Prevalence of ventilator-associated events and antibiogram of bacterial isolates of ventilator-associated pneumonia in a tertiary care hospital of Uttarakhand.

Background and Objectives: Despite progress in diagnosing and managing ventilator-associated pneumonia (VAP), ongoing monitoring of ventilator-associated events (VAE) is crucial due to VAP's persistent prominence as the primary cause of Hospital-Acquired Infection (HAI) among Intensive Care unit patients. This study was done to illuminate the prevalence of VAE and antibiogram of bacterial isolates of VAP in a tertiary care hospital of Uttarakhand. Materials and Methods: This cross-sectional study focused on ICU patients. Adult patients ventilated for > 2 days were monitored daily, with VAE data analyzed using Center of Disease Control & Prevention (CDC) criteria. Specimens were sent to the Microbiology Department and cultured on Blood agar and MacConkey agar. Identification and antimicrobial profiles of isolates were determined using Vitek-2 Compact. Results: 1220 ventilated individuals were assessed in total. VAE was diagnosed in 6.4% (78/1220) of the patients, the same later developed ventilator associated condition (VAC), 74 developed the infection-related VAC (IVAC), and 60 developed the possible/probable VAP (PVAP) among the 78 VAE cases. Klebsiella pneumoniae (35%), Acinetobacter baumannii (33%), and Pseudomonas aeruginosa (16%) were the most common isolated organisms. Colistin (57%) was the most effective against Klebsiella pneumoniae, followed by amikacin (28.5%) and trimethoprim+sulfamethoxazole (24%). Pseudomonas aeruginosa was most susceptible to imipenem (70%), meropenem, cefoperazone+sulbactam, and colistin (60%). Acinetobacter baumannii was most susceptible to colistin (85%), tigecycline (65%), and trimethoprim+sulfamethoxazole (25%). Conclusion: The most common cause of HAI is VAP. The purpose of this study is to determine the importance of starting suitable antibiotics early for prognosis and the difficulty of diagnosing VAP.

Nonequilibrium dynamics in Ising-like models with biased initial condition.

We investigate the dynamical fixed points of the zero temperature Glauber dynamics in Ising-like models. The stability analysis of the fixed points in the mean field calculation shows the existence of an exponent that depends on the coordination number z in the Ising model. For the generalized voter model, a phase diagram is obtained based on this study. Numerical results for the Ising model for both the mean field case and short ranged models on lattices with different values of z are also obtained. A related study is the behavior of the exit probability E(x_{0}), defined as the probability that a configuration ends up with all spins up starting with x_{0} fraction of up spins. An interesting result is E(x_{0})=x_{0} in the mean field approximation when z=2, which is consistent with the conserved magnetization in the system. For larger values of z, E(x_{0}) shows the usual finite size dependent nonlinear behavior both in the mean field model and in the Ising model with nearest neighbor interaction on different two dimensional lattices. For such a behavior, a data collapse of E(x_{0}) is obtained using y=(x_{0}-x_{c})/x_{c}L^{1/ν} as the scaling variable and f(y)=1+tanh(λy)/2 appears as the scaling function. The universality of the exponent and the scaling factor is investigated.

Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis.

Fingolimod (Gilenya) received regulatory approval from the US FDA in 2010 as the first-in-class sphingosine 1-phosphate (S1P) receptor (S1PR) modulator and was the first oral disease-modifying therapy (DMT) used for the treatment of the relapsing forms of multiple sclerosis (MS). Development of this new class of therapeutic compounds has continued to be a pharmacological goal of high interest in clinical trials for treatment of various autoimmune disorders, including MS. S1P is a physiologic signaling molecule that acts as a ligand for a group of cell surface receptors. S1PRs are expressed on various body tissues and regulate diverse physiological and pathological cellular responses involved in innate and adaptive immune, cardiovascular, and neurological functions. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are well known for their major role in MS pathogenesis and play an important regulatory role in the egress of lymphocytes from lymphoid organs to the lymphatic circulation. Thus, S1PR1-directed pharmacological interventions aim to modulate its role in immune cell trafficking through sequestration of autoreactive lymphocytes in the lymphoid organs to reduce their recirculation and subsequent infiltration into the central nervous system. Indeed, receptor subtype selectivity for S1PR1 is theoretically favored to minimize safety concerns related to interaction with other S1PR subtypes. Improved understanding of fingolimod's mechanism of action has provided strategies for the development of the more selective second-generation S1PR modulators. This selectivity serves to reduce the most important safety concern regarding cardiac-related side effects, such as bradycardia, which requires prolonged first-dose monitoring. It has led to the generation of smaller molecules with shorter half-lives, improved onset of action with no requirement for phosphorylation for activation, and preserved efficacy. The shorter half-lives of the second-generation agents allow for more rapid reversal of their pharmacological effects following treatment discontinuation. This may be beneficial in addressing further treatment-related complications in case of adverse events, managing serious or opportunistic infections such as progressive multifocal leukoencephalopathy, and eliminating the drug in pregnancies. In March 2019, a breakthrough in MS treatment was achieved with the FDA approval for the second S1PR modulator, siponimod (Mayzent), for both active secondary progressive MS and relapsing-remitting MS. This was the first oral DMT specifically approved for active forms of secondary progressive MS. Furthermore, ozanimod received FDA approval in March 2020 for treatment of relapsing forms of MS, followed by subsequent approvals from Health Canada and the European Commission. Other second-generation selective S1PR modulators that have been tested for MS, with statistically significant data from phase II and phase III clinical studies, include ponesimod (ACT-128800), ceralifimod (ONO-4641), and amiselimod (MT-1303). This review covers the available data about the mechanisms of action, pharmacodynamics and kinetics, efficacy, safety, and tolerability of the various S1PR modulators for patients with relapsing-remitting, secondary progressive, and, for fingolimod, primary progressive MS.

ToRCH-screening in pediatric cataract revisited: A North Indian tertiary care centre study.

Purpose: To analyze and report ToRCH-serology screening profile (Toxoplasma gondii [TOX], rubella [RV], cytomegalovirus [CMV], and herpes simplex virus [HSV-I/II]) in pediatric cataract. Methods: In this prospective analytical study, 1,026 consecutive children were screened, of which 46 children with clinically diagnosed congenital (n = 26) and developmental cataract (n = 20) were included. Post-traumatic and familial cataracts were excluded. Sera of all children were tested both qualitatively and quantitatively for IgG/IgM-antibodies against ToRCH agents in a sequential manner. Results: Overall, IgM/IgG-seropositivity against ≥1 ToRCH agent was reported in 91.3% (42/46) children. IgM (±IgG) positivity against ≥1 ToRCH agent was reported in 26.08% (12/46) children (nine congenital and three developmental cataract; P = 0.18), which included 8.7% (4/46) children reported positive against ≥2 agents. Finally, 13% (6/46) children were reported to be sero-clinical-positive (three were infants and three were> 1 year age, P = 0.55; five congenital and one developmental cataract, P = 0.21). Either alone or combined, RV attributed to the majority (50%; 6/12) of the IgM (±IgG) and sero-clinical-positive (50%; 3/6) children. None of the children were HSV-II IgM-positive. Laboratory-confirmed congenital rubella syndrome was reported in 4.3% (2/46) children. One sero-clinical-positive infant with rare coexisting bilateral persistent fetal vasculature was also reported. IgG-alone positivity was reported highest with CMV in 67.4% (31/46) children, whereas 43.4% (20/46) children were found nonimmune to RV. Conclusion: The current study emphasizes the need to interpret ToRCH-screening in pediatric cataract with caution. Interpretation should include both serial qualitative and quantitative assays in tandem with clinical correlation to minimize the diagnostic errors. Clinicians should remain vigilant regarding sero-clinical-positivity in older children too who might pose a threat to the spread of infection.

Cognitive evolution in natalizumab-treated multiple sclerosis patients.

BACKGROUND: Cognitive dysfunction affects up to 65% of multiple sclerosis (MS) patients and progresses over time. Natalizumab has been shown to be superior to placebo in preserving cognition for the first two years of therapy. OBJECTIVES: The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response. METHODS: This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the Symbol Digit Modalities Test (SDMT). Patient demographics were collected at baseline. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (≤2 or >2 years), assessment as a within-subjects factor, and Multiple Sclerosis Severity Score (MSSS) as a covariate. RESULTS: Aside from the MSSS (p = 0.0074), the two groups were identical. No patient showed evidence of sustained cognitive deterioration over the 24-month period. Baseline parameters including impaired cognition did not influence the trajectory of cognitive change over 24 months. CONCLUSIONS: Our results suggest that natalizumab preserves cognition following four to seven years of continuous therapy. This occurs irrespective of baseline characteristics, including impaired cognition.