Search

Understanding factors associated with improvements in subjective shoulder function after arthroscopic rotator cuff repair (ARCR) helps clinicians identify targets for postoperative rehabilitation. The aim of this study was to investigate the factors associated with subjective shoulder function after ARCR.

After arthroscopic rotator cuff repair (ARCR), it is crucial for clinicians to predict the functional recovery in the early postoperative period for considering rehabilitation strategies. The aim of this study was to identify the prognostic factors in the early postoperative period for achieving full recovery of range of motion (ROM) at 6 months after ARCR.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P= 0.326), 34% versus 33% (P= 0.660), and 19% versus 23% (P= 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69–1.15, P= 0.373), 0.98 (0.78–1.22, P= 0.852), and 0.92 (0.83–1.21, P= 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

Heating crystal samples of 9,10-diphenylanthracene endoperoxide (1) and its deuterated derivative (1-d10) to 200 °C led to singlet-oxygen chemiluminescence (CL) from the mixtures of the crystalline and molten states. To understand the events in the heated samples, the reactions of 1and 1-d10in crystals were investigated by powder X-ray diffraction measurements and thermal analyses. The used crystals of 1and 1-d10obtained from a mixture of ethyl acetate (EA) and n-hexane contained EA. Other crystals of 1obtained by slow recrystallization with the same solvents had a solvent-free structure (form II) different from the reported one (form I). The results confirmed that the EA-containing crystals of 1and 1-d10were transformed to form II in two steps at 40–50 and 60–75 °C under heating at elevated temperature. Thus, the crystal samples had the form-II structure soon after heating to 200 °C. The behavior of the heated samples indicates that the crystal lattice inhibits the thermal reactivity of 1. Thus, the temperature for initiating the thermolytic reaction of 1becomes higher than the melting point. An exploration of the potential energy surface (PES) obtained by density functional theory (DFT) calculations also supports that the deoxygenation of 1is prevented by retaining the anthracene framework in the crystalline state. This study indicates that the method to use a CL-active compound is a powerful tool to analyze the reaction behavior in the crystalline state.Thermolytic reactions of 9,10-diphenylanthracene endoperoxide and its deuterated derivative in heated crystals were investigated by powder X-ray diffraction measurements and thermal analyses. Observed reaction behaviors indicate that the crystal lattice of the reactant inhibits the reactivity of the endoperoxides giving a situation where the temperature for initiating the thermolytic reactions becomes higher than the melting point.

BackgroundEnoyl-CoA hydratase short-chain 1 (ECHS1) is an enzyme involved in the metabolism of branched chain amino acids and fatty acids. Mutations in the ECHS1gene lead to mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, resulting in the accumulation of intermediates of valine. This is one of the most common causative genes in mitochondrial diseases. While genetic analysis studies have diagnosed numerous cases with ECHS1variants, the increasing number of variants of uncertain significance (VUS) in genetic diagnosis is a major problem.MethodsHere, we constructed an assay system to verify VUS function for ECHS1gene. A high-throughput assay using ECHS1knockout cells was performed to index these phenotypes by expressing cDNAs containing VUS. In parallel with the VUS validation system, a genetic analysis of samples from patients with mitochondrial disease was performed. The effect on gene expression in cases was verified by RNA-seq and proteome analysis.ResultsThe functional validation of VUS identified novel variants causing loss of ECHS1function. The VUS validation system also revealed the effect of the VUS in the compound heterozygous state and provided a new methodology for variant interpretation. Moreover, we performed multiomics analysis and identified a synonymous substitution p.P163= that results in splicing abnormality. The multiomics analysis complemented the diagnosis of some cases that could not be diagnosed by the VUS validation system.ConclusionsIn summary, this study uncovered new ECHS1cases based on VUS validation and omics analysis; these analyses are applicable to the functional evaluation of other genes associated with mitochondrial disease.

Objectives: Gastrointestinal (GI) perforations are one of the major adverse events of endoscopic procedures. Polyglycolic acid (PGA) sheets with fibrin glue have been reported to close GI perforations. However, its clinical outcome has not yet been fully investigated; thus, we conducted a multicenter retrospective observational study to assess the efficacy of PGA sheeting for GI perforation. Methods: The medical records of patients who underwent PGA sheeting for endoscopic GI perforations between April 2013 and March 2018 in 18 Japanese institutions were retrospectively analyzed. PGA sheeting was applied when the clip closure was challenging or failed to use. Perforations were filled with one or several pieces of PGA sheets followed by fibrin glue application through an endoscopic catheter. Nasal or percutaneous drainage and endoscopic clipping were applied as appropriate. Clinical outcomes after PGA sheeting for intraoperative or delayed perforations were separately evaluated. Results: There were 66 intraoperative and 24 delayed perforation cases. In intraoperative cases, successful closure was attained in 60 cases (91%). The median period from the first sheeting to diet resumption was 6 days (interquartile range [IQR], 4–8.8 days). Large perforation size (≥ 10 mm) and duodenal location showed marginal significant relationship to higher closure failure of intraoperative perforations. In delayed perforation cases, all cases had successful closure. The median period from the first sheeting to diet resumption was 10 days (IQR, 6–37.8 days). No adverse events related to PGA sheeting occurred. Conclusion: Endoscopic PGA sheeting could be a therapeutic option for GI perforations related to GI endoscopic procedures.

AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis.

This study investigated neuronal sources of slow cortical potentials (SCPs) evoked during vagus nerve stimulation (VNS) in patients with epilepsy who underwent routine electroencephalography (EEG) after implantation of the device.

Adamantylideneadamantane 1,2-dioxetane (Adox), one of the most stable 1,2-dioxetanes, was used to investigate the kinetic properties of its chemiluminescent thermolytic reaction in the crystalline state by monitoring chemiluminescence (CL) in real time. Soon after heating of single crystals at 140 °C, it was found that the thermolytic reactions of Adox in the crystals proceeded with zero-order kinetics for several minutes. During the period showing the zero-order kinetics, CL intensities were dependent on the volumes of crystals, and the inside crystals were maintained in a thermal steady state with a constant thermal diffusivity. After this period, the heated crystals of Adox started to break showing different kinetics. This study indicates that a crystalline-state CL reaction is useful to track its progress in real time for analyzing the kinetics.Chemiluminescence (CL) reactions of adamantylideneadamantane 1,2-dioxetane in crystals were investigated by heating crystal samples including single crystals, to show that the reactions proceeded with the zero-order kinetics in the initial stage and CL intensities were dependent on the volumes of crystals during this stage. Therefore, a crystalline-state CL reaction is useful to track its progress in real time.

Direct and indirect clipping treatments are used worldwide to treat colonic diverticular bleeding (CDB), but their effectiveness has not been examined in multicenter studies with more than 100 cases. We sought to determine the short‐ and long‐term effectiveness of direct versus indirect clipping for CDB in a nationwide cohort. We studied 1041 patients with CDB who underwent direct clipping (n= 360) or indirect clipping (n= 681) at 49 hospitals across Japan (CODE BLUE‐J Study). Multivariate analysis adjusted for age, sex, and important confounding factors revealed that, compared with indirect clipping, direct clipping was independently associated with reduced risk of early rebleeding (<30 days; adjusted odds ratio [AOR] 0.592, p= 0.002), late rebleeding (<1 year; AOR 0.707, p= 0.018), and blood transfusion requirement (AOR 0.741, p= 0.047). No significant difference in initial hemostasis rates was observed between the two groups. Propensity‐score matching to balance baseline characteristics also showed significant reductions in the early and late rebleeding rates with direct clipping. In subgroup analysis, direct clipping was associated with significantly lower rates of early and late rebleeding and blood transfusion need in cases of stigmata of recent hemorrhage with non‐active bleeding on colonoscopy, right‐sided diverticula, and early colonoscopy, but not with active bleeding on colonoscopy, left‐sided diverticula, or elective colonoscopy. Our large nationwide study highlights the use of direct clipping for CDB treatment whenever possible. Differences in bleeding pattern and colonic location can also be considered when deciding which clipping options to use.

Graphical abstract:

ObjectiveNeonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis.DesignRetrospective observational study from January 2004 to March 2020.SettingPopulation based.PatientsPatients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches.InterventionsNone.Main outcome measuresDisease types, initial symptoms, biochemical findings, molecular diagnosis and prognosis.ResultsOf the 281 patients, multisystem mitochondrial disease was found in 194, Leigh syndrome in 26, cardiomyopathy in 38 and hepatopathy in 23 patients. Of the 321 initial symptoms, 236 occurred within 2 days of birth. Using biochemical approaches, 182 patients were diagnosed by mitochondrial respiratory chain enzyme activity rate and 89 by oxygen consumption rate. The remaining 10 patients were diagnosed using a genetic approach. Genetic analysis revealed 69 patients had nuclear DNA variants in 36 genes, 11 of 15 patients had mitochondrial DNA variants in five genes and four patients had single large deletion. The Cox proportional hazards regression analysis showed the effects of Leigh syndrome (HR=0.15, 95% CI 0.04 to 0.63, p=0.010) and molecular diagnosis (HR=1.87, 95% CI 1.18 to 2.96, p=0.008) on survival.ConclusionsNeonatal-onset mitochondrial disease has a heterogenous aetiology. The number of diagnoses can be increased, and clarity regarding prognosis can be achieved by comprehensive biochemical and molecular analyses using appropriate tissue samples.

Background and aims: At specialized facilities, endoscopic submucosal dissection (ESD) has currently been performed even for difficult cases such as tumors extending to a diverticulum that previously required surgery. This study aims to classify the type of lesion according to the degree of infiltration to a diverticulum and assessed the safety and efficacy of ESD for each type of lesion. Methods: We retrospectively reviewed ESD for lesions at NTT Medical Center Tokyo between January 2014 and April 2019. Lesions were classified as follows: Type 1: lesions in contact with or within 3 mm of the edge of a diverticulum; Type 2: lesions that partially infiltrated into a diverticulum; and Type 3: lesions that infiltrated into and completely covered the diverticulum. Furthermore, ESD strategies were divided into A and B, which indicates that a lesion was resected separately from the diverticulum and along the entire diverticulum, respectively. The clinicopathological characteristics and clinical outcomes were analyzed according to the strategy. Results: A total of 47 lesions satisfied inclusion criteria (19 Type 1, 12 Type 2, and 16 Type 3 lesions). 19 Type 1 and 8 Type 2 lesions were resected using Strategy A, while 4 Type 2 and 16 Type 3 lesions were resected using Strategy B. En bloc resection was achieved in all cases. In Strategy A, the R0 resection rate was 96.3% and the curative resection rate was 88.9%. On the contrary, in Strategy B, the R0 resection rate was 95.0% and the curative resection rate was 90.0%. In Strategy B, one of the patients developed post-operative bleeding that required endoscopic hemostasis; another patient developed delayed perforation that required emergency surgery. Conclusions: ESD for colorectal neoplasms in proximity or extending to a diverticulum is challenging, but this procedure can be a safe and effective therapeutic option.

Objective. The aim of this study was to clarify the effect of a stable concentration of propofol on interictal high‐frequency oscillations (HFOs), which may contribute to identifying the epileptogenic zone intraoperatively for resection surgery. Methods. Nine patients with drug‐resistant focal epilepsy who underwent invasive pre‐surgical evaluation with chronic subdural electrodes were recruited. Five‐minute electrocorticograms during wakefulness, slow‐wave sleep, and under a stable brain concentration of propofol were recorded with the same electrodes. In each patient, 1–10 pairs of electrodes were selected for both electrodes with EEG changes within 5 seconds from the ictal onset (ictal pattern for 5 seconds [IP5]) and those outside the area of IP5 with no interictal epileptiform discharges (non‐epileptiform [nEPI]). The numbers of ripples (80‐250 Hz) and fast ripples (>250 Hz) were measured semi‐automatically using an established algorithm. Statistical testing was performed with a mixed effect model. Results. Thirty‐seven pairs of electrodes from nine patients were analysed for IP5 and 29 pairs from seven patients were analysed for nEPI. The numbers of HFOs differed between the areas (IP5 and nEPI) and among the conditions (wakefulness, slow‐wave sleep, propofol anaesthesia) (all p <0.01). The HFO occurrence rates were significantly higher for IP5 than those for nEPI in all conditions (for both ripples and fast ripples in all conditions; p <0.01). Significance. The occurrence rates of HFOs for IP5 were significantly higher than those for nEPI under propofol anaesthesia. These are fundamental findings for intraoperative HFO analysis, however, the following limitations should be considered: physiological HFOs could not be completely differentiated from pathological HFOs; in order to apply an HFO detector, an appropriate cut‐off threshold is needed; an artefact of the impulse response filter appears as an HFO; and the series was comprised of a small number of heterogeneous patients.

Unexpected failures of a Heck reaction in the lab led to the detection of 5-hydroperoxy-1-methyl-2-pyrrolidinone (NMP-5-OOH) in the cosolvent 1-methyl-2-pyrrolidinone (NMP). This hydroperoxide, formed by autoxidation in the presence of air, oxidized the ligand tri(o-tolyl)phosphine (P(o-tol)3) to tri(o-tolyl)phosphine oxide (O═P(o-tol)3) and ultimately slowed down the Heck reaction. Because of this finding, control strategies were implemented for NMP quality and air exclusion during manufacturing campaigns, which ensured delivery of metric tons of compound 2en route to Ronacaleret Hydrochloride used in clinical studies. Similar detrimental impact of NMP-5-OOH to the ligand-free Heck reaction was also demonstrated.