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Abstract Background Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). Methods Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1–3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. Results The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. Conclusions Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.

Abstract Objective A U-shaped relationship between energy cost of walking (C w ) and walking speed indicates that there is a specific speed minimizing the C w , called economical speed (ES). It is mostly slower in older adults than young adults; however, effects of leg length on the ES have been ignored. We investigated effects of aging and exercise habituation on the normalized ES by leg length (ESnormalized). We quantified time delay of stride length and step frequency in sedentary young (SY), active young (AY), and active elderly (AE) adults in response to sinusoidal gait speed change at 30-s and 180-s periods with an amplitude of ± 0.56 m･s− 1. Results The ES was significantly slower in the following sequence: AE, SY, and AY, whereas ESnormalized was slower in the AE than in other young groups, with no difference between AY and SY. AE and SY showed greater step variabilities at the 180-s period, whereas AY showed relatively smaller step variabilities at both periods. Collectively, the ESnormalized slowed due to aging, not due to exercise habituation. When optimizing the appropriate SL-SF combination for sinusoidal speed changes, young and elderly adults may adopt different strategies. Exercise habituation may reduce step variabilities in young adults.

Abstract Background Several factors have been shown to contribute to hypoxic-induced declined in aerobic capacity. In the present study, we investigated the effects of resting hypoxic ventilatory and cardiac responses (HVR and HCR) on hypoxic-induced declines in peak oxygen uptake ( $$\dot{\mathrm V}$$ V ˙ O2peak). Methods Peak oxygen uptakes was measured in normobaric normoxia (room air) and hypoxia (14.1% O2) for 10 young healthy men. The resting HVR and HCR were evaluated at multiple steps of hypoxia (1 h at each of 21, 18, 15 and 12% O2). Arterial desaturation (ΔSaO2) was calculate by the difference between SaO2 at normoxia—at each level of hypoxia (%). HVR was calculate by differences in pulmonary ventilation between normoxia and each level of hypoxia against ΔSaO2 (L min−1 %−1 kg−1). Similarly, HCR was calculated by differences in heart rate between normoxia and each level of hypoxia against ΔSaO2 (beats min−1 %−1). Results $$\dot{\mathrm V}$$ V ˙ O2peak significantly decreased in hypoxia by 21% on average (P < 0.001). HVR was not associated with changes in $$\dot{\mathrm V}$$ V ˙ O2peak. ΔSaO2 from normoxia to 18% or 15% O2 and HCR between normoxia and 12% O2 were associated with changes in $$\dot{\mathrm V}$$ V ˙ O2peak (P < 0.05, respectively). The most optimal model using multiple linear regression analysis found that ΔHCR at 12% O2 and ΔSaO2 at 15% O2 were explanatory variables (adjusted R 2 = 0.580, P = 0.02). Conclusion These results suggest that arterial desaturation at moderate hypoxia and heart rate responses at severe hypoxia may account for hypoxic-induced declines in peak aerobic capacity, but ventilatory responses may be unrelated.

Abstract Background The time courses of the joint elevation angles of the thigh, shank, and foot in one stride during walking can be well approximated by a “plane” in a triaxial space. This intersegmental coordination (IC) of the lower limb elevation angles is referred to as the planar covariation law. We examined the effects of exercise habituation and aging on the thickness of the IC plane of the lower limbs under sinusoidal speed changing conditions. Methods Seventeen sedentary young (SY), 16 active young (AY), and 16 active elderly (AE) adults walked on a treadmill in accordance with a sinusoidal speed changing protocol at 120, 60, and 30 s periods with an amplitude of ± 0.56 m·s−1. Motion of the lower limbs from the sagittal direction was recorded to calculate the elevation angles of the lower limbs. When the best-fit IC plane was determined, the smallest standard deviation of the IC plane was considered as the anteroposterior gait variability of the lower limbs. The coefficient of variance of the step width was also quantified to evaluate the lateral step variability (CVSW). Results The standard deviation of the IC plane was significantly greater in the order of SY, AY, and AE, regardless of the sinusoidal wave periods of the changing speed. The CVSW was not significantly different among the three groups. Conclusions Exercise habituation influences anteroposterior gait variability of the lower limbs, but not lateral step variability, even in young adults. Given these, gait adaptability for sinusoidal speed changes does not always decline with aging. Trial registration UMIN000031456 ( R000035911 ; registered February 23, 2018).

Abstract Background A specific walking speed minimizing the U-shaped relationship between energy cost of transport per unit distance (CoT) and speed is called economical speed (ES). To investigate the effects of reduced body weight on the ES, we installed a body weight support (BWS) apparatus with a spring-like characteristics. We also examined whether the 'calculated' ES was equivalent to the 'preferred' walking speed (PWS) with 30% BWS. Methods We measured oxygen uptake and carbon dioxide output to calculate CoT values at seven treadmill walking speeds (0.67–2.00 m s− 1) in 40 healthy young males under normal walking (NW) and BWS. The PWS was determined under both conditions on a different day. Results A spring-like behavior of our BWS apparatus reduced the CoT values at 1.56, 1.78, and 2.00 m s− 1. The ES with BWS (1.61 ± 0.11 m s− 1) was faster than NW condition (1.39 ± 0.06 m s− 1). A Bland-Altman analysis indicated that there were no systematic biases between ES and PWS in both conditions. Conclusions The use of BWS apparatus with a spring-like behavior reduced the CoT values at faster walking speeds, resulting in the faster ES with 30% BWS compared to NW. Since the ES was equivalent to the PWS in both conditions, the PWS could be mainly determined by the metabolic minimization in healthy young males. This result also derives that the PWS can be a substitutable index of the individual ES in these populations.

Abstract Background Acute mountain sickness (AMS) is a common, transient condition characterized primarily by headaches, and it can also be associated with fatigue, dizziness, and nausea with vomiting. The symptoms of AMS are most pronounced after the first night spent at a new altitude. At sea level, changes in barometric pressure per given time have been associated with migraine headaches. We sought to investigate whether changes in barometric pressure, subjective sleep quality index, and other candidates contributed to the risk of developing AMS on Mount Fuji in Japan. Method We surveyed 353 trekkers who stayed overnight at a mountain lodge before summitting Mount Fuji. We collected information regarding sex, age, sleeping altitude at the hut, and perceived sleep quality index including sleep time. AMS was assessed with the Lake Louise Scoring system. Barometric pressure and ambient temperature were collected at the 5th station (2305 m) and at the summit (3776 m). Result The overall prevalence of AMS in our cohort was 41.4% (Lake Louise Score ≥ 3 with headache, n=146). Using logistic regression, three factors were combined to generate a robust model for determining the risk of AMS (with or without AMS). These included (1) Δ barometric pressure during ascent per hour, (2) sleepiness on rising, and (3) sleep refreshment assessed by perceived sleep quality index. Conclusion These results suggest that climbers who stay overnight at the lodge should keep a better physical condition of sleep, and would pay attention to information of barometric pressure condition to decrease their risk of AMS at the summit of Mount Fuji. Our observatory data indicated that an overnight staying in half way up to the summit does not necessarily reduce the AMS risk in both sexes and irrespective of age, at least, until 3776 m elevation.

Abstract Objective As human thermoregulatory responses to maintain core body temperature (Tcore) under multiple stressors such as cold, hypoxia, and dehydration (e.g., exposure to high-altitude) are varied, the combined effects of cold, hypoxia, and dehydration status on Tcore in rats were investigated. The following environmental conditions were constructed: (1) thermoneutral (24 °C) or cold (10 °C), (2) normoxia (21% O2) or hypoxia (12% O2), and (3) euhydration or dehydration (48 h water deprivation), resulted in eight environmental conditions [2 ambient temperatures (Ta) × 2 oxygen levels × 2 hydration statuses)]. Each condition lasted for 24 h. Results Normoxic conditions irrespective of hypoxia or dehydration did not strongly decrease the area under the curve (AUC) in Tcore during the 24 period, whereas, hypoxic conditions caused greater decreases in the AUC in Tcore, which was accentuated with cold and dehydration (Ta × O2 × hydration, P = 0.040 by three-way ANOVA). In contrast, multiple stressors (Ta × O2 × hydration or Ta × O2 or O2 × hydration or Ta × hydration) did not affect locomotor activity counts (all P > 0.05), but a significant simple main effect for O2 and Ta was observed (P 0.05). In conclusion, decreases in Tcore were most affected by multiple environmental stressors such as cold, hypoxia, and dehydration.

Abstract Background Ground golf is a popular sport among the elderly in Japan. Several types of exercise can reduce the body's mean arterial pressure (MAP), but little is known about how ground golf affects the MAP. We investigated the effects of ground golf on the MAP and the oxygen uptake ( V ̇ O 2 $$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ ) in a healthy elderly population. Participants and methods Thirteen elderly Japanese people (3 males and 10 females, mean age of 66 years) participated. All participants played 8 holes of ground golf 6 times, as game (G)1 to G6. The MAP, heart rate (HR), and V ̇ O 2 $$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ were measured at rest and every 5 min during each game. Results A linear trend analysis revealed that participants’ MAP values progressively decreased as each game proceeded with marginal differences (p = 0.054). There were no significant differences in HR between at rest and any of the games. The V ̇ O 2 $$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ during the games (except for G6) were significantly higher than that at-rest (p < 0.05). The resting MAP values were negatively associated with the ground golf-induced changes in MAP (r = 0.786, p = 0.001). The participants with greater changes in V ̇ O 2 $$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ during the games showed significantly greater reductions in MAP (r = 0.276, p = 0.043). Conclusions Playing ground golf reduced the participants’ MAP and increased their V ̇ O 2 $$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ . Participants with higher resting MAP experienced greater reductions in MAP by playing ground golf, which suggests that ground golf can be a useful recreational sport for the elderly.

Abstract Background Since walking is a daily activity not to require the maximal effort in healthy populations, a very few universal bio-parameters and/or methods have been defined to evaluate individual walking characteristics in those populations. A concept of “economy” is a potential candidate; however, walking economy highly depends on speed, so direct comparisons of economy values are difficult between studies. We investigated whether the vertical component of net walking “efficiency” (Effvert; %) is constant across speed. In that case, direct comparisons of Effvert will be possible between studies or individuals at any voluntary speed. Methods Thirty young male participants walked at eight speeds on the level or ± 5% gradients, providing vertical speeds (v vert). Differences in energy expenditure between level and uphill or downhill gradients (ΔEE) were calculated. The metabolic rate for vertical component (MRvert) was calculated by multiplying ΔEE with body mass (BM). The mechanical power output for vertical component (Pmech) was calculated by multiplying BM, gravitational acceleration, and v vert. Effvert was obtained from the ratio of Pmech to MRvert at each v vert. Delta efficiency (Delta-E; %) was also calculated from the inverse slope of the regression line representing the relationship of Pmech to MRvert. Results Upward Effvert was nearly constant at around 35% and downward Effvert ranged widely (49–80%). No significant differences were observed between upward Delta-E (35.5 ± 8.8%) and Effvert at any speeds, but not between downward Delta-E (44.9 ± 12.8%) and Effvert. Conclusions Upward ΔEE could be proportional to v vert. Upward, but not downward, Effvert should be useful not only for healthy populations but also for clinical patients to evaluate individual gait characteristics, because it requires only two metabolic measurements on the level and uphill gradients without kinematic information at any voluntary speed. Trial registration UMIN000017690 (R000020501; registered May 26th, 2015, before the first trial) and UMIN000031456 (R000035911; registered Feb. 23rd, 2018, before the first trial).

Abstract Background Energy cost of transport per unit distance (CoT) against speed shows U-shaped fashion in walking and linear fashion in running, indicating that there exists a specific walking speed minimizing the CoT, being defined as economical speed (ES). Another specific gait speed is the intersection speed between both fashions, being called energetically optimal transition speed (EOTS). We measured the ES, EOTS, and muscle activities during walking and running at the EOTS under hyperoxia (40% fraction of inspired oxygen) on the level and uphill gradients (+ 5%). Methods Oxygen consumption V̇O2 $$ \left(\dot{V}{\mathrm{O}}_2\right) $$ and carbon dioxide output V̇CO2 $$ \left(\dot{V}{\mathrm{CO}}_2\right) $$ were measured to calculate the CoT values at eight walking speeds (2.4–7.3 km h−1) and four running speeds (7.3–9.4 km h− 1) in 17 young males. Electromyography was recorded from gastrocnemius medialis, gastrocnemius lateralis (GL), and tibialis anterior (TA) to evaluate muscle activities. Mean power frequency (MPF) was obtained to compare motor unit recruitment patterns between walking and running. Results V̇O2 $$ \dot{V}{\mathrm{O}}_2 $$, V̇CO2 $$ \dot{V}{\mathrm{CO}}_2 $$, and CoT values were lower under hyperoxia than normoxia at faster walking speeds and any running speeds. A faster ES on the uphill gradient and slower EOTS on both gradients were observed under hyperoxia than normoxia. GL and TA activities became lower when switching from walking to running at the EOTS under both FiO2 conditions on both gradients, so did the MPF in the TA. Conclusions ES and EOTS were influenced by reduced metabolic demands induced by hyperoxia. GL and TA activities in association with a lower shift of motor unit recruitment patterns in the TA would be related to the gait selection when walking or running at the EOTS. Trial registration UMIN000017690 (R000020501). Registered May 26, 2015, before the first trial.