Clinical impact of concomitant BIO-three use in advanced or recurrent non-small cell lung cancer treated with immune-checkpoint inhibitor.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been approved as first-line therapy for advanced non-small cell lung cancer (NSCLC). The probiotic MIYAIRI 588 can potentially improve the outcomes of patients with advanced NSCLC treated with ICI. However, the impact of other probiotics on ICI-treatment efficacy remains unclear. Thus, we aimed to clarify the association between BIO-three use and treatment outcomes in patients with advanced NSCLC treated with ICI. METHODS: This retrospective study included patients aged ≥ 18 years with advanced or recurrent NSCLC who had received ICI monotherapy or ICI plus chemotherapy. Concomitant therapy with probiotic bacteria was defined as receiving it within 180 days before ICI therapy. RESULTS: Here, 289 patients were enrolled, including 23 (8.0%) receiving BIO-three. In the multivariable analysis, the progression-free survival (PFS) and overall survival (OS) of patients receiving BIO-three tended to be longer than those of patients not receiving probiotic therapy (PFS, hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.43-1.30; p = 0.33; OS, HR 0.69; 95% CI 0.37-1.28; p = 0.24). After propensity score matching with weighted adjustment, patients receiving BIO-three tended to have prolonged PFS (median PFS [range] 7.6 months [2.6-17.4] vs 3.2 months [1.6-7.0]; HR 0.53; 95% CI 0.25-1.12; p = 0.09) and OS (median OS [range] 25.6 months [10.8-not reached] vs 10.9 months [7.3-not reached]; HR 0.57; 95% CI 0.24-1.36; p = 0.20) than those not receiving probiotic therapy. CONCLUSION: This study suggests the prognostic impact of concomitant BIO-three use in patients with advanced NSCLC on ICI treatment.

[Exploring the reality of seafarers' deaths and injuries and preventive measures from the cases of overwork-related disorders].

OBJECTIVES: Till date, only few studies have detailed the reality of overwork-related disorders among seafarers. Therefore, in this study, we aimed to evaluate the prevalence of overwork-related disorders among seafarers and assess factors such as patient attributes, diseases diagnosed at the time of determination, workload factors, and other aspects, thereby suggesting relevant preventative measures. METHODS: Among all the patients identified with overwork-related disorders from April 2010 to March 2017, 2,280 cases of cerebrovascular and cardiovascular diseases and 3,517 cases of mental disorders were selected. To identify seafarer-related cases, keywords related to seafarers were extracted. Subsequently, 33 cases of cardiovascular disease and 19 cases of mental disorders were obtained. RESULTS: The average age of the patients with cerebrovascular and cardiovascular diseases was 56.7 years; for those with mental disorders, it was 45.2 years. The patients were most commonly engaged in fishing, transportation, and postal services. Most patients were employed in the deck department or were captains. The most common types of vessels were fishing and cargo ships. Among the diseases diagnosed at the time of determination, cerebrovascular diseases accounted for 20 cases (60.6%) and cardiovascular diseases accounted for 13 cases (39.4%), with cerebral and myocardial infarctions being the most frequent conditions. Among mental disorders, "mood disorders" accounted for 7 cases (36.8%), and "neurotic disorders, stress-related disorders, and somatoform disorders" accounted for 12 cases (63.2%), with major depressive episodes, post-traumatic stress disorder, and adjustment disorders being the most common. The most common workload factor for patients with cerebrovascular and cardiovascular diseases was "long-term excessive work," and among non-workload factors, "long working hours" and "irregular working hours" were prevalent. For mental disorders, 8 cases were attributed to "extreme psychological stress." Specific events leading to these diseases included "interpersonal relationships," "experiencing accidents or disasters," and "work quantity and quality." CONCLUSIONS: Both cerebrovascular and cardiovascular diseases, as well as mental disorders, showed a notable aging trend among seafarers. Thus, measures that consider the characteristics of elderly workers, such as their physical function, are important. Additionally, as seafarers are distributed across various industries and occupations, measures should be specifically tailored to their industry and job type. Our study confirmed that long working hours and irregular working hours were prevalent in both cases. Therefore, there is an urgent need for further efforts to prevent and mitigate overwork-related deaths among seafarers, including organizational support from onshore workplaces and enhancement of medical and operational support using information and communication technology.

Advanced Techniques for MR Neuroimaging.

This special issue of Magnetic Resonance in Medical Sciences is dedicated to "Advanced Techniques for MR Neuroimaging," featuring nine review articles authored by leading experts. The reviews cover advancements in reproducible research practices, diffusion tensor imaging along the perivascular space, myelin imaging using magnetic susceptibility source separation, spinal cord quantitative MRI analysis, tractometry of visual white matter pathways, deep learning-based image enhancement, arterial spin labeling, the potential of radiomics, and MRI-based quantification of brain oxygen metabolism. These articles provide a comprehensive update on cutting-edge technologies and their applications in clinical and research settings, highlighting their impact on improving diagnostic accuracy and understanding of neurological disorders.

Early-pregnancy N-terminal pro-brain natriuretic peptide level is inversely associated with hypertensive disorders of pregnancy diagnosed after 35 weeks of gestation.

Hypertensive disorders of pregnancy (HDP) are among the major causes of high maternal and fetal/neonatal morbidity and mortality rates. Patients with HDP have significantly elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at diagnosis; however, the NT-proBNP levels during early pregnancy are largely unknown. This study aimed to validate the association between HDP and NT-proBNP levels. This retrospective study evaluated 103 pregnant women who developed HDP diagnosed after 35 weeks of gestation and 667 who did not. The HDP group had significantly lower early-pregnancy NT-proBNP levels than the without HDP group. However, the two groups did not significantly differ in terms of the late-pregnancy NT-proBNP levels. After adjusting for confounding factors such as age, body mass index, parity, and blood pressure levels, high early-pregnancy NT-proBNP levels were associated with a lower HDP risk. Early-pregnancy NT-proBNP levels ≥ 60.5 pg/mL had a negative predictive value of 97.0% for ruling out HDP, with a sensitivity of 87.4% and specificity of 62.5%. In conclusion, elevated early-pregnancy NT-proBNP levels were associated with a lower HDP risk. Moreover, a cutoff point of ≥ 60.5 pg/mL for early-pregnancy NT-proBNP levels had a high negative predictive value and sensitivity for ruling out HDP. These findings can provide new clinical implications.

The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Fabrication of Cu2Sn1-xGexS3 Thin-Film Solar Cells via Sulfurization of Cu2GeS3/Cu2SnS3 Stacked Precursors.

Cu2Sn1-xGexS3 (CTGS) is a compound composed of relatively abundant elements in the crust of the earth. The band gap of CTGS can be tuned by substituting elements at the Sn and Ge sites, making it an attractive material for low-environmental-impact solar cells. In this study, CTGS thin films were fabricated with a controlled [Ge]/([Ge] + [Sn]) composition ratio (x) by combining the co-evaporation method and sulfurization in an infrared furnace. Furthermore, the effect of Na on the CTGS and changes in the solar cell properties were investigated by stacking and sulfurizing NaF on the precursor fabricated using the co-evaporation method. As a result, CTGS with varying x was successfully fabricated by varying the deposition time of the Cu2GeS3 layer using co-evaporation. Additionally, CTGS prepared by doping with Na showed enlarged CTGS crystals compared to Na-free CTGS. The fabricated CTGS solar cells achieved a power conversion efficiency of more than 4.5% after doping with Na.

C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

Patients with infusion-related reactions on fixed-dose rituximab treatment have higher body surface area than those without infusion-related reactions in adults with frequently relapsing minimal change nephrotic syndrome: a retrospective study.

BACKGROUND: Infusion-related reactions (IRRs) are major side effects of rituximab administration. Male sex, high body weight, body surface area (BSA), and body mass index are predictive markers of rituximab-induced IRRs. However, as rituximab was not administered at a fixed dosage in a previous study, whether a higher dosage or factors associated with a larger physique are more strongly associated with rituximab-induced IRRs is unknown. MAIN BODY: Thirteen adults with frequently relapsing minimal change nephrotic syndrome (MCNS) who received an initial rituximab dose of 500 mg between September 2015 and November 2022 were retrospectively evaluated. Data on IRRs were collected from medical records. The incidence of rituximab-induced IRRs was 38.5% (5/13). The IRR group had a significantly higher BSA than the non-IRR group (median, 1.86 vs. 1.48 m2; p = 0.045). Additionally, rituximab dosage normalized by BSA in the IRR group was significantly lower than that in the non-IRR group (median, 268.8 vs. 337.9 mg/m2; p = 0.045). CONCLUSIONS: Our study revealed that adults with frequently relapsing MCNS who experienced IRRs tend to have a higher BSA, even with fixed-dose rituximab treatment. Therefore, when patients with higher BSA receive rituximab treatment, clinicians should be careful about monitoring patient condition whether the dosage is fixed or not.

Characteristics of mental disorders among information technology workers in 238 compensated cases in Japan.

This study aimed to investigate the circumstances, characteristics, and background factors of mental disorders within the information technology (IT) industry, which is known for the frequent occurrence of mental disorders from overwork and poor psychosocial work environment. The study analyzed 238 cases of mental disorders and suicides in the IT industry from fiscal years 2010 to 2018 on the database constructed by the Japan Research Center for Overwork-Related Disorders. The results showed a higher number of cases among men (n=178, 74.8%) and an increasing number among women. The data for diagnosis of mental diseases indicated a high number of depressive episodes (150 cases, 63.0%). Regarding work-induced psychological burden, 37 cases (15.5%) reported "extremely long working hours" for "special events" and 65 cases (27.3%) reported "constantly long working hours". For "specific events", 87 cases (36.6%) reportedly "caused (major) changes in the content and amount of work". Among women, 13 cases (21.7%) of "sexual harassment" (SH), which showed an increasing trend. Therefore, in the IT industry, the working hours must be properly managed. Mental health measures should also accompany improved psychosocial environment in the workplace, and prohibition of SH at work in particular.

Analysis of Risk Factors for Febrile Neutropenia in Patients with Small-Cell Lung Cancer Receiving Carboplatin Plus Etoposide Therapy.

INTRODUCTION: Febrile neutropenia (FN) is an oncologic emergency requiring immediate empiric antibiotic therapy. Although carboplatin plus etoposide combination chemotherapy is associated with a relatively high frequency of FN, the risk factors are unclear. Hence, this retrospective study aimed to identify predictive markers of carboplatin/etoposide-induced FN. METHODS: We conducted a retrospective cohort analysis of patients with previously untreated small-cell lung cancer (SCLC) who received combination chemotherapy with carboplatin (area under the concentration curve: 5 mg/mL·min, day 1) and etoposide (80 or 100 mg/m2, days 1-3) between July 2007 and June 2022. FN was assessed during the 21 days after initiation of carboplatin and etoposide therapy according to the Japanese Society of Medical Oncology's definition. Fisher's exact test for categorical variables and Mann-Whitney U test for continuous variables were used to compare the two groups. Statistical significance was set at p values <0.05. Explanatory variables with p values <0.05 in the univariate analysis were included in the multivariate logistic regression analysis. RESULTS: Among the 176 eligible patients, the incidence of FN during the first cycle of chemotherapy was 25.0% (44/176). Multivariate analysis revealed that co-administration of proton pump inhibitors (PPIs) or potassium-competitive acid blockers (PCABs) and body mass index (BMI) were significantly associated with FN (p = 0.0035 and 0.0011, respectively). Patients with both co-administration of PPIs or PCABs and a BMI ≤22.509 kg/m2 presented with significantly higher frequencies of FN compared with the other patients (13/24 [54.2%] vs. 31/152 [20.4%] patients; odds ratio: 4.56, 95% confidence interval: 1.70-12.48; p = 0.00147). CONCLUSION: Patients who received carboplatin plus etoposide for SCLC with co-administration of PPIs or PCABs and a BMI ≤22.509 kg/m2 more frequently present with FN than those without the two factors.

Creation of synthetic contrast-enhanced computed tomography images using deep neural networks to screen for renal cell carcinoma.

In this study, we elucidate if synthetic contrast enhanced computed tomography images created from plain computed tomography images using deep neural networks could be used for screening, clinical diagnosis, and postoperative follow-up of small-diameter renal tumors. This retrospective, multicenter study included 155 patients (artificial intelligence training cohort [n = 99], validation cohort [n = 56]) who underwent surgery for small-diameter (≤40 mm) renal tumors, with the pathological diagnosis of renal cell carcinoma, during 2010-2020. We created a learned deep neural networks using pix2pix. We examined the quality of the synthetic enhanced computed tomography images created using this deep neural networks and compared them with real enhanced computed tomography images using the zero-mean normalized cross-correlation parameter. We assessed concordance rates between real and synthetic images and diagnoses according to 10 urologists by creating a receiver operating characteristic curve and calculating the area under the curve. The synthetic computed tomography images were highly concordant with the real computed tomography images, regardless of the existence or morphology of the renal tumor. Regarding the concordance rate, a greater area under the curve was obtained with synthetic computed tomography (area under the curve = 0.892) than with only computed tomography (area under the curve = 0.720; p < 0.001). In conclusions, this study is the first to use deep neural networks to create a high-quality synthetic computed tomography image that was highly concordant with a real computed tomography image. Our synthetic computed tomography images could be used for urological diagnoses and clinical screening.

[A Case of Intractable Chylorrhea Following Breast Cancer Surgery with a History of Liver Cirrhosis].

We present a case of intractable chylorrhea following breast cancer surgery in a 75-year-old female. During a close examination for a mass in her left breast, which was indicated by a CT scan performed to test for nausea, cancer of the left breast and an enlarged left axillary lymph node were observed. The FNA of the axillary lymph node was unsuitable as a sample since no lymph node cell-derived components were observed. A left breast mastectomy and axillary lymph node dissection were performed for the evaluation of cT2N1M0, Stage ⅡB. On postoperative day 3, cloudy drainage was observed, leading to a diagnosis of chylorrhea. Despite management by a fat-restricted diet and peripheral infusion on postoperative day 4, chyle from the drainage remained high, with a TG of 257 mg/dL, a cell count of 525/mm3(70% lymphocytes), and a postoperative drainage volume of over 500 mL per day. On postoperative day 8, octreotide subcutaneous injection was started, and drainage could be reduced. Locally injected picibanil solution through the drain on postoperative days 12 and 17 further decreased the drainage to 20 mL/day, and the drain was removed. The patient was discharged on postoperative day 22. The occurrence of chylorrhea was a concern due to the risk of distal hepatic collateral flow, regional lymph nodes and vessels, and high hepatic flow pressure due to liver cirrhosis.

Analysis of Risk Factors for Infusion-Related Reactions Following Rituximab Administration in Patients with Desensitization before Renal Transplantation.

Infusion-related reactions (IRRs) are the major side effects of rituximab administration. Although several studies have reported predictive markers for IRRs in patients with malignancies, there are no such reports for patients without malignancies. Accordingly, we aimed to clarify the predictive markers for rituximab-induced IRRs in renal transplant recipients. This retrospective study included 116 inpatients aged ≥18 years who received an initial dose of 150 mg/m2 of rituximab for desensitization before renal transplantation with loxoprofen and diphenhydramine before rituximab infusion between June 2007 and February 2022. Overall, 45 patients were evaluated and 71 patients were excluded in this study. IRRs were observed in 12 (26.7%) patients. The proportion of men in the IRRs group was significantly higher than that in the non-IRRs group (p = 0.023). Additionally, body weight, body surface area (BSA), and body mass index (BMI) were significantly higher in the IRRs group than in the non-IRRs group (body weight, p = 0.0058; BSA, p = 0.0051; BMI, p = 0.017). Their cutoff values for predicting rituximab-induced IRRs, based on the receiver-operating characteristic curve, were 74.850 kg, 1.910 m2 and 24.164 kg/m2, respectively. In conclusion, the male sex, high actual body weight, BSA, and BMI may be new predictive markers for rituximab-induced IRRs in renal transplant recipients. Therefore, clinicians should carefully monitor patients who receive rituximab before renal transplantation and present with the predictive markers.

Long working hours and risk of hypertensive intracerebral haemorrhage among Japanese workers claiming compensation for overwork-related intracerebral haemorrhage: an unmatched case-control study.

OBJECTIVES: Overwork-related cerebrovascular and cardiovascular diseases (CCVDs) constitute a major occupational and public health issue worldwide. However, to our knowledge, few studies have reported the underlying pathophysiological mechanisms. We aimed to determine whether patients with extreme workload have a greater risk of developing hypertensive intracerebral haemorrhage (ICH) located in the deep brain areas than patients without extreme workload. We also determined the association between the number of hours of overtime work and the risk of developing hypertensive ICH. DESIGN: Unmatched case-control study. SETTING: Database of patients claiming compensation for overwork-related CCVDs in Japan. PARTICIPANTS: A total of 1215 patients who claimed overwork-related ICH in Japan, of whom 621 had their compensation claim approved (patients with extreme workload) and 622 did not. PRIMARY AND SECONDARY OUTCOME MEASURES: Logistic regression analysis was performed to calculate the risk of developing hypertensive ICH in patients with extreme workload compared with those without extreme workload, adjusted for confounders such as age, occupation, smoking status, alcohol consumption and medical history. We also calculated the risk of developing hypertensive ICH in compensated patients by average monthly overtime working hours. RESULTS: Patients with extreme workloads had a significantly higher odds ratio (OR) for developing hypertensive ICH (1.44, 95% CI: 1.10 to 1.88) than those without extreme workloads. ORs for developing hypertensive ICH according to overtime working hours showed a dose-response relationship; an overtime of 100 hours/month was associated with a significantly higher OR (1.31, 95% CI: 0.89 to 1.91; 1.41, 95% CI: 0.95 to 2.11; and 1.50, 95% CI: 1.01 to 2.22 for 60-79.9, 80-99.9 and≥100 hours/month, respectively) than that for workloads of less than 60 hours/month. CONCLUSIONS: Regarding Japanese workers, overtime work could be associated with the risk of developing hypertensive ICH, and hypertension may play an important role in overwork-related ICH.

Metagenomic profile of caudal fin morphology of farmed red sea bream Pagrus major.

The morphology of farm-reared fish often differs from that of their wild counterparts, impacting their market value. Two caudal fin tip shapes, acutely angled and blunted, are recognized in farmed populations of red sea bream Pagrus major. The angled form is preferred by consumers over the blunt since it resembles that of wild fish. Discovering the cause of the blunted tip is crucial to maximizing the commercial value of farmed red sea bream. We hypothesized that the blunt fin tip is the result of opportunistic bacteria and conducted partial 16S rRNA metagenomic barcoding and generated a clone library of the 16S rRNA gene to compare bacterial communities of the 2 fin forms. Metagenomic barcoding revealed an abundance of 5 bacterial genera, Sulfitobacter, Vibrio, Tenacibaculum, Psychrobacter, and an unknown genus of Rhodobacteraceae, on the caudal fin surface. Sulfitobacter was significantly more common on the angled caudal fin than the blunted. Vibrio is the dominant genus on the blunted caudal fin. The clone library identified these genera to species level, and Sulfitobacter sp., Vibrio harveyi, Tenacibaculum maritimum, and Psychrobacter marincola were frequently observed in blunt caudal fins. Our results suggest that opportunistic pathogenic bacteria such as V. harveyi and T. maritimum are not the primary cause of caudal fin malformation, and multiple factors such as combinations of injury, stress, and pathogenic infection may be involved. The reason for the significantly greater occurrence of Sulfitobacter sp. in the angled caudal fin is unknown, and further investigation is needed.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Characteristics of long working hours and subsequent psychological and physical responses: JNIOSH cohort study.

OBJECTIVES: This study aimed to examine the prospective association among objectively measured average working hours (AWHs), frequency of long working hours (FLWHs; defined as ≥205 working hours/month (≥45 hours/week)) for 6 months, and workers' self-reported psychological and physical health. METHODS: The study included 15 143 workers from 5 Japanese companies. We collected monthly attendance records over 6 months before distributing a questionnaire survey on psychological/physical stress responses and work-related demographics. We then evaluated the associations of those attendance records with psychological/physical measures using analysis of covariance adjusted for sex, age, employment, job type, working conditions, work site and experience of emergency state due to COVID-19. RESULTS: Irritability, anxiety and depression were significantly greater at ≥180 hours (≥45 hours/week), and fatigue and lack of vigour were greater at ≥205 hours than those of the normal working-hour group (140-180 hours/month [35-45 hours/week]). Psychological indices increased significantly with FLWH, with ≥3 times for irritability, depression and fatigue; ≥2 times for lack of vigour; and ≥1 time for anxiety when compared with no long working hours. No significant associations were observed between AWH or FLWH and physical stress responses. CONCLUSIONS: Longer AWH was associated with higher levels of psychological stress responses. The effects of FLWH in the past 6 months varied among the psychological stress responses and did not occur for physical complaints. Under circumstances requiring long hours, workers' mental health should be protected through minimising the frequency of long work hours.