Preoperative treatment response prediction for pancreatic cancer by multiple microRNAs in plasma exosomes: Optimization using machine learning and network analysis.

BACKGROUND/OBJECTIVES: MicroRNAs (miRNAs) are involved in chemosensitivity through their biological activities in various malignancies, including pancreatic cancer (PC). However, single-miRNA models offer limited predictability of treatment response. We investigated whether a multiple-miRNA prediction model optimized via machine learning could improve treatment response prediction. METHODS: A total of 20 and 66 patients who underwent curative resection for PC after gemcitabine-based preoperative treatment were included in the discovery and validation cohorts, respectively. Patients were classified according to their response to preoperative treatment. In the discovery cohort, miRNA microarray and machine learning were used to identify candidate miRNAs (in peripheral plasma exosomes obtained before treatment) associated with treatment response. In the validation cohort, miRNA expression was analyzed using quantitative reverse transcription polymerase chain reaction to validate its ability to predict treatment response. RESULTS: In the discovery cohort, six and three miRNAs were associated with good and poor responders, respectively. The combination of these miRNAs significantly improved predictive accuracy compared with using each single miRNA, with area under the curve (AUC) values increasing from 0.485 to 0.672 to 0.909 for good responders and from 0.475 to 0.606 to 0.788 for poor responders. In the validation cohort, improved predictive performance of the miRNA combination over single-miRNA prediction models was confirmed, with AUC values increasing from 0.461 to 0.669 to 0.777 for good responders and from 0.501 to 0.556 to 0.685 for poor responders. CONCLUSIONS: Peripheral blood miRNA profiles using an optimized combination of miRNAs may provide a more advanced prediction model for preoperative treatment response in PC.

Frequency of Going Outdoors and Risk of Poor Oral Health Among Older Japanese Adults: A Longitudinal Cohort From the Japan Gerontological Evaluation Study.

BACKGROUND: The association between the frequency of going outdoors and the risk of poor oral health has been reported in several studies; however, the findings have been inconclusive. METHODS: We conducted a 3-year longitudinal study of 19,972 Japanese adults aged ≥65 years who reported no poor oral condition at baseline in 2013. The respondents rated their frequency of going outdoors in three categories (≤1, 2-3, or ≥4 times/week), and the oral conditions reported in 2016 included tooth loss, chewing difficulty, swallowing difficulty, dry mouth, and composite outcomes. The associations between the frequency of going outdoors and the risk of poor oral health were examined as relative risk ratios (RRs) and 95% confidence intervals (CIs) using multivariable Poisson regression, while mediation analysis was performed to investigate indirect effects. RESULTS: During the follow-up, 32.5% of participants developed poor oral health. In the mediation analysis, indirect effects were observed through low instrumental activities of daily living, depressive symptoms, little social network diversity, and underweight. Compared to going outdoors ≥4 times/week, the multivariable RRs of composite poor oral health conditions were 1.12 (95% CI, 1.05-1.20) for 2-3 times/week and 1.22 (95% CI, 1.07-1.39) for ≤1 time/week (P-trend < 0.001). Similar associations were observed for tooth loss, chewing difficulty, and swallowing difficulty; the corresponding RRs were 1.07 (95% CI, 0.97-1.19) and 1.36 (95% CI, 1.13-1.64) (P-trend = 0.002), 1.18 (95% CI, 1.06-1.32) and 1.30 (95% CI, 1.05-1.60) (P-trend < 0.001), and 1.15 (95% CI, 1.01-1.31) and 1.38 (95% CI, 1.08-1.77) (P-trend = 0.002), respectively. CONCLUSION: The frequency of going outdoors was inversely associated with the risk of poor oral health through several modifiable risk factors in the older population.

Impact of Patent Lumbar Arteries on Aneurysm Sac Enlargement with Type II Endoleak after Endovascular Aneurysm Repair.

OBJECTIVE: This study aimed to investigate the impact of the number of patent lumbar arteries (LAs) on sac enlargement after endovascular aneurysm repair (EVAR). METHODS: This was a retrospective cohort single centre registry study. Between January 2006 and December 2019, 336 EVARs were reviewed using a commercially available device excluding type I or type III endoleaks during a follow up of ≥ 12 months. Patients were divided into four groups based on the pre-operative patency of the inferior mesenteric artery (IMA) and high (≥ 4) or low (≤ 3) number of patent LAs: Group 1, patent IMA and high number of patent LAs; Group 2, patent IMA and low number of patent LAs; Group 3, occluded IMA and a high number of patent LAs; Group 4, occluded IMA and low number of patent LAs. RESULTS: Groups 1, 2, 3, and 4 included 124, 104, 45, and 63 patients, respectively. The median follow up duration was 65.1 months. Significant differences in the incidence of overall type II endoleak (T2EL) at discharge between Group 1 and Group 2 (59.7% vs. 36.5%, p < .001) and between Group 3 and Group 4 (33.3% vs. 4.8%, p < .001) were observed. In patients with a pre-operatively patent IMA, the rate of freedom from aneurysm sac enlargement was significantly lower in Group 1 than in Group 2 (69.0% vs. 81.7% five years after EVAR, p < .001). In patients with a pre-operatively occluded IMA, the freedom rate from aneurysm sac enlargement was not significantly different between Groups 3 and Group 4 (95.0% vs. 100% five years after EVAR, p = .075). CONCLUSION: A high number of patent LAs seemed to have a significant role in sac enlargement with T2EL when the IMA was patent pre-operatively, whereas a high number of patent LAs seemed to have limited influence on sac enlargement when the IMA was occluded pre-operatively.

Intravenous methylprednisolone pulse therapy and the risk of in-hospital mortality among acute COVID-19 patients: Nationwide clinical cohort study.

BACKGROUND: Steroids are widely used to modulate the inflammatory reactions associated with coronavirus disease 2019 (COVID-19); however, the optimal upper limit dose of steroid use for acute COVID-19 care remains unclear and currently available data may suffer from a time-dependent bias of no effectiveness or reversed causation given the desperate situation of treatment during this pandemic. Accordingly, the aim of this study was to elucidate the impact of intravenous pulse therapy with methylprednisolone (500 mg or greater per day) on the risk of in-hospital mortality among patients with COVID-19 by controlling for time-dependent bias. METHODS: We performed a prospective cohort study with 67,348 hospitalised acute COVID-19 patients at 438 hospitals during 2020-2021 in Japan. The impact of intravenous methylprednisolone pulse therapy on the risk of in-hospital mortality was examined based on hazard ratios (HRs) and 95% confidence intervals (95% CIs), with stratification according to the status of invasive mechanical ventilation (iMV). Time-dependent bias was controlled for in a marginal structural model analysis, with reference to patients without methylprednisolone therapy. RESULTS: During the study period, 2400 patients died. In-hospital mortality rates of iMV-free patients without or with methylprednisolone pulse therapy were 2.3% and 19.5%, and the corresponding values for iMV-receiving patients were 24.7% and 28.6%, respectively. The marginal structural model analysis showed that intravenous pulse therapy with methylprednisolone was associated with a lower risk of in-hospital mortality among patients receiving-iMV (HR 0.59; 95% CI 0.52-0.68). In contrast, pulse therapy with methylprednisolone increased the risk of in-hospital mortality among iMV-free patients (HR 3.38; 95% CI 3.02-3.79). The benefits of pulse therapy for iMV-receiving patients were greater than in those treated with intermediate/higher doses (40-250 mg intravenously) of methylprednisolone (HR 0.80; 95% CI 0.71-0.89). CONCLUSION: The results of our study suggest that intravenous methylprednisolone showed dose-response efficiencies, and pulse therapy may benefit critically ill patients with acute COVID-19, such as those requiring iMV.

Long-term Weight Loss as a Predictor of Mortality in Hemodialysis Patients.

BACKGROUND: Serial weight decrease can be a prognostic predictor in chronic hemodialysis (HD) patients. We investigated the impact of long-term post-HD body weight (BW) changes on all-cause mortality among HD patients. METHODS: This longitudinal cohort study and post-hoc analysis evaluated participants of a previous randomized controlled trial conducted between 2006 and 2011 who were followed up until 2018. Weight change slopes were generated with repeated measurements every 6 months during the trial for patients having ≥5 BW measurements. Participants were categorized into four groups based on quartiles of weight change slopes; the median weight changes per 6 months were -1.02 kg, -0.25 kg, +0.26 kg, and +0.86 kg for first, second, third, and fourth quartile, respectively. Cox proportional hazard regression was used to evaluate differences in subsequent survival among the four groups. BW trajectories were plotted with a backward time-scale and multilevel regression analysis to visualize the difference in BW trajectories between survivors and non-survivors. RESULTS: Among the 461 patients, 404 were evaluated, and 168 (41.6%) died within a median follow-up period of 10.2 years. The Cox proportional hazard regression adjusted for covariates and baseline BW showed that a higher rate of weight loss was associated with higher mortality. The hazard ratios were 2.02 (95% confidence interval [CI], 1.28-3.20), 1.77 (95% CI, 1.10-2.85), 1.00 (reference), and 1.11 (95% CI, 0.67-1.83) for the first, second, third (reference), and fourth quartiles, respectively. BW trajectories revealed a significant decrease in BW in non-survivors. CONCLUSION: Weight loss elucidated via serial BW measurements every 6 months is significantly associated with higher mortality among HD patients.

Work and Family Conflicts, Depression, and "Ikigai": A Mediation Analysis in a Cross-cultural Study Between Japanese and Egyptian Civil Workers.

BACKGROUND: Total work-family conflicts (TWFCs) could associate with mental health, and having ikigai (a purpose of life) may mediate this association. METHODS: In a cross-cultural study of 4,792 Japanese Aichi Workers' Cohort study participants and 3,109 Egyptian civil workers, the Midlife Development in the United States (MIDUS) questionnaire measured TWFCs and the Center for Epidemiological Studies Depression (CES-D) 11-item scale measured depression. We used logistic regression models to estimate odds ratios (ORs) of having depression and a high-ikigai across levels of TWFCs (low, moderate, and high), and the PROCESS macro of Hayes to test the mediation effect. RESULTS: The prevalence of high TWFCs, depression, and having a high ikigai were 17.9%, 39.4%, and 70.1% in Japanese women, 10.5%, 26.8%, and 70.1% in Japanese men, 23.7%, 58.2%, and 24.7% in Egyptian women, and 19.1%, 38.9%, and 36.9% in Egyptian men, respectively. Compared with participants with low TWFCs, the multivariable ORs of depression in Japanese women and men with high TWFCs were 4.11 (95% confidence interval [CI], 2.99-5.65) and 5.42 (95% CI, 4.18-7.02), and those in Egyptian women and men were 4.43 (95% CI, 3.30-5.95) and 4.79 (95% CI, 3.53-6.48), respectively. The respective ORs of having a high-ikigai were 0.46 (95% CI, 0.33-0.64) and 0.40 (95% CI, 0.31-0.52) in Japanese women and men and were 0.34 (95% CI, 0.24-0.48) and 0.28 (95% CI, 0.20-0.39) in Egyptian women and men. No interaction between TWFCs and country was observed for the associations with depression or ikigai. Ikigai mediated (up to 18%) the associations between the TWFCs and depression, especially in Egyptian civil workers. CONCLUSION: TWFCs were associated with depression, and having low ikigai mediated these associations in Japanese and Egyptian civil workers.

Impact of the Patency of Inferior Mesenteric Artery on 7-Year Outcomes After Endovascular Aneurysm Repair.

PURPOSE: The impact of preoperative patent inferior mesenteric artery (IMA) on late outcomes following endovascular aneurysm repair (EVAR) remains unclear. This study aimed to investigate the specific influence of IMA patency on 7-year outcomes after EVAR. MATERIALS AND METHODS: In this retrospective cohort study, 556 EVARs performed for true abdominal aortic aneurysm cases between January 2006 and December 2019 at our institution were reviewed. Endovascular aneurysm repairs performed using a commercially available device with no type I or type III endoleak (EL) during follow-up and with follow-up ≥12 months were included. A total of 336 patients were enrolled in this study. The cohort was divided into the patent IMA group and the occluded IMA group according to preoperative IMA status. The late outcomes, including aneurysm sac enlargement, reintervention, and mortality rates, were compared between both groups using propensity-score-matched data. RESULTS: After propensity score matching, 86 patients were included in each group. The median follow-up period was 56 months (interquartile range: 32-94 months). The incidence of type II EL at discharge was 50% in the patent IMA group and 19% in the occluded IMA group (p<0.001). The type II EL from IMA and lumbar arteries was significantly higher in the patent IMA group than in the occluded IMA group (p<0.001 and p=0.002). The rate of freedom from aneurysm sac enlargement with type II EL was significantly higher in the occluded IMA group than in the patent IMA group (94% vs 69% at 7 years; p<0.001). The rate of freedom from reintervention was significantly higher in the occluded IMA group than in the patent IMA group (90% vs 74% at 7 years; p=0.007). Abdominal aortic aneurysm-related death and all-cause mortality did not significantly differ between groups (p=0.32 and p=0.34). CONCLUSIONS: Inferior mesenteric artery patency could affect late reintervention and aneurysm sac enlargement but did not have a significant impact on mortality. Preoperative assessment and embolization of IMA might be an important factor for improvement in late EVAR outcomes. CLINICAL IMPACT: The preoperative patency of the inferior mesenteric artery was significantly associated with a higher incidence of sac enlargement and reintervention with type II endoleak following endovascular aneurysm repair, even after adjustment for patient background. Preoperative assessment and embolization of inferior mesenteric artery might be an important factor for improvement in late EVAR outcomes.

Comparison of the Outcomes of Total Endovascular Aortic Arch Repair Between Branched Endograft and Chimney Endograft Technique in Zone 0 Landing.

PURPOSE: Zone 0 landing in thoracic endovascular aortic repair (TEVAR) has recently gained increasing attention for the treatment of high-risk patients. The aim of this study was to compare the outcomes of total endovascular aortic arch repair between branched TEVAR (bTEVAR) and chimney TEVAR (cTEVAR) in the landing zone (LZ) 0. MATERIALS AND METHODS: This was a single-center, retrospective, and observational cohort study. From January 2010 to March 2020, 40 patients (bTEVAR, n=25; cTEVAR, n=15; median age: 79 years) were enrolled in this study, with a median follow-up period of 4.1 years. These patients were considered unsuitable for open surgical treatment. RESULTS: All procedures were successful and no cases of conversion to open repair were noted during the 30-day postoperative period. The 30-day mortality was 2.5% (n=1; bTEVAR [0 of 25, 0%] vs cTEVAR [1 of 15, 6.7%]; p=0.375), the perioperative stroke rate was 10.0% (n=4; bTEVAR [4 of 25, 16.0%] vs cTEVAR [0 of 15, 0%], p=0.278), and type 1a endoleak rate was 15.0% (n=6; bTEVAR [0 of 25, 0%] vs cTEVAR [6 of 15, 40.0%], p=0.001). The risk factor for stroke was atheroma grade of ≥2 in the brachiocephalic artery (p<0.001). The risk factor for type 1a endoleak was cTEVAR (p=0.001). The 8-year survival rate was 49.9%. The aorta-related death-free rate and aortic event-free rate at 8 years were 94.4% (bTEVAR: 95.5% vs cTEVAR: 93.3%, p=0.504) and 60.7% (bTEVAR: 70.7% vs cTEVAR: 40.0%, p=0.048), respectively. CONCLUSIONS: Total endovascular aortic arch repair using bTEVAR and cTEVAR is feasible for the treatment of aortic arch diseases in high-risk patients who are unsuitable for open surgery. However, as the rate of stroke is high, strict preoperative evaluation to prevent stroke is needed. No rupture of the aneurysm was observed in cTEVAR, but patients should be selected carefully because of the high incidence of type 1a endoleak.

Effectiveness of Proximal Landing Zones 0, 1, and 2 Hybrid Thoracic Endovascular Aortic Repair: A Single Centre 12 Year Experience.

OBJECTIVE: Hybrid thoracic endovascular aortic repair (TEVAR) is being accepted increasingly as a first line treatment for arch repair at the present authors' institution. This study aimed to clarify the effectiveness of zones 0, 1, and 2 landing hybrid TEVAR. METHODS: This was a retrospective single centre case series. From April 2008 to March 2020, 348 patients (median age 72 years; interquartile range [IQR] 65, 77 years) were enrolled, with a median follow up period of 5.6 years (IQR 2.6, 8.7 years). The procedures included zone 0 in 135 patients (38.8%), zone 1 in 82 patients (23.6%), and zone 2 proximal landing zone (LZ) hybrid TEVAR in 131 patients (37.6%). The pathologies consisted of dissecting aortic aneurysms in 123 (35.3%) patients. Emergency procedures were performed in 39 (11.2%) patients. RESULTS: The 30 day mortality (n = 2, 0.6%) and hospital deaths (n = 6, 1.7%) were registered. The stroke rate was 1.1% (n = 4), while early and late endoleak rates were 4.8% (n = 17) and 1.7% (n = 6), respectively. Type 1a endoleak and retrograde type A dissection occurred in seven (2.0%) and three (0.9%) patients, respectively. The cumulative survival, freedom from aorta related deaths, and freedom from aortic events in 10 years were 75.0%, 97.2%, and 84.1%, respectively. The freedom from aortic events in each landing zone in 10 years was 82.3%, 81.4%, and 87.9% for zones 0, 1, and 2, respectively. The 10 year survival rates were 82.5% and 73.6%; the 10 year aorta related death free rates were 94.9% and 98.6%, and the 10 year aortic event free rates were 82.3% and 85.5% in the zone 0 and zone 1 and 2 TEVAR, respectively. CONCLUSION: Satisfactory early and long term results of hybrid arch repair at zones 0, 1, and 2 were achieved. To avoid complications and aortic events, the treatment strategy of hybrid arch repair for aortic arch pathologies should be tailored using accurate pre-operative assessment of the ascending aorta and the aortic arch.

Impact of modifiable healthy lifestyle adoption on lifetime gain from middle to older age.

OBJECTIVE: this study explored whether the modification of selected lifestyles is likely to increase life expectancy from middle age onwards, regardless of the presence of major comorbidities. METHODS: we examined a prospective cohort of 20,373 men and 26,247 women aged 40-80 years. Eight modifiable lifestyle factors were assessed: consumption of fruit, fish and milk, walking and/or sports participation, body-mass index, smoking status, alcohol consumption and sleep duration. Modifiable healthy lifestyle factors scored one point each, for a maximum of eight points. The impact of modifiable healthy lifestyle adoption on lifetime gain during the ages of 40-102 years was analysed. FINDINGS: during the median 21 years of follow-up, 8,966 individuals (3,683 men and 5,283 women) died. Life expectancy at 40 years (95% confidence intervals) for 7-8 health lifestyle points was 46.8 (45.6-48.1) and 51.3 (50.0-52.6) years for men and women, respectively. The potential impact of modifiable healthy lifestyle adoption on lifetime gain persisted over the age of 80 years or more, in individuals with ≥5 factors (P < 0.001), particularly older men. The benefits were more pronounced among patients with major comorbidities, such as cardiovascular disease, cancer, hypertension, diabetes, kidney disease and those with multimorbidity throughout all age categories. CONCLUSION: adopting modifiable healthy lifestyles was associated with lifetime gain, even in individuals aged 80 years or more, regardless of the presence of any major comorbidities in each life stage since middle age. The findings imply the importance of improving the one's lifestyle for an increased lifespan, even among older patients and/or those with multimorbidity.