M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast-Schwann cell-signaling relay.

BACKGROUND: Although peripheral nerves have an intrinsic self-repair capacity following damage, functional recovery is limited in patients. It is a well-established fact that macrophages accumulate at the site of injury. Numerous studies indicate that the phenotypic shift from M1 macrophage to M2 macrophage plays a crucial role in the process of axon regeneration. This polarity change is observed exclusively in peripheral macrophages but not in microglia and CNS macrophages. However, the molecular basis of axonal regeneration by M2 macrophage is not yet fully understood. Herein, we aimed to identify the M2 macrophage-derived axon regeneration factor. METHODS: We established a peripheral nerve injury model by transection of the inferior alveolar nerve (IANX) in Sprague-Dawley rats. Transcriptome analysis was performed on the injured nerve. Recovery from sensory deficits in the mandibular region and histological reconnection of IAN after IANX were assessed in rats with macrophage depletion by clodronate. We investigated the effects of adoptive transfer of M2 macrophages or M2-derived cathepsin S (CTSS) on the sensory deficit. CTSS initiating signaling was explored by western blot analysis in IANX rats and immunohistochemistry in co-culture of primary fibroblasts and Schwann cells (SCs). RESULTS: Transcriptome analysis revealed that CTSS, a macrophage-selective lysosomal protease, was upregulated in the IAN after its injury. Spontaneous but partial recovery from a sensory deficit in the mandibular region after IANX was abrogated by macrophage ablation at the injured site. In addition, a robust induction of c-Jun, a marker of the repair-supportive phenotype of SCs, after IANX was abolished by macrophage ablation. As in transcriptome analysis, CTSS was upregulated at the injured IAN than in the intact IAN. Endogenous recovery from hypoesthesia was facilitated by supplementation of CTSS but delayed by pharmacological inhibition or genetic silencing of CTSS at the injured site. Adoptive transfer of M2-polarized macrophages at this site facilitated sensory recovery dependent on CTSS in macrophages. Post-IANX, CTSS caused the cleavage of Ephrin-B2 in fibroblasts, which, in turn, bound EphB2 in SCs. CTSS-induced Ephrin-B2 cleavage was also observed in human sensory nerves. Inhibition of CTSS-induced Ephrin-B2 signaling suppressed c-Jun induction in SCs and sensory recovery. CONCLUSIONS: These results suggest that M2 macrophage-derived CTSS contributes to axon regeneration by activating SCs via Ephrin-B2 shedding from fibroblasts.

Oral Glucose Tolerance Test (OGTT) Evidence for the Postprandial Anti-Hyperglycemic Property of Salacca zalacca (Gaertn.) Voss Seed Extract.

Salak seed extract (Salacca zalacca) is known for its high antioxidant content and low caffeine levels, making it a promising candidate for the development of value-added health products. However, there is a lack of scientific evidence for its anti-hyperglycemic effects. To address this, we investigated the in vitro and in vivo anti-hyperglycemic and antioxidant effects of salak seed extract. The HPLC chromatogram of salak seed extract shows a prominent peak that corresponds to chlorogenic acid. In vitro studies revealed that salak seeds inhibited α-glucosidase activity and glucose uptake in Caco-2 cells in a concentration-dependent manner, while also exhibiting antioxidant properties. The extract exhibits a non-competitive inhibition on α-glucosidase activity, with an IC50 and Ki of 16.28 ± 7.22 and 24.81 µg/mL, respectively. In vivo studies utilizing streptozotocin-nicotinamide-induced diabetic mice showed that the extract significantly reduced fasting blood glucose (FBG) levels in the oral glucose tolerance test. Continuous administration of the salak seed extract resulted in lower FBG levels by 13.8% as compared with untreated diabetic mice, although this change was not statistically significant. The estimated LD50 value of salak seed extract exceeds 2000 mg/kg, and no toxicity symptoms have been detected. Our research supports that salak seed extract has the potential to serve as a functional food or supplement that may be beneficial in reducing postprandial hyperglycemia among people with type 2 diabetes. This effect was explained by the salak's inhibitory mechanisms of glucose absorption due to inhibition of both α-glucosidase activity and intestinal glucose uptake, coupled with its antioxidant effects.

Residential radon exposure in Astana and Aqsu, Kazakhstan.

A pilot study was carried out to measure indoor radon concentrations in a uranium mining area of northern Kazakhstan. A total of 80 places at kindergartens, elementary schools, and dwellings were selected in Aqsu village and Astana city as the uranium mining area and background area for comparison, respectively. In Astana and Aqsu, the 3-month radon concentrations from late summer to autumn in 2022 were measured using the RADUET passive radon detectors. Radon concentrations ranged from 4 to >2000 Bq m-3(mean ± standard deviation: 290 ± 173 Bq m-3) throughout the study areas. The concentrations were higher in Aqsu, and 70% of the dwellings there exceeded 300 Bq m-3, whereas only 5% of them exceeded 300 Bq m-3in Astana. Accordingly, the new dose conversion factor for radon recommended by International Commission on Radiological Protection Publication 137 was applied to calculate the annual effective dose. The annual effective dose from the inhalation of radon was estimated to be 3.6 ± 4.6 mSv y-1for Astana and 23.7 ± 15.6 mSv y-1, for Aqsu, which are both higher than the world average value of 2.5 mSv y-1.

Association Between Patient Satisfaction and Preoperative Task-Shifting From Anesthesiologists to Perianesthesia Nurses: A Questionnaire Survey Study.

PURPOSE: We examined whether patients' satisfaction improved when patients' preoperative consultations were conducted with perianesthesia nurses (PANs) in collaboration with anesthesiologists, as compared with preoperative consultations conducted by anesthesiologists only. DESIGN: We conducted a study using questionnaires regarding outpatient satisfaction among patients who visited the perioperative management department of Yokohama City University Medical Center between July and December 2018. METHODS: There were 1,595 outpatients during the survey period. After exclusion criteria were applied, we analyzed 590 valid responses. FINDINGS: Regarding the level of understanding, 96.9% of the patients in the nurse-and-anesthesiologist group and 95.6% of the patients in the anesthesiologist-only group answered, "easy to understand," indicating no significant difference. A reduction in concerns, worries, and anxiety was reported by 86.3% of the patients in the nurse-and-anesthesiologist group and 70.4% in the anesthesiologist-only group, indicating a significant difference. Furthermore, 94.1% of the patients in the nurse-and-anesthesiologist group and 87.9% in the anesthesiologist-only group indicated patients' satisfaction with the overall evaluation, indicating another significant difference. A multiple logistic regression analysis was conducted to analyze the anxiety reduction and overall evaluation. We uncovered significant differences in PANs' examinations regarding anxiety reduction and overall evaluation. CONCLUSIONS: Collaboration between anesthesiologists and PANs might be associated with satisfaction and reduced anxiety in preoperative patients without adversely affecting patients' comprehension of anesthesia. Further research is necessary to verify the impacts of PANs' involvement in anesthesia patient care on intra and postoperative patient outcomes and on the cost and efficiency of anesthetic care.

Antihyperglycemic effects of Lysiphyllum strychnifolium leaf extract in vitro and in vivo.

CONTEXT: Lysiphyllum strychnifolium (Craib) A. Schmitz (LS) (Fabaceae) has traditionally been used to treat diabetes mellitus. OBJECTIVE: This study demonstrates the antidiabetic and antioxidant effects of aqueous extract of LS leaves in vivo and in vitro. MATERIALS AND METHODS: The effects of aqueous LS leaf extract on glucose uptake, sodium-dependent glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) mRNA expression in Caco-2 cells, α-glucosidase, and lipid peroxidation were evaluated in vitro. The antidiabetic effects were evaluated using an oral glucose tolerance test (OGTT) and a 28-day consecutive administration to streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic mice. RESULTS: The extract significantly inhibited glucose uptake (IC50: 236.2 ± 36.05 µg/mL) and downregulated SGLT1 and GLUT2 mRNA expression by approximately 90% in Caco-2 cells. Furthermore, it non-competitively inhibited α-glucosidase in a concentration-dependent manner with the IC50 and Ki of 6.52 ± 0.42 and 1.32 µg/mL, respectively. The extract at 1000 mg/kg significantly reduced fasting blood glucose levels in both the OGTT and 28-day consecutive administration models as compared with untreated STZ-NA-induced diabetic mice (p < 0.05). Significant improvements of serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and GLUT4 levels were observed. Furthermore, the extract markedly decreased oxidative stress markers by 37-53% reduction of superoxide dismutase 1 (SOD1) in muscle and malondialdehyde (MDA) in muscle and pancreas, which correlated with the reduction of MDA production in vitro (IC50: 24.80 ± 7.24 µg/mL). CONCLUSION: The LS extract has potent antihyperglycemic activity to be used as alternative medicine to treat diabetes mellitus.

Effects of wearing surgical masks on fraction of inspired oxygen in spontaneously breathing patients: improving safety for frontline healthcare professionals under pandemic situations.

BACKGROUND: During pandemic situations, many guidelines recommend that surgical masks be worn by both healthcare professionals and infected patients in healthcare settings. The purpose of this study was to clarify the levels and changes of oxygen concentration over time while oxygen was administered over a surgical mask. METHODS: Patients scheduled to undergo general anesthesia (n = 99) were enrolled in this study. First, patients were administered oxygen at 6 L/min via an oxygen mask over a surgical mask for 5 min. The patients removed the surgical mask and then took a 3-min break; thereafter, the same amount of oxygen was administered for another 5 min via the oxygen mask. We measured the fraction of inspired oxygen (FiO2), the end-tidal CO2 (EtCO2), and respiratory frequency every minute for 5 min, both while administering oxygen with and without a surgical mask. The FiO2 was measured at the beginning of inspiration and the EtCO2 was measured at the end of expiration. RESULTS: The FiO2 at 5 min was significantly lower when breathing with a surgical mask than that without it (mean difference: 0.08 [95% CI: 0.067-0.10]; p <  0.001). In contrast, the EtCO2 at 5 min was significantly higher when breathing with a surgical mask than that without it (mean difference: 11.9 mmHg [95% CI: 10.9-12.9]; p <  0.001). CONCLUSION: The FiO2 was lower when oxygen was administered over surgical masks than when patients did not wear surgical masks. Oxygen flow may need to be adjusted in moderately ill patients requiring oxygen administration.

Changes in oral function, swallowing function, and quality of life in patients with head and neck cancer: a prospective cohort study.

BACKGROUND: Head and neck cancer (HNC) treatment can cause oral morbidities, such as oral dryness and dysphagia, affecting the patient's quality of life (QOL). The relationship between oral functions and QOL in patients with early-stage HNC remains poorly studied. This study aimed to evaluate changes in the QOL of patients with early-stage HNC and identify factors that affect the QOL of these patients. METHODS: In this prospective cohort study, 37 patients who underwent early-stage (Stage I/Stage II) HNC treatment were evaluated for their oral function, swallowing function, and the QOL score at baseline (BL) and 12 months after surgical treatment (12 M). The participants were divided into two groups: patients who returned to the BL QOL score at 12 M (RE; n = 26) and those who did not (NR; n = 11). RESULTS: In total, 29.7% (11/37) patients with early-stage HNC did not return to the BL QOL score at 12 M. There was no significant difference between the RE and NR groups regarding the oral and swallowing function. Moreover, oral and swallowing function of all patients returned to the BL at 12 M. The NR group showed lower QOL scores than the RE group in the global health status, and "sticky saliva" parameters in the questionnaires. CONCLUSION: Restoration of the oral function is insufficient to improve the QOL of patients with early-stage HNC. The treatment of these patients should instead consider several factors that affect their QOL.

Mapping of QTLs controlling epicotyl length in adzuki bean (Vigna angularis).

Epicotyl length (ECL) of adzuki bean (Vigna angularis) affects the efficiency of mechanized weeding and harvest. The present study investigated the genetic factors controlling ECL. An F2 population derived from a cross between the breeding line 'Tokei1121' (T1121, long epicotyls) and the cultivar 'Erimo167' (common epicotyls) was phenotyped for ECL and genotyped using simple sequence repeats (SSRs) and single-nucleotide polymorphism (SNP) markers. A molecular linkage map was generated and fifty-two segregating markers, including 27 SSRs and 25 SNPs, were located on seven linkage groups (LGs) at a LOD threshold value of 3.0. Four quantitative trait loci (QTLs) for ECL, with LOD scores of 4.0, 3.4, 4.8 and 6.4, were identified on LGs 2, 4, 7 and 10, respectively; together, these four QTLs accounted for 49.3% of the phenotypic variance. The segregation patterns observed in F5 residual heterozygous lines at qECL10 revealed that a single recessive gene derived from T1121 contributed to the longer ECL phenotype. Using five insertion and deletion markers, this gene was fine mapped to a ~255 kb region near the end of LG10. These findings will facilitate marker-assisted selection for breeding in the adzuki bean and contribute to an understanding of the mechanisms associated with epicotyl elongation.

Characteristic evaluation of a simple hand-made semiconductor dosimeter for mammography.

Daily quality control of mammography equipment is important for providing optimal images and determining appropriate doses. To popularise dosimeters, the Measurement Division, the Japanese Society of Radiological Technology hold a seminar on making simple dosimeters. At this seminar, a hand-made dosimeter for mammography (HD-M) can be made at low cost. However, HD-Ms employ semiconductors, and their energy responses are subject to significant variations. This investigation involved the determination of precautions when using HD-Ms, examining their energy response characteristics and measurable energy ranges. HD-M has four types of selectors for response correction. When the selector and the tube voltage were equal, the HD-M readings matched that of the ionisation chamber within 5%. However, in case of target filter combinations and measuring tube voltages that the selector does not support, the HD-M readings differed by up to 53% from the ionisation chamber values. HD-M may use different measurement circuits and semiconductor elements depending on the time of the seminar. In this study, it was clarified that the correction factork, which is the average value of the ratio of the measured value of the ionisation chamber dosimeter to the measured value of HD-M, changes from 0.62 to 1.53 depending on irradiation conditions such as the combination of target filters and the tube voltage. It was demonstrated that HD-M functions sufficiently as a dosimeter for daily management by determining the correction factor using the method proposed in this study.

Occupational eye lens dose in endoscopic retrograde cholangiopancreatography using a dedicated eye lens dosimeter.

Increased x-ray exposure to physicians' eye lenses during radiology procedures is a significant concern. In this study, x-ray exposure to the eye was measured using an anthropomorphic head phantom, with and without radiation-protective devices, to examine the dose of x-ray radiation that physicians are exposed to during endoscopic retrograde cholangiopancreatography (ERCP). X-ray exposure of the eye was measured using novel dedicated direct eye lens dosimeters that could specifically measureHp(3) during the ERCP procedure. The spatial dose in the height direction of the physician was measured using an ionization chamber dosimeter. Eye dosimeters were attached inside and outside the lead (Pb) glasses attached to the head of the human phantom to demonstrate its protective effect. Irradiation from the system lasted for 30 min. When the overcouch x-ray tube system is used, the cumulative radiation dose over the 30 min x-ray fluoroscopy time, without the use of radiation-protective devices, to the left and right eyes was 3.7 and 1.5 mSv, respectively. This dose was estimated to be the dose to the lens per therapeutic ERCP examination. With radiation-protective glasses, the dose reduced to 1.8 and 1.0 mSv for the left and right eye, respectively. The results of our study indicated that radiation exposure to the eye was reduced by up to 80.0% using Pb glasses and by 96.8% using radiation-protective curtains. Our study indicates that a physician's maximum radiation exposure to the eyes during an ERCP procedure may be above the level recommended by the International Commission on Radiological Protection when the physician does not use radiation-protective devices. The eyewear, which is larger and fitted more closely to the face, provided a better protection effect even with a low lead equivalence, demonstrating that the shape of eyewear is important for protective function.

Industrialization of Developing Economies in the Global Economy with an Infectious Disease.

Manufacturing has long been the center of industrialization strategies for poor developing countries. This article first investigates the effects of labor supply constraints on industrialization, which may have been caused by the coronavirus disease 2019 (COVID-19). Then, it examines how manufacturing automation could affect industrialized developing economies based on the premise that manufacturers may accelerate production automation in response to the COVID-19 pandemic. The model predicts declines in developing economies' manufacturing competitiveness and a heterogeneous pattern of recovery from the COVID-19 recession. In comparison, developing economies with large manufacturing bases would recover relatively quickly, whereas those with weaker manufacturing bases would suffer from a long-term decline and manufacturing contraction trends (undesirable deindustrialization). Manufacturing automation can enhance economic welfare, causing a contraction in the unproductive nontradable good (service) sector. However, with low labor mobility, the welfare effect is ambiguous, thereby widening the wage gap between skilled and unskilled labor.

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma.

PURPOSE: Immune-related adverse events (irAEs) have been associated with the efficacy of programmed cell death protein 1 (PD-1) inhibitors in patients with urothelial cancer. We therefore evaluated the relationship between irAEs and pembrolizumab efficacy in urothelial cancer patients. METHODS: Patients with urothelial cancer who were treated with pembrolizumab in a second-line setting or later between January 2018 and December 2018 were identified by reviewing their medical records from the Cancer Institute Hospital, Japanese Foundation for Cancer Research. Data were updated as of December 31, 2018. Kaplan-Meier curves for overall survival (OS) and time to treatment failure (TTF) according to irAE grade were evaluated using the log-rank test. Risk factors for exacerbation of irAEs were also evaluated with multivariate analysis. RESULTS: In this retrospective study, 43 patients received pembrolizumab. We identified irAEs in 22 of the 43 patients (51.2%), including 11 patients (25.6%) with grade 2 or 3 events. In patients with irAE grade 0 or 1, median TTF was 127 days, and median OS was 160 days according to the Kaplan-Meier method. On the other hand, in patients with irAE grade ≥2, median TTF and OS were not reached. Multivariate analysis also revealed that risk factors for exacerbation of irAEs (to grade ≥2) were positively associated with lymphocyte count at baseline (>2,000/µL) before pembrolizumab treatment (p = 0.021). CONCLUSIONS: Development of irAEs was associated with survival outcome of pembrolizumab treatment in patients with advanced urothelial cancer.

Internal doses in experimental mice and rats following exposure to neutron-activated 56MnO2 powder: results of an international, multicenter study.

The experiment was performed in support of a Japanese initiative to investigate the biological effects of irradiation from residual neutron-activated radioactivity that resulted from the A-bombing. Radionuclide 56Mn (T1/2 = 2.58 h) is one of the main neutron-activated emitters during the first hours after neutron activation of soil dust particles. In our previous studies (2016-2017) related to irradiation of male Wistar rats after dispersion of 56MnO2 powder, the internal doses in rats were found to be very inhomogeneous: distribution of doses among different organs ranged from 1.3 Gy in small intestine to less than 0.0015 Gy in some of the other organs. Internal doses in the lungs ranged from 0.03 to 0.1 Gy. The essential pathological changes were found in lung tissue of rats despite a low level of irradiation. In the present study, the dosimetry investigations were extended: internal doses in experimental mice and rats were estimated for various activity levels of dispersed neutron-activated 56MnO2 powder. The following findings were noted: (a) internal radiation doses in mice were several times higher in comparison with rats under similar conditions of exposure to 56MnO2 powder. (b) When 2.74 × 108 Bq of 56MnO2 powder was dispersed over mice, doses of internal irradiation ranged from 0.81 to 4.5 Gy in the gastrointestinal tract (small intestine, stomach, large intestine), from 0.096 to 0.14 Gy in lungs, and doses in skin and eyes ranged from 0.29 to 0.42 Gy and from 0.12 to 0.16 Gy, respectively. Internal radiation doses in other organs of mice were much lower. (c) Internal radiation doses were significantly lower in organs of rats with the same activity of exposure to 56MnO2 powder (2.74 × 108 Bq): 0.09, 0.17, 0.29, and 0.025 Gy in stomach, small intestine, large intestine, and lungs, respectively. (d) Doses of internal irradiation in organs of rats and mice were two to four times higher when they were exposed to 8.0 × 108 Bq of 56MnO2 (in comparison with exposure to 2.74 × 108 Bq of 56MnO2). (e) Internal radiation doses in organs of mice were 7-14 times lower with the lowest 56MnO2 amount (8.0 × 107 Bq) in comparison with the highest amount, 8.0 × 108 Bq, of dispersed 56MnO2 powder. The data obtained will be used for interpretation of biological effects in experimental mice and rats that result from dispersion of various levels of neutron-activated 56MnO2 powder, which is the subject of separate studies.

Efficacy of an email-based recording and reminding system for limiting daytime non-functional tooth contact in patients with temporomandibular disorders: A randomized controlled trial.

BACKGROUND: Oral parafunctional activities such as daytime non-functional tooth contact (nFTC) are considered aetiological factors for temporomandibular disorders (TMD). OBJECTIVES: To evaluate the effectiveness of an email-based recording and reminding system for limiting daytime nFTC in patients with TMDs. METHODS: Thirty patients with TMDs (mean age, 30.7 ± 8.7 years) were randomly assigned to three groups according to the intervention for limiting nFTC: cognitive behavioural therapy (CBT) with an email-based recording and reminding system for 20 days (e-CBT group, n = 10), CBT with a sticky note reminder for 20 days (s-CBT group, n = 10) and simple verbal instructions to avoid nFTC that were provided before the experimental period (control group, n = 10). The frequency of nFTC, range of pain-free unassisted mouth opening and pain intensity during painful unassisted maximum mouth opening was evaluated before and after the experimental period. RESULTS: The frequency of nFTC significantly decreased after the intervention in the e-CBT and s-CBT groups. Among the three groups, the decrease in the nFTC frequency was the maximum in the e-CBT group (P < .01). In addition, the range of pain-free unassisted mouth opening showed a significant increase in all three groups, with the maximum improvement in the e-CBT group (analysis of variance, P < .01). CONCLUSIONS: The present findings suggest that our email-based recording and reminding system may have the potential to effectively control daytime nFTC and could be an effective strategy for the management of TMDs.

Individual optimal dose of amrubicin to prevent severe neutropenia in Japanese patients with lung cancer.

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.

Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer.

PURPOSE: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC). METHODS: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2). CONCLUSIONS: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.

Effectiveness of Magnesium in Preventing Shivering in Surgical Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Clinical trials regarding the antishivering effect of perioperative magnesium have produced inconsistent results. We conducted a systematic review and meta-analysis with Trial Sequential Analysis to evaluate the effect of perioperative magnesium on prevention of shivering. METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and 2 registry sites for randomized clinical trials that compared the administration of magnesium to a placebo or no treatment in patients undergoing surgeries. The primary outcome of this meta-analysis was the incidence of shivering. The incidence of shivering was combined as a risk ratio with 95% CI using a random-effect model. The effect of the route of administration was evaluated in a subgroup analysis, and Trial Sequential Analysis with a risk of type 1 error of 5% and power of 90% was performed. The quality of each included trial was evaluated, and the quality of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation approach. We also assessed adverse events. RESULTS: Sixty-four trials and 4303 patients (2300 and 2003 patients in magnesium and control groups, respectively) were included. The overall incidence of shivering was 9.9% in the magnesium group and 23.0% in the control group (risk ratio, 0.42; 95% CI, 0.33-0.52). Subgroup analysis revealed that the incidence of shivering was lower with IV (risk ratio, 0.29; 95% CI, 0.29-0.54; Grading of Recommendation Assessment, Development, and Evaluation, moderate), epidural (risk ratio, 0.24; 95% CI, 0.13-0.43; Grading of Recommendation Assessment, Development, and Evaluation, low), and intrathecal administration (risk ratio, 0.64; 95% CI, 0.43-0.96; Grading of Recommendation Assessment, Development, and Evaluation, moderate). Only trials with low risk of bias were included for Trial Sequential Analysis. The Z-cumulative curve for IV magnesium crossed the Trial Sequential Analysis monitoring boundary for benefit even though only 34.9% of the target sample size had been reached. The Z-cumulative curve for epidural or intrathecal administration did not cross the Trial Sequential Analysis monitoring boundary for benefit. No increase in adverse events was reported. CONCLUSIONS: Perioperative IV administration of magnesium effectively reduced shivering and Trial Sequential Analysis suggested that no more trials are required to confirm that IV magnesium effectively reduces shivering.

Effects of exercise therapy on painful temporomandibular disorders.

Temporomandibular disorders (TMD) are common chronic musculoskeletal pain conditions among orofacial pain. Painful TMD condition such as myalgia and arthralgia can be managed by exercise therapy. However, as it is hard to access actual effect of each modality that is included in an exercise therapy programme due to multiple choice of the management modality, their efficacy remains controversial. Therefore, this review focused on the effects of exercise therapy for the management of painful TMD. The aims of this review were to summarise the effects of exercise therapy for major symptoms of painful TMD and to establish a guideline for the management of painful TMD, resulting in higher quality and reliability of dental treatment. In this review, exercise modalities are clearly defined as follows: mobilisation exercise, muscle strengthening exercise (resistance training), coordination exercise and postural exercise. Furthermore, pain intensity and range of movements were focused as outcome parameters in this review. Mobilisation exercise including manual therapy, passive jaw mobilisation with oral appliances and voluntary jaw exercise appeared to be a promising option for painful TMD conditions such as myalgia and arthralgia. This review addressed not only the effects of exercise therapy on various clinical conditions of painful TMD shown in the past, but also an urgent need for consensus among dentists and clinicians in terms of the management of each condition, as well as terminology.

Accuracy of the ClearSight™ system in patients undergoing abdominal aortic aneurysm surgery.

PURPOSE: The ClearSight™ device monitors continuous pressure and cardiac output via pulse contour analysis. ClearSight™, however, may not be reliable in patients with reduced peripheral perfusion caused by high peripheral resistance. This study aimed to elucidate the accuracy and trending ability of ClearSight™ in patients undergoing abdominal aortic aneurysm (AAA) surgery by comparing the ClearSightTM-derived cardiac index (CICS) with that measured using three-dimensional echocardiography (CI3D). METHODS: The study included 20 patients who underwent elective AAA surgery. CICS and CI3D were measured simultaneously at eight time points during the surgery. Trending ability was investigated after aortic clamping and unclamping. We used CI3D as the reference method. RESULTS: Bland-Altman analysis showed a wide limit of agreement between CICS and CI3D (percentage error 41.3%). Subgroup analysis showed a lower percentage error (33.2%) in patients with CI ≥ 2.5 L/min/m2. The cubic splines related to the CI3D and CI discrepancy were negatively sloped, indicating that CI3D had significant influence on the CI discrepancy (p < 0.001). Four-quadrant plot analysis showed that the tracking ability of ClearSight™ after aortic clamping and declamping were clinically unacceptable (81.3% and 78.6%, respectively). Also, the polar plot analysis showed that the concordance rate of ClearSight™ after aortic clamping and declamping were clinically unacceptable (58.3% and 66.7%, respectively). CONCLUSIONS: ClearSight™ was not sufficiently accurate in patients undergoing AAA surgery. The tracking ability of ClearSight™ after aortic clamping was below the acceptable limit.

Identification of CCL5/RANTES as a novel contraction-reducible myokine in mouse skeletal muscle.

Skeletal muscle is an endocrine organ that secretes several proteins, which are collectively termed myokines. Although many studies suggest that exercise regulates myokine secretion, the underlying mechanisms remain unclear and all the exercise-dependent myokines have not yet been identified. Therefore, in this study, we attempted to identify novel exercise-dependent myokines by using our recently developed in vitro contractile model. Differentiated C2C12 myotubes were cultured with or without electrical pulse stimulation (EPS) for 24 h to induce cell contraction, and the myokines secreted in conditioned medium were analyzed using a cytokine array. Although most myokine secretions were not affected by EPS, the secretion of Chemokine (C-C motif) ligand 5 (CCL5) (regulated on activation, normal T cell expressed and secreted (RANTES)) was significantly reduced by EPS. This was further confirmed by ELISA and quantitative PCR. Contraction-dependent calcium transients and activation of 5'-AMP activating protein kinase (AMPK) appears to be involved in this decrease, as the chelating Ca2+ by EGTA blocked contraction-dependent CCL5 reduction, whereas the pharmacological activation of AMPK significantly reduced it. However, Ccl5 gene expression was increased by AMPK activation, suggesting that AMPK-dependent CCL5 decrease occurred via post-transcriptional regulation. Finally, mouse experiments revealed that voluntary wheel-running exercise reduced serum CCL5 levels and Ccl5 gene expression in the fast-twitch muscles. Overall, our study provides the first evidence of an exercise-reducible myokine, CCL5, in the mouse skeletal muscle. Although further studies are required to understand the precise roles of the skeletal muscle cell contraction-induced decrease in CCL5, this decrease may explain some exercise-dependent physiological changes such as those in immune responses.