Factors Associated With Quality-of-Dying-and-Death Classes Among Critically Ill Patients.

Importance: Improving end-of-life care in the intensive care unit (ICU) is a priority, but clinically modifiable factors of quality of dying and death (QODD) are seldom identified. Objectives: To comprehensively identify factors associated with QODD classes of dying ICU patients, emphasizing clinically modifiable factors based on the integrative framework of factors associated with for bereavement outcomes. Design, Setting, and Participants: This observational cohort study was conducted at medical ICUs of 2 Taiwanese medical centers from January 2018 to March 2020 with follow-up through December 2022. Eligible participants included primary family surrogates responsible for decision making for critically ill ICU patients at high risk of death (Acute Physiology and Chronic Health Evaluation II score >20) but who survived more than 3 days after ICU admission. Data analysis was conducted from July to September 2023. Main Outcomes and Measures: QODD was measured by the 23-item ICU-QODD questionnaire. Factors associated with patient membership in 4 previously determined QODD classes (high, moderate, poor to uncertain, and worst) were examined using a 3-step approach for latent class modeling with the high QODD class as the reference category. Results: A total of 309 family surrogates (mean [SD] age, 49.83 [12.55] years; 184 women [59.5%] and 125 men [40.5%]) were included in the study. Of all surrogates, 91 (29.4%) were the patients' spouse and 66 (53.7%) were the patients' adult child. Patient demographics were not associated with QODD class. Two family demographics (age and gender), relationship with the patient (spousal or adult-child), and length of ICU stay were associated with QODD classes. Patients of surrogates perceiving greater social support were less likely to be in the poor to uncertain (adjusted odds ratio [aOR], 0.89; 95% CI, 0.83-0.94) and worst (aOR, 0.92; 95% CI, 0.87-0.96) QODD classes. Family meetings were associated with the poor to uncertain QODD class (aOR, 8.61; 95% CI, 2.49-29.74) and worst QODD class (aOR, 7.28; 95% CI, 1.37-38.71). Death with cardiopulmonary resuscitation was associated with the worst QODD class (aOR, 7.51; 95% CI, 1.12-50.25). Family presence at patient death was uniformly negatively associated with the moderate QODD class (aOR, 0.16; 95% CI, 0.05-0.54), poor to uncertain QODD class (aOR, 0.21; 95% CI, 0.05-0.82), and worst QODD class (aOR, 0.08; 95% CI, 0.02-0.38). Higher family satisfaction with ICU care was negatively associated with the poor to uncertain QODD class (aOR, 0.93; 95% CI, 0.87-0.98) and worst QODD class (aOR, 0.86; 95% CI, 0.81-0.92). Conclusions and Relevance: In this cohort study of critically ill patients and their family surrogates, modifiable end-of-life ICU-care characteristics played a more significant role in associations with patient QODD class than did immutable family demographics, preexisting family health conditions, patient demographics, and patient clinical characteristics, thereby illuminating actionable opportunities to improve end-of-life ICU care.

Conditional score approaches to errors-in-variables competing risks data in discrete time.

Analysis of competing risks data has been an important topic in survival analysis due to the need to account for the dependence among the competing events. Also, event times are often recorded on discrete time scales, rendering the models tailored for discrete-time nature useful in the practice of survival analysis. In this work, we focus on regression analysis with discrete-time competing risks data, and consider the errors-in-variables issue where the covariates are prone to measurement errors. Viewing the true covariate value as a parameter, we develop the conditional score methods for various discrete-time competing risks models, including the cause-specific and subdistribution hazards models that have been popular in competing risks data analysis. The proposed estimators can be implemented by efficient computation algorithms, and the associated large sample theories can be simply obtained. Simulation results show satisfactory finite sample performances, and the application with the competing risks data from the scleroderma lung study reveals the utility of the proposed methods.

The distinct and potentially conflicting effects of tDCS and tRNS on brain connectivity, cortical inhibition, and visuospatial memory.

Noninvasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS), are emerging as promising tools for enhancing cognitive functions by modulating brain activity and enhancing cognitive functions. Despite their potential, the specific and combined effects of tDCS and tRNS on brain functions, especially regarding functional connectivity, cortical inhibition, and memory performance, are not well-understood. This study aims to explore the distinct and combined impacts of tDCS and tRNS on these neural and cognitive parameters. Using a within-subject design, ten participants underwent four stimulation conditions: sham, tDCS, tRNS, and combined tDCS + tRNS. We assessed the impact on resting-state functional connectivity, cortical inhibition via Cortical Silent Period (CSP), and visuospatial memory performance using the Corsi Block-tapping Test (CBT). Our results indicate that while tDCS appears to induce brain lateralization, tRNS has more generalized and dispersive effects. Interestingly, the combined application of tDCS and tRNS did not amplify these effects but rather suggested a non-synergistic interaction, possibly due to divergent mechanistic pathways, as observed across fMRI, CSP, and CBT measures. These findings illuminate the complex interplay between tDCS and tRNS, highlighting their non-additive effects when used concurrently and underscoring the necessity for further research to optimize their application for cognitive enhancement.

A Four-Gene Panel in Rectal Swab Samples as a Biomarker for Colorectal Cancer Screening.

BACKGROUND: The dysregulation of gene expression is one of the key molecular features of colorectal cancer (CRC) development. This study aimed to investigate whether such dysregulation is reflected in rectal swab specimens of CRC patients and to evaluate its potential as a non-invasive approach for screening. METHODS: We compared the expression level of 14 CRC-associated genes in tumor and adjacent non-tumor tissue of CRC patients and examined the correlation of their levels in tissue with paired rectal swab specimens. The level of these 14 genes in rectal swab specimens was compared among patients with CRC or polyp and control subjects, and the diagnostic potential of each dysregulated gene and the gene panel were evaluated. RESULTS: The expression of CXCR2, SAA, COX1, PPARδ, PPARγ, Groγ, IL8, p21, c-myc, CD44 and CSF1 was significantly higher in CRC, and there was a significant correlation in the levels of most of them between the CRC and rectal swab specimens. In the training study, we showed that CD44, IL8, CXCR2 and c-myc levels were significantly higher in the rectal swab specimens of the CRC patients. Such result was confirmed in the validation study. A panel of these four genes was developed, and ROC analysis showed that this four-gene panel could identify CRC patients with an AUC value of 0.83 and identify overall polyp and precancerous adenoma patients with AUC values of 0.6522 and 0.7322, respectively. Finally, the predictive study showed that the four-gene panel demonstrated sensitivities of 63.6%, 76.9% and 88.9% in identifying overall polyp, precancerous adenoma and CRC patients, respectively, whereas the specificity for normal subjects was 72.2%. CONCLUSION: The expression of CRC-associated genes in rectal swab specimens reflects the dysregulation status in colorectal tissue, and the four-gene panel is a potential non-invasive biomarker for early precancerous adenoma and CRC screening.

Evaluating the cancer aging and research group model in predicting immunochemotherapy toxicity among elderly patients with diffuse large B-cell lymphoma.

BACKGROUND: The management of diffuse large B-cell lymphoma (DLBCL) in elderly patients is complicated by an increased risk of treatment-related toxicity associated with aging. This study aimed to validate the effectiveness of the Cancer Aging and Research Group (CARG) model in elderly patients with DLBCL receiving rituximab-based chemotherapy. METHODS: In this prospective study, elderly DLBCL patients (aged 65 years or older) receiving rituximab-based chemotherapy were consecutively assessed between August 2016 and December 2021 at one medical center in Taiwan using the CARG model to predict treatment-related toxicity. Patients were categorized into low-, medium-, and high-risk groups based on their CARG scores. Comparisons were made regarding toxicities and survival rates among these groups. RESULTS: Ninety-one patients, with a median age of 70 years (range 65-96), were included. A substantial 81 % (74 patients) experienced grade 3-5 toxicity. The overall 2-year survival rate was 63.8 % after a median follow-up of 28 months (range, 2-46). The risk of grade 3-5 toxicity was 83 %, 78 %, and 87 %, respectively, among the low-, medium-, and high-risk groups (p = 0.60). The receiver operating characteristic (ROC) curve for CARG was 0.521 (95 % CI, 0.376-0.666), which was significantly lower than that for the Eastern Cancer Oncology Group score (ROC = 0.701, 95 % CI, 0.571-0.831). Similarly, compared with those of low-risk patients, hazard ratios for overall survival were 9.22 (95 % CI, 1.23-69.1; p = 0.031) and 14.6 (95 % CI, 1.90-112; p = 0.010) for medium- and high-risk patients, respectively. CONCLUSION: While CARG exhibited limitations in predicting treatment-related toxicity in elderly DLBCL patients, it demonstrated potential efficacy in predicting survival outcomes.

Paclitaxel-Ifosfamide-based Therapy as Salvage Treatment in Platinum-resistant Recurrent/Metastatic Head and Neck Cancer.

BACKGROUND: Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy. PATIENTS AND METHODS: In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival. RESULTS: The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%). CONCLUSION: The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group.

Identification of novel genetic susceptibility loci for calcium-containing kidney stone disease by genome-wide association study and polygenic risk score in a Taiwanese population.

Approximately 80% of kidney stone diseases contain calcium. Inherited genetic factors are among the variables that influence the development of calcium-containing kidney stone diseases (CKSD). Previous genome-wide association studies (GWAS) on stone diseases have been reported worldwide; however, these are not focused on calcium-containing stones. We conducted a GWAS to identify germline genetic polymorphisms associated with CKSD in a Medical Center in Taiwan; hence, this study was based primarily on a hospital-based database. CKSD was diagnosed using the chart records. Patients infected with urea-splitting-microorganisms and those with at least two urinary pH value below 5.5 were excluded. None of the patients had cystic stones based on stone analysis. Those over 40 years of age with no history of CKSD and no microscopic hematuria on urinalysis were considered as controls. The DNA isolated from the blood of 14,934 patients (63.7% male and 36.3% female) with CKSD and 29,868 controls (10,830 men and 19,038 women) at a medical center was genotyped for approximately 714,457 single nucleotide polymorphisms (SNPs) with minor allele frequency of ≥ 0.05. We used PLINK 1.9 to calculate the polygenic risk score (PRS) to investigate the association between CKSD and controls. The accuracy of the PRS was verified by dividing it into the training and testing groups. The statistical analyses were calculated with the area under the curve (AUC) using IBM SPSS version 22. We identified 432 susceptibility loci that reached a genome-wide threshold of P < 1.0 × 10- 5. A total of 132 SNPs reached a threshold of P < 5 × 10- 8 using a stricter definition of significance on chromosomes 4, 13, 16, 17, and 18. At the top locus of our study, SNPs in DGKH, PDILT, BCAS3, and ABCG2 have been previously reported. RN7SKP27, HDAC4, PCDH15, AP003068.2, and NFATC1 were novel findings in this study. PRS was adjusted for sex and age, resulting in an AUC of 0.65. The number of patients in the top quartile of PRS was 1.39 folds in the risk of CKSD than patients in the bottom quartile. Our data identified the significance of GWAS for patients with CKSD in a hospital-based study. The PRS also had a high AUC for discriminating patients with CKSD from controls. A total of 132 SNP loci of SNPs significantly associated with the development of CKSD. This first survey, which focused on patients with CKSD, will provide novel insights specific to CKSD and its potential clinical biomarkers.

Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants.

COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2, 6, 9, and 15, with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 µM to 0.84 µM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 µM, surpassing nirmatrelvir (IC50: 1.17-152.9 µM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 µM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 µM) and Mpro_Q189I (EC50: 13.2 µM) compared to wild-type SRIPs (EC50: 0.06 µM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants.

Diagnostic accuracy and clinical impact of renal biopsy cytology.

BACKGROUND: The role of fine needle biopsy cytology in the workup of renal mass lesions remains controversial. With advances in imaging technology and clinical management for renal masses, a critical reevaluation of the role of renal biopsy is needed. This study was designed to provide a comprehensive evaluation of the performance and clinical impact of fine needle biopsy in patients with renal masses. METHODS: A 5-year retrospective study of ultrasound or computer tomography (CT)-guided fine needle biopsies of renal masses diagnosed via cytopathology was conducted. Overall diagnostic rate, sensitivity, and diagnostic accuracy were calculated. Further analysis of the impact of fine needle biopsy cytology on clinical management was performed. RESULTS: A total of 227 cases of fine-needle aspiration and/or biopsy (FNA/B) of renal masses were identified, including 76 with subsequent nephrectomies. Complications were rare (<1%). The diagnostic rate and sensitivity of FNA/B were 83.3% and 89.5%, respectively. Diagnostic accuracy was 98.7% at the major categorical level and 94.7% at the tumor subtype level. Subsequent clinical actions were associated with a definitive cytologic diagnosis of malignancy/neoplasia (p < .05) and were affected by tumor subtype (p < .05). CONCLUSION: This study demonstrates that FNA/B of renal masses is a safe and reliable minimally invasive diagnostic tool with excellent accuracy in confirmation of malignancy and subclassification of tumors. Diagnoses made on FNA/B play a key role in guiding a personalized clinical treatment plan.

Impaired lung function and lung cancer risk in 461 183 healthy individuals: a cohort study.

BACKGROUND: It has been known that smoking and various lung diseases including lung cancer can cause lung function impairment. However, the impact of different types of lung function impairments, such as preserved ratio impaired spirometry (PRISm) and airflow obstruction (AO), on the incidence and mortality of lung cancer in both general and never-smoker populations remains unclear. We wished to examine the effect of lung function impairments on lung cancer risks. METHODS: This was a retrospective cohort study (1 January 1994 to 31 December 2017) of individuals from a health surveillance programme in Taiwan who underwent baseline spirometry tests at the entry point. PRISm was defined as an FEV1/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio >0.7 and FEV1 <0.8, while AO was defined as an FEV1/FVC ratio <0.7. Cox proportional hazards models and cubic spline curves were used to examine the associations between lung function impairments and lung cancer risks. RESULTS: The study included 461,183 individuals, of whom 14.3% had PRISm and 7.9% had AO. A total of 4038 cases of lung cancer and 3314 lung cancer-related deaths were identified during the 23 years of follow-up. Individuals with PRISm and AO exhibited a higher risk of lung cancer incidence and mortality compared with those with normal lung function. The adjusted HRs and 95% CIs were 1.14 (1.03 to 1.26) and 1.23 (1.10 to 1.37) in the overall cohort, and 1.08 (0.93 to 1.24), and 1.23 (1.05 to 1.45) in the never-smoker cohort. The risks of both developing and dying of lung cancer increased with the severity levels of lung function impairments and lower FEV1 values. CONCLUSION: Impaired lung function is associated with increased risks of developing lung cancer and subsequent mortality. The study highlights the importance of considering lung function in lung cancer screening for better candidate selection.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Arabidopsis Fhit-like tumor suppressor resumes early terminated constitutive triple response1-10 mRNA translation.

The Arabidopsis (Arabidopsis thaliana) constitutive triple response1-10 (ctr1-10) mutant produces a reduced level of CTR1 protein and exhibits a weak ctr1 mutant phenotype. Sequence analysis revealed highly active translation of the upstream open reading frame (uORF) at the extended 5'-UTR of the ctr1-10 mRNA, resulting from T-DNA insertion. Enhancer screening for ctr1-10 isolated the fragile histidine triad-1 (fhit-1) mutation. The fhit-1 ctr1-10 mutant phenotypically resembled strong ctr1 mutants and barely produced CTR1, and the fhit-1 mutation reduced the translation efficiency of ctr1-10 but not that of CTR1 mRNA. The human (Homo sapiens) Fhit that involves tumorigenesis and genome instability has the in vitro dinucleotide 5',5'″-P1, P3-triphosphate hydrolase activity, and expression of the human HsFHIT or the hydrolase-defective HsFHITH96N transgene reversed the fhit-1 ctr1-10 mutant phenotype and restored CTR1 levels. Genetic editing that in situ disrupts individual upstream ATG codons proximal to the ctr1-10 mORF elevated CTR1 levels in ctr1-10 plants independent of FHIT. EUKARYOTIC INITIATION FACTOR3G (eIF3G), which is involved in translation and reinitiation, interacted with FHIT, and both were associated with the polysome. We propose that FHIT resumes early terminated ctr1-10 mORF translation in the face of active and complex uORF translation. Our study unveils a niche that may lead to investigations on the molecular mechanism of Fhit-like proteins in translation reinitiation. The biological significance of FHIT-regulated translation is discussed.

Improving small-scale fishermen's subjective well-being in Indonesia: Does the internet use play a role?

The expansion of Internet access from urban to rural and coastal areas has changed all aspects of life, including lifestyles and work practices. Although several studies have shown that Internet use is essential in the fisheries sector, more information about the link between Internet usage and subjective well-being among small-scale fishermen is needed. This study is the first attempt to investigate the effect of Internet use on subjective well-being, particularly for small-scale fishers. This study used cross-sectional data from 220 respondents in East Java, Indonesia. Two-stage predictor substitution (2SPS) approaches were used to address the endogeneity issue in the estimation. The results revealed that fishing tools, access to credit, and region positively and significantly influenced small-scale fishers' determination to use the Internet. Savings and off-farm employment significantly and negatively affect adoption decisions. The main findings suggest that Internet use significantly increases small-scale fishermen's subjective well-being (proxied by happiness and life satisfaction). This suggests that improving the Internet infrastructure in coastal areas is needed to support economic activities in the fisheries sector and boost the well-being of small-scale fishers.

Exploring the impact of culture techniques and patient demographics on the success rate of primary culture of human periodontal ligament stem cells.

Background/purpose: Periodontal ligament stem cells (PDLSCs) have the potential for regenerating periodontal tissue. The study aims to investigate the impact of demographics (ages, gender, disease) and culture techniques (shipping storage time and culture method) on the success of primary culture. Materials and methods: PDLSCs were collected from 51 teeth of 26 patients and cultured via outgrowth (OG) and enzymatic digestion (ED) methods. Cells characteristics were confirmed by flow cytometry, MTT, and ARS. The primary culture success rate was evaluated with a serial chi-square test to determine the relationship with culture technique (ED/OG and ≤4 h/prolonged culture) and patient demographics (Young/Old, Female/Male, and Health/Periodontitis). Results: The overall success rate of Health group (69.7%) was higher than Periodontitis (38.9%). Culturing within 4 h possessed a higher success rate (71.8%) than prolonged group (16.7%) regardless of patient demographics, and using OG method (81.5%) revealed more promising. Subgroup analysis of 39 cases (culture within 4 h) found that the success rate of OG was higher than ED in the Old group (87.5%-25.0%) and in the Periodontitis group (83.3%-25.0%). Conclusion: Primary culturing of PDLSCs within 4 h and using the outgrowth method led to higher success rates regardless of patient demographics. It can achieve successful PDLSCs culture of older patients or patients with periodontal disease by appropriate culture technique.

Quantifying payloads of antibody‒drug conjugates using a postcolumn infused-internal standard strategy with LC‒MS.

BACKGROUND: Antibody‒drug conjugates (ADCs) are innovative biopharmaceutics consisting of a monoclonal antibody, linkers, and cytotoxic payloads. Monitoring circulating payload concentrations has the potential to identify ADC toxicity; however, accurate quantification faces challenges, including low plasma concentrations, severe matrix effects, and the absence of stable isotope-labeled internal standards (SIL-IS) for payloads and their derivatives. Previous studies used structural analogs as internal standards, but different retention times between structural analogs and target analytes may hinder effective matrix correction. Therefore, a more flexible approach is required for precise payload quantification. RESULTS: We developed an LC‒MS/MS method incorporating a postcolumn-infused internal standard (PCI-IS) strategy for quantifying payloads and their derivatives of trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan, including DM1, MCC-DM1, DXd, SN-38, and SN-38G. Structural analogs (maytansine, Lys-MCC-DM1, and exatecan) were selected as PCI-IS candidates, and their accuracy performance was evaluated based on the percentage of samples within 80%-120% quantification accuracy. Compared to the approach without PCI-IS correction, exatecan enhanced the accuracy performance from 30-40%-100% for SN-38 and DXd, while maytansine and Lys-MCC-DM1 showed comparable accuracy for DM1 and MCC-DM1. This validated PCI-IS analytical method showed superior normalization of matrix effect in all analytes compared to the conventional internal standard approach. The clinical application of this approach showed pronounced differences in DXd and SN-38 concentrations before and after PCI-IS correction. Moreover, only DXd concentrations after PCI-IS correction were significantly higher in patients with thrombocytopenia (p = 0.037). SIGNIFICANCE: This approach effectively addressed the issue of unavailability of SIL-IS for novel ADC payloads and provided more accurate quantification, potentially yielding more robust statistical outcomes for understanding the exposure-toxicity relationship in ADCs. It is anticipated that this PCI-IS strategy may be extrapolated to quantify payloads and derivatives in diverse ADCs, thereby providing invaluable insights into drug toxicity and fortifying patient safety in ADC usage.

Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions.

BACKGROUND: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.

Hemophagocytic syndrome in A patient of upper urinary tract urothelial cancer after Bacillus Calmette-Guérin instillation: A case report.

Bacillus Calmette-Guérin (BCG) therapy is an adjuvant treatment for urothelial carcinomas of the upper urinary tract (UTUC). BCG therapy can result in various side effects. We present a case of a 67-year-old female with a history of UTUC who developed disseminated tuberculosis following BCG instillation into the upper urinary tract after conservative management. This complex clinical scenario required a multidisciplinary approach, including antibiotic therapy, immunoglobulin infusion, and tailored tuberculosis treatment. The case underscores the importance of vigilance, early detection, and tailored interventions in managing disseminated tuberculosis arising from BCG therapy and rare complications like hemophagocytic syndrome.

Hippocampal subfields in remitted schizophrenia.

BACKGROUND: Current evidence of volume changes in hippocampal subdivisions in schizophrenia remains inconsistent, and few studies have investigated the relationship between regional hippocampal volumes and symptom remission. METHODS: In this cross-sectional study, we recruited 31 patients with schizophrenia and 31 healthy controls (HCs). Symptomatic remission in schizophrenia was determined according to Remission in Schizophrenia Working Group criteria. The volumes of hippocampal longitudinal subregions and transverse subfields were measured using manual and automatic techniques, respectively. Between-group regional hippocampal volume differences were analyzed using multivariate analysis of covariance followed by univariate analysis of covariance. RESULTS: Compared with the HCs, the patients with schizophrenia had smaller bilateral heads and tails along the longitudinal axis; they also had reduced volumes of the bilateral CA1, CA3, CA4, GC-ML-DG, molecular layer, tail, left subiculum, left HATA, and right parasubiculum along the transverse axis in the hippocampus (all corrected p < 0.05). Furthermore, compared with the HCs and patients with remitted schizophrenia, the patients with nonremitted schizophrenia had smaller bilateral hippocampal tail subfields (corrected p < 0.05). CONCLUSION: Our results indicated that the pathophysiology and symptomatic remission of schizophrenia are related to changes in the volumes of hippocampal subdivisions. These volume changes might be clinically relevant as biomarkers for schizophrenia identification and treatment.

Serum Cytokines Correlate with Pretreatment Body Mass Index-adjusted Body Weight Loss Grading and Cancer Progression in Patients with Stage III Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemoradiotherapy Followed by Surgery.

Serum Cytokines Correlate with Pretreatment Body Mass Index-Adjusted Body Weight Loss Grading and Cancer Progression in Patients with Stage III Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemoradiotherapy Followed by Surgery. Circulating cytokines have been linked to the development of esophageal squamous cell carcinoma (ESCC) and its associated malnutrition process. Nonetheless, given the varied disease stages and treatment modalities in previous studies, the clinical relevance of their findings is limited. We retrospectively studied 52 patients with stage III ESCC who underwent neoadjuvant chemoradiotherapy and curative-intent surgery. We investigated the association of clinicopathological features, pretreatment laboratory data, and pretreatment inflammatory status, as indicated by the levels of albumin, C-reactive protein, and 10 circulating cytokines, namely tumor necrosis factor-alpha (TNF-α), interferon-gamma, interleukin-1-beta (IL-1ß), IL-4, IL-6, IL-8, IL-12, IL-13, IL-17A, and IL-23, with malnutrition, as shown by body mass index-adjusted body weight loss (BMI-BWL) grading, cancer progression. Half the patients showed severe malnutrition and high BMI-BWL grades (3 and 4). Multivariate analysis revealed an independent association between the levels of three cytokines (TNF-α, ≤ 5.8 pg/ml; IL-1ß, > 0.4 pg/ml; IL-6, ≤ 12.4 pg/ml) and high BMI-BWL grades and between IL-4 levels > 22.5 pg/ml and cancer progression. All 10 cytokines were closely correlated with each other. In conclusion, TNF-α, IL-1ß, and IL-6 were independent markers of malnutrition status and IL-4 was a prognostic factor for cancer progression in this patient population.