Ceruloplasmin, Vitamin C, and Uric Acid Levels in Patients With Myocardial Infarction: A Comparative Cross-Sectional Study.

INTRODUCTION: Global mortality is significantly influenced by myocardial infarction. Scientists have examined the role of the copper-containing protein ceruloplasmin in heart attacks. It helps to regulate oxidative stress, iron metabolism, and inflammation. Vitamin C's antioxidative qualities lend credence to the idea that it could help prevent cardiovascular disease. Several studies have shown that elevated uric acid levels are related to a higher risk of myocardial infarction. With this background, we conducted this study to estimate levels of ceruloplasmin, vitamin C, and uric acid in patients with myocardial infarction. MATERIALS AND METHODS: A tertiary care hospital in central India carried out this comparative cross-sectional study. The study was conducted between December 2022 and April 2023. Patients of any gender with newly diagnosed myocardial infarction who received admission to the intensive care unit and had ST-segment elevation of at least 2 mm in two or more consecutive electrocardiogram leads were included in the patient group. The control group consisted of individuals who did not exhibit any changes associated with myocardial infarction. Based on sex, age, and body mass index, the 75 control and 75 patients were matched. Ceruloplasmin, vitamin C, and uric acid were analyzed and compared. RESULTS: The uric acid levels among the patient group were 10.34 ± 3.23 mg/dL, and among the controls, they were 3.45 ± 1.12 mg/dL (p<0.001). The ceruloplasmin levels among the patient group were 64.34 ± 4.21 mg/dL, and among the controls, they were 29.23 ± 3.82 mg/dL (p<0.001). The vitamin C levels among the patient group were 13.80 ± 0.94 µmol/L, and among the controls, they were 45.62 ± 4.34 µmol/L (p<0.001). CONCLUSION: The patients with myocardial infarction demonstrated significantly elevated levels of ceruloplasmin and uric acid, while their vitamin C levels were lower in comparison. It is crucial to comprehend the underlying mechanisms through which these parameters influence the development of myocardial infarction.

Benralizumab in children with severe eosinophilic asthma: Pharmacokinetics and long-term safety (TATE study).

BACKGROUND: Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children. METHODS: TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (Cmax ), clearance, half-life (t1/2 ), and blood eosinophil count. Clearance and t1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed. RESULTS: Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean Cmax was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death. CONCLUSION: PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT04305405.

Assessing the Burden of COVID-19 among Children Aged 6-14 Years in Karnataka, India: A Cross-sectional Survey.

Background: India experienced three coronavirus disease (COVID-19) waves, with the third attributed to the highly contagious Omicron variant. Before the national vaccination rollout for children above 6, understanding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) positivity in the pediatric population was essential. This study aims to assess the burden of Covid-19 infection and to estimate the seroprevalence in children aged 6 to 14 years in the state of Karnataka. Material and Methods: We surveyed 5,358 children aged 6-14 across Karnataka using 232 health facilities, from June 6 to 14, 2022. We determined the sample size using the PPS (Population Proportional to Size) technique and employed cluster sampling. We tested all participants for SARS-CoV-2 IgG with an enzyme-linked immunosorbent assay (ELISA) kit and SARS-CoV-2 RNA with reverse transcription-polymerase chain reaction (RT-PCR). We sequenced samples with a cycle threshold (CT) value below 25 using whole genomic sequencing (WGS). Result: We found an adjusted seroprevalence of IgG at 75.38% statewide, and we found 0.04% of children RT-PCR positive for COVID-19. We determined a case-to-infection ratio of 1:37 and identified the SARS-CoV-2 strains as Omicron, BA.5, and BA.2.10. Conclusion: The study showed a high seroprevalence of IgG among children with low active infection. Omicron, BA. 5, and BA. 2.10 variants were detected through WGS.

Evaluation of agreement in macular vascular density measured by different protocols: 4.5 mm × 4.5 mm and 6 mm × 6 mm.

PURPOSE: To evaluate the agreement in the macular vascular density (MVD) measured by two protocols: 4.5 mm × 4.5 mm and 6 mm × 6 mm. DESIGN: Cross-sectional observational study. METHODS: Healthy volunteers between the age group of 19 and 39 years were recruited. Topcon DRI OCT Triton plus (Topcon Corporation, Tokyo, Japan) was used to acquire the fovea-centered optical coherence tomography angiography (OCTA) image using two protocols: 4.5 mm × 4.5 mm and 6 mm × 6 mm. MVD was measured by the manufacturer software in the superficial capillary plexus slab in five regions: central, superior, nasal, inferior, and temporal subfields of early treatment diabetic retinopathy study grid in each protocol. RESULTS: The study included 79 eyes of 40 healthy volunteers. The difference in the mean MVD between two protocols was 3.84% in right eye and 4.2% in left eye in central subfield, 0.93% in right eye and 1.13% in left eye in superior subfield, 0.06% in right eye and 1.45% in left eye in nasal subfield, 1.65% in right eye and 0.7% in left eye in inferior subfield, 0.4% in right eye and 0.54% in left eye in temporal subfield. The measurements were significantly higher in 6 mm × 6 mm in central subfield in both the eyes and in nasal field in the left eye. Whereas, the measurements were significantly higher in 4.5 mm × 4.5 mm in superior and inferior subfield in both the eyes and in temporal subfield in the left eye. CONCLUSION: The protocols should not be used interchangeably and it is necessary to include recommendation of the field of view to measure MVD while standardizing OCTA reporting.

Benralizumab does not elicit therapeutic effect in patients with chronic spontaneous urticaria: results from the phase 2b multinational, randomised, double-blind, placebo-controlled ARROYO trial.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils. OBJECTIVES: To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment. METHODS: The 24-week, randomised, double-blind, placebo-controlled, phase 2b portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomised to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in ISS7 at Week 12. The key secondary endpoint was change from baseline in UAS7 at Week 12. Additional secondary endpoints included other metrics to assess CSU at Week 24; blood eosinophil levels; and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups. RESULTS: Of 155 patients, 59 were randomised to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at Week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% confidence interval -4.09 to 0.50) nor in change from baseline in UAS7 score at Week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.4016; benralizumab 60 mg vs. placebo, P = 0.0819). Depletion of blood eosinophil levels was observed at Week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab. CONCLUSIONS: Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo.

Central Fracture-Dislocation of the Hip with Ipsilateral Femoral Neck Fracture in an Elderly Patient with Parkinsonism Managed with Dual Mobility Total Hip Arthroplasty: A Case Report and Review of Literature.

Introduction: The combination of a central fracture-dislocation of the hip, acetabulum fracture, and neck of the femur fracture is a rare injury, with a few reports described in the literature. Guidelines regarding managing this type of injury in single or multiple stages, the requirement of acetabular augmentation with plates, metal rings or cages, and the implant selection in elderly patients are not adequately defined while planning a total hip arthroplasty (THA). The successful management of such a complex fracture pattern in an elderly patient with neurodegenerative disorder is described in our case report. Case Report: An 81-year-old male presented to our outpatient department with a 2-month-old neglected post-traumatic central fracturedislocation of the right hip with an ipsilateral femoral neck fracture. The patient had a known case of Parkinson's disease on treatment with oral medication. A single-stage hybrid THA with dual mobility (DM) prosthesis was done with femoral head autograft acetabular impaction bone grafting. The patient was mobilized full weight bearing with the support of a walker on the 2nd post-operative day. At the 1-year follow-up the functional Harris hip score was 87. Radiographs revealed a well-healed acetabular fracture with the incorporation of a bone graft. No signs of implant loosening were observed. We did not encounter any complications such as dislocation, infection, and heterotrophic ossificans. Conclusion: Management of central fracture-dislocation of the hip with delayed one-staged THA has a good functional outcome. DM cup is essential in patients with parkinsonism and other neurodegenerative disorders.

Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus.

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.

The Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide 400 µg Administered by Inhalation as Single and Multiple (Twice Daily) Doses in Healthy Chinese Participants.

Purpose: To date, aclidinium pharmacokinetic (PK) studies have focused on Caucasian populations, and no data are available for Chinese populations. We aimed to characterize the PK and safety profile of aclidinium and its metabolites (LAS34823 and LAS34850) following single and multiple (twice-daily; BID) dosing in healthy Chinese participants, and to compare PK data between Chinese and Caucasian populations. Materials and methods: In this Phase I, open-label study (NCT03276052), healthy participants from a single site in China received aclidinium bromide 400 µg via a dry powder inhaler. The Day 1 single dose was followed by a washout period of 96 hours. On Days 5 through 8, participants received BID doses. Results: Twenty healthy Chinese participants, aged 18-45 years, were enrolled. Aclidinium absorption was rapid (median time to maximum concentration [tmax] 0.08 hours post-dose following single/multiple doses). LAS34823 had a similar median tmax of 0.08 hours, whereas LAS34850 tmax occurred later (median 2.50-3.00 hours). Aclidinium, LAS34823, and LAS34850 concentrations declined in a bi-phasic manner; geometric mean half-life was 13.5 hours (single dosing) and 21.4 hours (multiple dosing), while steady state was generally achieved after 5 days' continuous dosing. Area under the concentration-time curve during a dosage interval (AUCτ) metabolite to parent ratios for LAS34823 were 2.6 (Day 1) and 2.9 (Day 9), while LAS34850 had ratios of 136.0 and 94.8, respectively. Aclidinium accumulation occurred after 5 days of BID dosing (LS mean accumulation ratio for AUCτ Day 9/Day 1: 214.1% [90% CI, 176.5, 259.6]); LAS34823 accumulation was similar, while LAS34850 accumulation was lower. Between-participant exposure variability was moderate to high for aclidinium and LAS34823, and low for LAS34850. Conclusion: Single and multiple doses of aclidinium were well tolerated in healthy Chinese participants. The safety profile of and exposure to aclidinium was consistent with previous studies conducted in Caucasian populations.

Opioid-Based vs Opioid-Free Anesthesia in Breast Cancer Surgery.

Introduction: Breast cancer is the most widely recognized malignant growth in ladies in India and accounts for 14% of all tumors in women. Modified radical mastectomy (MRM) is a surgery done for breast cancer. It leads to about 30% chances of postoperative nausea and vomiting (PONV) and 40% pain in the immediate postoperative period. Objectives: Changes in blood pressure after intubation, waiting time for postoperative pain medication, and possibility of adverse effects. Methodology: After the approval of ethical committee, the study was conducted in the procedure and possible complications associated with the procedure were explained to patients. Written informed consent was obtained from each patient. Result and Conclusion: We conclude that opioid-free anesthesia is "more effective in reducing the incidence of postoperative nausea and vomiting, produces stable hemodynamics, and reduces incidence of side effects when compared with opioid-based general anesthesia in patients undergoing breast cancer surgeries."

Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques.

Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 simian-human immunodeficiency virus (SHIV) challenges in female macaques. Both routes of vaccination induce comparable levels of serum IgG with neutralizing and non-neutralizing activities. The protection in MVA-ID group correlates positively with serum neutralizing and antibody-dependent phagocytic activities, and envelope-specific vaginal IgA; while the limited protection in MVA-IM group correlates only with serum neutralizing activity. MVA-ID immunizations induce greater germinal center Tfh and B cell responses, reduced the ratio of Th1 to Tfh cells in blood and showed lower activation of intermediate monocytes and inflammasome compared to MVA-IM immunizations. This lower innate activation correlates negatively with induction of Tfh responses. These data demonstrate that the MVA-ID vaccinations protect against intravaginal SHIV challenges by modulating the innate and T helper responses.

Effect of ethyl gallate and propyl gallate on dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6 J mice: preventive and protective.

OBJECTIVE AND DESIGN: Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition of the digestive system marked by oxidative stress, leukocyte infiltration, and elevation of inflammatory mediators. In this study, we demonstrate the protective effect of ethyl gallate (EG), a phytochemical, and propyl gallate (PG), an anti-oxidant, given through normal drinking water (DW) and copper water (CW) in various combinations, which had a positive effect on the amelioration of DSS-induced ulcerative colitis in C57BL/6 J mice. MATERIALS AND METHODS: We successfully determined the levels of proinflammatory cytokines and anti-oxidant enzymes by ELISA, tracked oxidative/nitrosative stress (RO/NS) by in vivo imaging (IVIS) using L-012 chemiluminescent probe, disease activity index (DAI), and histopathological and morphometric analysis of colon in DSS-induced colitis in a model. RESULTS: The results revealed that oral administration of ethyl gallate and propyl gallate at a dose of 50 mg/kg considerably reduced the severity of colitis and improved both macroscopic and microscopic clinical symptoms. The level of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) in colonic tissue was considerably reduced in the DSS + EG-treated and DSS + PG-treated groups, compared to the DSS alone-treated group. IVIS imaging of animals from the DSS + EG and DSS + PG-treated groups showed a highly significant decrease in RO/NS species relative to the DSS control group, with the exception of the DSS + PG/CW and DSS + EG + PG/CW-treated groups. We also observed lower levels of myeloperoxidase (MPO), nitric oxide (NO), and lipid peroxidation (LPO), and restored levels of GST and superoxide dismutase (SOD) in DSS + EG-DW/CW, DSS + PG/DW, and DSS + EG + PG/DW groups compared to DSS alone-treated group. In addition, we showed that the EG, PG, and EG + PG treatment significantly reduced the DAI score, and counteracted the body weight loss and colon shortening in mice compared to DSS alone-treated group. In this 21-day study, mice were treated daily with test substances and were challenged to DSS from day-8 to 14. CONCLUSION: Our study highlights the protective effect of ethyl gallate and propyl gallate in various combinations which, in pre-clinical animals, serve as an anti-inflammatory drug against the severe form of colitis, indicating its potential for the treatment of IBD in humans. In addition, propyl gallate was investigated for the first time in this study for its anti-colitogenic effect with normal drinking water and reduced effect with copper water.

Development of a Minimalistic Physiologically Based Pharmacokinetic (mPBPK) Model for the Preclinical Development of Spectinamide Antibiotics.

Spectinamides 1599 and 1810 are lead spectinamide compounds currently under preclinical development to treat multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. These compounds have previously been tested at various combinations of dose level, dosing frequency, and route of administration in mouse models of Mycobacterium tuberculosis (Mtb) infection and in healthy animals. Physiologically based pharmacokinetic (PBPK) modeling allows the prediction of the pharmacokinetics of candidate drugs in organs/tissues of interest and extrapolation of their disposition across different species. Here, we have built, qualified, and refined a minimalistic PBPK model that can describe and predict the pharmacokinetics of spectinamides in various tissues, especially those relevant to Mtb infection. The model was expanded and qualified for multiple dose levels, dosing regimens, routes of administration, and various species. The model predictions in mice (healthy and infected) and rats were in reasonable agreement with experimental data, and all predicted AUCs in plasma and tissues met the two-fold acceptance criteria relative to observations. To further explore the distribution of spectinamide 1599 within granuloma substructures as encountered in tuberculosis, we utilized the Simcyp granuloma model combined with model predictions in our PBPK model. Simulation results suggest substantial exposure in all lesion substructures, with particularly high exposure in the rim area and macrophages. The developed model may be leveraged as an effective tool in identifying optimal dose levels and dosing regimens of spectinamides for further preclinical and clinical development.

Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models.

Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV, respectively) are mosquito-borne, neuroinvasive human pathogens for which no FDA-approved therapeutic exists. Besides the biothreat posed by these viruses when aerosolized, arthropod transmission presents serious health risks to humans, as demonstrated by the 2019 outbreak of EEE disease in the United States that resulted in 38 confirmed cases, 19 deaths, and neurological effects in survivors. Here, we describe the discovery of a 2-pyrrolidinoquinazolinone scaffold, efficiently synthesized in two to five steps, whose structural optimization resulted in profound antiviral activity. The lead quinazolinone, BDGR-49, potently reduced cellular VEEV and EEEV titers by >7 log at 1 µM and exhibited suitable intravenous and oral pharmacokinetic profiles in BALB/c mice to achieve excellent brain exposure. Outstanding in vivo efficacy was observed in several lethal, subcutaneous infection mouse models using an 8-day dosing regimen. Prophylactically administered BDGR-49 at 25 mg kg-1 per day fully protected against a 10× LD50 VEEV Trinidad donkey (TrD) challenge in BALB/c mice. Similarly, we observed 70% protection when 10× LD50 EEEV FL93-939-infected C57BL/6 mice were treated prophylactically with BDGR-49 at 50 mg kg-1 per day. Last, we observed 100% therapeutic efficacy when mice, challenged with 10× LD50 VEEV TrD, were dosed at 48 hours after infection with BDGR-49 at 25 mg kg-1 per day. Mouse brain viral titers at 96 hours after infection were reduced to values near the limit of detection. Collectively, these results underscore the substantial development potential of a well-tolerated, brain-penetrant lead compound that shows promise in preventing and treating encephalitic alphavirus disease.

Promoting Patient Safety: Exploring Device-Associated Healthcare Infections and Antimicrobial Susceptibility Pattern in a Multidisciplinary Intensive Care Units.

INTRODUCTION: Device-associated healthcare infections are among the prevailing threats to patient safety worldwide. They constitute the third most common adverse event during healthcare delivery, resulting in heightened morbidity, mortality, and healthcare costs. Patients in intensive care units (ICUs) are at increased risk for device-associated healthcare infections. Focused active surveillance is a crucial measure for assessing the prevalence of healthcare-associated infections and controlling the transmission of pathogens, ultimately contributing to the establishment of quality outcome indicators. This study aimed to investigate and establish the baseline rates of healthcare-associated infections associated with medical devices in adult multidisciplinary ICUs within a tertiary care institute. MATERIAL AND METHODS:  This hospital-based prospective observational study was conducted in two adult ICUs of a tertiary care institute in Central India over nine months. Targeted active surveillance for three device-associated health care infections namely central line-associated bloodstream infection (CLABSI), catheter-associated urinary tract infection (CAUTI), and ventilator-associated event (VAE) was conducted as per the Center for Disease Control (CDC)/National Healthcare Safety Network (NHSN) 2016 surveillance definitions and criteria. Pathogens associated with device-associated healthcare infections were identified and their antimicrobial susceptibility profile was studied. RESULTS:  During the study period, a total of 5,773 patient days were investigated. Of 1,270 patients, 28 episodes of device-associated healthcare infections were detected in 26 patients, this suggests a collective occurrence of five device-associated healthcare infections for every 1,000 patient days in the ICUs. The device utilization ratios of the central line, mechanical ventilator, and urinary catheters were 0.33, 0.27, and 0.68, respectively. VAE, CLABSI, and CAUTI rates were 8.92, 5.68, and 0.76 per 1,000 device days, respectively. The most common pathogen isolated from device-associated healthcare infections was Klebsiella pneumoniae (39%) followed by Acinetobacter baumanii (22%). The majority (82.3%) of pathogens were multidrug resistant. The death rate among device-associated healthcare infections was 69.2% with a crude excess mortality rate of 37.7%. CONCLUSION: The study sheds light on the proportion, types of device-associated healthcare infections, and underlying etiological agents associated with these infections in our institute's ICUs, thereby facilitating a better understanding of the healthcare-associated infection landscape within our facility. Moreover, the susceptibility pattern of pathogens associated with these infections offers crucial information for guiding the selection of appropriate antimicrobial therapies and infection control measures.

V2 hotspot optimized MVA vaccine expressing stabilized HIV-1 Clade C envelope Gp140 delays acquisition of heterologous Clade C Tier 2 challenges in Mamu-A*01 negative Rhesus Macaques.

Stabilized HIV envelope (Env) trimeric protein immunogens have been shown to induce strong autologous neutralizing antibody response. However, there is limited data on the immunogenicity and efficacy of stabilized Env expressed by a viral vector-based immunogen. Here, we compared the immunogenicity and efficacy of two modified vaccinia Ankara (MVA) vaccines based on variable loop 2 hotspot (V2 HS) optimized C.1086 envelope (Env) sequences, one expressing the membrane anchored gp150 (MVA-150) and the other expressing soluble uncleaved pre-fusion optimized (UFO) gp140 trimer (MVA-UFO) in a DNA prime/MVA boost approach against heterologous tier 2 SHIV1157ipd3N4 intrarectal challenges in rhesus macaques (RMs). Both MVA vaccines also expressed SIVmac239 Gag and form virus-like particles. The DNA vaccine expressed SIVmac239 Gag, C.1086 gp160 Env and rhesus CD40L as a built-in adjuvant. Additionally, all immunizations were administered intradermally (ID) to reduce induction of vaccine-specific IFNγ+ CD4 T cell responses. Our results showed that both MVA-150 and MVA-UFO vaccines induce comparable Env specific IgG responses in serum and rectal secretions. The vaccine-induced serum antibody showed ADCC and ADCVI activities against the challenge virus. Comparison with a previous study that used similar immunogens via intramuscular route (IM) showed that ID immunizations induced markedly lower SHIV specific CD4 and CD8 T cell responses compared to IM immunizations. Following challenge, MVA-UFO vaccinated animals showed a significant delay in acquisition of SHIV1157ipd3N4 infection but only in Mamu-A*01 negative macaques with an estimated vaccine efficacy of 64% per exposure. The MVA-150 group also showed a trend (p=0.1) for delay in acquisition of SHIV infection with an estimated vaccine efficacy of 57%. The vaccine-induced IFNγ secreting CD8 T cell responses showed a direct association and CD4 T cells showed an inverse association with delay in acquisition of SHIV infection. These results demonstrated that both MVA-150 and MVA-UFO immunogens induce comparable humoral and cellular immunity and the latter provides marginally better protection against heterologous tier 2 SHIV infection. They also demonstrate that DNA/MVA vaccinations delivered by ID route induce better antibody and lower CD4 and CD8 T cell responses compared to IM.

Colchicine-Binding Site Agent CH-2-77 as a Potent Tubulin Inhibitor Suppressing Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer. Unlike other subtypes of breast cancer, TNBC lacks hormone and growth factor receptor targets. Colchicine-binding site inhibitors (CBSI) targeting tubulin have been recognized as attractive agents for cancer therapy, but there are no CBSI drugs currently FDA approved. CH-2-77 has been reported to have potent antiproliferative activity against a panel of cancer cells in vitro and efficacious antitumor effects on melanoma xenografts, yet, its anticancer activity specifically against TNBC is unknown. Herein, we demonstrate that CH-2-77 inhibits the proliferation of both paclitaxel-sensitive and paclitaxel-resistant TNBC cells with an average IC50 of 3 nmol/L. CH-2-77 also efficiently disrupts the microtubule assembly, inhibits the migration and invasion of TNBC cells, and induces G2-M cell-cycle arrest. The increased number of apoptotic cells and the pattern of expression of apoptosis-related proteins in treated MDA-MB-231 cells suggest that CH-2-77 induces cell apoptosis through the intrinsic apoptotic pathway. In vivo, CH-2-77 shows acceptable overall pharmacokinetics and strongly suppresses the growth of orthotopic MDA-MB-231 xenografts without gross cumulative toxicities when administered 5 times a week. The in vivo efficacy of CH-2-77 (20 mg/kg) is comparable with that of CA4P (28 mg/kg), a CBSI that went through clinical trials. Importantly, CH-2-77 prevents lung metastasis originating from the mammary fat pad in a dose-dependent manner. Our data demonstrate that CH-2-77 is a promising new generation of tubulin inhibitors that inhibit the growth and metastasis of TNBC, and it is worthy of further development as an anticancer agent.

Age, gender, peers, life skills and quality of life influence risk of cell phone addiction among college teachers in Karnataka, India : a state level epidemiological analysis.

BACKGROUND: Cell phones are an integral part of modern day life and have become companions for individuals irrespective of age, gender and socio-economic status. In this study, we assessed the factors affecting risk of cell phone addiction among teachers attending Life Skills Training and Counselling Services (LSTCS) program in Karnataka. METHODS: This cross sectional secondary data analysis utilised data from baseline assessment of trainees attending a Life Skills Training and Counselling Services program (LSTCP). Various factors hypothesised to be affecting risk of cell phone addiction (outcome) was analysed using univariate and multivariable logistic regression analysis. All the analysis was done using STATA 12.0 software. RESULTS: Multivariable logistic regression analysis was conducted with risk of cell phone addiction as outcome. A conceptual framework of hypothesized exposure variables was developed based on expert consultation and literature review. Overall, data of 1981 participants was utilized. Gender (AOR=1.91; 95% CI=1.27-2.77), number of peers (AOR=1.01; 95 CI=1-1.008) and social quality of life (AOR=1.01; 95% CI=1.00-1.03) were associated with increased risk of cell phone addiction. Age (AOR=0.98; 95%CI=0.96-1.00), empathy (AOR=0.96;95%;CI=0.93-0.99), communication skills(AOR=0.92, 95%;CI=0.88-0.96) and physical quality of life (AOR=0.96; 95% CI=0.95-0.98) were associated with reduced risk of cell phone addiction. CONCLUSIONS: This study on precursors of risk of cell phone addiction, conducted mostly among apparently healthy individuals, provide important insights into interventions to reduce risk of cell phone addiction. The complexity of associations between peers, gender, quality of life and risk of cell phone addiction needs further exploration.

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors.

The involvement of cancer stem cells (CSCs) in driving tumor dormancy and drug resistance is well established. Most therapeutic regimens however are ineffective in targeting these regenerative populations. We report the development and evaluation of a monoclonal antibody, mAb150, which targets the metastasis associated antigen, Annexin A2 (AnxA2) through recognition of a N-terminal epitope. Treatment with mAb150 potentiated re-entry of CSCs into the cell cycle that perturbed tumor dormancy and facilitated targeting of CSCs as was validated by in vitro and in vivo assays. Epigenetic potentiation further improved mAb150 efficacy in achieving total tumor regression by targeting regenerative populations to achieve tumor regression, specifically in high-grade serous ovarian adenocarcinoma.

Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.

The lengthy treatment time for tuberculosis (TB) is a primary cause for the emergence of multidrug resistant tuberculosis (MDR-TB). One approach to improve TB therapy is to develop an inhalational TB therapy that when administered in combination with oral TB drugs eases and shortens treatment. Spectinamides are new semisynthetic analogues of spectinomycin with excellent activity against Mycobacterium tuberculosis (Mtb), including MDR and XDR Mtb strains. Spectinamide-1599 was chosen as a promising candidate for development of inhalational therapy. Using the murine TB model and intrapulmonary aerosol delivery of spectinamide-1599, we characterized the pharmacokinetics and efficacy of this therapy in BALB/c and C3HeB/FeJ mice infected with the Mtb Erdman strain. As expected, spectinamide-1599 exhibited dose-dependent exposure in plasma, lungs, and ELF, but exposure ratios between lung and plasma were 12-40 times higher for intrapulmonary compared to intravenous or subcutaneous administration. In chronically infected BALB/c mice, low doses (10 mg/kg) of spectinamide-1599 when administered thrice weekly for two months provide efficacy similar to that of higher doses (50-100 mg/kg) after one month of therapy. In the C3HeB/FeJ TB model, intrapulmonary aerosol delivery of spectinamide-1599 (50 mg/kg) or oral pyrazinamide (150 mg/kg) had limited or no efficacy in monotherapy, but when both drugs were given in combination, a synergistic effect with superior bacterial reduction of >1.8 log10 CFU was observed. Throughout the up to eight-week treatment period, intrapulmonary therapy was well-tolerated without any overt toxicity. Overall, these results strongly support the further development of intrapulmonary spectinamide-1599 as a combination partner for anti-TB therapy.

Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis.

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of antituberculosis agents, and the lead spectinamide 1810 has demonstrated excellent efficacy, safety, and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of Mycobacterium tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of CFU in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by the ratio of maximum free drug concentration to MIC (fCmax/MIC) and the ratio of the area under the free concentration-time curve to the MIC (fAUC/MIC) rather than the cumulative percentage of time that the free drug concentration is above the MIC (f%TMIC). A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis.