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Abstract The immune system has garnered attention due to its association with disease progression in amyotrophic lateral sclerosis (ALS). However, the role of peripheral immune cells in this context remains controversial. Here, we conducted single-cell RNA-sequencing of peripheral blood mononuclear cells to comprehensively profile immune cells concerning the rate of disease progression in patients with ALS. Our analysis revealed increased frequencies of T helper 17 cells (Th17) relative to regulatory T cells, effector CD8 T cells relative to naïve CD8 T cells, and CD16highCD56low mature natural killer cells relative to CD16lowCD56high naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.

Abstract Background Primary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS. Methods We enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews. Results The Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992–0.999). Conclusions This study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews.

BackgroundThe rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS.MethodsWe collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses.ResultsIn total, 26 proteins changed significantly (p 1.5 or

Abstract Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child–Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.

Currently, no drugs directly treat liver fibrosis. Previously, we have shown that treatment with miR-29a-3p improved liver fibrosis in a mouse model. To investigate the effectiveness of nucleic acid therapy at a lower dose, a modified nucleic acid was prepared based on miR-29a-3p. The original microRNA was changed to an RNA-DNA hybrid structure: the 2′ position of the RNA was modified with a fluorine base, and locked nucleic acid and phosphorothioate were crosslinked (hereafter called modified nucleic acid). In a mouse model of chronic liver disease treated with carbon tetrachloride (CCl4), the inhibitory effect on liver fibrosis was evaluated with oral administration of the modified nucleic acid. The modified nucleic acid was detected in the liver and gastrointestinal tract within 15 min of oral administration. After 5 weeks of stimulation with CCl4, oral administration of the modified nucleic acid for 2 weeks improved liver fibrosis; CCl4 stimulation was continued during this period as well. This treatment also suppressed the worsening of liver fibrosis. We developed a method to improve liver fibrosis orally using nuclease-resistant nucleic acids without using a drug delivery system. This method may be used as a new treatment for inhibiting the progression of liver fibrosis.

Introduction Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.Methods and analysis An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.Ethics and dissemination This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.Trial Registration number jRCT2051220002; Pre-results, NCT04744532; Pre-results

Abstract Background Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established. Aim To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies. Methods We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment. Results In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p

Abstract While the short-term relationship between clouds and aerosols is well known, no adequate data is available to verify the longer-term, annual to decadal, relationship. It is important to quantify the aerosol–cloud interaction (ACI) for mitigating uncertainty in climate prediction. Here the long-term ACI over the mid-to-high latitudes of the Northern Hemisphere was analyzed by using seasonally-resolved ion fluxes reconstructed from a southeastern Greenland ice core (SE-Dome ice core) as aerosol proxies, and satellite-based summer cloud amount between 1982 and 2014. As a result, SO4 2− flux in the ice core shows significant positive correlation with total cloud amounts ( $${CC}_{T}$$ CC T ) and cloud droplet concentration ( $${N}_{d}$$ N d ) in the summer over the southeastern Greenland Sea, implying that the sulfate aerosols may contribute to the variability of $${CC}_{T}$$ CC T via microphysical cloud processes. Significant positive correlations are persistent even under the constrained conditions when cloud formation factors such as relative humidity, air temperature at cloud height, and summer North Atlantic Oscillation are limited within ± 1σ variability. Hence sulfate aerosols should control the interannual variability of summer $${CC}_{T}$$ CC T In terms of decadal changes, $${CC}_{T}$$ CC T was approximately 3–5% higher in the 1960s–1970s than in the 1990s–2000s, which can be explained by changes in the, $${{{\text{SO}}}_{4}}^{2-}$$ SO 4 2 - flux preserved in the SE-Dome ice core.

Background: Cardiac amyloidosis is a fatal disease of severe heart failure caused by the accumulation of amyloid in the myocardium. This disease is often advanced by the time cardiac symptoms appear; therefore, early detection and treatment are critical for a good prognosis. Recently, it has been suggested that cardiac amyloidosis is implicated in several orthopedic diseases, including carpal tunnel syndrome (CTS), which is often reported to precede cardiac dysfunction. Shoulder disease has also been suggested to be associated with cardiac amyloidosis; however, there have been no reports investigating the rate of amyloid deposition in shoulder specimens and the simultaneous prevalence of cardiac amyloidosis. Herein, we investigated the prevalence of intraoperative specimen amyloid deposition and cardiac amyloidosis in shoulder disease and CTS to determine the usefulness of shoulder specimen screening as a predictor of cardiac amyloidosis development. Methods: A total of 41 patients undergoing arthroscopic shoulder surgery and 33 patients undergoing CTS surgery were enrolled in this study. The shoulder group included rotator cuff tears, contracture of the shoulder, synovitis, and calcific tendonitis. In the shoulder group, a small sample of synovium and the long head of the biceps brachii tendon were harvested, while the transverse carpal ligament was harvested from the CTS group. The intraoperative specimens were pathologically examined for amyloid deposition, and patients with amyloid deposition were examined for the presence of cardiac amyloidosis by cardiac evaluation. Results: In the shoulder group, three cases (7.3%) of transthyretin amyloid deposition were found, all of which involved rotator cuff tears. None of these three cases with amyloid deposition were associated with cardiac amyloidosis. When examining the specimens, the amyloid deposition rate in the long head of the biceps brachii tendon was higher than that in the synovium. In the CTS group, 12 cases (36.4%) of transthyretin amyloid deposition were observed. Of these cases, seven underwent cardiac evaluation and two were identified with cardiac amyloidosis. Conclusion: While the prevalence of amyloid deposition and cardiac amyloidosis in the CTS group was consistent with previous reports, the shoulder group showed a lower deposition rate and no concomitant cardiac amyloidosis. Therefore, it remains debatable whether investigating amyloid deposition in samples obtained from shoulder surgery is beneficial for the early detection of cardiac amyloidosis.

Abstract There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/β-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this.

Abstract Alcohol abuse is associated with several diseases, such as hepatocellular carcinoma, cirrhosis, and extrahepatic malignancies. Recently, we reported albumin platelet product (APP) and modified APP (mAPP) as novel indices of liver fibrosis staging and prognosis in patients without alcoholic liver diseases. This retrospective cohort study aimed to extend application of APP and mAPP in prognosis prediction of patients with alcoholic liver diseases. We enrolled 222 patients with alcoholic liver diseases based on their medical records. Cut-off values of APP = 4.349 and mAPP = 2.484 were adopted based on a past report. Hazard ratios of APP and mAPP were compared to those of albumin-bilirubin score and fibrosis-4 index. The primary and secondary endpoints were carcinogenesis and death, respectively. Thus, APP = 4.349 and mAPP = 2.484 significantly differentiated cancer-free survival and overall survival in univariate analysis. Hazard ratios of mAPP = 2.484 were greater than those of the albumin-bilirubin score of -2.270 and fibrosis-4 index of 3.25. Multivariate analysis revealed mAPP = 2.484 as an independent risk factor for carcinogenesis and overall death. In conclusion, mAPP is a simple index to stratify patient’s risk for carcinogenesis and death.

Abstract Aim Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real‐world clinical setting. Methods In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first‐line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non‐elderly (

Background/Objectives: Sporadic Creutzfeldt–Jakob disease (sCJD) is a fatal neurodegenerative disorder traditionally diagnosed based on the World Health Organization (WHO) criteria in 1998. Recently, Hermann et al. proposed updated diagnostic criteria incorporating advanced biomarkers to enhance early detection of sCJD. This study aimed to evaluate the sensitivity and specificity of Hermann’s criteria compared with those of the WHO criteria in a large cohort of patients suspected of prion disease in Japan. Methods: In this retrospective cohort study, we examined the new criteria using data of 2004 patients with suspected prion disease registered with the Japanese Prion Disease Surveillance (JPDS) between January 2009 and May 2023. Patients with genetic or acquired prion diseases or incomplete data necessary for the diagnostic criteria were excluded, resulting in 786 eligible cases. The sensitivity and specificity of the WHO and Hermann’s criteria were calculated by comparing diagnoses with those made by the JPDS Committee. Results: Of the 786 included cases, Hermann’s criteria helped identify 572 probable cases compared with 448 by the WHO criteria. The sensitivity and specificity of the WHO criteria were 96.4% and 96.6%, respectively. Hermann’s criteria demonstrated a sensitivity of 99.3% and a specificity of 95.2%, indicating higher sensitivity but slightly lower specificity. Fifty-five cases were classified as “definite” by both criteria. Conclusions: The findings suggest that Hermann’s criteria could offer improved sensitivity for detecting sCJD, potentially reducing diagnostic oversight. However, caution is advised in clinical practice to avoid misdiagnosis, particularly in treatable neurological diseases, by ensuring thorough exclusion of other potential conditions.

Abstract Background Gait decline in older adults is related to falling risk, some of which contribute to injurious falls requiring medical attention or restriction of activity of daily living. Among injurious falls, distal radius fracture (DRF) is a common initial fragility fracture associated with the subsequent fracture risk in postmenopausal females. The recent invention of an inertial measurement unit (IMU) facilitates the assessment of free-living gait; however, little is known about the daily gait characteristics related to the risk of subsequent fractures. We hypothesized that females with DRF might have early changes in foot kinematics in daily gait. The aim of this study was to evaluate the daily-life gait characteristics related to the risk of falls and fracture. Methods In this cross-sectional study, we recruited 27 postmenopausal females with DRF as their first fragility fracture and 28 age-matched females without a history of fragility fractures. The participants underwent daily gait assessments for several weeks using in-shoe IMU sensors. Eight gait parameters and each coefficient of variance were calculated. Some physical tests, such as hand grip strength and Timed Up and Go tests, were performed to check the baseline functional ability. Results The fracture group showed lower foot angles of dorsiflexion and plantarflexion in the swing phase. The receiver operating characteristic curve analyses revealed that a total foot movement angle (TFMA)

Despite their importance for regional water resource planning and as indicators of climate change, records of in situ glacier mass balance remain short and spatially sparse in the Himalaya. Here, we present an updated series of in situ mass-balance measurements from Rikha Samba Glacier, Nepal, between 2011 and 2021. The updated in situ mass balance is −0.39 ± 0.32 m w.e. for this period. We use an energy-mass balance model to extend the annual mass-balance series back to 1974. The model is forced using daily meteorological variables from ERA5-Land reanalysis data that is linearly bias-corrected using observations from an automatic weather station situated near the glacier terminus. The modeled mass balance is consistent with the in situ mass-balance series measured 2011–2021 and with previous glaciological and geodetic estimates. The model results indicate a mass balance of −0.56 ± 0.27 m w.e. a−1 over the reconstruction period of 1974–2021, which is comparable to the mass losses experienced by other Himalayan glaciers during this time. An assessment of the sensitivity of the glacier mass balance to meteorological forcing suggests that a change in temperature of ±1 K has a stronger effect on the calculated mass balance compared to a ±20% change in either precipitation, or relative humidity, or solar radiation.

Accurately quantifying runoff sources and understanding hydrological processes in glaciated mountain basins is essential for effective water resource management in the face of climate change. This study aimed to determine the contributions from various runoff sources in glaciated basins within the inner Tien-Shan mountains of Kyrgyzstan by utilizing integrated land surface, glacier energy-mass balance, and river routing models. To account for local topographic influences on solar radiation and cloud transmissivity processes, gridded meteorological forcing data were downscaled. The integrated models were then evaluated against observed discharge, glacier mass balance, and snow water equivalent, with a focus on the Kara-Batkak glacier reference site. Shortwave radiation correction was particularly important for improving the accuracy of model simulations. The results indicate that the peak glacier melt contribution occurs in July and August, with some basins reaching up to 54%. On an annual basis, the average contribution from glaciers across the basins was found to be 19%, while the ratios of snowmelt and rainfall were 58% and 23%, respectively. This study highlights the utility of integrated modelling approaches in understanding and quantifying runoff components in data-scarce high mountain regions. The incorporation of observed glacier data proved to be crucial for accurately representing hydrological processes under current climatic conditions. These findings underscore the significance of considering glacier dynamics and their influence on water resources to inform effective water management strategies in glaciated mountain basins.

Abstract Hepatocellular carcinoma invasion of the bile duct is rare and has a poor prognosis. A 77‐year‐old man presented at the emergency department with persistent pain in the right hypochondrium. Blood tests and imaging studies revealed a 70‐mm occupying lesion in the right lobe of the liver and dilated intrahepatic bile ducts. He was diagnosed with obstructive jaundice and cholangitis. Imaging studies showed an internal mass with poor contrast effects. A liver biopsy was performed to confirm the diagnosis and hepatocellular carcinoma was suspected. Endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, and peroral cholangioscopy were performed to determine the treatment strategy. The bile duct invasion did not extend to the porta hepatis; therefore, right hepatic lobectomy and radical resection were performed. Bile duct invasion in hepatocellular carcinoma is rare and often difficult to diagnose by computed tomography or conventional endoscopic retrograde cholangiopancreatography. However, endoscopic ultrasound and peroral cholangioscopy enable safe and accurate diagnosis of the extent of invasion.

BackgroundA distal radius fracture (DRF) is a common initial fragility fracture among women in their early postmenopausal period, which is associated with an increased risk of subsequent fractures. Gait assessments are valuable for evaluating fracture risk; inertial measurement units (IMUs) have been widely used to assess gait under free-living conditions. However, little is known about long-term changes in patients with DRF, especially concerning daily-life gait. We hypothesized that, in the long term, the daily-life gait parameters in patients with DRF could enable us to reveal future risk factors for falls and fractures. ObjectiveThis study assessed the spatiotemporal characteristics of patients with DRF at 4 weeks and 6 months of recovery. MethodsWe recruited 16 women in their postmenopausal period with DRF as their first fragility fracture (mean age 62.3, SD 7.0 years) and 28 matched healthy controls (mean age 65.6, SD 8.0 years). Daily-life gait assessments and physical assessments, such as hand grip strength (HGS), were performed using an in-shoe IMU sensor. Participants’ results were compared with those of the control group, and their recovery was assessed for 6 months after the fracture. ResultsIn the fracture group, at 4 weeks after DRF, lower foot height in the swing phase (P=.049) and higher variability of stride length (P=.03) were observed, which improved gradually. However, the dorsiflexion angle in the fracture group tended to be lower consistently during 6 months (at 4 weeks: P=.06; during 6 months: P=.07). As for the physical assessments, the fracture group showed lower HGS at all time points (at 4 weeks: P

Background: Constipation has been recently recognized as a complication associated with motor and autonomic dysfunction in patients with motor neuron disease (MND), typified by amyotrophic lateral sclerosis (ALS). However, the long-term characteristics of constipation remain unclear in patients with MND. We longitudinally investigated the prevalence and risk factors of constipation in a consecutive cohort of patients with MND. Methods: Data from Japanese patients with MND enrolled in a single-center registry from June 2017 to December 2021 were retrospectively investigated. The diagnosis of ALS was based on the updated Awaji criteria, and other MND subtypes were also included. The presence or absence of constipation symptoms was determined by referring to the Rome III criteria. The clinical backgrounds and symptoms of patients with and without constipation were compared. Results: Among 155 consecutive patients (female, 63; age, 66.5 ± 12.4 years), 30.3% had constipation at diagnosis and 52.9% after a median follow-up of 18 months. Univariate analysis showed that female sex, use of tracheostomy and invasive ventilation, and delivery of enteral nutrition were more frequent in the constipation group. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score was significantly lower in the constipation group, especially for the sub-items related to physical motor function. Multivariate analysis showed that the use of enteral nutrition was an independent risk of constipation, with an odds ratio of 3.69 (95% CI, 1.49–9.17; p = 0.005). Conclusion: Constipation had a high prevalence in patients with MND with impaired motor function. Controlling defecation is important in patients with MND, especially during enteral nutrition.

Abstract Tropospheric reactive bromine (Bry) influences the oxidation capacity of the atmosphere by acting as a sink for ozone and nitrogen oxides. Aerosol acidity plays a crucial role in Bry abundances through acid‐catalyzed debromination from sea‐salt‐aerosol, the largest global source. Bromine concentrations in a Russian Arctic ice‐core, Akademii Nauk, show a 3.5‐fold increase from pre‐industrial (PI) to the 1970s (peak acidity, PA), and decreased by half to 1999 (present day, PD). Ice‐core acidity mirrors this trend, showing robust correlation with bromine, especially after 1940 (r = 0.9). Model simulations considering anthropogenic emission changes alone show that atmospheric acidity is the main driver of Bry changes, consistent with the observed relationship between acidity and bromine. The influence of atmospheric acidity on Bry should be considered in interpretation of ice‐core bromine trends.

Background: Reverse total shoulder arthroplasty (RSA) has been approved since 2014 in Japan, and the number of RSA cases has been accumulating. However, only short-to medium-term outcomes have been reported, with a small number of case series, because of its short history in Japan. This study aimed to evaluate complications after RSA in hospitals affiliated with our institute, with comparison to those in other countries. Methods: A multicenter retrospective study was performed at 6 hospitals. In total, 615 shoulders (mean age: 75.7 ± 6.2 years; mean follow-up: 45.2 ± 19.6 months) with at least 24 months of follow-up were included in this study. The active range of motion was assessed pre-and postoperatively. The 5-year survival rate was evaluated for reoperation for any reason in 137 shoulders with at least 5 years of follow-up using Kaplan–Meier analysis. Postoperative complications were evaluated, including dislocation; prosthesis failure; deep infection; periprosthetic, acromial, scapular spine, and clavicle fractures; neurological disorders; and reoperation. Furthermore, imaging assessments, including scapular notching, prosthesis aseptic loosening, and heterotopic ossification were evaluated on postoperative radiography at the final follow-up. Results: All range of motion parameters were significantly improved postoperatively (P

Abstract Early detection of cervical myelopathy (CM) is important for a favorable outcome, as its prognosis is poor when left untreated. We developed a screening method for CM using machine learning-based analysis of the drawing behavior of 38 patients with CM and 66 healthy volunteers. Using a stylus pen, the participants traced three different shapes displayed on a tablet device. During the tasks, writing behaviors, such as the coordinates, velocity, and pressure of the stylus tip, along with the drawing time, were recorded. From these data, features related to the drawing pressure, and time to trace each shape and combination of shapes were used as training data for the support vector machine, a machine learning algorithm. To evaluate the accuracy, a receiver operating characteristic curve was generated, and the area under the curve (AUC) was calculated. Models with triangular waveforms tended to be the most accurate. The best triangular wave model identified patients with and without CM with 76% sensitivity and 76% specificity, yielding an AUC of 0.80. Our model was able to classify CM with high accuracy and could be applied to the development of disease screening systems useful outside the hospital setting.

Abstract In recent years, the treatment of breast cancer has advanced dramatically and neoadjuvant chemotherapy (NAC) has become a common treatment method, especially for locally advanced breast cancer. However, other than the subtype of breast cancer, no clear factor indicating sensitivity to NAC has been identified. In this study, we attempted to use artificial intelligence (AI) to predict the effect of preoperative chemotherapy from hematoxylin and eosin images of pathological tissue obtained from needle biopsies prior to chemotherapy. Application of AI to pathological images typically uses a single machine‐learning model such as support vector machines (SVMs) or deep convolutional neural networks (CNNs). However, cancer tissues are extremely diverse and learning with a realistic number of cases limits the prediction accuracy of a single model. In this study, we propose a novel pipeline system that uses three independent models each focusing on different characteristics of cancer atypia. Our system uses a CNN model to learn structural atypia from image patches and SVM and random forest models to learn nuclear atypia from fine‐grained nuclear features extracted by image analysis methods. It was able to predict the NAC response with 95.15% accuracy on a test set of 103 unseen cases. We believe that this AI pipeline system will contribute to the adoption of personalized medicine in NAC therapy for breast cancer.

The southern Patagonian glaciers are known for having extremely high ablation rates. Foehn winds are one of the suspected causes, however, their influence on the annual ablation, their interannual variations, and their relationship with climate change is not well understood. We analysed the in-situ meteorological data from 2003–2020 recorded at Glaciar Perito Moreno. Daily temperature lapse rates varied substantially, from −7.8°C km−1 to 10.4°C km−1, due to foehn, fog, and katabatic winds. We find that, on average, foehn events occurred 1073 hours per year, and accounted for 20% of the annual surface ablation. This increase in surface ablation rates during foehn events occurs as a result of the enhanced sensible heat flux and net shortwave radiation. The downglacier-directed foehn winds warm the air mass over the glacier, but because of the high humidity of the foehn here, they often release latent heat by condensation. Variations in the Amundsen Sea Low influence foehn occurrence by modulating the westerly winds, which is related to the hemispherical ocean and atmospheric variability. Our results show that the local climate play an important role in the surface melting of Patagonian glaciers.

We quantify the surface elevation changes along Yala Glacier in Langtang Valley, Nepal Himalaya, since 1981 using geodetic methods to understand the recent evolution and current state of small debris-free glaciers across the region. We analyse differential global positioning system measurements and aerial stereo imagery that were acquired along Yala Glacier in 2007, 2009, 2012 and 2015 to generate digital elevation models for each calculation period. Continuous surface lowering has mainly been observed across the down-glacier area during the calculation periods, although a large degree of variability exists, with this lowering trend propagating up-glacier in recent years. The area-weighted glacier mass balances range from −0.98 ± 0.27 to −0.26 ± 0.30 m w.e. a−1 for the five calculation periods (1981–2007, 2007–2009, 2009–2012, 2012–2015 and 2007–2015). These calculated mass-balance data reveal that Yala Glacier has undergone accelerated mass loss since the late 2000s, which is consistent with the results of previous in situ measurement and remote-sensing studies.

Abstract Campylobacter species are the pathogens of the intestinal tract, which infrequently cause bacteremia. To reveal the clinical characteristics of Campylobacter bacteremia, we performed a retrospective, multicenter study. Patients diagnosed with Campylobacter bacteremia in three general hospitals in western Japan between 2011 and 2021 were included in the study. Clinical, microbiological, and prognostic data of the patients were obtained from medical records. We stratified the cases into the gastroenteritis (GE) and fever predominant (FP) types by focusing on the presence of gastrointestinal symptoms. Thirty-nine patients (24 men and 15 women) were included, with a median age of 57 years and bimodal distribution between those in their 20 s and the elderly. The proportion of GE and FP types were 21 (53.8%) and 18 (46.2%), respectively. Comparing these two groups, there was no significant difference in patient backgrounds in terms of sex, age, and underlying diseases. Campylobacter jejuni was exclusively identified in the GE type (19 cases, 90.5%), although other species such as Campylobacter fetus and Campylobacter coli were isolated in the FP type as well. Patients with the FP type underwent intravenous antibiotic therapy more frequently (47.6% vs. 88.9%), and their treatment (median: 5 days vs. 13 days) and hospitalization (median: 7 days vs. 21 days) periods were significantly longer. None of the patients died during the hospitalization. In summary, we found that nearly half of the patients with Campylobacter bacteremia presented with fever as a predominant manifestation without gastroenteritis symptoms.

Abstract To determine the pathogenesis of trapeziometacarpal (TMC) joint instability, which leads to osteoarthritis, we investigated the anatomical relationships among the surrounding ligaments, muscles (first dorsal interosseous [FDI] and opponens pollicis [OPP]), and joint capsule. We examined the bone morphology and cortical bone thickening in 25 cadaveric thumbs using micro-computed tomography and performed macroscopic and histological analyses. The dorsal trapezium had a tubercle with cortical bone thickening, corresponding to the attachment of the FDI aponeurosis intermingled with the joint capsule. Radially, the thin joint capsule was observed to underlie the muscular part of the OPP. Therefore, the dorsal ligaments, which have been previously considered static stabilizers, could be interpreted as parts of the capsuloaponeurotic complex consisting of the FDI aponeurosis and joint capsule. In the radial aspect, muscular OPP activation may be essential for TMC joint stabilization. Our findings may contribute to the appropriate management of TMC osteoarthritis.

Summer sea ice retreat in the high latitude North Atlantic since 2000 is associated with increases in oceanic emissions of dimethyl sulfide, according to a record of methane sulfonic acid fluxes from an ice core in southeast Greenland.

Abstract Background Cervical myelopathy is a progressive disease, and early detection and treatment contribute to prognosis. Evaluation of cervical intervertebral instability by simple X-ray is used in clinical setting and the information about instability is important to understand the cause of myelopathy, but evaluation of the intervertebral instability by X-ray is complicated. To reduce the burden of clinicians, a system that automatically measures the range of motion was developed by comparing the flexed and extended positions in the lateral view of a simple X-ray of the cervical spine. The accuracy of the system was verified by comparison with spine surgeons and residents to determine whether the system could withstand actual use. Methods An algorithm was created to recognize the four corners of the vertebral bodies in a lateral cervical spine X-ray image, and a system was constructed to automatically measure the range of motion between each vertebra by comparing X-ray images of the cervical spine in extension and flexion. Two experienced spine surgeons and two residents performed the study on the remaining 23 cases. Cervical spine range of motion was measured manually on X-ray images and compared with automatic measurement by this system. Results Of a total of 322 cervical vertebrae in 46 images, 313 (97%) were successfully estimated by our learning model. The mean intersection over union value for all the 46-test data was 0.85. The results of measuring the CRoM angle with the proposed cervical spine motion angle measurement system showed that the mean error from the true value was 3.5° and the standard deviation was 2.8°. The average standard deviations for each measurement by specialist and residents are 2.9° and 3.2°. Conclusions A system for measuring cervical spine range of motion on X-ray images was constructed and showed accuracy comparable to that of spine surgeons. This system will be effective in reducing the burden on and saving time of orthopedic surgeons by avoiding manually measuring X-ray images. Trial registration Retrospectively registered with opt-out agreement.

BackgroundArtificial intelligence (AI) has gained tremendous popularity recently, especially the use of natural language processing (NLP). ChatGPT is a state-of-the-art chatbot capable of creating natural conversations using NLP. The use of AI in medicine can have a tremendous impact on health care delivery. Although some studies have evaluated ChatGPT’s accuracy in self-diagnosis, there is no research regarding its precision and the degree to which it recommends medical consultations. ObjectiveThe aim of this study was to evaluate ChatGPT’s ability to accurately and precisely self-diagnose common orthopedic diseases, as well as the degree of recommendation it provides for medical consultations. MethodsOver a 5-day course, each of the study authors submitted the same questions to ChatGPT. The conditions evaluated were carpal tunnel syndrome (CTS), cervical myelopathy (CM), lumbar spinal stenosis (LSS), knee osteoarthritis (KOA), and hip osteoarthritis (HOA). Answers were categorized as either correct, partially correct, incorrect, or a differential diagnosis. The percentage of correct answers and reproducibility were calculated. The reproducibility between days and raters were calculated using the Fleiss κ coefficient. Answers that recommended that the patient seek medical attention were recategorized according to the strength of the recommendation as defined by the study. ResultsThe ratios of correct answers were 25/25, 1/25, 24/25, 16/25, and 17/25 for CTS, CM, LSS, KOA, and HOA, respectively. The ratios of incorrect answers were 23/25 for CM and 0/25 for all other conditions. The reproducibility between days was 1.0, 0.15, 0.7, 0.6, and 0.6 for CTS, CM, LSS, KOA, and HOA, respectively. The reproducibility between raters was 1.0, 0.1, 0.64, –0.12, and 0.04 for CTS, CM, LSS, KOA, and HOA, respectively. Among the answers recommending medical attention, the phrases “essential,” “recommended,” “best,” and “important” were used. Specifically, “essential” occurred in 4 out of 125, “recommended” in 12 out of 125, “best” in 6 out of 125, and “important” in 94 out of 125 answers. Additionally, 7 out of the 125 answers did not include a recommendation to seek medical attention. ConclusionsThe accuracy and reproducibility of ChatGPT to self-diagnose five common orthopedic conditions were inconsistent. The accuracy could potentially be improved by adding symptoms that could easily identify a specific location. Only a few answers were accompanied by a strong recommendation to seek medical attention according to our study standards. Although ChatGPT could serve as a potential first step in accessing care, we found variability in accurate self-diagnosis. Given the risk of harm with self-diagnosis without medical follow-up, it would be prudent for an NLP to include clear language alerting patients to seek expert medical opinions. We hope to shed further light on the use of AI in a future clinical study.

The question of how humans got language is crucial for understanding the uniqueness of the human mind and the cognitive resources and processes shared with nonhuman species. We discuss the origin of symbolic elements in hominins and how a pragmatic grammar emerged from action-based event-structures. In the context of comparative neurobiological findings, we report support for the global workspace hypothesis and social brain hypothesis. In addition, reverse linguistic analysis informs us about the particular role of a pragmatic grammar stage. We assume that this stage was associated with changes to the hominin genotype. Homo erectus may have used a pragmatic grammar which consisted of two or three symbolic elements. Extended syntax and morphology, including hierarchical branching, are not based on genotype changes but may reflect cultural accumulations related to socioecological adaptations. We conclude that the biological capacity for language may have emerged already 1.8 million years ago with the appearance of genus Homo.

Objective Early detection and intervention are essential for the mitigation of degenerative cervical myelopathy (DCM). However, although several screening methods exist, they are difficult to understand for community-dwelling people, and the equipment required to set up the test environment is expensive. This study investigated the viability of a DCM-screening method based on the 10-second grip-and-release test using a machine learning algorithm and a smartphone equipped with a camera to facilitate a simple screening system. Methods Twenty-two participants comprising a group of DCM patients and 17 comprising a control group participated in this study. A spine surgeon diagnosed the presence of DCM. Patients performing the 10-second grip-and-release test were filmed, and the videos were analyzed. The probability of the presence of DCM was estimated using a support vector machine algorithm, and sensitivity, specificity, and area under the curve (AUC) were calculated. Two assessments of the correlation between estimated scores were conducted. The first used a random forest regression model and the Japanese Orthopaedic Association scores for cervical myelopathy (C-JOA). The second assessment used a different model, random forest regression, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Results The final classification model had a sensitivity of 90.9%, specificity of 88.2%, and AUC of 0.93. The correlations between each estimated score and the C-JOA and DASH scores were 0.79 and 0.67, respectively. Conclusions The proposed model could be a helpful screening tool for DCM as it showed excellent performance and high usability for community-dwelling people and non-spine surgeons.

Abstract Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.

Introduction: Breast cancer is one of the most frequent primary tumors that cause spinal metastases. Metastasis consequences impair both the patient's overall prognosis and quality of life. We previously developed a porous hydroxyapatite collagen composite (HAp/Col) as an osteoconductive scaffold. HAp/Col is a commercially available artificial bone that is frequently utilized in spinal fusion. Because of its high absorbance capacity, HAp/Col is regarded as a good chemical carrier. Methods: This study investigated the effect of local administration of paclitaxel combined with HAp/Col scaffold on breast cancer metastasis. High-performance liquid chromatography was used to assess the in vitro release of paclitaxel from HAp/Col. In an in vivo rat model, the inhibitory effects of paclitaxel-impregnated scaffolds on local osteogenesis was examined, and then the local suppression effects on metastatic cancer were investigated. Results: In vitro testing revealed that roughly 30% of the paclitaxel was released within 96 hours. Paclitaxel-impregnated HAp/Col inhibited local osteogenesis for the first 8 weeks in a rat femur. However, at 12 weeks following surgery, this negative effect appeared to have subsided. In the metastatic model, all rats in the control group reached the humane endpoint 14 days after surgery. On the other hand, the average time to the endpoint in the paclitaxel group was 26.5 days, which was substantially longer than that in the control group. Long-term survivors treated with paclitaxel had no remaining tumor cells in the femoral bone, and osteogenesis was seen surrounding the HAp/Col. Conclusions: Paclitaxel-impregnated HAp/Col reduced local tumor development and extended the time to the target endpoint in rats with metastases from breast cancer. This study shows that local implantation of paclitaxel-impregnated HAp/Col may be a viable therapeutic option for the management of breast cancer metastases.

Abstract. Objectives:. The factors that significantly influence the symptomatic implant removal rates after plate fixation for midshaft clavicle fractures remain controversial. The purpose of this study was to compare the symptomatic implant removal rates between 2 different types of plating technique and to evaluate independently associated factors. Design:. Retrospective cohort study. Setting:. Acute care center. Patients/Participants:. A total of 71 patients 16 years or older who were diagnosed with displaced midshaft clavicle fractures from April 2016 to March 2020. Intervention:. Thirty-nine patients were treated with superior plating (Group SP), and the remaining 32 patients were treated with anteroinferior plating (Group AIP). Main Outcome Measurements:. Symptomatic implant removal rates after plate fixation for midshaft clavicle fractures. Results:. Symptomatic implant removal rates were significantly lower in Group AIP (28.1%) than in Group SP (53.8%) (P = 0.033). Multivariate analyses showed that symptomatic implant removal rates were significantly decreased by three independent factors, namely AIP (odds ratio [OR] = 0.323) (P = 0.037), greater age (45 years or older) (OR = 0.312) (P = 0.029), and high body mass index (≥25 kg/m2) (OR = 0.117) (P = 0.034). Conclusions:. AIP significantly and independently decreased the symptomatic implant removal rate. Among the three explanatory factors showing significant difference, plating technique is the only factor that can be altered by medical institutions. Therefore, we recommend this technique for displaced midshaft clavicle fractures to reduce a second surgery such as symptomatic implant removal. Level of Evidence:. Level 3, retrospective cohort study

Identifying the characteristics of fallers is important for preventing falls because such events may reduce quality of life. It has been reported that several variables related to foot positions and angles during gait (e.g., sagittal foot angle and minimum toe clearance) differ between fallers and non-fallers. However, examining such representative discrete variables may not be sufficient to detect crucial information, which may be contained in the large portions of unanalyzed data. Therefore, we aimed to identify the comprehensive characteristics of foot position and angle during the swing phase of gait in non-fallers and fallers using principal component analysis (PCA). Thirty non-fallers and 30 fallers were recruited for this study. We performed PCA to reduce the dimensions of foot positions and angles during the swing phase and obtained principal component scores (PCSs) for each principal component vector (PCV), which were then compared between groups. The results revealed that the PCS of PCV3 in fallers was significantly larger than that in non-fallers (p = 0.003, Cohen’s d = 0.80). We reconstructed waveforms of foot positions and angles during the swing phase using PCV3 and our main findings can be summarized as follows. Compared to non-fallers, fallers have a 1) low average foot position in the z-axis (i.e., height) during the initial swing phase 2) small average foot angle in the x-axis (i.e., rotation in the sagittal plane), during the initial swing phase, and 3) large variability in foot position in the y-axis (i.e., anterior/posterior position) during the initial swing phase. We can conclude that these are characteristics of gait related to fallers. Therefore, our findings may be beneficial for evaluating fall risk during gait using a device such as a shoe- or insole-embedded inertial measurement unit.

Introduction: Currently, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can be induced to differentiate at the cellular level but not to form mature tissues or organs suitable for transplantation. ESCs/iPSCs form immature teratomas after injection into immunodeficient mice. In humans, immature teratomas often transform into fully differentiated mature teratomas after administration of anticancer agents. Methods: We first investigated the ability of cisplatin to induce changes in mouse ESCs/iPSCs in vitro. Next, we designed experiments to analyze ESC/iPSC-derived immature teratoma tissue in vivo after treatment of cisplatin. Groups of six mice carrying ESC- or iPSC-derived teratomas were given either low or high dose intraperitoneal injection of cisplatin, while the control group received saline for 4 weeks. Results: Treatment of ESC/iPSC cultures with cisplatin for 3 days caused a dose-related decrease in cell numbers without inducing any morphological changes to the cells. ESC/iPSC-derived teratomas showed lower growth rates with a significantly higher mature components ratio in a concentration dependent manner after cisplatin treatment (P

Abstract L-type neutral amino acid transporter 1 (LAT1) is a heterodimeric membrane transport protein involved in neutral amino acid transport. LAT1 is highly expressed in various malignant solid tumors and plays an essential role in cell proliferation. However, its role in malignant lymphoma remains unknown. Here, we evaluated LAT1 expression level in tissues from 138 patients with Non-Hodgkin lymphoma (NHL). Overexpression of LAT1 was confirmed in all types of NHL and we found that there is a significant correlation between the level of LAT1 expression and lymphoma grade. The LAT1 expression was higher in aggressive types of lymphomas when compared with static types of lymphomas, suggesting that active tumor proliferation requires nutrient uptake via LAT1. The expression level of LAT1 was inversely correlated with patients’ survival span. Furthermore, pharmacological inhibition of LAT1 by a specific inhibitor JPH203 inhibits lymphoma cell growth. In conclusion, our study demonstrated that LAT1 expression can be used as a prognostic marker for patients with NHL and targeting LAT1 by JPH203 can be a novel therapeutic modality for NHL.

Abstract Tuberculous meningitis is possibly complicated with multiple cerebral infarctions and basal meningitis, and the mortality and neurological prognosis is reportedly poor. This case suggested that clinicians should consider tuberculous meningitis as a differential diagnosis of patients with disturbed consciousness in an aging country Japan.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent. ObjectiveThis protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS). MethodsEPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2′-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. ResultsThis trial began data collection in September 2021 and is expected to be completed in October 2023. ConclusionsThis study can provide useful data to understand the characteristics of EPI-589. Trial RegistrationJapan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6 International Registered Report Identifier (IRRID)DERR1-10.2196/42032

We drilled an 81.2-m-long ice core in the accumulation area (5860 m a.s.l.) of Trambau Glacier in the Rolwaling region during October–November 2019. The drilling operation was conducted with a lightweight electro-mechanical drill system after two reconnaissance fieldworks in 2017 and 2018, during which two shallow firn cores were drilled with a hand auger. The drill system and ice core samples were transported by helicopters at a high elevation of 6000 m a.s.l. A further challenging issue was the ice core transportation between Nepal and Japan, as no regular commercial flight was available for the frozen samples. The addition of dry ice imported from India immediately prior to leaving Nepal allowed the ice core samples to be successfully transported to a cold room in Japan, and remain in a frozen state. Stratigraphic observations during the drilling operation suggest the drill site has been affected by melting and refreezing.