A mathematical model to study low-dose metronomic scheduling for chemotherapy.

Metronomic chemotherapy refers to the frequent administration of chemotherapeutic agents at a lower dose and presents an attractive alternative to conventional chemotherapy with encouraging response rates. However, the schedule of the therapy, including the dosage of the drug, is usually based on empiricism. The confounding effects of tumor-endothelial-immune interactions during metronomic administration of drugs have not yet been explored in detail, resulting in an incomplete assessment of drug dose and frequency evaluations. The present study aimed to gain a mechanistic understanding of different actions of metronomic chemotherapy using a mathematical model. We have established an analytical condition for determining the dosage and frequency of the drug depending on its clearance rate for complete tumor elimination. The model also brings forward the immune-mediated clearance of the tumor during the metronomic administration of the chemotherapeutic agent. The results from the global sensitivity analysis showed an increase in the sensitivity of drug and immune-mediated killing factors toward the tumor population during metronomic scheduling. Our results emphasize metronomic scheduling over the maximum tolerated dose (MTD) and define a model-based approach for approximating the optimal schedule of drug administration to eliminate tumors while minimizing harm to the immune cells and the patient's body.

VapC12 ribonuclease toxin modulates host immune response during Mycobacterium tuberculosis infection.

Mechanistic understanding of antibiotic persistence is a prerequisite in controlling the emergence of MDR cases in Tuberculosis (TB). We have reported that the cholesterol-induced activation of VapC12 ribonuclease is critical for disease persistence in TB. In this study, we observed that relative to the wild type, mice infected with ΔvapC12 induced a pro-inflammatory response, had a higher pathogen load, and responded better to the anti-TB treatment. In a high-dose infection model, all the mice infected with ΔvapC12 succumbed early to the disease. Finally, we reported that the above phenotype of ΔvapC12 was dependent on the presence of the TLR4 receptor. Overall, the data suggests that failure of a timely resolution of the early inflammation by the ΔvapC12 infected mice led to hyperinflammation, altered T-cell response and high bacterial load. In conclusion, our findings suggest the role of the VapC12 toxin in modulating the innate immune response of the host in ways that favor the long-term survival of the pathogen inside the host.

Exploration of functional relations among differentially co-expressed genes identifies regulators in glioblastoma.

The conventional computational approaches to investigating a disease confront inherent constraints as they often need to improve in delving beyond protein functional associations and grasping their deeper contextual significance within the disease framework. Such context-specificity can be explored using clinical data by evaluating the change in interaction between the biological entities in different conditions by investigating the differential co-expression relationships. We believe that the integration and analysis of differential co-expression and the functional relationships, primarily focusing on the source nodes, will open novel insights about disease progression as the source proteins could trigger signaling cascades, mostly because they are transcription factors, cell surface receptors, or enzymes that respond instantly to a particular stimulus. A thorough contextual investigation of these nodes could lead to a helpful beginning point for identifying potential causal linkages and guiding subsequent scientific investigations to uncover mechanisms underlying observed associations. Our methodology includes functional protein-protein Interaction (PPI) data and co-expression information and filters functional linkages through a series of critical steps, culminating in the identification of a robust set of regulators. Our analysis identified eleven key regulators-AKT1, BRCA1, CAMK2G, CUL1, FGFR3, KIF3A, NUP210, PRKACB, RAB8A, RPS6KA2 and TGFB3-in glioblastoma. These regulators play a pivotal role in disease classification, cell growth control, and patient survivability and exhibit associations with immune infiltrations and disease hallmarks. This underscores the importance of assessing correlation towards causality in unraveling complex biological insights.

Bloodborne viral infections: Seroprevalence and relevance of preoperative screening in Indian eye care system - A retrospective study.

PURPOSE: To report the seroprevalence of bloodborne viral infection (BBVI) in patients undergoing ophthalmic surgeries and assess the utility and feasibility of preoperative screening for BBVI in India's current eye care system. METHODS: This retrospective, hospital-based, descriptive study included data from patients undergoing preoperative screening for Hepatitis B virus (HBV), Hepatitis C virus (HCV), and human immunodeficiency virus (HIV) at a tertiary eye care institute from 2018 to 2022. Rapid diagnostic tests (RDTs) were performed on the blood samples after obtaining informed consent from the patients. Seroreactive patients underwent surgery with additional safety precautions. The demographic data and surgical details of these patients were collected and analyzed. ANOVA was used to carry out statistical analysis between groups. During the study period, the number of healthcare workers (HCWs) sustaining needle stick injury (NSI) and accidental sharp injury (ASI) in the operating theater (OT) and details of these injuries were recorded. RESULTS: Samples from 28,563 patients were included. The seroprevalence of BBVI was 1.87% (536/28563). Hepatitis B virus (322, 60.1%) was the most commonly detected infection, and HIV (59, 11%) was the least detected infection. The mean age of the seroreactive patients was 60.3 ± 30.8 years. The incidence of NSI was 0.49/1000 surgeries. Nurses (11) and technicians (4) in the OT sustained maximum NSI. None of the HCWs had seroconversion after NSI. CONCLUSION: The overall seroprevalence of BBVI in the current study is lower than that reported in previously published studies from eye care organizations. Currently, mandatory preoperative screening for BBVI to prevent transmission of these infections to HCWs working in the eye care sector in India appears to be less cost-effective.

Trends in keratoplasty from central and northern India. Part II: Types of keratoplasty.

PURPOSE: To report the types of keratoplasty and analyze trends over a period of two decades in central and northern India. METHODS: This was a retrospective review of eye bank registries of six tertiary eye care centers located in central and north India from 2005 to 2021. The indications and various keratoplasty procedures were compared between 2005-2012 and 2013-2021 to analyze the trend. RESULTS: A total of 13,223 corneal grafts were performed, of which therapeutic penetrating keratoplasty (TPK) (5719, 43.3%) was the most common procedure, followed by optical penetrating keratoplasty (OPK) (5528, 41.8%), Descemet stripping endothelial keratoplasty (DSEK) (1279, 9.7%), deep anterior lamellar keratoplasty (DALK) (376, 2.8%), Descemet membrane endothelial keratoplasty (DMEK) (215, 1.6%), patch grafts (75, 0.6%), and keratoprostheses (31, 0.2%). Overall, OPK procedures decreased (-14.1%, P < 0.001), but TPK (+3.1%, P < 0.019), DSEK (+7.1%, P < 0.001), and DMEK (+1.9%, P < 0.001) procedures increased. Although there was an increasing trend in the use of DALK (+0.8%, P < 0.083) and keratoprostheses (+0.3%, P = 0.074) procedures, the trends were not statistically significant. CONCLUSION: In keeping with worldwide trends, an increasing trend in lamellar keratoplasties was observed in central and northern India during the past decade. The trend was significant for DSEK. However, as corneal ulcers and scars were the major indications for keratoplasty, TPK and OPK remained the most common procedures.

Trends in keratoplasty from central and Northern India. Part I: Indications for keratoplasty.

PURPOSE: To report the indications for keratoplasty and analyze trends in two decades in India. METHODS: This was a retrospective review of eye bank registries of six tertiary eye care centers located in central and northern India from 2005 to 2021. The patterns of corneal pathology and changes in trends were analyzed. RESULTS: Between 2005 and 2021, 13223 corneal grafts were performed in the six collaborating tertiary eye care centers. The most common indication for keratoplasty in both decades was corneal ulcer (41.1%), followed by corneal scar (25.5%), failed graft (12.0%), post-cataract surgery corneal edema (11.7%), corneal dystrophies (3.1%), corneal ectasia (1.8%), corneal trauma (0.3%), congenital corneal opacity (0.3%), and others (4.1%). An increasing trend was seen in corneal ulcers, failed grafts, and keratoconus. A reducing trend was seen in corneal scar and aphakic bullous keratopathy. There was no change in pseudophakic bullous keratopathy and Fuchs endothelial corneal dystrophy. CONCLUSION: Corneal ulcers, corneal scars, failed grafts, and post-cataract surgery corneal edema remained the foremost indications for keratoplasty in two decades in India. An increasing trend was seen in corneal ulcers and failed grafts which are of concern as these indications carry a poorer outcome. Capacity building in lamellar keratoplasty techniques is the need of the hour as pseudophakic bullous keratopathy was an important indication, and an increasing trend was noticed in keratoconus.

Preferred practice patterns for keratoconus: An e-survey among Indian cornea specialists.

PURPOSE: This study aimed to report practice patterns in the management of keratoconus in India. METHODS: An e-survey was conducted among members of the Cornea Society of India to assess preferred practice patterns for keratoconus. RESULTS: Of the 912 members, 234 (25.7%) completed the survey. About 88.4% worked in private eye care facilities and 76.1% in cities. Of all the respondents, 91.5% had access to a Scheimpflug-based device or an Orbscan II®; 71.4% of the respondents dispensed scleral contact lenses, and 66.7% dispensed Rose K contact lenses; 92.7% of the respondents performed corneal cross-linking (CXL); and 73.1% of the respondents performed deep anterior lamellar keratoplasty (DALK). A Scheimpflug device or Orbscan II®, Rose K or scleral contact lenses, and CXL were more readily available (P < 0.05) in private eye care facilities. The diagnostic criteria for keratoconus followed by the majority of the respondents (52.1%) were increase in corneal curvature, elevation, and thickness. An increase in keratometry values greater than 0.5 or 1.0D in a 6-month to 1-year period was considered the most favored criterion for keratoconus progression. Epithelium-off, 0.1% riboflavin solution in dextran, and accelerated protocol were the more commonly reported techniques in CXL. About 77.2% of the respondents routinely performed CXL in corneas <400 microns thick. Spectacles (91.0% of the respondents) and topography-guided photorefractive keratectomy (37.6% of the respondents) were, respectively, the preferred optical and surgical methods used to improve vision. CONCLUSION: While keratoconus management in India is comparable to other developed healthcare systems, the concentration of trained corneal surgeons in cities and private eyecare facilities may lead to less equitable distribution of treatment across the country.