A bootstrapping method to optimize go/no-go decisions from single-arm, signal-finding studies in oncology.

Phase Ib trials are common in oncology development but often are not powered for statistical significance. Go/no-go decisions are largely driven by observed trends in response data. We applied a bootstrapping method to systematically compare tumor dynamic end points to historical control data to identify drugs with clinically meaningful efficacy. A proprietary mathematical model calibrated to phase Ib anti-PD-1 therapy trial data (KEYNOTE-001) was used to simulate thousands of phase Ib trials (n = 30) with a combination of anti-PD-1 therapy and four novel agents with varying efficacy. A redacted bootstrapping method compared these results to a simulated phase III control arm (N = 511) while adjusting for differences in trial duration and cohort size to determine the probability that the novel agent provides clinically meaningful efficacy. Receiver operating characteristic (ROC) analysis showed strong ability to separate drugs with modest (area under ROC [AUROC] = 83%), moderate (AUROC = 96%), and considerable efficacy (AUROC = 99%) from placebo in early-phase trials (n = 30). The method was shown to effectively move drugs with a range of efficacy through an in silico pipeline with an overall success rate of 93% and false-positive rate of 7.5% from phase I to phase III. This model allows for effective comparisons of tumor dynamics from early clinical trials with more mature historical control data and provides a framework to predict drug efficacy in early-phase trials. We suggest this method should be employed to improve decision making in early oncology trials.

Theophylline as a quorum sensing and biofilm inhibitor in Pseudomonas aeruginosa and Chromobacterium violaceum.

Quorum sensing (QS) is pivotal in coordinating virulence factors and biofilm formation in various pathogenic bacteria, making it a prime target for disrupting bacterial communication. Pseudomonas aeruginosa is a member of the "ESKAPE" group of bacterial pathogens known for their association with antimicrobial resistance and biofilm formation. The current antibiotic arsenal falls short of addressing biofilm-related infections effectively, highlighting the urgent need for novel therapeutic agents. In this study, we explored the anti-QS and anti-biofilm properties of theophylline against two significant pathogens, Chromobacterium violaceum and P. aeruginosa. The production of violacein, pyocyanin, rhamnolipid, and protease was carried out, along with the evaluation of biofilm formation through methods including crystal violet staining, triphenyl tetrazolium chloride assay, and fluorescence microscopy. Furthermore, computational analyses were conducted to predict the targets of theophylline in the QS pathways of P. aeruginosa and C. violaceum. Our study demonstrated that theophylline effectively inhibits QS activity and biofilm formation in C. violaceum and P. aeruginosa. In P. aeruginosa, theophylline inhibited the production of key virulence factors, including pyocyanin, rhamnolipid, protease, and biofilm formation. The computational analyses suggest that theophylline exhibits robust binding affinity to CviR in C. violaceum and RhlR in P. aeruginosa, key participants in the QS-mediated biofilm pathways. Furthermore, theophylline also displays promising interactions with LasR and QscR in P. aeruginosa. Our study highlights theophylline as a versatile anti-QS agent and offers a promising avenue for future research to develop novel therapeutic strategies against biofilm-associated infections.

Antibiofilm potential of gallic acid against Klebsiella pneumoniae and Enterobacter hormaechei: in-vitro and in-silico analysis.

Biofilm refers to a community of microorganisms that adhere to a substrate and play a crucial role in microbial pathogenesis and developing infections associated with medical devices. Enterobacter hormaechei and Klebsiella pneumoniae are classified as significant nosocomial pathogens within the ESKAPE category and cause diverse infections. In addition to their reputation as prolific biofilm formers, these pathogens are increasingly becoming drug-resistant and pose a substantial threat to the healthcare setting. Due to the inherent resistance of biofilms to conventional therapies, novel strategies are imperative for effectively controlling E. hormaechei and K. pneumoniae biofilms. This study aimed to assess the anti-biofilm activity of gallic acid (GA) against E. hormaechei and K. pneumoniae. The results of biofilm quantification assays demonstrated that GA exhibited significant antibiofilm activity against E. hormaechei and K. pneumoniae at concentrations of 4 mg mL-1, 2 mg mL-1, 1 mg mL-1, and 0.5 mg mL-1. Similarly, GA exhibited a dose-dependent reduction in violacein production, a QS-regulated purple pigment, indicating its ability to suppress violacein production and disrupt QS mechanisms in Chromobacterium violaceum. Additionally, computational tools were utilized to identify the potential target involved in the biofilm formation pathway. The computational analysis further indicated the strong binding affinity of GA to essential biofilm regulators, MrkH and LuxS, suggesting its potential in targeting the c-di-GMP and quorum sensing (QS) pathways to hinder biofilm formation in K. pneumoniae. These compelling findings strongly advocate GA as a promising drug candidate against biofilm-associated infections caused by E. hormaechei and K. pneumoniae.

Synergistic Effect of Thymol-Ciprofloxacin Combination on Planktonic Cells and Biofilm of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic bacteria causing severe and life-threatening infections in individuals with weakened immune systems. P. aeruginosa forms antibiotic-resistant biofilms, rendering it challenging to treat; hence, alternate therapies are required to eliminate it. Treatment of infections using a combination of drugs is gaining momentum to combat drug-resistant pathogens, including P. aeruginosa. This study explores the synergistic effects of Thymol in combination with Ciprofloxacin, Amikacin and Colistin against planktonic cells and biofilm of P. aeruginosa. Thymol in combination with Ciprofloxacin yields the fractional inhibitory concentration index values 0.156 and 0.375 in P. aeruginosa strains, GC14 and ATCC 9027, respectively, highlighting a robust synergistic effect on both the planktonic and biofilm of P. aeruginosa. The results showed that Thymol (512 µg/mL) and Ciprofloxacin (0.125 µg/mL) were the most effective combination with 95 and 93.5% total biofilm inhibition in GC14 and PA27, respectively, compared to the Thymol (512 µg/mL) and Ciprofloxacin (0.125 µg/mL) alone. Our findings suggest that the combinations of Thymol and Ciprofloxacin may be a potential therapeutic strategy to address the issue of infections caused by P. aeruginosa biofilms.

Hallmarks of neurodegenerative disease: A systems pharmacology perspective.

Age-related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease-modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

Effective Dose of Prophylactic Oxytocin Infusion During Cesarean Delivery in 90% Population of Nonlaboring Patients With Preeclampsia Receiving Magnesium Sulfate Therapy and Normotensives: An Up-Down Sequential Allocation Dose-Response Study.

BACKGROUND: Oxytocin administration during cesarean delivery is the first-line therapy for the prevention of uterine atony. Patients with preeclampsia may receive magnesium sulfate, a drug with known tocolytic effects, for seizure prophylaxis. However, no study has evaluated the minimum effective dose of oxytocin during cesarean delivery in women with preeclampsia. METHODS: This study compared the effective dose in 90% population (ED90) of oxytocin infusion for achieving satisfactory uterine tone during cesarean delivery in nonlaboring patients with preeclampsia who were receiving magnesium sulfate treatment with a control group of normotensives who were not receiving magnesium sulfate. This prospective dual-arm dose-finding study was based on a 9:1 biased sequential allocation design. Oxytocin infusion was initiated at 13 IU/h, on clamping of the umbilical cord, in the first patient of each group. Uterine tone was graded as satisfactory or unsatisfactory by the obstetrician at 4 minutes after initiation of oxytocin infusion. The dose of oxytocin infusion for subsequent patients was decided according to the response exhibited by the previous patient in the group; it was increased by 2 IU/h after unsatisfactory response or decreased by 2 IU/h or maintained at the same level after satisfactory response, in a ratio of 1:9. Oxytocin-associated side effects were also evaluated. Dose-response data for the groups were evaluated using a log-logistic function and ED90 estimates were derived from fitted equations using the delta method. RESULTS: The ED90 of oxytocin was significantly greater for the preeclampsia group (n = 27) than for the normotensive group (n = 40) (24.9 IU/h [95% confidence interval {CI}, 22.4-27.5] and 13.9 IU/h [95% CI, 12.4-15.5], respectively); the difference in dose requirement was 10.9 IU/h (95% CI, 7.9-14.0; P < .001). The number of patients with oxytocin-related hypotension, defined as a decrease in systolic blood pressure >20% from baseline or to <90 mm Hg, was significantly greater in the preeclampsia group (92.6% vs 62.5%; P = .030), while other side effects such as ST-T depression, nausea/vomiting, headache, and flushing, were not significantly different. There was no significant difference in the need for additional uterotonic or uterine massage, estimated blood loss, and need for re-exploration for uncontrolled bleeding. CONCLUSIONS: Patients with preeclampsia receiving preoperative magnesium therapy need a greater intraoperative dose of oxytocin to achieve satisfactory contraction of the uterus after fetal delivery, as compared to normotensives.

Prevalence of Tuberculosis Infection among Adults of Thiruvananthapuram District of Kerala as Measured by Interferon Gamma Release Assay - A Cross-Sectional Study.

Background: To achieve the goals of the end tuberculosis (TB) strategy, strategies for management of TB infection (TBI) have to be expanded. The first step to devise policies is to understand the distribution and determinants of TBI in the community. The objectives of the study were to estimate the prevalence of TBI using Interferon Gamma Release Assay (IGRA) and its determinants among the adult population of Thiruvananthapuram district, Kerala. Materials and Methods: A community-based, cross-sectional study using the stratified cluster sampling was carried out among the adults. TBI was detected using IGRA conducted on whole blood sample. Data on determinants were collected using a structured questionnaire by the face-to-face interview. The prevalence of TBI was estimated. Univariate and multivariate analysis was conducted to identify the determinants. Results: Age standardized prevalence of TBI among 396 adults was 20.5% (95% confidence interval [CI] 16.52-24.48). On adjusting for the possible confounders, increasing age (adjusted odds ratio [OR] 1.028; 95% CI 1.008-1.048; P = 0.005), history of contact with active TB disease (adjusted OR 7.61; 95% CI 4.43-13.05; P < 0.001), childhood contact (adjusted OR 8.20; 95% CI 3.14-21.41; P < 0.001), and household contact (adjusted OR 10.12; 95% CI 5.39-18.98; P < 0.001) were found to be the determinants of TBI in this population. Conclusion: The present study observed that nearly one-fifth of the adult population in the Thiruvananthapuram district has TBI. For the programmatic management, factors such as increasing age and contact history may be considered for the elimination of TBI in the state.

Overview of statistical methods usage in Indian anaesthesia publications.

Background and Aims: Despite the importance of statistics being well established for medical research, it remains a neglected area of understanding and learning. The present survey aimed to examine the use of various statistical methods in a two-year sample (2019-2020) of representative Indian anaesthesia journals and compare it with an international top-ranked journal. Methods: The literature survey included analysis of 748 original articles from 'Indian Journal of Anaesthesia' (179), 'Journal of Anaesthesiology Clinical Pharmacology' (125) and 'Anesthesia & Analgesia' (444) published over the period. Original research articles were identified from the table of contents of each issue. Articles were assessed for statistical methods, categorised as being descriptive, elementary, multivariable, advanced multivariate or diagnostic/classification. Results: Compared to Anesthesia & Analgesia, the Indian journals (considered together) had a significantly greater use of mean (standard deviation) (91.2% versus 70%) and percentages (79.5% versus 67.6%) (P = 0.000 each); and lesser for Wilcoxon (5.4% versus 14.6%) and Pearson/Spearman (5.1% versus 13.5%) correlation tests (P = 0.000 each), multivariable tests including various regression methods (P < 0.001), classification/diagnostic tests [Receiver operating characteristic (ROC) curve analysis, P = 0.022; sensitivity/specificity, P = 0.000; precision, P = 0.006; and relative risk/risk ratio, P = 0.010] and a virtual absence of complex multivariate tests. Conclusion: The findings show limited use of advanced complex statistical methods in Indian anaesthesia journals, usually being restricted to descriptive or elementary. There was a strong bias towards using randomised controlled designs. The findings suggest an urgent and focussed need on training in research methodology, including statistical methods, during postgraduation and continued medical training.

Bacterium isolated from coffee waste pulp biosorps lead: Investigation of EPS mediated mechanism.

Kleibsiella pneumoniae Kpn555, isolated from coffee waste pulp showed high level of tolerance to lead with a minimum inhibitory concentration of 900 mg/L. On its growth in nutrient broth supplemented with lead, brown clumps were visualised at the bottom of the flask. On scanning and transmission electron microscopic studies the brown clumps were corroborated to be bacterial cells with lead biosorbed on the cell surface and accumulated inside the cytoplasm. Biochemical and FT-IR analysis of the extracellular polymeric substance produced on exposure to lead revealed its chemical nature as glycolipid with protein moieties. Purified EPS (100 mg/L) could remove 50% of lead from aqueous solution (200 mg/L). Isolation of plasmid from Klebsiella pneumoniae Kpn555 revealed the presence of a plasmid of size 30-40 kb. This capability of the bacteria was proven to be plasmid mediated as the Escherichia coli DH5α cells transformed with the plasmid of Klebsiella pneumoniae Kpn555 also could tolerate 900 mg/L of lead and form brown clumps. This study shows that these bacteria, aided by EPS could serve as an effective agent for the removal of lead from contaminated water environmental samples.

Early Warning Scores at Time of ICU Admission to Predict Mortality in Critically Ill COVID-19 Patients.

OBJECTIVE: To assess ability of National Early Warning Score 2 (NEWS2), systemic inflammatory response syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and CRB-65 calculated at the time of intensive care unit (ICU) admission for predicting ICU mortality in patients of laboratory confirmed coronavirus disease 2019 (COVID-19) infection. METHODS: This prospective data analysis was based on chart reviews for laboratory confirmed COVID-19 patients admitted to ICUs over a 1-mo period. The NEWS2, CRB-65, qSOFA, and SIRS were calculated from the first recorded vital signs upon admission to ICU and assessed for predicting mortality. RESULTS: Total of 140 patients aged between 18 and 95 y were included in the analysis of whom majority were >60 y (47.8%), with evidence of pre-existing comorbidities (67.1%). The most common symptom at presentation was dyspnea (86.4%). Based upon the receiver operating characteristics area under the curve (AUC), the best discriminatory power to predict ICU mortality was for the CRB-65 (AUC: 0.720 [95% confidence interval [CI]: 0.630-0.811]) followed closely by NEWS2 (AUC: 0.712 [95% CI: 0.622-0.803]). Additionally, a multivariate Cox regression model showed Glasgow Coma Scale score at time of admission (P < 0.001; adjusted hazard ratio = 0.808 [95% CI: 0.715-0.911]) to be the only significant predictor of ICU mortality. CONCLUSIONS: CRB-65 and NEWS2 scores assessed at the time of ICU admission offer only a fair discriminatory value for predicting mortality. Further evaluation after adding laboratory markers such as C-reactive protein and D-dimer may yield a more useful prediction model. Much of the earlier data is from developed countries and uses scoring at time of hospital admission. This study was from a developing country, with the scores assessed at time of ICU admission, rather than the emergency department as with existing data from developed countries, for patients with moderate/severe COVID-19 disease. Because the scores showed some utility for predicting ICU mortality even when measured at time of ICU admission, their use in allocation of limited ICU resources in a developing country merits further research.

Successful management of a case of true radicular dens invaginatus using platelet-rich fibrin and guided tissue regeneration.

A radicular variant of dens invaginatus (DI) is a rare form of dens invaginatus which develops in the root of the tooth after the crown development is completed. This report involves successful management of a case with guided tissue regeneration and describes the cone beam computed tomography (CBCT) characteristics of true radicular DI. A 20-year-old woman reported with recurrent swelling and pus discharge associated with her maxillary left central incisor (#21). Cone beam computed tomography (CBCT) of the region revealed #21 had an invagination in the mesial aspect of the coronal third of the root with a para radicular low-density region perforating both the cortices. A diagnosis of true radicular variant of DI was made by exclusion. The case was managed with Biodentine® , platelet-rich fibrin and freeze-dried demineralised bone graft. A 2-year review showed that the tooth was functional with normal periodontal parameters and normal response to electric pulp sensibility test.

Adult forensic age estimation using mandibular first molar radiographs: A novel technique.

OBJECTIVE: To develop an independent procedure for estimating age for Indian individuals using radiographs of multi-rooted posterior teeth with accuracy needed in forensic age prediction. MATERIALS AND METHODS: Orthopantomography (OPG) was obtained for 88 subjects. The subjects were divided into two sub sets; study subset (n = 60) which were used to find regression formula to calculate the age from pulp chamber height and test subset (n = 28) which were used to test the accuracy of this formula. RESULTS: There was a statistically significant strong correlation between chronological age and pulp chamber crown root trunk height ratio (r = -0.56; P = 0.000). The regression equation for estimating the age, derived from the study subset was estimated age = -100.920 (PCTHR) +55.415. (PCTHR is the pulp chamber crown root trunk height ratio). This equation was applied on the test subset and there was no significant difference between estimated ages and chronological ages (P = 0.639). The mean absolute error (MAE) was 6.96 years, which was within acceptable error limits for forensic age estimation (<±10 years). CONCLUSION: The procedure developed to estimate the age using height reduction in pulp chamber was found to be fairly accurate to perform forensic age prediction in Indian individuals.

Design and development of a heart rate variability analyzer.

Heart rate variability (HRV), analysis gives an insight into the state of the autonomic nervous system which modulates the cardiac activity. Here a digital signal controller based handy device is developed which acquires the beat to beat time interval, processes it using techniques based on non-linear dynamics, fractal time series analysis, and information theory. The technique employed, that can give reliable results by assessing heart beat signals fetched for a duration of a few minutes, is a huge advantage over the already existing methodologies of assessing cardiac health, those being dependant on the tedious task of acquiring Electro Cardio Gram(ECG) signals, which in turn requires the subject to lie down at a stretch for a couple of hours. The sensor used, relies on the technique of Photoplethysmography, rendering the whole approach as noninvasive. The device designed, calculates parameters like, Largest Lyapunov Exponent, Fractal dimension, Correlation Dimension, Approximate Entropy and α-slope of Poincare plots, which based on the range in which they fall, the cardiac health condition of the subject can be assessed to even the extend of predicting upcoming disorders. The design of heart beat sensor, the technique used in the acquisition of heart beat data, the relevant algorithm developed for the analysis purpose, are presented here.

Pharmacy student perceptions of adverse event reporting.

OBJECTIVE: To assess US pharmacy students' knowledge and perceptions of adverse event reporting. METHODS: To gauge pharmacy students' impressions of adverse event reporting, a 10-question survey instrument was administered that addressed student perceptions of the reporting procedures of the Food and Drug Administration (FDA) and pharmaceutical manufacturers, as well as student understanding of the Health Insurance Portability and Accountability Act (HIPAA) and its relationship to adverse event reporting. RESULTS: Two hundred twenty-eight pharmacy students responded to the survey. The majority of respondents believed that the FDA is more likely than a pharmaceutical company to take action regarding an adverse event. There were misconceptions relating to the way adverse event reports are handled and the influence of HIPAA regulations on reporting. CONCLUSIONS: Communication between the FDA and pharmaceutical manufacturers regarding adverse event reports is not well understood by pharmacy students. Education about adverse event reporting should evolve so that by the time pharmacy students become practitioners, they are well acquainted with the relevance and importance of adverse event reporting.

Antimicrobial photodynamic therapy: An overview.

Inflammatory periodontal disease caused by dental plaque is characterized by the clinical signs of inflammation and loss of periodontal tissue support. The mechanical removal of this biofilm and adjunctive use of antibacterial disinfectants and antibiotics have been the conventional methods of periodontal therapy. But the removal of plaque and the reduction in the number of infectious organisms can be impaired in sites with difficult access. The possibility of development of resistance to antibiotics by the target organism has led to the development of a new antimicrobial concept with fewer complications. Photodynamic therapy (PDT) involves the use of low power lasers with appropriate wavelength to kill micro organisms treated with a photosensitizer drug. PDT could be a useful adjunct to mechanical as well as antibiotics in eliminating periopathogenic bacteria.

Estimating historical radiation doses to a cohort of U.S. radiologic technologists.

Data have been collected and physical and statistical models have been constructed to estimate unknown occupational radiation doses among 90,000 members of the U.S. Radiologic Technologists cohort who responded to a baseline questionnaire during the mid-1980s. Since the availability of radiation dose data differed by calendar period, different models were developed and applied for years worked before 1960, 1960- 1976 and 1977-1984. The dose estimation used available film-badge measurements (approximately 350,000) for individual cohort members, information provided by the technologists on their work history and protection practices, and measurement and other data derived from the literature. The dosimetry model estimates annual and cumulative occupational badge doses (personal dose equivalent) for each technologist for each year worked from 1916 through 1984 as well as absorbed doses to organs and tissues including bone marrow, female breast, thyroid, ovary, testes, lung and skin. Assumptions have been made about critical variables including average energy of X rays, use of protective aprons, position of film badges, and minimum detectable doses. Uncertainty of badge and organ doses was characterized for each year of each technologist's working career. Monte Carlo methods were used to generate estimates of cumulative organ doses for preliminary cancer risk analyses. The models and predictions presented here, while continuing to be modified and improved, represent one of the most comprehensive dose reconstructions undertaken to date for a large cohort of medical radiation workers.

Estimating post-marketing exposure to pharmaceutical products using ex-factory distribution data.

The pharmaceutical industry has an obligation to identify adverse reactions to drug products during all phases of drug development, including the post-marketing period. Estimates of population exposure to pharmaceutical products are important to the post-marketing surveillance of drugs, and provide a context for assessing the various risks and benefits, including drug safety, associated with drug treatment. This paper describes a systematic approach to estimating post-marketing drug exposure using ex-factory shipment data to estimate the quantity of medication available, and dosage information (stratified by indication or other factors as appropriate) to convert the quantity of medication to person time of exposure. Unlike the non-standardized methods often used to estimate exposure, this approach provides estimates whose calculations are explicit, documented, and consistent across products and over time. The methods can readily be carried out by an individual or small group specializing in this function, and lend themselves to automation. The present estimation approach is practical and relatively uncomplicated to implement. We believe it is a useful innovation.