Monitoring trends in the absolute lymphocyte count and the neutrophil-to-lymphocyte ratio in patients with breast cancer receiving eribulin.

BACKGROUND: Studies have shown that the absolute lymphocyte count (ALC) and the neutrophil-to-lymphocyte ratio (NLR) are related to the outcomes in patients with breast cancer receiving specific chemotherapies. However, the reports have focussed on the initial blood test and there is a lack of evidence or data to support that dynamic changes of ALC or NLR are associated with the patients' survival outcomes. METHODS: We retrospectively reviewed electronic medical records from patients with breast cancer treated with eribulin from 2015 to 2019 at our institution. Blood test data were available prior to starting eribulin (baseline), and at 1, 3 and 6 months after initiating eribulin. We classified the patients into ALC and NLR high and low groups using the following cut-offs: 1000/µl for ALC and 3 for NLR. We defined ALC and NLR trends as increasing or decreasing compared with the initial data. We assessed the associations between the ALC and NLR with progression-free survival and overall survival. RESULTS: There were 136 patients with breast cancer treated with eribulin. Of these patients, 60 had complete blood tests and follow-up data. Neither a high ALC nor a low baseline NLR was associated with the survival outcome. One month after initiating eribulin treatment, a high ALC and a low NLR were significantly associated with longer progression-free survival (p = 0.044 for each). Three months after initiating eribulin, a high ALC was significantly associated with better overall survival (p = 0.006). A high NLR at 3 or 6 months after initiating eribulin was associated with worse overall survival (p = 0.017 and p = 0.001, respectively). The ALC and NLR trends across times were not associated with survivals. CONCLUSION: We showed that 1, 3 and 6 months after initiating eribulin, a high ALC and a low NLR may be related to the patients' survival outcomes. The ALC and NLR trends were not associated with survival. Accordingly, we believe patients who maintain a high ALC and a low NLR may have better clinical outcomes after initiating eribulin.

Inhibition of Autophagy Aggravates Arachis hypogaea L. Skin Extracts-Induced Apoptosis in Cancer Cells.

The skin of Arachis hypogaea L. (peanut or groundnut) is a rich source of polyphenols, which have been shown to exhibit a wider spectrum of noteworthy biological activities, including anticancer effects. However, the anticancer activity of peanut skin extracts against melanoma and colorectal cancer (CRC) cells remains elusive. In this study, we systematically investigated the cytotoxic, antiproliferative, pro-apoptotic, and anti-migration effects of peanut skin ethanolic extract and its fractions on melanoma and CRC cells. Cell viability results showed that the ethyl acetate fraction (AHE) of peanut skin ethanolic crude extract and one of the methanolic fractions (AHE-2) from ethyl acetate extraction exhibited the highest cytotoxicity against melanoma and CRC cells but not in nonmalignant human skin fibroblasts. AHE and AHE-2 effectively modulated the cell cycle-related proteins, including the suppression of cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), phosphorylation of Retinoblastoma (p-Rb), E2F1, Cyclin A, and activation of tumor suppressor p53, which was associated with cell cycle arrest and paralleled their antiproliferative efficacies. AHE and AHE-2 could also induce caspase-dependent apoptosis and inhibit migration activities in melanoma and CRC cells. Moreover, it is noteworthy that autophagy, manifested by microtubule-associated protein light chain 3B (LC3B) conversion and the aggregation of GFP-LC3, was detected after AHE and AHE-2 treatment and provided protective responses in cancer cells. Significantly, inhibition of autophagy enhanced AHE- and AHE-2-induced cytotoxicity and apoptosis. Together, these findings not only elucidate the anticancer potential of peanut skin extracts against melanoma and CRC cells but also provide a new insight into autophagy implicated in peanut skin extracts-induced cancer cell death.

Comparisons of EQ-5D-Y and PedsQL in pediatric patients with mild-to-moderate chronic kidney disease in longitudinal analyses.

OBJECTIVE: To characterize longitudinal changes and correlations between the measures of EQ-5D-Y and generic PedsQL and their associations with clinical changes in children and adolescents with mild-to-moderate chronic kidney disease (CKD). METHODS: Participants were recruited from January 2017 to September 2021 in a medical center in Taiwan. Both instruments were administered in their initial visits and every 6-month subsequent visits. Spearman's Rho (ρ) was used to assess correlations between the scores of EQ-5D-Y and PedsQL measures in longitudinal changes. Cohen's effect size (ES) was used to evaluate the changes of scores/subscales over time. In addition, factors associated with longitudinal changes in the score/subscales were explored. RESULTS: A total of 121 participants were enrolled, and 83 with ≥ 3 HRQOL measures during the 3.5 years follow-up were assessed their changes of HRQOL measures. The correlations (ρ > 0.3) appeared between the changes in the visual analog scale (VAS) of EQ-5D-Y and emotional and social subscales of PedsQL. ES was small (< 0.5) in the VAS and level-sum-score (LSS) of EQ-5D-Y scores for the clinical changes in comorbidities, while some PedsQL subscales were medium to high (0.5-0.8 or > 0.8). Hypertension, mineral bone disorder/anemia, and hyperuricemia associated with the changes in both HRQOL scores were varied by their various domains. CONCLUSION: Both EQ-5D-Y and PedsQL of HRQOL measures were responsive to worsened childhood CKD-related comorbidities during the follow-up; however, convergent validity between them was limited in some domains. The LSS of EQ-5D-Y showed greater changes than the VAS by comorbidity status; further comparison with utility weight is needed to determine the better performance of EQ-5D-Y.

Censoring in the time trade-off valuation of worse-than-dead EQ-5D-5L health states: can a time-based willingness-to-accept question be the solution?

PURPOSE: The left censoring of values at -1 by design of the composite time trade-off (cTTO) tasks leads to excessive amount of -1 values in some EQ-5D-5L valuation studies. This study aimed to investigate whether a time-based willingness-to-accept (tWTA) question can be used to elicit values lower than -1 and improve the estimation of EQ-5D-5L values. METHODS: At the end of each cTTO task in the Taiwanese EQ-5D-5L valuation study, if the value of the health state was indicated to be lower than -1, a tWTA question eliciting the indifference point between a hypothetical life (i.e. x number of years in full health followed by 10 years in the health state) and immediate death was used to estimate its uncensored value. We compared the statistical characteristics of the censored and uncensored data. RESULTS: Four hundred and twenty-nine of 1,000 respondents were offered the tWTA question in a total of 1,071 cTTO tasks. In 79.55% of those tasks, indifference was not reached. Spearman's correlation with level summary score was -0.41 and -0.40 for negative uncensored and censored data, respectively. The logical inconsistency rates of the uncensored and censored data were 0.88% vs. 0.29%, respectively. Modelling of the uncensored data resulted in coefficients with greater uncertainty and much lower predictions. CONCLUSIONS: The elicitation of values lower than -1 using a tWTA question that grants more time for trading seems not a promising solution to the value censoring of the cTTO tasks. Other strategies for valuation of very poor health states should be explored.

Does the Timing of Eribulin Treatment for Advanced or Metastatic Breast Cancer Matter? Evidence from a Real-World Setting.

BACKGROUND: This study aimed to examine the effectiveness and safety of eribulin used as an early-line (EL, i.e., first-/second-line) versus late-line (LL, i.e., third-line and beyond) chemotherapy for recurrent advanced or metastatic breast cancer (A/MBC) patients. METHODS: This study conducted a retrospective observation of A/MBC patients initiating eribulin between January 1, 2015, and June 30, 2019, using medical database at a university-affiliated teaching hospital in Taiwan. Patients were assigned into either the EL or LL group based on the timing of respective eribulin treatments and were observed for at least 6 months up to December 2019 for progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), disease response, and occurrence of adverse events. The Kaplan-Meier and Cox proportional hazard regression survival analyses were performed. RESULTS: Of 127 patients, 23.6% (n = 30) and 76.4% (n = 97) were assigned to the EL and LL groups, respectively, between which no difference in patient characteristics was noted. Median PFS and TTF were 6.5 months and 5.0 months for the EL and 4.2 months and 3.4 months for the LL, respectively. Median OS could not be estimated in the EL group and was 20.5 months in the LL group. Eribulin as an EL treatment was the only factor associated with longer TTF and OS, whereas the number of metastatic sites was additionally associated with PFS in the multivariate analysis. No complete response was reported in either group, but a partial response was obtained in 6.7% in the EL group and 3.1% in the LL group. The common adverse events between two groups were similar, including leukopenia (80.0%), neutropenia (76.7%), and anemia (60.0%). CONCLUSIONS: The eribulin used as an EL of chemotherapy was effective for A/MBC patients with known toxicities in this study, while eribulin as the LL chemotherapy showed consistent results with previous reports.

Do health preferences differ among Asian populations? A comparison of EQ-5D-5L discrete choice experiments data from 11 Asian studies.

INTRODUCTION: Many countries have established their own EQ-5D value sets proceeding on the basis that health preferences differ among countries/populations. So far, published studies focused on comparing value set using TTO data. This study aims to compare the health preferences among 11 Asian populations using the DCE data collected in their EQ-5D-5L valuation studies. METHODS: In the EQ-VT protocol, 196 pairs of EQ-5D-5L health states were valued by a general population sample using DCE method for all studies. DCE data were obtained from the study PI. To understand how the health preferences are different/similar with each other, the following analyses were done: (1) the statistical difference between the coefficients; (2) the relative importance of the five EQ-5D dimensions; (3) the relative importance of the response levels. RESULTS: The number of statistically differed coefficients between two studies ranged from 2 to 16 (mean: 9.3), out of 20 main effects coefficients. For the relative importance, there is not a universal preference pattern that fits all studies, but with some common characteristics, e.g. mobility is considered the most important; the relative importance of levels are approximately 20% for level 2, 30% for level 3, 70% for level 4 for all studies. DISCUSSION: Following a standardized study protocol, there are still considerable differences in the modeling and relative importance results in the EQ-5D-5L DCE data among 11 Asian studies. These findings advocate the use of local value set for calculating health state utility.

Predicting the serum digoxin concentrations of infants in the neonatal intensive care unit through an artificial neural network.

BACKGROUND: Given its narrow therapeutic range, digoxin's pharmacokinetic parameters in infants are difficult to predict due to variation in birth weight and gestational age, especially for critically ill newborns. There is limited evidence to support the safety and dosage requirements of digoxin, let alone to predict its concentrations in infants. This study aimed to compare the concentrations of digoxin predicted by traditional regression modeling and artificial neural network (ANN) modeling for newborn infants given digoxin for clinically significant patent ductus arteriosus (PDA). METHODS: A retrospective chart review was conducted to obtain data on digoxin use for clinically significant PDA in a neonatal intensive care unit. Newborn infants who were given digoxin and had digoxin concentration(s) within the acceptable range were identified as subjects in the training model and validation datasets, accordingly. Their demographics, disease, and medication information, which were potentially associated with heart failure, were used for model training and analysis of digoxin concentration prediction. The models were generated using backward standard multivariable linear regressions (MLRs) and a standard backpropagation algorithm of ANN, respectively. The common goodness-of-fit estimates, receiver operating characteristic curves, and classification of sensitivity and specificity of the toxic concentrations in the validation dataset obtained from MLR or ANN models were compared to identify the final better predictive model. RESULTS: Given the weakness of correlations between actual observed digoxin concentrations and pre-specified variables in newborn infants, the performance of all ANN models was better than that of MLR models for digoxin concentration prediction. In particular, the nine-parameter ANN model has better forecasting accuracy and differentiation ability for toxic concentrations. CONCLUSION: The nine-parameter ANN model is the best alternative than the other models to predict serum digoxin concentrations whenever therapeutic drug monitoring is not available. Further cross-validations using diverse samples from different hospitals for newborn infants are needed.

EQ-5D-Y for the assessment of health-related quality of life among Taiwanese youth with mild-to-moderate chronic kidney disease.

OBJECTIVE: To assess if health-related quality of life (HRQOL) of children with chronic kidney disease (CKD) and different comorbid conditions can be identified based on the EQ-5D child-friendly version (EQ-5D-Y). DESIGN: Prospective cross-sectional study. SETTING: A tertiary care medical center in Taiwan. STUDY PARTICIPANTS: All CKD patients aged 7-18 years treated at the center between May 2014 and December 2016. MAIN OUTCOME MEASURES: HRQOL assessment was done using EQ-5D-Y. Spearman correlation tests were used for construct validity of the traditional Chinese version of EQ-5D-Y. Test-retest reliability was determined through Cohen's kappa values and intraclass correlation coefficients (ICC). Laboratory results and CKD-related morbid conditions were ascertained and assessed their associations with HRQOL score using multivariate linear regression. RESULTS: Of 68 participants, 53 of them completed two HRQOL assessments of HRQOL at least 6-month. Cross-sectional analysis revealed fair to moderate correlations between EQ visual analogue score and patient characteristics. Older children at assessment (P < 0.01), girls (P = 0.03) and presence of mineral bone disorders had a significantly negative impact on HRQOL. Children self-reported EQ-5D-Y dimensions were found to be fairly to highly reliable (kappa = 0.2 to 0.8), except for 'pain/discomfort' and 'anxiety/depression'. CONCLUSIONS: The EQ-5D-Y discriminated among children with different level of CKD-related clinical burden, but the psychometric properties may be limited in some HRQOL dimensions. Further research will need to address factors that may threaten validity and reliability data provided by children and adolescents.

Economic outcomes of pharmacist-physician medication therapy management for polypharmacy elderly: A prospective, randomized, controlled trial.

BACKGROUND/PURPOSE: With an increasing geriatric population, the need for effective management of chronic conditions and medication use in the elderly is growing. Medication use in the elderly presents significant challenges due to changes in pharmacodynamic and pharmacokinetic profiles. We aimed to examine the impact of a collaborative physician-pharmacist medication therapy management (MTM) program for polypharmacy elderly patients. METHODS: Elderly patients with multiple chronic conditions on polypharmacy were enrolled in this prospective, randomized, and controlled study over 16 months of implementation. The intervention group consisted of patients randomized to a collaborative pharmacist-physician MTM program. They were monitored continuously by a clinical pharmacist, while patients in the control group received only usual care with follow-up assessment. Primary outcome was economic differences, measured in total medical expenditure. Secondary outcomes of clinical and humanistic effects were compared between the two groups. RESULTS: The total number of enrolled patients was 87 and 91 in the MTM and usual groups, respectively. The difference-in-difference estimate on medical expenditure during the 16-month implementation period was $3,758,373 New Taiwan Dollars ($127,015 US Dollars) less than the usually care group. Impact was also seen in humanistic outcomes while lipid profiles and mortality trended toward improvement. CONCLUSION: The pharmacist-physician collaborative MTM program for polypharmacy elderly had significant cost savings and improvement in humanistic measures, demonstrating the importance of clinical pharmacists and MTM programs for elderly patients in Taiwan. The results suggest the possibility of clinical benefits, but the study was not substantially powered to find a statistical difference.

Development and validation of a Chinese medication literacy measure.

BACKGROUND: Despite the impact of medication literacy (ML) on patients' safe use of medications, existing instruments are mostly for general health literacy measurement or designed for specific disease populations, with few specifically designed for ML. OBJECTIVE: To develop and validate the first Chinese medication literacy measure (ChMLM). METHODS: The ChMLM was developed by a multidisciplinary and bilingual expert panel and subsequently pilot-tested. The final version had 17 questions in four sections: vocabulary, non-prescription drug, prescription drug and drug advertisement. Face-to-face interviews were administered in a convenience sample of adults with diverse sociodemographic characteristics. Internal consistency was assessed by Cronbach's alpha. Content validity was confirmed by the expert panel, and hypothesis testing was performed to assess construct validity. RESULTS: A total of 634 adults were interviewed. The mean (SD) total ChMLM score was 13.0 (2.8). The internal validity was acceptable (Cronbach's alpha=0.72). Nine of the ten a priori hypotheses were fulfilled. Younger age, higher income and higher education levels were significantly associated with a higher ChMLM score. Furthermore, higher scores on the ChMLM were associated with higher confidence or less difficulty in writing, reading, speaking and listening abilities in a health-care encounter. No association was found between ChMLM total scores and frequency of doctor's visits. CONCLUSION: The ChMLM is a valid and reliable ML measure. It may help pharmacists and other health-care providers to target patients and problem areas that need interventions with the ultimate goal of preventing medication errors and harm.

Severe hypertriglyceridemia secondary to venlafaxine use in an older adult on dialysis -case report.

BACKGROUND: Although the prescribing information for Venlafaxine extended release includes a discussion about possible increases in total cholesterol and triglycerides (TG) seen in healthier adult patients during premarketing clinical trials, no post-marketing studies or case reports, that discuss the effects of venlafaxine on TG in elderly patients with chronic kidney disease. CASE PRESENTATION: We report a 71 year-old male patient with end-stage renal disease on hemodialysis, with a history of coronary artery disease, mild hyperlipidemia, and hypertension. This patient twice demonstrated the severe rises in triglycerides while taking the antidepressant, i.e., venlafaxine, and discontinuing the long-term use of fenofirate. The adverse drug reaction sub-committee at the hospital rated the second event as a "probable reaction" using the Naranjo nomogram, accordingly. CONCLUSIONS: This case demonstrates the risk of changes in lipid profiles while taking venlafaxine and receiving on and off fenofibrate therapy in the older adult patient with chronic kidney disease and under hemodialysis. Regular monitoring for lipid changes after starting venlafaxine is strongly advised for patients with existing risk factors.

Innovative analysis of diazepam, zolpidem and their main metabolites in human urine by micelle-to-solvent stacking in capillary electrophoresis.

Diazepam and zolpidem are the most widely used medications for managing insomnia. However, significant concerns regarding the potential risks of misuse and abuse problems arose in many literatures. While urine analysis is a valuable diagnostic tool, a challenge arises from the fact that some parent drugs may remain undetectable in urine. This necessitates concurrent monitoring of their metabolites. Here, we described an innovative on-line sample preconcentration technique known as micelle to solvent stacking (MSS) for the analysis of diazepam, zolpidem, and their main metabolites in urine. Several key parameters warrant further discussion to optimize the MSS model, enhancing its performance in terms of sensitivity and resolution. After optimizing the conditions, we conducted a validation test, achieving high correlation coefficients (greater than 0.9977) for intra-day and inter-day regression lines. Additionally, both the relative standard deviation (RSD) and relative error (RE) remained below 6.10% and 12.55%, respectively. The limits of detection (LODs, S/N = 3) for all five analytes ranged from 2.0 to 56 ng/mL. Compared to the conventional capillary zone electrophoresis method, this new approach exhibited remarkable sensitivity enhancements, ranging from 123 to 235-fold. Upon applying this method to actual urine samples from patients, we successfully detected nordiazepam, zolpidem, and its metabolites. This simple and sensitive approach has promising applications in supporting patient medication safety and bolstering forensic investigations.

Correction: Valuation of the EQ-5D-5L in Taiwan.

[This corrects the article DOI: 10.1371/journal.pone.0209344.].

Concurrent use of antiplatelets, anticoagulants, or digoxin with Chinese medications: a population-based cohort study.

PURPOSE: We examined the extent of concurrent use of antiplatelets, anticoagulants, or digoxin with Chinese medications (CMs) and identified its associated factors. METHODS: A retrospective cohort study was conducted using one million random samples from the Longitudinal Health Insurance Database 2005 in Taiwan. High-risk Western medications (HRWMs) focused on in this study were antiplatelets (aspirin, clopidogrel, dipyridamole, ticlopidine), anticoagulants (heparin, warfarin), and digoxin. Concurrent use was described as having an overlapping use period of HRWM with CMs any time in 2005. Baseline demographics, comorbidities, and health service utilizations between patients with and without concurrent HRWM-CM use were compared. Logistic regression analyses were performed to identify factors associated with incident concurrent use. RESULTS: Of the 70,698 eligible HRWM users, 13.2 % used CMs concurrently for an average duration of 26.7 ± 43 days. The incidence of concurrent HRWM-CM use, which excluded prior CM use within 6 months preceding the first CM use, was 6.3 %. Warfarin or ticlopidine users were more likely to be prescribed with CMs than were the other HRWM users. Factors associated with an increasing incidence of concurrent HRWM-CM use included female sex, age 45-54 years, middle monthly income, higher number of outpatient visits or distinct prescribed medications, and a previous diagnosis of heart diseases, stroke, or hypertension. In contrast, age ≥ 65 years and higher medical expenditure were associated with a lower incidence of concurrent use. CONCLUSIONS: In the Taiwanese population, approximately one in eight HRWM users were concomitantly prescribed CMs. Whether such concurrent use is associated with adverse clinical outcomes warrants further investigations.

Impacts of medication non-adherence to major modifiable stroke-related diseases on stroke prevention and mortality: a meta-analysis.

BACKGROUND: Medication adherence is one of the crucial attempts in primary stroke prevention. The available evidence lacks comprehensive reviews exploring the association of medication adherence with stroke prevention. OBJECTIVES: To investigate the effects of non-adherence to medications used to treat the modifiable risk of diseases on stroke-associated outcomes in primary stroke prevention. METHODS: Study records were searched from PubMed, Embase, and CINAHL. Those studies reported risks relevant to stroke-associated outcomes and medication non-adherence for patients diagnosed with four modifiable stroke-related diseases (atrial fibrillation [AF], hyperlipidemia, hypertension, and type 2 diabetes mellitus) but without stroke history were included for meta-analysis and further subgroup, sensitivity, and publication bias analyses. A random effect model was performed to analyse the pooled risk estimates of relative risk (RR) and 95% confidence intervals (CIs). RESULTS: Thirty-nine studies (with 2,117,789 participants in total) designed as cohort or case-control studies were included. Those patients presenting with four stroke-related diseases and categorised as medication non-adherent tended to result in stroke and/or associated death (all pooled RR ≥ 1 and 95% CI did not include 1). The findings of stratification and sensitivity analysis for each stroke-related disease showed a similar trend. Non-adherent patients with AF were prone to stroke occurrence (RR 1.852; 95% CI 1.583-2.166) but inclined to reduced bleeding (RR 0.894; 95% CI 0.803-0.996). The existence of publication bias warrants further interpretation. CONCLUSIONS: Non-adherence to medications for the four stroke-related diseases contributes to the development of stroke and/or mortality in primary stroke prevention. More efforts are needed to improve patients' medication adherence.

Beyond 10-year lead-times in EQ-5D-5L: leveraging alternative lead-times in willingness-to-accept questions to capture preferences for worse-than-dead states and their implication.

BACKGROUND: A fixed 10-year lead-time in composite time-trade-off (C-TTO) tasks might compromise the precision of utility values below - 1. This study explored how alternative lead-times (ALTs) influence EQ-5D-5L value sets and their implications in economic evaluations. METHODS: Leveraging data from Taiwan's EQ-5D-5L valuation and capitalizing on its exploratory willingness-to-accept question, we explored participants' quantification of "worse-than-dead (WTD)" health states with ALTs up to 50 years. We then derived alternative value sets incorporating these ALTs through interval regression and compared them against those from conventional models. To evaluate their impact on health change valuation, we simulated utility differences for all possible EQ-5D-5L health-state-pairs using each value set. RESULTS: With a salient floor effect observed in the C-TTO values, the model with ALT led to a wider range of predicted utilities ( - 2.3897 ~ 1), compared with those of conventional models (generalized least squares (GLS): - 0.7773 ~ 1; Tobit-GLS: - 0.9583 ~ 1). Compared to the Tobit-GLS model, the model with ALT increased the numerical distance in 80% of health-state-pairs, with 11% decreasing and 9% altering direction (e.g., positive to negative) in utility differences. CONCLUSIONS: While ALTs offer insights into patient preferences, their integration into economic evaluations might require rescaling. Future research should prioritize advanced rescaling methods or enhanced elicitation strategies for populations with substantial censoring. This is pivotal for improving the elicitation of extreme WTD states and accurately discerning the relative distances between health states. Countries developing EQ-5D-5L value sets should consider pilot studies and incorporating region-specific questions on social determinants, especially where pronounced floor effects are suspected.

Post-discharge use of antipsychotics in patients with hospital-acquired delirium and associated risk of mortality - A population-based nested case-control study.

OBJECTIVE: To evaluate post-discharge use of antipsychotics in patients with incident hospital-acquired delirium and the associated risk of mortality. METHODS: We conducted a nested case-control study for patients newly diagnosed with hospital-acquired delirium and subsequently discharged from hospital using Taiwan's National Health Insurance Database (NHID) from 2011 to 2018. RESULTS: The use of antipsychotics after discharge did not increase the risk of mortality (adjusted OR: 1·03; 95% CI: 0·98-1·09). CONCLUSIONS: The findings suggested that using antipsychotics after discharge in patients with hospital-acquired delirium may not increase the risk of mortality.

A non-invasive mouse model that recapitulates disuse-induced muscle atrophy in immobilized patients.

Disuse muscle atrophy occurs consequent to prolonged limb immobility or bed rest, which represents an unmet medical need. As existing animal models of limb immobilization often cause skin erosion, edema, and other untoward effects, we here report an alternative method via thermoplastic immobilization of hindlimbs in mice. While significant decreases in the weight and fiber size were noted after 7 days of immobilization, no apparent skin erosion or edema was found. To shed light onto the molecular mechanism underlying this muscle wasting, we performed the next-generation sequencing analysis of gastrocnemius muscles from immobilized versus non-mobilized legs. Among a total of 55,487 genes analyzed, 787 genes were differentially expressed (> fourfold; 454 and 333 genes up- and down-regulated, respectively), which included genes associated with muscle tissue development, muscle system process, protein digestion and absorption, and inflammation-related signaling. From a clinical perspective, this model may help understand the molecular/cellular mechanism that drives muscle disuse and identify therapeutic strategies for this debilitating disease.

Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers.

Protein kinase C delta (PKCδ) is prominently expressed in the nuclei of EGFR-mutant lung cancer cells, and its presence correlates with poor survival of the patients undergoing EGFR inhibitor treatment. The inhibition of PKCδ has emerged as a viable approach to overcoming resistance to EGFR inhibitors. However, clinical-grade PKCδ inhibitors are not available, highlighting the urgent needs for the development of effective drugs that target PKCδ. In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. This was achieved by incorporating a triazole ring group into the original sotrastaurin configuration. Our findings revealed that the sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCδ and effectively suppressed nuclear PKCδ in resistant cells in comparison to sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers.

Quality of care in the course of subcutaneous versus intravenous trastuzumab administration in patients with breast cancer: an integrated time-motion study with mixed-methods research.

OBJECTIVES: This study aimed to compare the time required and concerns raised by various perspectives of participants regarding administering subcutaneous and intravenous trastuzumab for patients with breast cancer (BC). DESIGN: This observational time-motion study design with mixed-methods research (cross-sectional surveys and semistructured interviews) was conducted. The time spent on preparing or administering trastuzumab by different healthcare professionals (HCPs) was recorded. The data were analysed by descriptive/inferential statistical analyses, followed by thematic analyses. SETTING: Outpatient and inpatient administration units of a single medical centre in Taiwan. PARTICIPANTS: The study included patients with early-stage BC who received subcutaneous or intravenous trastuzumab (n=93), and HCPs including two attending physicians, a nurse practitioner, two pharmacists and two nurses. RESULT: Based on the perspectives of patients and HCPs, the subcutaneous form of trastuzumab was more efficient, less expensive and produced less discomfort in outpatient units than inpatient units. More participants preferred the subcutaneous form over the intravenous form in both outpatient and inpatient units. Pharmacists and nurse practitioners spent threefold more time on patients when preparing and administering the intravenous form in both outpatient and inpatient units. The concerns raised by patients and HCPs varied in certain aspects, including the injection skills, speed, mental distress (eg, needle phobia) and pain associated with the subcutaneous form. Almost all patients preferred receiving the subcutaneous form in outpatient units after the initial COVID-19 outbreak. CONCLUSION: Patients with early-stage BC preferred receiving subcutaneous trastuzumab in outpatient units rather than inpatient units or the intravenous form before and after the COVID-19 outbreak. Such findings may serve as real-world evidence to facilitate better quality of care regarding administration of subcutaneous or intravenous trastuzumab in medical settings, and its feasible resolutions to balance the quality, concerns and efficiency of anticancer administration during the COVID-19 pandemic.