without hypothermia, the authors serially analyzed serum biomarkers (S100-B, glial fibrillary acidic protein [GFAP], neuron-specific enolase [NSE], tumor necrosis factor-α, interleukin-6 [IL-6], estrogen [Eg], and progesterone [Pg]). This analysis was performed using the sandwich enzyme-linked immunosorbent assay technique at admission and 7 days later for 86 patients, irrespective of assigned group. The long-term predictive values of serum biomarkers for dichotomized Glasgow Outcome Scale (GOS) score, functional independence measure, and survival status at 6 and 12 months were analyzed using an adjusted binary logistic regression model and receiver operating characteristic curve. RESULTS A favorable GOS score (4-5) at 1 year was predicted by higher admission IL-6 (above 108.36 pg/ml; area under the curve [AUC] 0.69, sensitivity 52%, and specificity 78.6%) and Day 7 Pg levels (above 3.15 ng/ml; AUC 0.79, sensitivity 70%, and specificity 92.9%). An unfavorable GOS score (1-3) at 1 year was predicted by higher Day 7 GFAP levels (above 9.50 ng/ml; AUC 0.82, sensitivity 78.6%, and specificity 82.4%). Survivors at 1 year had significantly higher Day 7 Pg levels (above 3.15 ng/ml; AUC 0.78, sensitivity 66.7%, and specificity 90.9%). Nonsurvivors at 1 year had significantly higher Day 7 GFAP serum levels (above 11.14 ng/ml; AUC 0.81, sensitivity 81.8%, and specificity 88.9%) and Day 7 IL-6 serum levels (above 71.26 pg/ml; AUC 0.87, sensitivity 81.8%, and specificity 87%). In multivariate logistic regression analysis, independent predictors of outcome at 1 year were serum levels of Day 7 Pg (favorable GOS-OR 3.24, CI 1.5-7, p = 0.003; and favorable survival-OR 2, CI 1.2-3.5, p = 0.01); admission IL-6 (favorable GOS-OR 1.04, CI 1.00-1.08, p = 0.04); and Day 7 GFAP (unfavorable GOS-OR 0.79, CI 0.65-0.95, p = 0.01; and unfavorable survival-OR 0.80, CI 0.66-0.96, p = 0.01). CONCLUSIONS Serial Pg, GFAP, and IL-6 monitoring could aid in prognosticating outcomes in patients with acute sTBI. A cause and effect relationship or a mere association of these biomarkers to outcome needs to be further studied for better understanding of the pathophysiology of sTBI and for choosing potential therapeutic targets. Clinical trial registration no.: CTRI/2009/091/000893 ( http://www.ctri.nic.in ).

Nebulised hypertonic saline (3%) among children with mild to moderately severe bronchiolitis--a double blind randomized controlled trial.

BACKGROUND: To Assess the efficacy of nebulised hypertonic saline (HS) (3%) among children with mild to moderately severe bronchiolitis. METHODS: Infants aged 6 weeks to 24 months, with a first episode of wheezing and Clinical Severity scores (Arch Dis Child 67:289-93, 1992) between 1 and 8, were enrolled over 4 months duration. Those with severe disease, co-morbidities, prior wheezing, recent bronchodilator and steroid use were excluded. Patients were randomized in a double-blind fashion, to receive two doses of nebulized 3% HS (Group 1) or 0.9% normal saline (Group 2) with 1.5 mg of L-Epineprine, delivered 30 min apart. Parents were contacted at 24 h and 7 days. The principal outcome measure was the mean change in clinical severity score at the end of 2 h of observation. RESULTS: A total of 100 infants (mean age 9.6 months, range 2-23 months; 61 % males) were enrolled. Patients in both groups had mild to moderately severe disease at presentation. On an intention-to-treat basis, the infants in the HS group had a significant reduction (3.57 ± 1.41) in the mean clinical severity score compared to those in the NS group (2.26 ± 1.15); [p < 0.001; CI: 0.78-1.82]. More children in the HS group (n = 35/50; 70.0%) were eligible for ER/OPD discharge at the end of 2 h than those in the NS group (n = 15/50; 30%; p < 0.001), and less likely to need a hospital re-visit (n = 5/50; 10.0%) in the next 24 h as compared to the NS group (n = 15/50, 30.0%; p < 0.001). The treatment was well tolerated, with no adverse effects. CONCLUSIONS: Nebulized 3% HS is effective, safe and superior to normal saline for outpatient management of infants with mild to moderately severe viral bronchiolitis in improving Clinical Severity Scores, facilitating early Out-Patient Department discharge and preventing hospital re-visits and admissions in the 24 h of presentation. TRIAL REGISTRATION: Clinicaltrials.gov NCTID012766821. Registered on January 12, 2011.

Pyruvate dose response studies targeting the vital signs following hemorrhagic shock.

OBJECTIVES: To determine the optimal effective dose of sodium pyruvate in maintaining the vital signs following hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Anesthetized, male Sprague-Dawley rats underwent computer-controlled HS for 30 minute followed by fluid resuscitation with either hypertonic saline, or sodium pyruvate solutions of 0.5 M, 1.0 M, 2.0 M, and 4.0 M at a rate of 5ml/kg/h (60 minute) and subsequent blood infusion (60 minute). The results were compared with sham and non- resuscitated groups. The animals were continuously monitored for mean arterial pressure, systolic and diastolic pressure, heart rate, pulse pressure, temperature, shock index and Kerdo index (KI). RESULTS: The Sham group remained stable throughout the experiment. Non-resuscitated HS animals did not survive for the entire experiment due to non-viable vital signs and poor shock and KI. All fluids were effective in normalizing the vital signs when shed blood was used adjunctively. Sodium pyruvate 2.0 M was most effective, and 4.0 M solution was least effective in improving the vital signs after HS. CONCLUSIONS: Future studies should be directed to use 2.0 M sodium pyruvate adjuvant for resuscitation on multiorgan failure and survival rate in HS.

Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome.

The biological effects of high-dose total body ionizing irradiation [(thereafter, irradiation (IR)] are attributed to primary oxidative breakage of biomolecule targets, mitotic, apoptotic and necrotic cell death in the dose-limiting tissues, clastogenic and epigenetic effects, and cascades of functional and reactive responses leading to radiation sickness defined as the acute radiation syndrome (ARS). The range of remaining and protracted injuries at any given radiation dose as well as the dynamics of post-IR alterations is tissue-specific. Therefore, functional integrity of the homeostatic tissue barriers may decline gradually within weeks in the post-IR period culminating with sepsis and failure of organs and systems. Multiple organ failure (MOF) leading to moribundity is a common sequela of the hemotapoietic form of ARS (hARS). Onset of MOF in hARS can be presented as "two-hit phenomenon" where the "first hit" is the underlying consequences of the IR-induced radiolysis in cells and biofluids, non-septic inflammation, metabolic up-regulation of pro-oxidative metabolic reactions, suppression of the radiosensitive hematopoietic and lymphoid tissues and the damage to gut mucosa and vascular endothelium. While the "second hit" derives from bacterial translocation and spread of the bacterial pathogens and inflammagens through the vascular system leading to septic inflammatory, metabolic responses and a cascade of redox pro-oxidative and adaptive reactions. This sequence of events can create a ground for development of prolonged metabolic, inflammatory, oxidative, nitrative, and carbonyl, electrophilic stress in crucial tissues and thus exacerbate the hARS outcomes. With this perspective, the redox mechanisms, which can mediate the IR-induced protracted oxidative post-translational modification of proteins, oxidation of lipids and carbohydrates and their countermeasures in hARS are subjects of the current review. Potential role of ubiquitous, radioresistant mesenchymal stromal cells in the protracted responses to IR and IR-related septicemia is also discussed.