Category: Nevin Manimala

JCO Precis Oncol. 2023 Feb;7:e2200606. doi: 10.1200/PO.22.00606.

ABSTRACT

PURPOSE: Adaptive clinical trials use algorithms to predict, during the study, patient outcomes and final study results. These predictions trigger interim decisions, such as early discontinuation of the trial, and can change the course of the study. Poor selection of the Prediction Analyses and Interim Decisions (PAID) plan in an adaptive clinical trial can have negative consequences, including the risk of exposing patients to ineffective or toxic treatments.

METHODS: We present an approach that leverages data sets from completed trials to evaluate and compare candidate PAIDs using interpretable validation metrics. The goal is to determine whether and how to incorporate predictions into major interim decisions in a clinical trial. Candidate PAIDs can differ in several aspects, such as the prediction models used, timing of interim analyses, and potential use of external data sets. To illustrate our approach, we considered a randomized clinical trial in glioblastoma. The study design includes interim futility analyses on the basis of the predictive probability that the final analysis, at the completion of the study, will provide significant evidence of treatment effects. We examined various PAIDs with different levels of complexity to investigate if the use of biomarkers, external data, or novel algorithms improved interim decisions in the glioblastoma clinical trial.

RESULTS: Validation analyses on the basis of completed trials and electronic health records support the selection of algorithms, predictive models, and other aspects of PAIDs for use in adaptive clinical trials. By contrast, PAID evaluations on the basis of arbitrarily defined ad hoc simulation scenarios, which are not tailored to previous clinical data and experience, tend to overvalue complex prediction procedures and produce poor estimates of trial operating characteristics such as power and the number of enrolled patients.

CONCLUSION: Validation analyses on the basis of completed trials and real world data support the selection of predictive models, interim analysis rules, and other aspects of PAIDs in future clinical trials.

PMID:36848613 | DOI:10.1200/PO.22.00606

JCO Precis Oncol. 2023 Feb;7:e2200522. doi: 10.1200/PO.22.00522.

ABSTRACT

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have a significant prognostic value in cancers. However, very few automated, deep learning-based TIL scoring algorithms have been developed for colorectal cancer (CRC).

MATERIALS AND METHODS: We developed an automated, multiscale LinkNet workflow for quantifying TILs at the cellular level in CRC tumors using H&E-stained images from the Lizard data set with annotations of lymphocytes. The predictive performance of the automatic TIL scores (${TIL}_s^{Link}$) for disease progression and overall survival (OS) was evaluated using two international data sets, including 554 patients with CRC from The Cancer Genome Atlas (TCGA) and 1,130 patients with CRC from Molecular and Cellular Oncology (MCO).

RESULTS: The LinkNet model provided outstanding precision (0.9508), recall (0.9185), and overall F1 score (0.9347). Clear continuous TIL-hazard relationships were observed between ${TIL}_s^{Link}$ and the risk of disease progression or death in both TCGA and MCO cohorts. Both univariate and multivariate Cox regression analyses for the TCGA data demonstrated that patients with high TIL abundance had a significant (approximately 75%) reduction in risk for disease progression. In both the MCO and TCGA cohorts, the TIL-high group was significantly associated with improved OS in univariate analysis (30% and 54% reduction in risk, respectively). The favorable effects of high TIL levels were consistently observed in different subgroups (classified according to known risk factors).

CONCLUSION: The proposed deep-learning workflow for automatic TIL quantification on the basis of LinkNet can be a useful tool for CRC. ${TIL}_s^{Link}$ is likely an independent risk factor for disease progression and carries predictive information of disease progression beyond the current clinical risk factors and biomarkers. The prognostic significance of ${TIL}_s^{Link}$ for OS is also evident.

PMID:36848612 | DOI:10.1200/PO.22.00522

Proc Natl Acad Sci U S A. 2023 Mar 7;120(10):e2208268120. doi: 10.1073/pnas.2208268120. Epub 2023 Feb 27.

ABSTRACT

Wildlife trafficking, whether local or transnational in scope, undermines sustainable development efforts, degrades cultural resources, endangers species, erodes the local and global economy, and facilitates the spread of zoonotic diseases. Wildlife trafficking networks (WTNs) occupy a unique gray space in supply chains-straddling licit and illicit networks, supporting legitimate and criminal workforces, and often demonstrating high resilience in their sourcing flexibility and adaptability. Authorities in different sectors desire, but frequently lack knowledge about how to allocate resources to disrupt illicit wildlife supply networks and prevent negative collateral impacts. Novel conceptualizations and a deeper scientific understanding of WTN structures are needed to help unravel the dynamics of interaction between disruption and resilience while accommodating socioenvironmental context. We use the case of ploughshare tortoise trafficking to help illustrate the potential of key advancements in interdisciplinary thinking. Insights herein suggest a significant need and opportunity for scientists to generate new science-based recommendations for WTN-related data collection and analysis for supply chain visibility, shifts in illicit supply chain dominance, network resilience, or limits of the supplier base.

PMID:36848572 | DOI:10.1073/pnas.2208268120

Proc Natl Acad Sci U S A. 2023 Mar 7;120(10):e2220080120. doi: 10.1073/pnas.2220080120. Epub 2023 Feb 27.

ABSTRACT

Here, we combine international air travel passenger data with a standard epidemiological model of the initial 3 mo of the COVID-19 pandemic (January through March 2020; toward the end of which the entire world locked down). Using the information available during this initial phase of the pandemic, our model accurately describes the main features of the actual global development of the pandemic demonstrated by the high degree of coherence between the model and global data. The validated model allows for an exploration of alternative policy efficacies (reducing air travel and/or introducing different degrees of compulsory immigration quarantine upon arrival to a country) in delaying the global spread of SARS-CoV-2 and thus is suggestive of similar efficacy in anticipating the spread of future global disease outbreaks. We show that a lesson from the recent pandemic is that reducing air travel globally is more effective in reducing the global spread than adopting immigration quarantine. Reducing air travel out of a source country has the most important effect regarding the spreading of the disease to the rest of the world. Based upon our results, we propose a digital twin as a further developed tool to inform future pandemic decision-making to inform measures intended to control the spread of disease agents of potential future pandemics. We discuss the design criteria for such a digital twin model as well as the feasibility of obtaining access to the necessary online data on international air travel.

PMID:36848570 | DOI:10.1073/pnas.2220080120

Horm Mol Biol Clin Investig. 2023 Feb 28. doi: 10.1515/hmbci-2022-0045. Online ahead of print.

ABSTRACT

OBJECTIVES: MicroRNA expression disruptions play an important function in the expansion of gastric cancer. Previous investigation has indicated that miR-372-5p doing as an oncogene in several malignancies. CDX1 and CDX2, as target genes of miR-372-5p, play the role of tumor suppressors and oncogenes in gastric cancer cells, respectively. The current investigation explored the effects of miR-372-5p regulation on CDX2 and CDX1 in AGS cell lines and studied their molecular mechanism.

METHODS: hsa-miR-372-5p miRCURY LNA miRNA Inhibitors and Mimic were transfected into AGS cell line. The cell viability and cell cycle calculation were defined by MTT assay and flow cytometry, respectively. The Expression levels of miR-372-5p, CDX1, CDX2 and transfection efficiency were measured using Real-time PCR. Statistical investigation p values <0.05 were considered to be meaningful.

RESULTS: miR-372-5p particularly was upregulated in control cells and also after transfection by mimic. While its expression was reduced by the inhibitor. Upregulation of miR-372-5p remarkably increased cell growth and led to accumulation in the G2/M phase, although the inhibitor decreased cell growth and accumulation in the S phase. Accordingly, upregulation of miR-372-5p increased CDX2 and decreased CDX1 expression. By inhibition of miR-372-5p, expression of CDX2 was decreased and expression of CDX1 was increased.

CONCLUSIONS: Up and down-regulation of miR-372-5P has a potential effect on the expression levels of its target genes, CDX1 and CDX22. Accordingly, the downregulation of miR-372-5p may be assumed as a possible therapeutic target in treating gastric cancer.

PMID:36848481 | DOI:10.1515/hmbci-2022-0045

PLoS One. 2023 Feb 27;18(2):e0282282. doi: 10.1371/journal.pone.0282282. eCollection 2023.

ABSTRACT

INTRODUCTION: In the earlier phase of the pandemic situation, the Government of Bangladesh (GoB) badly suffered to adhere their people to preventive measures probably due to less knowledge and attitude toward Covid-19. To tackle the second wave of coronavirus, the GoB has again enforced an array of preventive measures, but still encountering the same problem after a year of the pandemic situation. As an attempt to find out the reasons behind this, our study aimed to assess the present knowledge and fear level regarding Covid-19, and attitude and practice of students toward Covid-19 preventive measures (CPM).

METHODS: A cross-sectional study was designed and conducted from 15th to 25th April 2021. A total of 382 participants met all the inclusion criteria and were considered for performing all the statistical analyses (Descriptive statistics, Mann-Whitney U test, Kruskal-Wallis H test, Multiple logistic regression, Spearman rank-order correlation).

RESULTS: All the participants were students aged 16 to 30 years. 84.8%, and 22.3% of participants had respectively more accurate knowledge, and moderate to high fear level regarding Covid-19. And, 66%, and 55% of participants had more positive attitude, and more frequent practice toward CPM, respectively. Knowledge, attitude, practice, and fear were interrelated directly or indirectly. It was found knowledgeable participants were more likely to have more positive attitude (AOR = 2.34, 95% CI = 1.23-4.47, P < 0.01) and very little fear (AOR = 2.17, 95% CI = 1.10-4.26, P < 0.05). More positive attitude was found as a good predictor of more frequent practice (AOR = 4.00, 95% CI = 2.44-6.56, P < 0.001), and very less fear had negative impact on both attitude (AOR = 0.44, 95% CI = 0.23-0.84, P < 0.01) and practice (AOR = 0.47, 95% CI = 0.26-0.84, P < 0.01).

CONCLUSIONS: The findings reflect that students had appreciable knowledge and very little fear, but disappointedly had average attitude and practice toward Covid-19 prevention. In addition, students lacked confidence that Bangladesh would win the battle against Covid-19. Thus, based on our study findings we recommend that policymakers should be more focused to scale up students’ confidence and attitude toward CPM by developing and implementing well-conceived plan of actions besides insisting them to practice CPM.

PMID:36848394 | DOI:10.1371/journal.pone.0282282

PLoS One. 2023 Feb 27;18(2):e0281670. doi: 10.1371/journal.pone.0281670. eCollection 2023.

ABSTRACT

The macro policy of the stock market is an important market information. The implementation goal of the macro policy of the stock market is mainly to improve the effectiveness of the stock market. However, whether this effectiveness has achieved the goal is worth verifying through empirical data. The exertion of this information utility is closely related to the effectiveness of the stock market. Use the run test method in statistics to collect and sort out the daily data of stock price index in recent 30 years, the linkage between 75 macro policy events and 35 trading days of market efficiencies before and after the macro event are tested since 1992 to 2022. The results show that 50.66% of the macro policies are positively linked to the effectiveness of the stock market, while 49.34% of the macro policies have reduced the effectiveness of the market operation. This shows that the effectiveness of China’s stock market is not high, and the nonlinear characteristics are obvious, so the policy formulation of the stock market needs further improvement.

PMID:36848368 | DOI:10.1371/journal.pone.0281670

PLoS One. 2023 Feb 27;18(2):e0282245. doi: 10.1371/journal.pone.0282245. eCollection 2023.

ABSTRACT

Klebsiella pneumoniae is a major zoonotic pathogen that causes a variety of severe illnesses as well as mastitis. The distribution of mastitis-causing K. Pneumoniae and its virulence factors vary by country and geographical location. The present study aimed to find out the occurrence of Multidrug-resistant (MDR) K. Pneumoniae and their capsular resistance genes which were undocumented previously in cow farms of district Peshawar, Pakistan. A total of 700 milk samples from symptomatic mastitic cows were screened for MDR K. Pneumoniae. Furthermore, the characterization of capsular resistance genes was done by molecular techniques. Among these samples, K. pneumoniae was found 180/700 (25.7%), while MDR K. pneumoniae was found 80/180 (44.4%). The antibiogram analysis revealed high resistance to Vancomycin (95%) while highly sensitive to Ceftazidime (80%). The distribution of capsular genes shows the most common serotype K2 gene 39/80 (48.7%), followed by serotype K1 gene 34/80 (42.5%), serotype K5 17/80 (21.2%), and serotype K54 13/80 (16.2), respectively. Moreover, the co-occurrence of serotypes K1+K2 was found at 11.25%, KI+K5 was 05%, K1+K54 was 3.75%, and K2+K5 was 7.5%, respectively. A statistically significant association (p ≤ 0.05) was found between predicted and discovered K. pneumoniae values. In conclusion, the presence of MDR K. pneumoniae in combination with capsular genes may be a possible threat to dairy farm animals and humans in Peshawar, Pakistan. It may give us special attention to follow up on hygienic practices in livestock management.

PMID:36848367 | DOI:10.1371/journal.pone.0282245

PLoS One. 2023 Feb 27;18(2):e0279765. doi: 10.1371/journal.pone.0279765. eCollection 2023.

ABSTRACT

BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for mortality from COVID-19. Remdesivir has been shown to shorten time to recovery in patients with severe COVID-19. However, exclusion of patients with severe kidney function impairment in clinical trials has led to concerns about kidney safety of remdesivir in patients with pre-existing kidney disease.

METHODS: Retrospective propensity score matched cohort study of hospitalized patients with COVID-19 admitted with estimated glomerular filtration rate (eGFR) between 15 – 60 mL/min/1.73m2. Remdesivir-treated patients were 1:1 matched to historical comparators admitted during the first wave of COVID-19 (between March-April 2020) prior to emergency use authorization of remdesivir using propensity scores accounting for factors predicting treatment assignment. Dependent outcomes included in-hospital peak creatinine, incidence of doubling of creatine, rate of kidney replacement therapy initiation and eGFR among surviving patients at day 90.

RESULTS: 175 remdesivir-treated patients were 1:1 matched to untreated historical comparators. Mean age was 74.1 (SD 12.8), 56.9% were male, 59% patients were white, and the majority (83.1%) had at least one co-morbidity. There were no statistically significant differences in peak creatinine during hospitalization (2.3mg/dL vs. 2.5 mg/dL, P = 0.34), incidence of doubling of creatinine (10.3% vs. 13.1%, P = 0.48), and rate of kidney replacement therapy initiation (4.6% vs. 6.3%, P = 0.49) in remdesivir-treated patients versus matched untreated historical comparators, respectively. Among surviving patients, there was no difference of the average eGFR at day 90 (54.7 ± 20.0 mL/min/1.73m2 for remdesivir-treated patients vs. 51.7 ± 19.5 mL/min/1.73m2 for untreated comparators, P = 0.41).

CONCLUSIONS: Remdesivir use in patients with impaired kidney function (eGFR between 15 – 60 mL/min/1.73m2) who present to the hospital with COVID-19 is not associated with increased risk of adverse kidney outcomes.

PMID:36848366 | DOI:10.1371/journal.pone.0279765

PLoS Med. 2023 Feb 27;20(2):e1004180. doi: 10.1371/journal.pmed.1004180. eCollection 2023 Feb.

ABSTRACT

BACKGROUND: Cash transfer programmes are increasingly used in humanitarian contexts to help address people’s needs across multiple sectors. However, their impact on the key objectives of reducing malnutrition and excess mortality remains unclear. mHealth interventions show great promise in many areas of public health, but evidence for their impact on reducing the risk factors for malnutrition is uncertain. We therefore implemented a trial to determine the impacts of 2 interventions in a protracted humanitarian context, a cash transfer conditionality and mHealth audio messages.

METHODS AND FINDINGS: A 2 × 2 factorial cluster-randomised trial was implemented in camps for internally displaced people (IDP) near Mogadishu, Somalia, starting in January 2019. The main study outcomes were assessed at midline and endline and included coverage of measles vaccination and the pentavalent immunisation series, timely vaccination, caregiver’s health knowledge, and child diet diversity. Twenty-three clusters (camps) were randomised to receive or not receive conditional cash transfers (CCTs) and an mHealth intervention, and 1,430 households were followed up over 9 months. All camps received cash transfers made at emergency humanitarian level (US$70/household/month) for 3 months followed by a further 6 months at a safety net level (US$35). To be eligible to receive cash, households in camps receiving CCT were required to take their children <5 years age to attend a single health screening at a local clinic and were issued with a home-based child health record card. Participants in camps receiving the mHealth intervention were asked (but not required) to listen to a series of audio messages about health and nutrition that were broadcast to their mobile phone twice a week for 9 months. Participants and investigators were not blinded. Adherence to both interventions was monitored monthly and found to be high (>85%). We conducted intention-to-treat analysis. During the humanitarian intervention phase, the CCT improved coverage of measles vaccination (MCV1) from 39.2% to 77.5% (aOR 11.7, 95% CI [5.2, 26.1]; p < 0.001) and completion of the pentavalent series from 44.2% to 77.5% (aOR 8.9, 95% CI [2.6, 29.8]; p = < 0.001). By the end of the safety net phase, coverage remained elevated from baseline at 82.2% and 86.8%, respectively (aOR 28.2, 95% CI [13.9, 57.0]; p < 0.001 and aOR 33.8, 95% CI [11.0, 103.4]; p < 0.001). However, adherence to timely vaccination did not improve. There was no change in the incidence of mortality, acute malnutrition, diarrhoea, or measles infection over the 9 months of follow-up. Although there was no evidence that mHealth increased Mother’s knowledge score (aOR 1.32, 95% CI [0.25, 7.11]; p = 0.746) household dietary diversity increased from a mean of 7.0 to 9.4 (aOR 3.75, 95% CI [2.04, 6.88]; p < 0.001). However, this was not reflected by a significant increase in child diet diversity score, which changed from 3.19 to 3.63 (aOR 2.1, 95% CI [1.0, 4.6]; p = 0.05). The intervention did not improve measles vaccination, pentavalent series completion, or timely vaccination, and there was no change in the incidence of acute malnutrition, diarrhoea, measles infection, exclusive breastfeeding, or child mortality. No significant interactions between the interventions were found. Study limitations included the limited time available to develop and test the mHealth audio messages and the necessity to conduct multiple statistical tests due to the complexity of the study design.

CONCLUSIONS: A carefully designed conditionality can help achieve important public health benefits in humanitarian cash transfer programmes by substantially increasing the uptake of child vaccination services and, potentially, other life-saving interventions. While mHealth audio messages increased household diet diversity, they failed to achieve any reductions in child morbidity, malnutrition, or mortality.

TRIAL REGISTRATION: ISRCTN ISRCTN24757827. Registered November 5, 2018.

PMID:36848361 | DOI:10.1371/journal.pmed.1004180