Introduction: Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first-line treatment of NSCLC; however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. Methods: Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 out of 22). Operation was performed between day 29 and 43. Positron emission tomographycomputed tomography scans were obtained at baseline and before the operation. The primary end point was safety. Efficacy end points included rate of major pathologic response (MPR) and objective response rate. Expression of programmed cell death ligand 1 was also evaluated (registration number: ChiCTR-OIC-17013726). Results: A total of 40 patients enrolled, all of whom received two doses of sintilimab and 37 underwent radical resection. A total of 21 patients (52.5%) experienced neoadjuvant treatment-related adverse events (TRAEs). Four patients (10.0%) experienced grade 3 or higher neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an objective response rate of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including six (16.2%) with a pathologic complete response in primary tumor and three (8.1%) in lymph nodes as well. Squamous cell NSCLC exhibited superior response compared with adenocarcinoma (MPR: 48.4% versus 0%). Decrease of maximum standardized uptake values after sintilimab treatment correlated with pathologic remission (p < 0.00001). Baseline programmed cell death ligand 1 expression of stromal cells instead of tumor cells was correlated with pathologic regression (p ¼ 0.0471).

The purpose of this study was to evaluate the relationship between mitochondrial Ca2+ concentration (MCC) and the extent of muscle injury in rats that have performed prolonged downhill walking (eccentric exercise). MCC was used as an indicator of elevated [Ca2+] in the muscles, and injury was estimated from histochemical analysis of muscle cross sections by determining the numbers of intact fibers per unit area in the muscles. Elevations in MCC in the soleus and vastus intermedius muscles over time postexercise were inversely related (P less than 0.05) to the number of intact fibers per square millimeter in the respective muscles after downhill walking. Verapamil administration attenuated the elevation in MCC and injury in histochemical sections resulting from the downhill walking in soleus muscle, but intraperitoneal injection of the chelators EDTA or ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'- tetraacetic acid significantly attenuated the increases in MCC and injury to both the vastus intermedius and soleus muscles in the downhill walkers. The chelators appear to exert their "protective" effects within the specific muscles that show the injury and do not significantly affect serum [Ca2+]. It is concluded that increases in MCC occur during exercise-induced fiber injury and that elevations in cellular Ca2+ may have a role in the etiology of the injury process.

Background: Frailty in the elderly population is currently a frontier and focus in the field of health and aging. The goal of this study was to explore the frailty status among the elderly of different genders and its influence on the risk of death during 11 years.Methods: Frailty index (FI) was used to evaluate the frailty status in the elderly based on the baseline data conducted in 2009; and death as outcome variables collected in 2020 were analyzed. The difference of the frailty level and mortality of different genders was compared. Cox regression and Kaplan–Meier curves were applied to evaluate the influence on the risk of death and the 11-year survival of the elderly at different level of frailty, respectively.Results: Totally, 1,246 elderly people were recruited. The mortality in men (43.7%, 227/519) was statistically higher than that in women (34.3%, 249/727) (x2 = 11.546, P = 0.001). Deficits accumulated exponentially with age, and at all ages, women accumulated more deficits than do men on average (B = 0.030 vs. 0.028, t = 4.137, P = 0.023). For any given level of frailty, the mortality rate is higher in men than in women, and the difference in mortality between genders reached the peak when FI value was 0.26. Cox regression analysis showed that FI value had a greater impact on the risk of death in older men (HR = 1.171, 95%CI: 1.139~1.249)than that in older women (HR = 1.119, 95%CI: 1.039~1.137). Survival analysis showed that the median 11-year survival time in women was longer than that in men (95.26 vs. 89.52 months, Log rank = 9.249, P = 0.002). Kaplan–Meier curves showed that the survival rate decreased with the increase of frailty, and at the same level of frailty, survival time in older women was longer than that in older men, except for severe frailty (FI ≥ 0.5).Conclusion: The frailty status and its influence on mortality are different among the older people of different genders; therefore, specific interventions for frailty should be conducted in the elderly population of different genders, as well as of different degrees of frailty.

To study the distribution of blood flow after blood volume expansion, seven miniature swine ran at high speed (17.6-20 km/h, estimated to require 115% of maximal O2 uptake) on a motor-driven treadmill on two occasions: once during normovolemia and once after an acute 15% blood volume expansion (homologous whole blood). O2 uptake, cardiac output, heart rate, mean arterial pressure, and distribution of blood flow (with radiolabeled microspheres) were measured at the same time during each of the exercise bouts. Maximal heart rate was identical between conditions (mean 266); mean arterial pressure was elevated during the hypovolemic exercise (149 +/- 5 vs. 137 +/- 6 mmHg). Although cardiac output was higher and arterial O2 saturation was maintained during the hypervolemic condition (10.5 +/- 0.7 vs. 9.3 +/- 0.6 l/min), O2 uptake was not different (1.74 +/- 0.08 vs. 1.74 +/- 0.09 l/min). Mean blood flows to cardiac (+12.9%), locomotory (+9.8%), and respiratory (+7.5%) muscles were all elevated during hypervolemic exercise, while visceral and brain blood flows were unchanged. Calculated resistances to flow in skeletal and cardiac muscle were not different between conditions. Under the experimental conditions of this study, O2 uptake in the miniature swine was limited at the level of the muscles during hypervolemic exercise. The results also indicate that neither intrinsic contractile properties of the heart nor coronary blood flow limits myocardial performance during normovolemic exercise, because both the pumping capacity of the heart and the coronary blood flow were elevated in the hypervolemic condition.

BackgroundFrailty and diabetes are two important health problems associated with aging in older individuals. This paper seeks to analyze the frailty in older adults suffering from diabetes and the combined effect of diabetes and frailty on mortality risk.MethodsThe frailty index (FI) model was employed when evaluating frailty among the older adults based on the baseline data conducted in 2009; and death as outcome variables collected in 2020 were analyzed. The influence of diabetes on age-related changes in frailty in the older adults and resulting mortality rates was analyzed. Cox regression and Kaplan-Meier curves were applied to evaluate the influence on the risk of death and the 11-year survival of the older adults with varying diabetes and frailty statuses.ResultsUltimately, 1,213 older people aged between 60 and 101, with an average age of (74.79 ± 8.58) at baseline, were included in the analysis. By 2020, there had been 447 deaths with mortality at 36.9% (447/1,213); there were 271 cases of diabetes, with a prevalence of 22.3% (271/1,213). The mean FI value for older adults with diabetes was higher than that of those without regardless of age, and the average annual relative growth rate of the FI value for older adults with diabetes was higher than that of those without diabetes (β = 0.039 vs. β = 0.035, t = 8.367, P &lt; 0.001). For all FI value levels, the mortality rate among older adults with diabetes was higher than that of those without. The Cox Regression analysis showed that, compared with those suffering from neither diabetes nor frailty, older adults with both had the higher mortality risk (HR = 1.760. P &lt; 0.001), followed by older adults suffering from frailty alone (HR = 1.594, P = 0.006), and then by older adults suffering from only diabetes (HR = 1.475, P = 0.033). The survival analysis showed that the median survival of those suffering from diabetes and frailty to be the shortest at just 57.23 (95% CI: 54.05 to 60.41) months, lower than the 83.78 (95% CI: 79.33 to 88.23) months in those suffering from frailty alone, and 119.93 (95% CI: 113.84 to 126.02) months in those with only diabetes, and 124.39 (95% CI: 119.76 to 129.02) months in older adults with neither diabetes nor frailty (P &lt; 0.001).ConclusionFrailty is common among older adults suffering from diabetes, and there is an increased risk of poor health outcomes, such as death, among older adults suffering from diabetes and frailty. When diagnosing, treating, and dealing with older adults with diabetes, attention should be paid to screening and assessing frailty in hopes of identifying it early so that appropriate measures of intervention can be taken to avoid or delay the resulting adverse effects.