Nevin Manimala

J Pharmacol Exp Ther. 2023 Aug 31:JPET-MR-2022-001551. doi: 10.1124/jpet.122.001551. Online ahead of print.

ABSTRACT

As pharmaceutical development moves from early stage in vitro experimentation to later in vivo and subsequent clinical trials, data and knowledge are acquired across multiple time and length scales, from the subcellular to whole patient cohort scale. Realising the potential of this data for informing decision making in pharmaceutical development requires the individual and combined application of machine learning (ML) and mechanistic multiscale mathematical modelling approaches. Here we outline how these two approaches, both individually and in tandem, can be applied at different stages of the drug discovery and development pipeline to inform decision making compound development. The importance of discerning between knowledge and data is highlighted in informing the initial use of ML or mechanistic Quantitative Systems Pharmacology (QSP) models. We discuss the application of sensitivity and structural identifiability analyses of QSP models in informing future experimental studies, to which ML may be applied, as well as how ML approaches can be used to inform mechanistic model development. Relevant literature studies are highlighted and we close by discussing caveats regarding the application of each approach in an age of constant data acquisition. Significance Statement We consider when best to apply Machine Learning (ML) and mechanistic Quantitative Systems Pharmacology (QSP) approaches in the context of the drug discovery and development pipeline. We discuss the importance of prior knowledge and data available for the system of interest and how this informs the individual and combined application of ML and QSP approaches at each stage of the pipeline.

PMID:37652709 | DOI:10.1124/jpet.122.001551

Osong Public Health Res Perspect. 2023 Aug;14(4):321-327. doi: 10.24171/j.phrp.2023.0145. Epub 2023 Aug 21.

ABSTRACT

BACKGROUND: The number of reported cases of Legionnaires’ disease (LD) in the Republic of Korea surged nationally in 2016; however, in 2022, this number was higher in Jeju Province than the previous national peak. A descriptive epidemiological study was conducted to analyze trends in the incidence of reported LD cases in Jeju Island from 2015 to 2022.

METHODS: The data for this study were obtained from case reports submitted to the Korea Disease Control and Prevention Agency through its Disease and Health Integrated Management System. The selection criteria were cases or suspected cases of LD reported among Jeju residents between 2015 and 2022. The 95% confidence interval of the crude incidence rate was calculated using the Poisson distribution.

RESULTS: Since 2020, the incidence rate of LD in Jeju has risen sharply, showing a statistically significant difference from the national incidence rate. A particular medical institution in Jeju reported a significant number of LD cases. Screening with the urine antigen test (UAT) also increased significantly.

CONCLUSION: Our findings indicate that the rapid increase in cases of LD in Jeju Province since 2020 was due to the characteristics of medical-care use among Jeju residents, which were focused on a specific medical institution. According to their clinical practice guidelines, this medical institution conducted UATs to screen patients suspected of pneumonia.

PMID:37652687 | DOI:10.24171/j.phrp.2023.0145

Osong Public Health Res Perspect. 2023 Aug;14(4):312-320. doi: 10.24171/j.phrp.2023.0069. Epub 2023 Aug 21.

ABSTRACT

BACKGROUND: We aimed to describe the epidemiological characteristics of carbapenemase-producing Enterobacteriaceae (CPE) outbreaks in healthcare settings in the Republic of Korea between 2017 and 2022.

METHODS: Under the national notifiable disease surveillance system, we obtained annual descriptive statistics regarding the isolated species, carbapenemase genotype, healthcare facility type, outbreak location and duration, and number of patients affected and recommended interventions. We used epidemiological investigation reports on CPE outbreaks reported to Korea Disease Control and Prevention Agency from June 2017 to September 2022.

RESULTS: Among the 168 reports analyzed, Klebsiella pneumoniae (85.1%) was the most frequently reported species, while K. pneumoniae carbapenemase (KPC, 82.7%) was the most common carbapenemase genotype. Both categories increased from 2017 to 2022 (p<0.01). General hospitals had the highest proportion (54.8%), while tertiary general hospitals demonstrated a decreasing trend (p<0.01). The largest proportion of outbreaks occurred exclusively in intensive care units (ICUs, 44.0%), and the frequency of concurrent outbreaks in ICUs and general wards increased over time (p<0.01). The median outbreak duration rose from 43.5 days before the coronavirus disease 2019 (COVID-19) pandemic (2017-2019) to 79.5 days during the pandemic (2020-2022) (p=0.01), and the median number of patients associated with each outbreak increased from 5.0 to 6.0 (p=0.03). Frequently recommended interventions included employee education (38.1%), and 3 or more measures were proposed for 45.2% of outbreaks.

CONCLUSION: In the Republic of Korea, CPE outbreaks have been consistently dominated by K. pneumoniae and KPC. The size of these outbreaks increased during the COVID-19 pandemic. Our findings highlight the need for continuing efforts to control CPE outbreaks using a multimodal approach, while considering their epidemiology.

PMID:37652686 | DOI:10.24171/j.phrp.2023.0069

Osong Public Health Res Perspect. 2023 Aug;14(4):291-299. doi: 10.24171/j.phrp.2023.0071. Epub 2023 Jul 27.

ABSTRACT

BACKGROUND: This study aimed to examine the prevalence and pattern of adverse events following childhood immunization and the responses of mothers in Ile-Ife, South West Nigeria.

METHODS: This descriptive cross-sectional study was conducted among 422 mothers of children aged 0 to 24 months attending any of the 3 leading immunization clinics in Ile-Ife, Nigeria. The respondents were selected using the multi-stage sampling technique. Data were collected using a pretested structured interviewer-administered questionnaire and analyzed using IBM SPSS ver. 26.0. The chi-square test was used to test associations, while binary logistic regression was used to determine the predictors of mothers’ responses to adverse events following immunization (AEFIs). A p-value of <0.05 was considered statistically significant.

RESULTS: The mean age of the respondents was 29.99±5.74 years. About 38% of the children had experienced an AEFI. Most mothers believed that the pentavalent vaccine was the most common cause of AEFIs (67.5%). Fever (88.0%) and pain and swelling (76.0%) were the most common AEFIs. More than half of the mothers (53.7%) administered home treatment following an AEFI. Younger mothers (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.20-5.01), mothers who delivered their children at a healthcare facility (OR, 3.24; 95% CI, 1.08-9.69), and mothers who were knowledgeable about reporting AEFIs (OR, 2.53; 95% CI, 1.04-7.70) were most likely to respond appropriately to AEFIs.

CONCLUSION: The proportion of mothers who responded poorly to AEFIs experienced by their children was significant. Therefore, strategies should be implemented to improve mothers’ knowledge about AEFIs to improve their responses.

PMID:37652684 | DOI:10.24171/j.phrp.2023.0071

Osong Public Health Res Perspect. 2023 Aug;14(4):252-262. doi: 10.24171/j.phrp.2023.0125. Epub 2023 Jul 27.

ABSTRACT

BACKGROUND: This study aimed to examine the scale, characteristics, risk factors, and modes of transmission in a coronavirus disease 2019 (COVID-19) outbreak at a high school in Seoul, Republic of Korea.

METHODS: An epidemiological survey was conducted of 1,118 confirmed cases and close contacts from a COVID-19 outbreak at an educational facility starting on May 31, 2021. In-depth interviews, online questionnaires, flow evaluations, and CCTV analyses were used to devise infection prevention measures. Behavioral and spatial risk factors were identified, and statistical significance was tested.

RESULTS: Among 3rd-year students, there were 33 confirmed COVID-19 cases (9.6%). Students who used a study room in the annex building showed a statistically significant 4.3-fold elevation in their relative risk for infection compared to those who did not use the study room. Moreover, CCTV facial recognition analysis confirmed that 17.8% of 3rd-year students did not wear masks and had the lowest percentage of mask-wearers by grade. The air epidemiological survey conducted in the study room in the annex, which met the 3 criteria for a closed space, confirmed that there was only 10% natural ventilation due to the poor ventilation system.

CONCLUSION: To prevent and manage the spread of COVID-19 in educational facilities, advance measures that consider the size, operation, and resources of each school are crucial. In addition, various survey methodologies should be used in future studies to quickly analyze a wider range of data that can inform an evidence-based quarantine response.

PMID:37652680 | DOI:10.24171/j.phrp.2023.0125

Gut. 2023 Aug 31:gutjnl-2023-329700. doi: 10.1136/gutjnl-2023-329700. Online ahead of print.

ABSTRACT

BACKGROUND: Endoluminal radiofrequency ablation (RFA) has been promoted as palliative treatment for patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) in order to improve biliary drainage and eventually prolong survival. No high level evidence is, however, available on this technique.

DESIGN: In this randomised controlled study, we compared endoluminal RFA plus stenting with stenting alone (control group) in patients with malignant biliary obstruction; metal stents were primarily placed. Primary outcome was overall survival; secondary outcomes were stent patency, quality of life and adverse events. In a superiority design, survival was assumed to be doubled by RFA as compared with 6.4 months in the control group (n=280).

RESULTS: A total of 161 patients (male:female 90:71, mean age 71±9 years) were randomised before recruitment was terminated for futility after an interim analysis. Eighty-five patients had CCA (73 hilar, 12 distal) and 76 had pancreatic cancer. There was no difference in survival in both subgroups: for patients with CCA, median survival was 10.5 months (95% CI 6.7 to 18.3) in the RFA group vs 10.6 months (95% CI 9.0 to 24.8), p=0.58)) in the control group. In the subgroup with pancreatic cancer, median survival was 6.4 months (95% CI 4.3 to 9.7) for the RFA vs 7.7 months (95% CI 5.6 to 11.3), p=0.73) for the control group. No benefit was seen in the RFA group with regard to stent patency (at 12 months 40% vs 36% in CCA and 66% vs 65% in PDAC), and quality of life was unchanged by either treatment and comparable between the groups. Adverse events occurred in seven patients in each groups.

CONCLUSION: A combination of endoluminal RFA and stenting was not superior to stenting alone in prolonging survival or improving stent patency in patients with malignant biliary obstruction.

TRIAL REGISTRATION NUMBER: NCT03166436.

PMID:37652677 | DOI:10.1136/gutjnl-2023-329700

Neurol Res. 2023 Aug 31:1-8. doi: 10.1080/01616412.2023.2252284. Online ahead of print.

ABSTRACT

BACKGROUND: Malondialdehyde (MDA) is an oxidative stress biomarker, which represents a unifying mechanism of brain injury that occurs throughout the ischemic stroke cascade. The current study aimed to examine whether or not acute ischemic stroke (AIS) patients who had elevated serum MDA levels at admission had an increased risk of mortality and a worse functional outcome three months later.

METHODS: An observational, prospective cohort study that enrolled 90 patients with AIS. The patients were examined in the first 24 hours and then followed up for three months to assess mortality, short-term neurological functional outcome, and neurological disability by the Modified Rankin Scale (MRS).

RESULTS: The mean of serum MDA level among AIS patients was 6.3 ± 3.7 nmol/ml. Non-survivor cases were associated with statistically significantly higher serum MDA levels compared to survivors (9.7 ± 4.3 vs. 5.3 ± 2.8, p < 0.001), respectively. Patients with severe stroke, according to NIHSS score, were associated with significantly (p < 0.05) higher MDA levels compared to moderate and mild cases (7.4 ± 4.3 vs. 5.4 ± 2.6 vs. 3.3 ± .6). At a cutoff point of ≥ 6.7 nmol/ml, the area under the curve (AUC) for serum MDA levels as a predictor of mortality was 0.8 (0.69-0.91; p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value were 77%, 80%, 89.5%, and 48.5%, respectively. Multivariate regression demonstrated that MDA level was a significant independent predictor of mortality among patients with AIS (OR = 1.29, 95% CI: 1.01 to 1.65; p = 0.041).

CONCLUSION: MDA serum level was significantly higher in non-survivors than in survivors patients, so MDA could be used as a predictor for early mortality and short-term outcome of cases with AIS.

PMID:37652662 | DOI:10.1080/01616412.2023.2252284

BMJ Open. 2023 Aug 31;13(8):e066948. doi: 10.1136/bmjopen-2022-066948.

ABSTRACT

INTRODUCTION: Although allogeneic stem cell transplantation (allo-SCT) is a curative treatment for many haematological malignancies, it is often associated with a high morbidity and mortality. Yet, little is known about the needs for supportive and palliative care among allo-SCT recipients. Moreover, targeted interventions that reduce symptom burden and suffering are still lacking. The present study aims to inform a supportive-palliative care intervention for patients with allo-SCT and their informal carers by exploring their experience and assessing their needs, especially their existential concerns, regarding four research topics: symptom burden and quality of life; coexistence of a chance for cure and a relevant risk of dying; change in goals of care; dying phase.

METHODS AND ANALYSIS: This is a descriptive mixed-methods study in progress with a convergent parallel design. Data on the four research topics will be collected and analysed separately in three steps: (1) qualitative semi-structured interviews among 20 patients, 20 informal carers and 12 healthcare providers (HCPs) and focus groups among 12-24 HCPs; (2) a quantitative cross-sectional survey with validated questionnaires and self-developed questions among 100 patients, 100 informal carers and 50 HCPs; (3) a retrospective case analysis of all deceased patients who underwent an allo-SCT between 2010 and 2019, with collection of quantitative and qualitative data. The qualitative and quantitative data sets will be finally merged for comparison and interpretation. Results will serve to develop a supportive-palliative care intervention.

ETHICS AND DISSEMINATION: The Ethics Commission of the Faculty of Medicine of the University of Cologne approved this study (20-1370_2). The study results will be published in peer-review journals, be presented at congresses and will be translated into clinical practice through the development of the palliative-supportive care intervention.

TRIAL REGISTRATION NUMBER: DRKS00027290 (German Clinical Trials Register).

PMID:37652589 | DOI:10.1136/bmjopen-2022-066948

BMJ Open. 2023 Aug 31;13(8):e071785. doi: 10.1136/bmjopen-2023-071785.

ABSTRACT

OBJECTIVE: The COVID-19 pandemic led to an increase in mortality in most countries in 2020, deviating from prior decreasing trends. In Japan, however, mortality was suggested to decrease in 2020. This study investigated long-term mortality trends and cause-specific contributions, focusing on the period of the COVID-19 pandemic in Japan.

DESIGN: We analysed Japanese age-standardised mortality rates (ASMRs) from 1995 to 2021 using vital statistics.

MAIN OUTCOME MEASURES: The cause-specific annual ASMR changes were calculated in comparison with the previous year over the abovementioned period.

RESULTS: There was a general downward trend in overall ASMR for both sexes until 2020 followed by a small increase in 2021. In men, the all-cause ASMR (per 100 000 persons) decreased from 1352.3 to 1328.8 in 2020 (-1.74% from 2019), and increased to 1356.3 in 2021 in men (+2.07% from 2020). In women, the all-cause ASMR decreased from 746.0 to 722.1 in 2020 (-3.20% from 2019), and increased to 737.9 (+2.19% from 2020) in 2021. ASMRs from malignant neoplasms, pneumonia, accidents and suicide (men only) continued to decrease during the COVID-19 pandemic while the trend of cardiovascular mortality increased in 2021. Analysis of ASMR changes revealed that COVID-19, senility, cardiovascular disease and ‘other causes not classified as major causes’ contributed to the all-cause mortality increase in 2021.

CONCLUSIONS: In Japan, the decreasing trend in overall mortality continued in 2020 despite the COVID-19 pandemic. However, approximately 2% mortality increase was observed in 2021, which was attributable to COVID-19, senility, cardiovascular disease and ‘other causes’. The year 2021 was a turning point of mortality trends in Japan, although continued monitoring is warranted.

PMID:37652585 | DOI:10.1136/bmjopen-2023-071785

Reg Anesth Pain Med. 2023 Aug 31:rapm-2023-104630. doi: 10.1136/rapm-2023-104630. Online ahead of print.

ABSTRACT

INTRODUCTION: Cancer-related pain is ubiquitous. Targeted procedural interventions may be an important and underutilized method for improving cancer-related pain and quality of life. The goal of this study was to determine the baseline educational experience and perceived post-graduation comfort of Pain Medicine fellows in performing procedures that can be used for cancer-related pain.

METHODS: Using Qualtrics, a 16-question survey was distributed to graduating fellows at accredited Pain Medicine Fellowship programs in the USA in June 2022. The fellows’ experience and comfort level performing eight procedures was analyzed using summary descriptive statistics and contingency table analysis with statistical significance determined by Pearson’s χ² test.

RESULTS: Survey respondents represented 30% of fellows among 44% of Pain Medicine programs during the 2021-2022 academic year. The majority of respondents reported no experience performing 7 of the 8 procedures for cancer-related pain (56.1%-90.6%). Graduating fellows reported overall comfort performing sympathetic neurolysis (65.7%), spinal cord stimulator trials (85.7%) and implantations (66.0%), but not intrathecal pump trials (36.9%) and implantations (31.3%), peripheral nerve stimulator implantations (41.7%), vertebral augmentations (31.3%), and vertebral body radiofrequency ablations (16.7%).

CONCLUSIONS: Experience performing 10 or more of the surveyed procedures, personal interest in treating cancer-related pain, and attendance of cancer-related pain lectures were found to significantly increase comfortability in performing cancer-related pain procedures post graduation, whereas cadaver-based learning did not. This study highlights the need for more robust procedural education for cancer-related pain and identifies procedural experience in non-cancer patients and lectures on cancer-related pain as ways to bridge this educational gap.

PMID:37652574 | DOI:10.1136/rapm-2023-104630