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Abstract Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the “Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit” to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions. Graphical Abstract

Passive smoking from environmental tobacco smoke not only increases the risk of lung cancer and cardiovascular disease but may also be a stressor triggering neuropsychiatric and other disorders. To prevent these diseases, understanding the relationship between passive smoking and stress is vital. In this study, we developed a simple and sensitive method to simultaneously measure nicotine (Nic) and cotinine (Cot) as tobacco smoke exposure biomarkers, and cortisol (CRT), serotonin (5-HT), melatonin (MEL), dopamine (DA), and oxytocin (OXT) as stress-related biomarkers. These were extracted and concentrated from saliva by in-tube solid-phase microextraction (IT-SPME) using a Supel-Q PLOT capillary as the extraction device, then separated and detected within 6 min by liquid chromatography–tandem mass spectrometry (LC−MS/MS) using a Kinetex Biphenyl column (Phenomenex Inc., Torrance, CA, USA). Limits of detection (S/N = 3) for Nic, Cot, CRT, 5-HT, MEL, DA, and OXT were 0.22, 0.12, 0.78, 0.39, 0.45, 1.4, and 3.7 pg mL−1, respectively, with linearity of calibration curves in the range of 0.01–25 ng mL−1 using stable isotope-labeled internal standards. Intra- and inter-day reproducibilities were under 7.9% and 14.6% (n = 5) relative standard deviations, and compound recoveries in spiked saliva samples ranged from 82.1 to 106.6%. In thirty nonsmokers, Nic contents positively correlated with CRT contents (R2 = 0.5264, n = 30), while no significant correlation was found with other biomarkers. The standard deviation of intervals between normal beats as the standard measure of heart rate variability analysis negatively correlated with CRT contents (R2 = 0.5041, n = 30). After passive smoke exposure, Nic levels transiently increased, Cot and CRT levels rose over time, and 5-HT, DA, and OXT levels decreased. These results indicate tobacco smoke exposure acts as a stressor in nonsmokers.

Abstract Background This study aimed to identify patients with upper urinary tract urothelial carcinoma (UTUC) having potential Lynch syndrome (pLS) by immunohistochemistry (IHC) of DNA mismatch repair gene-related proteins (MMRPs) and Amsterdam criteria II and explore their clinical characteristics. Methods We retrospectively collected the clinical data of 150 consecutive patients with UTUC who underwent surgical resection at our institution between February 2012 and December 2020, and immunohistochemistry (IHC) of four MMRPs (MLH1, MSH2, MSH6, and PMS2) on all UTUC specimens was performed. Patients who tested positive for Amsterdam criteria (AMS) II and/or IHC screening were classified as having pLS and others as non-pLS, and their characteristics were explored. Results In this study, 5 (3%) and 6 (4%) patients were positive for AMS II and IHC screening, respectively. Two patient were positive for both AMS II and IHC screening, resulting in 9 (6%) patients with pLS. The pLS group was predominantly female (67% vs. 36%; p = 0.0093) and had more right-sided tumors (100% vs. 43%; p = 0.0009) than the non-pLS group. Of the 6 patients who were positive for IHC screening, 4 showed a combined loss of MSH2/MSH6 (n = 3) and MLH1/PMS2 (n = 1). Other two patients showed single loss of MSH6 and PSM2. Conclusions AMS II and IHC screening identified pLS in 6% of patients with UTUC. The IHC screening-positive group tends to have relatively high rate of combined loss, but some patients have single loss. AMS II may overlook patients with LS, and a universal screening may be required for patients with UTUC as well as those with colorectal and endometrial cancer.

Visceral hypersensitivity and leaky gut, which are mediated via corticotropin-releasing factor (CRF) and Toll-like receptor 4 are key pathophysiology of irritable bowel syndrome (IBS). Metformin was reported to improve these gastrointestinal (GI) changes. In this study, we attempted to determine the effects of imeglimin, which was synthesized from metformin on GI function in IBS rat models. Imeglimin blocked lipopolysaccharide- or CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were prevented by compound C or naloxone. These results suggest that imeglimin may be effective for the treatment of IBS by improved visceral sensation and colonic barrier via AMPK and opioid receptor.

Objectives: Few studies examined the association between deterioration of masticatory ability assessed by objective marker and physical function. Therefore, we examined the association between salivary flow rate which is one of the objective and surrogate marker of masticatory ability and lower Timed Up & Go (TUG) performance which is one of major measurement of physical function among aging Japanese. Methods: This cross-sectional study enrolled 464 Japanese aged 60–84 years old. Participants chewed tasteless and odorless gum for 5 min, calculated stimulated salivary flow rate (g/min) during all chews. The 3 m TUG was conducted, and 75th percentile value (6.8 s for men and 7.0 s for women) or higher was defined as lower TUG performance. Logistic regression analysis was used to examine the association between stimulated salivary flow rate and lower TUG performance. Results: We found that the stimulated salivary flow rate tended to be negatively associated with the TUG time. We also observed significant negative association between stimulated salivary flow rate and lower TUG performance; the multivariable-adjusted OR (95% confidence interval, CIs) of lower TUG performance for the highest quartile of stimulated salivary flow rate compared with the lowest quartile was 0.34 (0.16–0.69, P for trend = 0.02). Further adjusting for BMI, the association was attenuated but remaind significant; the OR (95% CIs) in highest quartile was 0.37 (0.18–0.76, P for trend = 0.04). Conclusions: Higher stimulated salivary flow, which means well masticatory ability, was inversely associated with lower TUG performance in the aging Japanese population.

Abstract This paper documents data for global, regional (EU-27), and country-specific (G20 member countries) energy and emission pathways required to achieve a defined carbon budget of between 400 GtCO2 and 500 GtCO2, developed to limit the mean global temperature rise to 1.5 °C, over 50% likelihood. The data were calculated with the 1.5 °C sectorial pathways of the One Earth Climate Model—an integrated energy assessment model devised at the University of Technology Sydney. The data consist of the following six zip-folder datasets (refer to Sect. 2 for an explanation of the data): (1) Appendix folder: Each file contains one worksheet, which summarizes the overall 1.5 °C scenario. (2) Sector folder (XLSX): Each file contains one worksheet, which summarizes the industry sectors analysed. (3) Sector folder (CSV): The data contained are the same as those described in point 2. (4) Sector emissions folder: Each file contains one worksheet, which summarizes the total annual emissions for each industry sector. (5) Scope emissions folder (XLSX): Each file contains one worksheet, which summarizes the total annual emissions for each industry sector—with the additional specificity of emission scope. (6) Scope emissions folder (CSV): The data contained are the same as those described in point 5.

Abstract Aim Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN. Materials and Methods A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial‐mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation. Results DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C‐reactive protein (CRP), CRP‐to‐albumin ratio (CRP/Alb), platelet‐to‐lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery. Conclusions DN in RCC is characterized by NETs production and systemic inflammation.

Background Understanding typical gait development is critical in developing suitable physical therapy methods for gait disorders. This study investigated the developmental changes and controlling mechanisms of straight gait. Methods We conducted an experimental procedure among 90 participants, including 76 typically developing children and 14 healthy adults. The children were divided according to age into 3–4, 5–6, 7–8, and 9-10-year age groups. We created two indices to quantify straight gait using the extrapolated center of mass (XCOM; goal index, XCOMG and actual progress index, XCOMP), which were calculated and compared between the groups. Stepwise multiple regression was used to examine the effects of each gait variable on XCOMG and XCOMP. To eliminate the effects of multicollinearity, correlation coefficients were calculated for all gait variables. Results Both XCOMG and XCOMP decreased gradually with age and were significantly larger in the 3–4 and 5–6 year groups than in the adult group. Multiple regression analysis showed that step velocity, step width, and the coefficiente of variation (CV) of the step width had independent coefficients of variation for the XCOMG, and the symmetry index of step time, step width, and the CV of the step width had independent CV for the XCOMP. These variables were selected as significant variables. The results showed that meandering gait was more pronounced at younger ages. Furthermore, straight gait observed in adulthood was achieved by the age of 7. Conclusion Pace (step velocity) and stability (step width and CV of step width) may contribute to XCOMG, which assesses the ability to proceed in the direction of the target. Stability and symmetry may contribute to XCOMP, which assesses the ability to walk straight in one’s own direction of progress. Physical therapists could apply these indices in children to assess their ability to walk straight.

Visceral hypersensitivity and impaired gut barrier are crucial pathophysiology of irritable bowel syndrome (IBS), and injection of lipopolysaccharide or corticotropin-releasing factor, and repeated water avoidance stress simulate these gastrointestinal changes in rat (IBS models). We previously demonstrated that losartan, an angiotensin II type 1 (AT1) receptor antagonist prevented these changes, and we attempted to determine the effects of EMA401, an AT2 receptor antagonist in the current study. EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS.

Knowledge about the developmental process of dynamic balance control comprised of upper arms and upper legs coordination and trunk and pelvis twist coordination is important to advance effective balance assessment for abnormal development. However, the mechanisms of these coordination and stability control during gait in childhood are unknown.This study examined the development of dynamic postural stability, upper arm and upper leg coordination, and trunk and pelvic twist coordination during gait, and investigated the potential mechanisms integrating the central nervous system with inter-limb coordination and trunk and pelvic twist coordination to control extrapolated center of the body mass (XCOM). This study included 77 healthy children aged 3–10 years and 15 young adults. The child cohort was divided into four groups by age: 3–4, 5–6, 7–8, and 9–10 years. Participants walked barefoot at a self-selected walking speed along an 8 m walkway. A three-dimensional motion capture system was used for calculating the XCOM, the spatial margin of stability (MoS), and phase coupling movements of the upper arms, upper legs, trunk, and pelvic segments. MoS in the mediolateral axis was significantly higher in the young adults than in all children groups. Contralateral coordination (ipsilateral upper arm and contralateral upper leg combination) gradually changed to an in-phase pattern with increasing age until age 9 years. Significant correlations of XCOMML with contralateral coordination and with trunk and pelvic twist coordination (trunk/pelvis coordination) were found. Significant correlations between contralateral coordination and trunk/pelvis coordination were observed only in the 5–6 years and at 7–8 years groups.Dynamic postural stability during gait was not fully mature at age 10. XCOM control is associated with the development of contralateral coordination and trunk and pelvic twist coordination. The closer to in-phase pattern of contralateral upper limb coordination improved the XCOM fluctuations. Conversely, the out-of-phase pattern (about 90 degrees) of the trunk/pelvis coordination increased theXCOM fluctuation. Additionally, a different control strategy was used among children 3–8 years of age and individuals over 9 years of age, which suggests that 3–4-year-old children showed a disorderly coordination strategy between limb swing and torso movement, and in children 5–8 years of age, limb swing depended on trunk/pelvis coordination.

Objectives: Surface pre-reacted glass-ionomer (S-PRG) fillers release antibacterial borate and fluoride ions. We fabricated nanoscale S-PRG fillers (S-PRG nanofillers) for antibacterial coating of tooth surfaces and assessed the antibacterial effects of this coating in vitro. In addition, we creating a canine model of periodontitis to evaluate the effectiveness of S-PRG nanofiller application on tooth roots and improvement of periodontal parameters. Methods: Human dentin blocks were coated with S-PRG nanofiller (average particle size: 0.48 μm) and then characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectrometer (EDX), and ion-releasing test. Antibacterial effects of dentin blocks coated with S-PRG nanofiller were examined using bacterial strains, Streptococcus mutans and Actinomyces naeslundii. Next, we created an experimental model of periodontitis in furcation of premolars of beagle dogs. Then, S-PRG nanofiller coating was applied onto exposed tooth root surfaces. Periodontal parameters, gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL), were measured from baseline until 4 weeks. In addition, bone healing was radiographically and histologically examined. Results: SEM and EDX revealed that S-PRG nanofillers uniformly covered the dentin surface after coating. Dentin blocks coated with S-PRG nanofiller showed ion-releasing property, bacterial growth inhibition, and sterilization effects. In the experimental periodontitis model, S-PRG nanofiller coating significantly reduced clinical inflammatory parameters, such as GI (P < 0.01) and BOP (P < 0.05), compared to uncoated samples. In addition, PPD and CAL significantly decreased by S-PRG nanofiller coating (2 weeks: P < 0.05; 3 and 4 weeks: P < 0.01), suggesting the improvement of periodontitis. Micro-CT and histology revealed that bone healing of furcation defects was enhanced by S-PRG nanofiller coating. Conclusion: S-PRG nanofiller coating provides antibacterial effects to tooth surfaces and improves clinical parameters of periodontitis.

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment. Keywords: Pioglitazone, Visceral sensation, Gut permeability

Background: Collagen is a basic component of the periodontium and plays an important role in the function of the periodontal unit. Therefore, coating with collagen/gelatin has been applied to enable dental implants to positively interact with peri-implant tissues. Although the micro/nanoscale topography is an important property of the surface of dental implants, smaller collagen/gelatin surface patterns have not been sufficiently developed. Furthermore, only few reports on the behavior of cells on gelatin surfaces with different patterns and sizes exist. In this study, we developed micro/nanometer-scaled gelatin surfaces using genipin crosslinking, with the aim of understanding the use of patterning in surface modification of dental implants.Results: Grooves, holes, and pillars, with widths or diameters of 2 µm, 1 µm, or 500 nm were fabricated using a combination of molding and genipin crosslinking of gelatin. The stability of the different gelatin patterns could be controlled by the degree of genipin crosslinking. The gelatin patterns at 20 mM concentration of genipin and 41% crosslinking maintained a stable, patterned shape for at least 14 days in a cell culture medium. A cell morphology study showed that the cells on groves were aligned along the direction of the grooves. In contrast, the cells on pillars and holes exhibited randomly elongated filopodia. The vinculin spots of the cells were observed on the top of ridges and pillars or the upper surface of holes. The results of a cell attachment assay showed that the number of surface-attached cells increased with increasing patterning of the gelatin surface. Unlike the cell attachment assay, the results of a cell proliferation assay showed that Saos-2 cells prefer grooves with diameters of approximately 2 µm and 1 µm and pillars with diameters of 1 µm and heights of 500 nm. The number of cells on pillars with heights of 2 µm was larger than those of the other gelatin surface patterns tested.Conclusion: These data support that a detailed design of the gelatin surface pattern can control both cell attachment and proliferation of Saos-2 cells. Thus, gelatin surfaces patterned using genipin crosslinking are now an available option for biocompatible material patterning.

Background and study aims No recommendations are available for optimal number of endoscopic biopsies for early gastric cancer (GC), and whether detection of early GC is improved by increasing the number of biopsy is unclear. We therefore evaluated the relationship between number of biopsies and diagnostic accuracy. Materials and methods We retrospectively evaluated 858 early GCs (623 from endoscopic submucosal dissection and 235 surgical specimens), which we classified as obtained after one, two, or three or more biopsies. We assessed diagnostic accuracy by number of biopsies, and in subgroups by tumor diameter, gross type, and surface color. Results Almost half the lesions were obtained after one biopsy each, 30 % after two biopsies, and 20 % after three or more biopsies. Although diagnostic accuracy increased with biopsy number, it was significantly greater for the two-biopsy group than the one-biopsy group, (92.5 % vs. 83.9 %, P = 0.0009), but did not significantly differ between the two- and three or more-biopsy groups. This finding was seen when tumors were evaluated by size, but not by elevated type and surface color, for which more biopsies did not improve diagnostic accuracy. Multivariate analysis demonstrated that two or more biopsies was the independent significant factors for diagnostic accuracy. Conclusions Two biopsies are the optimal number required to diagnose early GC.

Levodopa possesses antinociceptive actions against several somatic pain conditions. However, we do not know at this moment whether levodopa is also effective to visceral pain. The present study was therefore performed to clarify whether levodopa is effective to visceral pain and its mechanisms. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously (80 mg/rat) or intracisternally (2.5 μg/rat) administered levodopa significantly increased the threshold of colonic distension-induced AWR in conscious rats. The dose difference to induce the antinociceptive action suggests levodopa acts centrally to exert its antinociceptive action against colonic distension. While neither sulpiride, a D2 dopamine receptor antagonist, nor SCH23390, a D1 dopamine receptor antagonist by itself changed the threshold of colonic distension-induced AWR, the intracisternally injected levodopa-induced antinociceptive action was significantly blocked by pretreatment with subcutaneously administered sulpiride but not SCH23390. Treatment with intracisternal SB334867, an orexin 1 receptor antagonist, significantly blocked the subcutaneously administered levodopa-induced antinociceptive action. These results suggest that levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain.

Calcium phosphate (CaP) coating is an effective method for surface-functionalization of bioinert materials and for production of osteoconductive implants. Recently, we developed a laser-assisted biomimetic process (LAB process) for facile and area-specific CaP coating. In this study, the LAB process was applied to chemically stable and mechanically durable poly(etheretherketone) (PEEK), which has become widely used as an orthopedic and dental implant material. The LAB process was carried out by irradiating pulsed Nd:YAG laser light (355 nm) onto a PEEK substrate that was immersed in supersaturated CaP solution. The CaP coating applicability depended on laser fluence, i.e., CaP successfully formed on PEEK surface after the LAB process at 2 W/cm2. Further increase in laser fluence did not result in the successful formation. At the optimal fluence of 2 W/cm2, the laser-irradiated PEEK surface was modified and heated to induce heterogeneous CaP precipitation within 10 min in CaP solution, followed by further CaP growth over the irradiation time (tested up to 30 min). The LAB process improved the cytocompatibility of PEEK surface with osteoblastic MC3T3-E1 cells. Furthermore, the LAB-processed CaP-coated PEEK substrate formed a dense hydroxyapatite layer on its surface in the simulated body fluid, suggesting the osteoconductivity of this material. The present LAB process can be a useful new tool to produce osteoconductive PEEK-based implants.

The molecular mechanism for meiotic entry remains largely elusive in flowering plants. Only Arabidopsis SWI1/DYAD and maize AM1, both of which are the coiled-coil protein, are known to be required for the initiation of plant meiosis. The mechanism underlying the synchrony of male meiosis, characteristic to flowering plants, has also been unclear in the plant kingdom. In other eukaryotes, RNA-recognition-motif (RRM) proteins are known to play essential roles in germ-cell development and meiosis progression. Rice MEL2 protein discovered in this study shows partial similarity with human proline-rich RRM protein, deleted in Azoospermia-Associated Protein1 (DAZAP1), though MEL2 also possesses ankyrin repeats and a RING finger motif. Expression analyses of several cell-cycle markers revealed that, in mel2 mutant anthers, most germ cells failed to enter premeiotic S-phase and meiosis, and a part escaped from the defect and underwent meiosis with a significant delay or continued mitotic cycles. Immunofluorescent detection revealed that T7 peptide-tagged MEL2 localized at cytoplasmic perinuclear region of germ cells during premeiotic interphase in transgenic rice plants. This study is the first report of the plant RRM protein, which is required for regulating the premeiotic G1/S-phase transition of male and female germ cells and also establishing synchrony of male meiosis. This study will contribute to elucidation of similarities and diversities in reproduction system between plants and other species.