Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain.

BACKGROUND: In the developing brain, self-renewing neural stem/progenitor cells (NSPC) give rise to neuronal and glial lineages. NSPC survival and differentiation can be altered by neurotropic viruses and by the anti-viral immune response. Several neurotropic viruses specifically target and infect NSPCs, in addition to inducing neuronal loss, which makes it difficult to distinguish between effects on NSPCs that are due to direct viral infection or due to the anti-viral immune response. METHODS: We have investigated the impact of anti-viral immunity on NSPCs in measles virus (MV)-infected neonates. A neuron-restricted viral infection model was used, where NSPCs remain uninfected. Thus, an anti-viral immune response was induced without the confounding issue of NSPC infection. Two-transgenic mouse lines were used: CD46+ mice express the human isoform of CD46, the MV entry receptor, under the control of the neuron-specific enolase promoter; CD46+/IFNγ-KO mice lack the key anti-viral cytokine IFNγ. Multi-color flow cytometry and Western Blot analysis were used to quantify effects on NSPC, neuronal, and glial cell number, and quantify effects on IFNγ-mediated signaling and cell markers, respectively. RESULTS: Flow cytometric analysis revealed that NSPCs were reduced in CD46+/IFNγ-KO mice at 3, 7, and 10 days post-infection (dpi), but were unaffected in CD46+ mice. Early neurons showed the greatest cell loss at 7 dpi in both genotypes, with no effect on mature neurons and glial cells. Thus, IFNγ protected against NSPC loss, but did not protect young neurons. Western Blot analyses on hippocampal explants showed reduced nestin expression in the absence of IFNγ, and reduced doublecortin and ßIII-tubulin in both genotypes. Phosphorylation of STAT1 and STAT2 occurred independently of IFNγ in the hippocampus, albeit with distinct regulation of activation. CONCLUSIONS: This is the first study to demonstrate bystander effects of anti-viral immunity on NSPC function. Our results show IFNγ protects the NSPC population during a neonatal viral CNS infection. Significant loss of NSPCs in CD46+/IFNγ-KO neonates suggests that the adaptive immune response is detrimental to NSPCs in the absence of IFNγ. These results reveal the importance and contribution of the anti-viral immune response to neuropathology and may be relevant to other neuroinflammatory conditions.

Does apneic oxygenation with nasopharyngeal cannula during intubation improve the oxygenation in patients with acute hypoxemic respiratory failure compared to the standard bag valve mask preoxygenation? An open-labeled randomized control trial.

OBJECTIVES: In the context of acute hypoxemic respiratory failure (AHRF), ensuring effective preoxygenation and apneic oxygenation emerges as the pivotal approach ensuring for averting hypoxemic adverse events during endotracheal intubation. To investigate this, we conducted an open-label randomized controlled trial, aiming to assess the comparative effectiveness of nasopharyngeal high-flow oxygenation in conjunction with Bag-Valve-Mask (BVM) versus standard BVM preoxygenation in patients experiencing AHRF within the emergency department (ED). METHODS: This prospective single-center, open-labeled, randomized controlled trial enrolled patients aged 18 years and above requiring rapid sequence intubation due to AHRF in the ED. Participants were randomly assigned in a 1:1 ratio to either the intervention arm (involving nasopharyngeal high-flow oxygenation and BVM preoxygenation) or the control arm (involving BVM preoxygenation alone). RESULTS: A total of 76 participants were enrolled in the study, evenly distributed with 38 individuals in each arm. Median (interquartile range [IQR]) SpO2 at 0 min postintubation was 95.5 (80%-99%) versus 89 (76%-98%); z-score: 1.081, P = 0.279 in the intervention and control arm, respectively. The most common postintubation complications included hypoxia (intervention arm: 56.7% vs. control arm: 66.7%) and circulatory/hypoxic arrest (intervention arm: 39.5% vs. control arm: 44.7%). There were no adverse complications in 36.7% (n = 11) of patients in the intervention arm. Despite the best possible medical management, almost half (52.6%) of patients in the intervention arm and 47.4% of patients in the control arm succumbed to their illnesses in the ED. CONCLUSION: The primary outcome revealed no statistically significant difference between the two arms. However, patients in the intervention arm exhibited fewer intubation-related adverse effects.

A Comparative Study of Acute Invasive Fungal Sinusitis During the First and Second Waves of the COVID-19 Pandemic.

We aimed to compare the demography, clinical profile, histopathology, fungal culture, radiology, surgery performed, medical therapy and outcomes of patients with acute invasive fungal sinusitis seen during the first and second waves of the COVID-19 pandemic by retrospectively reviewing their case records. Of 238 patients, 43(18.1%) presented during the first wave and 195(81.9%) during the second wave. Patients seen during the first wave were older (p = 0.04) and more likely to have visual impairment (p = 0.004), frozen eye (p = 0.012), altered sensorium (p = 0.007) and stage 3 disease (p = 0.03). Those seen during the second wave were more often COVID-19 positive and had newly diagnosed diabetes mellitus (p = 0.04)and stage 1 disease (p = 0.03). Most patients had a positive culture for Rhizopus species during both waves. Histopathology showed broad aseptate hyphae in all patients but angioinvasion was seen more often during the first wave (p = 0.04). The majority of patients were treated with endoscopic+/- open debridement followed by intravenous amphotericin B and oral posaconazole. While the overall survival rate was similar (first wave 65.1%; second wave 79%; p = 0.106), mortality after discharge was greater during the first wave (11.6% vs 1.5%; p = 0.001). Mortality was higher in patients with stage 3 disease (p = 0.003). Significant differences in clinical presentation, histopathology, radiological stage of disease and post-discharge survival were noted between the two waves of the COVID-19 pandemic, the causes for which were multi-factorial.

Prospective review of 188 cases of epistaxis presenting to the emergency department: Etiology and outcome.

Background: Due to a myriad of risk factors, epistaxis is a very frequent presentation to the emergency room (ER). This study aims to ascertain the prevalence of epistaxis in our population, risk factors, effectiveness of ER treatment, complications, and ER outcome. Materials and Methods: This was a prospective observational study performed in the ER of a referral tertiary care center in south India. Data were categorized, coded, and analyzed to determine the objective of the study. Results: During the study's six-month duration, 188 (0.6%) patients presented with epistaxis. The mean age was 42.9 (SD: 16.49) years, with a male preponderance of 143 (76.1%). A majority of these patients (n: 156; 82.9%) were triaged as priority II, with hypertension (n: 53, 28.2%) as the commonest comorbidities. Trauma-related epistaxis (n: 107, 56.9%) was the most frequent cause. Anterior nasal packing was carried out for 85 (45.2%) patients, posterior nasal packing was carried out for one (0.5%) patient, and bleeding had spontaneously resolved in the majority (n: 102; 54.3%) patients. Seven (3.7%; p-value: 0.001) patients had recurrent epistaxis, and of those, three (1.6%) required urgent resuscitation with crystalloid fluid and blood products. Two of these patients had bleeding dyscrasias, four had history of trauma, and one patient presented with uncontrolled hypertension. Two (1.1%) patients came back to us with recurrent bleeding within 12 h of discharge. Majority (69.2%; 130) were discharged stable, (23.9%; 45) were admitted for observation and (6.9%; 13) were discharged against medical advice. There was no mortality among these study populations. Conclusion: Middle-young, aged males most commonly presented with epistaxis. Most of them were secondary to trauma. Anterior nasal bleeding was the most common source and hemostasis could be obtained by anterior nasal packing. Majority could be discharged stable from the ER. However, this cohort had seen patients in life-threatening conditions, so the severity cannot be overlooked.

Comparison of Phenytoin and Fosphenytoin in Treatment of Active Seizures in the Emergency Department.

Background and Objective: Ongoing seizure in the Emergency Department is a medical emergency and its aggressive management is essential. Prompt antiepileptic therapy with early cessation of seizure would minimize the morbidity and risk of recurrence. To compare time to seizure control with fosphenytoin to phenytoin protocol in the ED. Materials and Methods: We conducted an observational study on patients with active seizure in the Emergency Department comparing phenytoin versus fosphenytoin protocol over one year. Results: During the study period, we recruited 121 patients in the phenytoin group and 124 patients in the fosphenytoin group. Generalized tonic-clonic seizure (73.5% in phenytoin vs. 68.5% in fosphenytoin arm) was the most common type of seizure in both the arms. The mean time taken for cessation of seizure in the fosphenytoin arm (17.48 ± 49.24) was less than half of that in the phenytoin arm (37.20 ± 58.17) (mean difference: 19.72, P = 0.004, 95% CI: -33.27 to -6.17). There was a significant decrease in recurrence rates of seizure with phenytoin compared to the fosphenytoin arm (17.7% vs. 31.4%: OR: 0.47, P = 0.013; 95% CI: 0.26-0.86). Favorable STESS (≤2) was higher with phenytoin compared to fosphenytoin (60.3% vs. 48.4%). The overall in-hospital mortality rate in both arms was negligible (0.8%). Conclusion: The mean time for cessation of active seizure with fosphenytoin was less than half that of phenytoin. Despite its higher cost and minor adverse effects when compared to phenytoin, benefits seem to outweigh its limitation.

Fluorine-Substituted Halide Solid Electrolytes with Enhanced Stability toward the Lithium Metal.

The high ionic conductivity and good oxidation stability of halide-based solid electrolytes evoke strong interest in this class of materials. Nonetheless, the superior oxidative stability compared to sulfides comes at the expense of limited stability toward reduction and instability against metallic lithium anodes, which hinders their practical use. In this context, the gradual fluorination of Li2ZrCl6-xFx (0 ≤ x ≤ 1.2) is proposed to enhance the stability toward lithium-metal anodes. The mechanochemically synthesized fluorine-substituted compounds show the expected distorted local structure (M2-M3 site disorder) and significant change in the overall Li-ion migration barrier. Theoretical calculations reveal an approximate minimum energy path for Li2ZrCl6-xFx (x = 0 and 0.5) with an increase in the Li+ migration energy barrier for Li2ZrCl5.5F0.5 in comparison to Li2ZrCl6. However, it is found that the fluorine-substituted compound exhibits substantially lower polarization after 800 h of lithium stripping and plating owing to enhanced interfacial stability against the lithium metal, as revealed by density functional theory and ex situ X-ray photoelectron spectroscopy, thanks to the formation of a fluorine-rich passivating interphase.

Molecular Mechanisms of Antifungal Resistance in Mucormycosis.

Mucormycosis is one among the life-threatening fungal infections with high morbidity and mortality. It is an uncommon and rare infection targeting people with altered immunity. This lethal infection induced by fungi belonging to the Mucorales family is very progressive in nature. The incidence has increased in recent decades owing to the rise in immunocompromised patients. Disease management involves a multimodal strategy including early administration of drugs and surgical removal of infected tissues. Among the antifungals, azoles and amphotericin B remain the gold standard drugs of choice for initial treatment. The order Mucorales are developing a high level of resistance to the available systemic antifungal drugs, and the efficacy still remains below par. Deciphering the molecular mechanisms behind the antifungal resistance in Mucormycosis would add vital information to our available antifungal armamentarium and design novel therapies. Therefore, in this review, we have discussed the mechanisms behind Mucormycosis antifungal resistance. Moreover, this review also highlights the basic mechanisms of action of antifungal drugs and the resistance landscape which is expected to augment future treatment strategies.

Medication - A boon or bane: Emergencies due to medication-related visits.

BACKGROUND: Medication-related visits (MRV) to the Emergency Department (ED) are substantial though weakly recognized and intervened. Data from developing countries on the prevalence of MRV-related ED admissions are scanty. This study is first of its kind in India to estimate the prevalence of MRV, its severity and the factors contributing to these visits. METHODOLOGY: This prospective observational study was done in the ED of an apex tertiary care center in August 2018. A convenient cross-sectional sample of patients presenting with emergencies regarding drug use or ill-use were included and a questionnaire filled after obtaining a written informed consent. RESULTS: During the study period, a cross-sectional sample of 443 patients was studied and the prevalence of MRV was 27.1% (120/443). The mean age was 55 (standard deviation: 15) years with a male preponderance (60.8%). Triage priority I patients comprised 39.1%. Common presenting complaints included vomiting (25%), seizure (20.8%), giddiness (20%), and abdomen pain (17.5%). Less than ½ (43.3%) were compliant to prescribed medication. The most common reasons for MRV were failure to receive drugs/noncompliance (47.5%), subtherapeutic dosage (25%), and adverse drug reaction (16.7%). Severity of MRV was classified as mild (50%), moderate (38.3%), and severe (11.7%). Out of these visits, 71 (59.2%) were deemed preventable. Three-fourths (73.3%) were stabilized and discharged from the ED. CONCLUSION: The fact that a quarter of the ED visits are due to MRV and that more than half of them are preventable is quite alarming. Diligent patient education by the treating physicians may perhaps help in decreasing the incidence of this deleterious event.

The adverse effects of Ketamine on Procedural Sedation and Analgesia (PSA) in the Emergency Department.

BACKGROUND: Procedural sedation and analgesia (PSA) in the emergency department (ED) is mainly used for wound irrigation, reduction of fractures, and wound closure. Ketamine is one of the most commonly used drugs for PSA in the ED. The study was conducted in the ED of a large tertiary care hospital in southern India to evaluate the adverse effects of Ketamine on PSA. MATERIALS AND METHODS: This is a prospective observational study performed in the ED for 6 months (October 2019-March 2020) in 151 patients who required Ketamine for PSA. Titrated doses of Ketamine was administered in all patients; hemodynamic variables and adverse events were recorded at timed intervals. RESULTS: During the study period, a total of 151 patients in the ED required PSA. The mean age of the study Cohort was 37 ± 15 years, and males accounted for 83%. All individuals obtained adequate sedation and pain relief. It was found that the incidence of adverse reactions to Ketamine was higher in young people (18- to 40-year-old), which was 63%. The most common adverse reaction in the study population was 39 cases of hypertension (44.8%), followed by vomiting in 25 cases (28.7%) and delusion in 6 cases (4%). There was no significant adverse effect in any patients which necessitated admission. CONCLUSION: Ketamine is a drug with good analgesic, sedative properties and has been shown to have a good safety profile with minimal adverse events for use as PSA in ED. Side effects were most common in the younger adult age group and hypertension was the most common side effect.

Type II interferon signaling in the brain during a viral infection with age-dependent pathogenesis.

Viral infections of the central nervous system (CNS) often cause disease in an age-dependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age-dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)-dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription-1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ-stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.

Engineered Ovarian Cancer Cell Lines for Validation of CAR T Cell Function.

A set of genetically engineered isogenic cell lines is developed to express either folate receptor alpha or mesothelin, and a control cell line negative for both antigens. These cell lines also express fluorescent and bioluminescent reporter transgenes. The cell lines are used to authenticate specificity and function of a T-cell biofactory, a living vector that is developed to express proportionate amounts of engineered proteins upon engaging with disease cells through their specific antigenic biomarkers. The engineered cell lines are also used to assess the cytolytic function and specificity of primary T cells engineered with chimeric antigen receptors; and the specificity of monoclonal antibodies. The strategy described can be used to generate other cell lines to present different disease-specific biomarkers for use as quality control tools.

Last Breath in the Emergency Department.

BACKGROUND: Early and aggressive time to intervention has been shown to increase the odds of survival and decrease mortality in critically ill patients. Since emergency medicine is a nascent specialty in India, a review and assessment of the mortality profile in the Emergency Department (ED) would help improve the quality of care. AIMS: The aim of the study is to determine the mortality profile and causes of preventable deaths at large ED in South India. METHODS: This retrospective chart review was conducted between January and December 2017. Patients admitted with Triage priority 1 and priority 2 of our ED, who died, despite treatment, were recruited in the study. Two ED consultants blinded from each other, independently audited all the charts to determine preventable and nonpreventable causes of death. RESULTS: There were a total of 69,369 patients during the study period who presented to the ED. Despite resuscitation 189 (0.7%) died, the mortality rate was 2.43%. Cardiac-related (32%) and sepsis-related (31%) causes were the most common cause of death, 23.8% were due to preventable causes and 16.9% of which were due to inappropriate management. In patients with sepsis, the odds of death due to preventable causes were significantly high (odds ratio 4.31, 95% confidence intervals: 1.96-9.47; P < 0.001). CONCLUSIONS: Cardiac- and sepsis-related causes of death, together accounted for most of the mortality. In patients with sepsis, the odds of death due to preventable causes were more than four times higher than those without preventable causes.

Profile and Outcome of Near-hanging Patients Presenting to Emergency Department in a Tertiary Care Hospital in South India - A Retrospective Descriptive Study.

BACKGROUND: Hanging is one of the common modes of deliberate self-harm presenting to emergency departments (EDs) across the world. Early intervention and aggressive resuscitation can decrease the morbidity and mortality associated with near-hanging. Our aim was to study the profile of patients presenting with near-hanging and their outcome to our adult ED. MATERIALS AND METHODS: Medical records of patients with age more than 15 years presenting with near-hanging to the ED was reviewed retrospectively. The following profile data such as age, gender, marital status, material used for hanging, and type of hanging were collected. The information regarding the outcome of the patients from the hospital also analyzed. The data were analyzed to express the mean (±standard deviation) for the quantitative variables and frequency for the qualitative variables (±percent) using SPSS statistical software. RESULTS: The analysis of 2 years data from August 2014 to July 2016 revealed 77 patients reached the ED with near-Hanging. The mean age of the patients - 31.1 years. Approximately, 43% were complete hanging, while rest were partial hanging. Majority of the patients used dressing materials for hanging themselves. Out of 77 patients, 64 were discharged alive while 2 patients died in the hospital and 11 were left against medical advice. CONCLUSIONS: Hanging is still a major mode of deliberate self-harm in South India both among men and women. The outcome of near-hanging is positively influenced by early admission and active treatment.

The neonatal anti-viral response fails to control measles virus spread in neurons despite interferon-gamma expression and a Th1-like cytokine profile.

Neonates are highly susceptible to viral infections in the periphery, potentially due to deviant cytokine responses. Here, we investigated the role of interferon-gamma (IFNγ), a key anti-viral in the neonatal brain. We found that (i) IFNγ, which is critical for viral control and survival in adults, delays mortality in neonates, (ii) IFNγ limits infiltration of macrophages, neutrophils, and T cells in the neonatal brain, (iii) neonates and adults differentially express pathogen recognition receptors and Type I interferons in response to the infection, (iv) both neonates and adults express IFNγ and other Th1-related factors, but expression of many cytokines/chemokines and IFNγ-responsive genes is age-dependent, and (v) administration of IFNγ extends survival and reduces CD4 T cell infiltration in the neonatal brain. Our findings suggest age-dependent expression of cytokine/chemokine profiles in the brain and distinct dynamic interplays between lymphocyte populations and cytokines/chemokines in MV-infected neonates.

Interferon Gamma: Influence on Neural Stem Cell Function in Neurodegenerative and Neuroinflammatory Disease.

Interferon-gamma (IFNγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNγ mediates non-cytolytic viral control in infected neurons. However, IFNγ also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNγ, neural stem/progenitor cells (NSPCs), the only pluripotent cells in the developing and adult brain, are often altered during CNS insults. Recent studies highlight the complex effects of IFNγ on NSPC activity in neurodegenerative diseases. However, the mechanisms that mediate these effects, and the eventual outcomes for the host, are still being explored. Here, we review the effects of IFNγ on NSPC activity during different pathological insults. An improved understanding of the role of IFNγ would provide insight into the impact of immune responses on the progression and resolution of neurodegenerative diseases.

Effective depletion of regulatory T cells allows the recruitment of mesothelin-specific CD8 T cells to the antitumor immune response against a mesothelin-expressing mouse pancreatic adenocarcinoma.

Vaccine-induced CD8(+) T-cell responses can eradicate developing tumors in vivo in mouse models. Translating these successes into approved treatments for cancer patients has been challenging, since many of these models lack expression of clinically proven/relevant tumor antigens. We have shown that mesothelin is a clinically relevant CD8(+) T-cell target in human pancreas cancer, which is also highly conserved among species. Here, we utilize the murine mesothelin-expressing pancreatic tumor model (Panc02) to identify the immune-relevant mesothelin-derived peptides and study interventions that enhance the antitumor response. We first screened overlapping peptides of the entire murine mesothelin protein to identify two new CD8(+) mesothelin-restricted epitopes. These peptides were then evaluated for recognition by vaccine-induced T cells from mice treated with vaccine in sequence with low-dose cyclophosphamide (CY) and an anti-CD25 IL-2Ralpha monoclonal antibody (PC61). These treatments are both known to deplete subpopulations of T regulatory cells (Tregs). Our findings demonstrate that combined Treg-depleting therapies synergize to enhance vaccine efficacy. Furthermore, our data supports mesothelin as a relevant antigen in murine and clinical models and the use of Panc02 as a clinically relevant murine model of pancreatic cancer for evaluating antigen-targeted immunotherapies in immune-tolerant hosts.