Characterization of rare cell phenotypes in peripheral blood and their utilisation as a surrogate tissue in pharmacodynamic biomarker assays

PhD ThesisRare peripheral blood cells are defined as white blood cells (WBC) at a population frequency of less than 1 in 1,000. Because blood is a relatively non-invasive and accessible sample, it has the potential to be exploited as a surrogate tissue for biomarker development. This PhD project therefore focused on the development and validation of pharmacodynamic biomarkers in rare WBCs using flow cytometry techniques. These biomarkers were developed and utilised for use in three clinical studies, the LY3143921 phase I trial, the SIOP Ependymoma II trial and the PROSPECT-NE observational study. An assay focusing on phosphorylated MCM2 (pMCM2) and ki-67 staining of peripheral blood cells was developed for an early phase clinical trial of LY3143921, a novel CDC7 inhibitor. These proteins were tested in vitro, ex vivo and in vivo. The results indicated a significant association between the number of ki-67 positive cells as a percentage of pMCM2 positive WBCs and drug exposure. Furthermore, an appropriate method was successfully developed to preserve pMCM2 and ki-67 signal in samples being transported from national clinical centres, to facilitate its incorporation in the clinical trial. An assay for the detection of acetylated histone H4 (acH4) was developed for patients receiving valproic acid, a HDAC inhibitor, as a part of the SIOP Ependymoma II trial. The applicability of the assay was tested in vitro, ex vivo and in patient samples. AcH4 signal was associated with drug exposure in vitro and ex vivo but was not associated with dose or concentration of valproic acid WBCs in patient samples. This finding was potentially related to the relatively low plasma drug concentrations observed at the dose levels studied. Additional patients with higher drug exposures need to be recruited to future studies to further investigate this issue. The protein of interest for the PROSPECT-NE observational study was ki-67, which was detected using the same assay as developed for the LY3143921 trial. This study focussed on the prognostic utility of ki-67, rather than its potential predictive or mechanistic properties. The results suggested significant differences in overall survival between patients with high and low ki-67 positive WBCs. There was no association observed between ki-67 positive WBCs and plasma ki-67 in this study. In conclusion, pMCM2 positivity in ki-67 positive cells was identified as a potentially useful pharmacodynamic biomarker, with applicability to an ongoing clinical trial. For acH4 positive cells, their utility as a pharmacodynamic biomarker remains questionable and requires further investigation. Lastly, a high proportion of ki-67 positive WBCs was found to be associated with decreased overall survival in people with cancer recruited to a Phase I clinical trial. These findings highlight the potential utility of peripheral rare WBCs as pharmacodynamic and prognostic biomarkers for clinical studies in an oncology setting

Anxiety and its risk factors among non-Japanese residents living in Japan undergoing COVID-19 situation: A cross-sectional survey

Introduction In the context of collective efforts taken in Japan to control the spread of COVID-19, the state of emergency and social distancing have caused a negative impact on the mental health of all residents, including foreign communities in Japan. This study aimed to evaluate the level of anxiety and its associated factors among non-Japanese residents residing in Japan during the COVID-19 pandemic. Methods A web-based survey in 13 languages was conducted among non-Japanese residents living in Japan during the COVID-19 situation. The State-Trait Anxiety Inventory assessed the level of anxiety–State (STAI-S) scores prorated from its six-item version. The multivariable logistic regression using the Akaike Information Criterion (AIC) method was performed to identify the associated factors of anxiety among participants. Results From January to March 2021, we collected 392 responses. A total of 357 valid responses were analyzed. 54.6% of participants suffered from clinically significant anxiety (CSA). In multivariable logistic model analysis, the CSA status or the high level of anxiety was associated with three factors, including having troubles/difficulties in learning or working, decreased sleep duration, and decreased overall physical health (p<0.05). Conclusion Our study suggests several possible risk factors of anxiety among non-Japanese residents living in Japan undergoing the COVID-19 pandemic, including the troubles or difficulties in learning or working, the decrease in sleep duration, and the decrease in overall physical health.Revisión por pare

Clinical Efficacy and Nephrotoxicity of the Loading Dose Colistin for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients

Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most common causes of nosocomial infections in critically ill patients. Colistin methanesulfonate (CMS), an inactive prodrug, has been considered as a last-resort treatment for CRAB infection in critically ill patients. The objective of this study was to assess 30-day survival and nephrotoxicity in critically ill patients who received non-loading dose (LD) versus LD of CMS for CRAB infection treatment. Between 2012 and 2017, this retrospective cohort analysis was performed at Chiang Mai University Hospital (CMUH), focusing on critically ill patients with CRAB infection who received either non-LD or LD of CMS. A total of 383 patients met the criteria for inclusion. At the 30th day of treatment, the survival rate of patients in the LD CMS group was 1.70 times (adjusted HR) of those in the non-LD group (95% CI = 1.17&ndash;2.50, p = 0.006). Clinical response was significantly higher in the LD CMS group than non-LD CMS group (aHR, 1.35, 95% CI, 1.01&ndash;1.82, p = 0.046). In addition, a microbiological response&mdash;eradication of pre-treatment isolated pathogens in post-treatment cultures&mdash;in patients with LD CMS was 1.57 times that of patients with non-LD CMS (95% CI, 1.15&ndash;2.15, p = 0.004). Additionally, there was a significant difference in nephrotoxicity between LD CMS and non-LD CMS (aHR, 1.57, 95% CI, 1.14&ndash;2.17, p = 0.006). Based on these results, LD CMS should be used to increase the opportunity of patients to achieve favourable outcomes. However, LD CMS was found associated with an increase in nephrotoxicity, so renal function should be closely monitored when LD colistin was administered

Efficacy of loading dose colistin versus carbapenems for treatment of extended spectrum beta lactamase producing Enterobacteriaceae

Abstract Colistin provides in vitro activity against numerous ESBL-producing and carbapenem-resistant bacteria. However, clinical information with respect to its utilization in infection caused by ESBL producers is limited. The aim of this study was a comparison of mortality rates of loading dose (LD) colistin and carbapenems as definitive therapies in a cohort of patients with infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae. A retrospective cohort study in 396 patients with ESBL-producing E.coli and K.pneumoniae infection at a university-affiliated hospital was conducted between 1 January 2005 and 30 June 2015 to compare outcomes of infected patients who received LD colistin (95 patients) with carbapenems (301 patients). The three primary outcomes were 30-day mortality, clinical response and microbiological response. The most common infection types were urinary tract infection (49.49%), followed by pneumonia (40.66%), bacteremia (13.64%), skin and soft tissue infections (4.80%) and intra-abdominal infection (3.03%). LD colistin group provided higher 30-day mortality when compared with carbapenems group (HR 7.97; 95% CI 3.68 to 17.25; P = 0.001). LD colistin was also independently associated with clinical failure (HR 4.30; 95% CI 1.93 to 9.57; P = 0.001) and bacteriological failure (HR 9.49; 95% CI 3.76 to 23.96; P = 0.001) when compared with those who received carbapenems. LD colistin treatment was associated with poorer outcomes, i.e. mortality rate, clinical response and microbiological response. Moreover, when adjusted confounding factors, LD colistin was still less effective than carbapenems. It should be noted that, however, the use of Vitek-2 to assess colistin susceptibility could provide inaccurate results. Also, the difference in baseline characteristics could still remain in retrospective study although compensation by hazard ratio adjustment was performed. Therefore, clinical utilization of LD colistin should be recommended as an alternative for treatment ESBL-producing Enterobacteriaceae only in the circumstances where carbapenems cannot be utilized, but this recommendation must be considered carefully

Comparative Safety and Effectiveness of Heterologous CoronaVac–ChAdOx1 versus Homologous CoronaVac Vaccination in a Real-World Setting: A Retrospective Cohort Study

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has outpaced vaccine availability and delivery from vaccine manufacturers, and thus, a scarcity of vaccines happened to many countries around the world. In Thailand, the mixing of different types of vaccines was approved and clinically implemented partially due to concerns about the availability and efficacy of one vaccine. Objective: This study aimed to investigate the effectiveness and safety of heterologous CoronaVac–ChAdOx1 nCoV-19 vaccines compared with the usual regimen of homologous CoronaVac–CoronaVac. A retrospective cohort study was conducted by dividing patients into the CoronaVac–CoronaVac group and the CoronaVac–ChAdOx1 group. Results: A total of 875 patients received vaccinations at Srisangwan Hospital between April to October 2021 and were included for analysis. The patients in both homologous and heterologous groups had low rates of COVID-19 infection. In addition, the hospitalization rates in the 40 days after the second vaccination were low in both regimens. Minimal adverse events (AE) were reported in both groups, including local AE (e.g., discomfort at the injection site, rash, soreness, swelling, and redness) and systemic AE (e.g., fever, headache, weariness, nausea, vomiting, diarrhoea, and myalgia). Moreover, several factors were associated with lower adverse events following immunization (AEFIs), including age ≥ 50 years, male, and body weight ≥ 50 kg. In contrast, thyroid disease, diabetes mellitus, allergic rhinitis, and psychiatric disorders were independent risk factors associated with an increase in AEFIs. Conclusions: The heterologous CoronaVac–ChAdOx1 and homologous CoronaVac–CoronaVac regimens were promising vaccination strategies for the prevention of SARS-CoV-2 infection. However, the heterologous CoronaVac–ChAdOx1 potentially caused fewer AEFIs compared with the homologous CoronaVac–CoronaVac regimen

The Incidence and Risk Factors of Urinary Tract Infection in Patients with Type 2 Diabetes Mellitus Using SGLT2 Inhibitors: A Real-World Observational Study

Background: The incidence and risk of urinary tract infection (UTI) in patients with type 2 diabetes mellitus (T2DM) who use sodium glucose co-transporter-2 (SGLT2) inhibitors are still controversial. Therefore, this study aimed to investigate the incidence and risk factors of using SGLT2 inhibitors, particularly in Thai patients. Methods: Electronic medication records of all patients, who started the treatment of T2DM between 1 January 2019 and 30 June 2021 at a tertiary hospital in Thailand, were reviewed. The patients were divided into SGLT2 inhibitor and non-SGLT2 inhibitor groups to compare the incidence of UTI. Results: The overall incidence rate of UTI was 33.49% in the SGLT2 inhibitor group and 11.72% in the non-SGLT2 inhibitor group. The incidence rates of UTI were not different between dapagliflozin and empagliflozin treatment (34.00% and 33.03%, respectively). Patients treated with SGLT2 inhibitors had a 3.70 higher risk of UTI compared with those treated with non-SGLT2 inhibitors (95%CI 2.60&ndash;5.29). Moreover, the significant risk factors for UTI found in this study were gender, age, and occupation. Conclusions: This study highlighted the high incidence of UTI in patients using dapagliflozin and empagliflozin compared with non-SGLT2 inhibitors. Additionally, patients of female gender and older age had a significantly higher risk of UTI when treated with SGLT2 inhibitors, whereas those with permanent jobs had a lower risk

Effective formative assessment for pharmacy students in Thailand: lesson learns from a school of pharmacy in Thailand

Abstract Introduction : Formative assessment (FA) is an assessment concept that is of interest in education. The Doctor of Pharmacy program is one of the programs in which FA is usually implemented. This study aimed to describe the correlation between FA scores and summative assessment (SA) scores and to suggest possible key success factors that affect the effectiveness of FA. Methods This study employed a retrospective design using mixed methods for data collection. Data in the semesters 1/2020 and 2/2020 of the Doctor of Pharmacy curriculum in a Thailand pharmacy school were used. Three sets of data were gathered, including the course information (e.g. FA methods, FA scores, and SA scores) from 38 records, self-reports from 326 students and 27 teachers, and 5 focus group discussions. The quantitative data were statistically analyzed using descriptive statistics and Pearson correlation, while the qualitative data were analyzed using a content analysis framework. Results The analysis revealed five main methods that were used for FA, including individual quizzes, individual reports, individual skill assessments, group presentations, and group reports. Of all 38 courses, 29 (76.32%) had significant correlations between FA and SA scores at p-values < 0.05. The individual FA score was related to the correlation coefficient of the courses (p-value = 0.007), but the group FA score was not related (p-value = 0.081). In addition, only the frequency of individual quiz had a significant effect on the correlation coefficient. Moreover, the key success factors which affected the effectiveness of FA were divided into six themes, including the appropriate method, an effective reflection, frequency of assessment, the appropriate score, the adequate support system, and teacher knowledge management. Conclusion The subjects that used individual FA methods provided a significant correlation between FA and SA, while those who used group FA methods did not show a significant correlation. Additionally, the key success factors in this study were appropriate assessment methods, frequency of assessment, effective feedback, appropriate scoring, and a proper support system

Prevalence and associated factors of anemia among breast cancer patients undergoing chemotherapy:A prospective study

PURPOSE: The purpose of this study was to ascertain the prevalence and factors associated with anemia (hemoglobin [Hb] 12 g/dL) in breast cancer patients undergoing chemotherapy. MATERIALS AND METHODS: We conducted a prospective longitudinal study to collect demographic and clinical data on adult breast cancer patients with or without anemia who were admitted to HKL, UMMC, and NCI. The incidence of anemia was determined by detecting whether or not anemia developed during the course of chemotherapy. Mild, moderate, or severe anemia was defined. A chi-squared and logistic regression model were used to assess the effect of demographic and clinical factors on the incidence of anemia and multiple logistic regression analysis was used to evaluate the associations of potential risk factors with the presence of CRA. RESULTS: The study enrolled a total of 292 breast cancer patients. Anemia occurred at a rate of 41.1% (n = 120). Our findings indicated that clinical factors such as the number of chemotherapy regimens, dose reduction, and type of chemotherapy, for example, docetaxel, as well as demographic covariates such as age and BMI, all contribute to the incidence of anemia in cancer patients. CONCLUSIONS: According to this study, the prevalence of anemia in breast cancer patients is high. Patients' age, BMI, number of chemotherapy regimens, and docetaxel were risk factors; thus, protocols are needed to identify subgroups of breast cancer likely to benefit from novel management strategies

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IntroductionIn the context of collective efforts taken in Japan to control the spread of COVID-19, the state of emergency and social distancing have caused a negative impact on the mental health of all residents, including foreign communities in Japan. This study aimed to evaluate the level of anxiety and its associated factors among non-Japanese residents residing in Japan during the COVID-19 pandemic.MethodsA web-based survey in 13 languages was conducted among non-Japanese residents living in Japan during the COVID-19 situation. The State-Trait Anxiety Inventory assessed the level of anxiety–State (STAI-S) scores prorated from its six-item version. The multivariable logistic regression using the Akaike Information Criterion (AIC) method was performed to identify the associated factors of anxiety among participants.ResultsFrom January to March 2021, we collected 392 responses. A total of 357 valid responses were analyzed. 54.6% of participants suffered from clinically significant anxiety (CSA). In multivariable logistic model analysis, the CSA status or the high level of anxiety was associated with three factors, including having troubles/difficulties in learning or working, decreased sleep duration, and decreased overall physical health (pConclusionOur study suggests several possible risk factors of anxiety among non-Japanese residents living in Japan undergoing the COVID-19 pandemic, including the troubles or difficulties in learning or working, the decrease in sleep duration, and the decrease in overall physical health.</div

Multivariable logistic model analysis for the CSA status.

Multivariable logistic model analysis for the CSA status.</p