Protective Effects of Hydrogen Gas Inhalation for Hindlimb Ischaemia-Reperfusion Injury in a Mouse Model.

OBJECTIVE: Ischaemia-reperfusion (I/R) injury is a severe post-operative complication that triggers an inflammatory response and causes severe damage. Hydrogen gas has anti-oxidant and anti-apoptotic properties and has been shown to be safe in humans. The study aimed to investigate whether hydrogen gas protects against skeletal muscle I/R injury. METHODS: Experimental basic research using mice. A total of 160 eight to 10 week old albino laboratory bred strain of house mice (25.8 ± 0.68 g) were used in this study. The mice were cable tied to the hindlimb under anaesthesia and then placed in an anaesthesia box filled with air and 2% isoflurane (control group); 80 mice were additionally subjected to 1.3% hydrogen gas in this mix (hydrogen group). After two hours, the cable ties were removed to initiate reperfusion, and hydrogen inhalation lasted for six hours in the hydrogen group. After six hours, the mice were taken out of the box and kept in cages under standard conditions until time for observation at 16 different time points after reperfusion: zero, two, four, six, eight, and 10 hours and one, two, three, four, five, six, seven, 14, 21, and 28 days. Five mice were sacrificed using excess anaesthesia at each time point, and the bilateral hindlimb tissues were harvested. The inflammatory effects of the I/R injury were assessed by evaluating serum interleukin-6 concentrations using enzyme linked immunosorbent assay, as well as histological and immunohistochemical analyses. Untreated mice with I/R injury were used as controls. RESULTS: Hydrogen gas showed protective effects associated with a reduction in inflammatory cell infiltration (neutrophils, macrophages, and lymphocytes), a reduced area of damaged muscle, maintenance of normal muscle cells, and replacement of damaged muscle cells with neoplastic myocytes. CONCLUSION: Inhalation of hydrogen gas had a protective effect against hindlimb I/R injury in mice, in part by reducing inflammatory cell infiltration and in part by preserving normal muscle cells.

Single cell RNA-sequencing of Ewing sarcoma tumors demonstrates transcriptional heterogeneity and clonal evolution.

Ewing sarcoma is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis, compared to the >70% 5-year survival of those with localized disease. Here, we utilized single cell RNA-sequencing to characterize the transcriptional landscape of primary Ewing sarcoma tumors and surrounding tumor microenvironment (TME). Copy-number analysis identified subclonal evolution within patients even prior to treatment. Primary tumor samples demonstrate a heterogenous transcriptional landscape with several conserved gene expression programs, including those composed of genes related to proliferation and EWS targets. We also were able to identify the composition of the TME and molecularly dissect the transcriptional profile of circulating tumor cells in peripheral blood at the time of diagnosis.

Impact of wound management strategies after revascularization for chronic limb-threatening ischemia.

OBJECTIVE: There is no established consensus or guidelines for wound management after revascularization for patients with chronic limb-threatening ischemia (CLTI) without severe infection. This study is designed to evaluate the clinical effect of the wound management strategy on toe wounds after revascularization for CLTI. METHODS: This retrospective cohort study was performed at eight institutions affiliated with Keio University School of Medicine in Japan and included 261 patients who underwent revascularization for CLTI between April 2019 and July 2021. We identified 132 patients with toe wounds from the database who had restored in-line blood flow to the foot. Patients were divided into two groups by the timing of toe resection after revascularization, which dictated the wound management policy. Group A (62 patients) underwent early toe amputation for suspected osteomyelitis, whereas group B (70 patients) underwent watchful waiting. The primary outcome was wound healing after revascularization; the secondary outcome was major amputation. We compared outcomes between groups A and B after propensity score matching. RESULTS: Using propensity score matching, each patient in group A (33 patients) was matched with a patient in group B (33 patients). Wound healing in matched group A was significantly better than that in matched group B (respectively: 1-year wound healing rate: 90.0% vs 68.2%, P < .001; median wound healing time: 65 days vs 258 days, P < .01). Although five major amputations were necessary in matched group B, none were required in matched group A (P = .05). The high rate of major amputations in group B was attributed to the sudden exacerbation of infection. Limb salvage rate in matched group A exceeded matched group B (100.0% vs 90.5%: 1-year limb salvage rate, P = .02). CONCLUSIONS: Early toe amputation for highly suspected osteomyelitis in patients with CLTI with toe wounds may expedite wound healing compared with watchful waiting, potentially avoiding unnecessary major amputation. Considering the wound management strategy is crucial when evaluating wound healing outcomes in patients with CLTI with revascularization.

In-person and virtual adaptation of an interprofessional palliative care communications skills training course for pediatric oncology clinicians.

Purpose: Effective, empathic communication is crucial for pediatric oncology clinicians when discussing palliative and end-of-life (PC/EOL) care with parents of children with cancer. Unfortunately, many parents report inadequate communication at these distressing times. This study evaluates the communication skills training (CST) clinicians received to deliver a PC/EOL communication intervention as part of a multi-site randomized-controlled trial (RCT). Methods: Clinicians from eight sites formed dyads (one physician and one nurse [RN] or advanced practice provider [APP]) and were trained over 3 days (in-person or virtually). Training was adapted from VitalTalk™ and included didactic instruction, videos, visual aids, and dedicated time to practice with simulated patients. Study participants completed a confidential, post-training online evaluation survey. A self-reported quality assurance checklist was used to measure fidelity to the communication protocol when delivered to parents during the RCT. Results: Thirty clinicians completed training; 26 completed post-training surveys including twelve (46.1%) physicians, 8 (30.8%) RNs and 6 (23.1%) APPs. Most were female (65.4%); white (80.8%), not Latinx (88.5%); 40-50 years old (53.9%); and in practice over 10 years (65.4%). Nine (34.6%) trained in-person; the rest trained virtually. Ninety-two percent reported the course was valuable or very valuable for developing their PC/EOL communication skills and 96% reported learning something new. Dyads trained virtually had similar fidelity to those trained in-person (95% and 90% respectively) when delivering the PC/EOL communication intervention to parents. Conclusion: This PC/EOL CST was valuable for improving pediatric oncology clinicians' communication skills, successfully implemented in-person and virtually, and translated effectively into practice.

Prevalence and Associated Factors for Primary Osteoarthritis of the Scaphotrapeziotrapezoid, Radiocarpal, and Distal Radioulnar Joints in the Japanese General Elderly Population.

PURPOSE: The incidence and etiology of primary osteoarthritis (OA) of the scaphotrapeziotrapezoid joint (STTJ), radiocarpal joint (RCJ), and distal radioulnar joint (DRUJ) remains unknown. The purpose of this study was to evaluate the prevalence and factors associated with primary wrist OA in a cross-sectional study of a basic resident registry. METHODS: A total of 1,297 residents between the ages of 50 and 89 years were randomly sampled from the registry of a Japanese town. A questionnaire was administered to all subjects, and each of them underwent radiographs of the bilateral hands, wrists, and elbows. STTJ, RCJ, and DRUJ radiographic osteoarthritis (ROA) were evaluated according to a previously described method. Associated factors for STTJ and DRUJ ROA were recorded. Associations between the incidence of ROA of the DRUJ, ulnar variance, and severity of elbow ROA were investigated. RESULTS: A total of 676 wrists (162 men and 176 women; mean age of 69.0 years) were investigated. The prevalence of STTJ, RCJ, and DRUJ ROA was 5.3%, 1.5%, and 21.2%, respectively. Factors associated with STTJ ROA were thumb carpometacarpal joint ROA, female sex, and increasing age. Factors associated with DRUJ ROA were elbow ROA, use of vibrating tools, increasing age, and positive ulnar variance. Prevalence of DRUJ ROA was 54.4% in wrists with severe-grade elbow ROA. Ulnar variance of the wrist in severe-grade elbow ROA was significantly larger than that in mild-grade or nonelbow ROA. CONCLUSIONS: The prevalence of ROA was highest in the DRUJ, followed by the STTJ, and lowest in the RCJ. The occurrence of ROA of the STTJ and DRUJ was affected by the presence of ROA of the adjacent joint. CLINICAL RELEVANCE: Primary DRUJ ROA occurs at a moderate frequency, similar to primary ROA of other extremity joints; however, primary STTJ and RCJ ROA is rare.

Breaking Up Isn't Hard to Do: Isolating Cell-free DNA Fragments in Osteosarcoma.

The novel use of blood-based biospecimens from a retrospective cohort of 50 patients with osteosarcoma was recently studied. The potential clinical utility of sorting cell-free DNA by fragment size was defined, with shorter tumor-specific DNA enrichment providing prognostic value and allowing for streamlined molecular profiling of circulating tumor material. See related article by Udomruk et al., p. 2085.

A multidisciplinary pediatric oncofertility team improves fertility preservation and counseling across 7 years.

BACKGROUND: Oncofertility is a developing field of increasing importance, particularly in pediatric oncology, where most patients are likely to survive long-term and have not yet had the opportunity to have children. AIMS: We performed a quality improvement initiative to increase our rates of fertility preservation counseling and referral through the implementation of a pediatric oncofertility team, and we report outcomes 7 years following implementation of our initiative. METHODS AND RESULTS: We compare our baseline oncofertility survey to 44 post-intervention survey respondents and electronic medical record documentation for 149 patients treated in 2019. Ninety-five percent of post-intervention survey respondents recalled fertility counseling (baseline 70%, p = .004) and 89.3% were appropriately referred for fertility preservation (baseline 50%, p = .017). Counseling was documented in 60.4% of charts; 81% of patients analyzed by chart review were appropriately referred for fertility preservation. Fertility preservation outcomes differed by sex assigned at birth. CONCLUSION: Creation of an oncofertility team produced improvements in fertility counseling and fertility preservation referral across an extended period of time.

Changes in the Functional Range of Motion of the Thumb Metacarpophalangeal Joint After Trapeziometacarpal Arthrodesis for Patients With Advanced Trapeziometacarpal Osteoarthritis.

PURPOSE: Advanced-stage trapeziometacarpal (TMC) osteoarthritis of the thumb often presents with concomitant hyperextension deformity of the metacarpophalangeal (MCP) joint. Although several studies have reported simultaneous procedures to correct this deformity, the indication for these procedures remains controversial. The purpose of this study was to evaluate changes in the range of motion (ROM) of the thumb MCP joint before and after TMC arthrodesis. METHODS: We evaluated the functional flexion and extension and functional ROM of the MCP joints during the performance of 10 activities of daily living tasks before and after TMC arthrodesis in 10 thumbs of 9 patients with Eaton stage III TMC osteoarthritis and hyperextension deformity of the MCP joint. RESULTS: The mean functional flexion of the MCP joint increased from 26° to 38°, and the mean functional extension of the MCP joint decreased from 16° to 5° of hyperextension. There was no change in the mean total arc of functional ROM of the MCP joint. CONCLUSIONS: The MCP joint motion shifted from extension to flexion after TMC arthrodesis, and the total arc of functional ROM of the MCP joint was similar before and after arthrodesis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Long-term Outcomes of the Endurant and Excluder Stent Grafts for Endovascular Aneurysm Repair in a Japanese Cohort.

PURPOSE: To compare the long-term outcomes of the most widely used third-generation stent grafts, the Endurant and Excluder stent grafts, in Japanese patients using a multicenter registry. MATERIALS AND METHODS: A retrospective analysis of endovascular aneurysm repairs for abdominal aortic and iliac artery aneurysms using either the Endurant or the Excluder stent grafts from January 2012 to July 2019 at 10 Japanese hospitals was performed. RESULTS: A total of 332 and 378 repairs using the Endurant and Excluder stent grafts, respectively, were analyzed. Although the patients' characteristics were generally similar in the two groups, the Endurant group exhibited significantly shorter (Endurant: 31.5±18.6 mm, Excluder: 37.4±21.0 mm; p<0.001), larger (Endurant: 22.4±4.2 mm, Excluder: 21.7±3.8 mm; p=0.029), and more reversed tapered (Endurant: 12.1%, Excluder: 5.8%; p=0.003) proximal necks. The incidence of instructions for use (IFU) violations was similar between the two groups (Endurant: 59.0%, Excluder: 54.5%; p=0.223). However, the Endurant group had significantly more proximal neck-related IFU violations (54.1% and 46.3%, respectively; p=0.039), more access-related IFU violations (8.1% and 4.0%, respectively; p=0.019), and fewer bilateral hypogastric artery embolizations (5.1% and 9.3%, respectively; p=0.035) compared with the Excluder group. The incidence of intraoperative (Endurant: 3.6%, Excluder: 3.7%; p=0.950) and perioperative complications (Endurant: 3.6%, Excluder: 3.4%, p=0.899) was equivalent in the two groups. However, there was a significantly higher incidence of postoperative type II endoleaks in the Excluder group (Endurant: 28%, Excluder: 46.0%, p<0.001). Aneurysm sac regression was more frequent in the Endurant group (Endurant: 40.7%, Excluder: 31.7%, p=0.013). The Endurant group also had significantly higher rates of sac increase (Endurant: 13.0%, Excluder: 7.7%, p=0.020). Kaplan-Meier curve and log-rank analyses revealed no statistical differences in late complications (p=0.868) and overall survival (p=0.926). CONCLUSIONS: There were no statistically significant differences between the Endurant and the Excluder stent grafts in terms of intraoperative, perioperative, and late complication rates; however, the anatomical characteristics of the patients were significantly different.

Implant removal following open reduction and internal fixation for distal radius fracture: A study based on the Diagnosis Procedure Combination database in Japan.

BACKGROUND: The rate of implant removal and the factors influencing its indication in patients with distal radius fracture (DRF) in Japan are unclear. METHODS: We retrospectively evaluated the incidence rate of implant removal in a large cohort of DRF patients obtained from the Diagnosis Procedure Combination database in Japan between April 2014 and March 2019. Patient- and hospital-related factors possibly affecting removal rate, including age, sex, annual number of open reduction and internal fixation (ORIF) for DRF procedures per hospital, number of hospital beds, advanced or general care hospital, and hospital location were analyzed as well. Hospital location was classified into three types based on population and population density as 1) large city, 2) local city, and 3) sparse area. RESULTS: Implant removal was performed in 3242 (26.3%) of 12,328 DRF patients receiving ORIF. According to multivariate analysis, the significant factors related to a decreased probability of removal were older patients, male, large annual number of ORIF for DRF procedures per hospital, large number of hospital beds, advanced care hospital, and hospital in large city. CONCLUSIONS: This study clarified the current implant removal rate and trends following ORIF for DRF in Japan. Both patient- and hospital-related factors significantly impacted the decision for implant removal.

Clinical Presentation and Characteristics of the Upper Extremity in Patients with Musculocontractural Ehlers-Danlos Syndrome.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by defective dermatan sulfate biosynthesis, characterized by multiple malformations (craniofacial features, ocular and visceral malformations) and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Repeated dislocations and deformities of the joints due to joint relaxation are observed, causing serious damage to the musculoskeletal system of the whole body; however, the motor function of the upper limbs and the morphology of the bone joints have not been systematically investigated. In this study, we present a detailed and comprehensive report on upper limb lesions of 13 patients with a mean age at the first visit of 21 years. Twelve patients (92.3%) had a history of dislocation. Eleven patients (84.6%) had shoulder dislocations, and two patients (15.4%) had elbow dislocations. Four patients (30.8%) had elbow osteoarthritis, and three patients (23.1%) had distal radioulnar joint (DRUJ) osteoarthritis. The phalanges and metacarpals are thin, and the ratio of medullary cavity of the metacarpal bone decreases with age. As bone and joint deformity progresses, patients with mcEDS should be recommended to receive regular follow-up, including radiology. The present findings suggest an important role for dermatan sulfate in the maintenance of the skeletal system.

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma.

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.

Changes in tendon length and excursion following extensor tendon grafting at the distal radioulnar joint.

LEVEL OF EVIDENCE: IV.

Dorsal Trans-Scaphoid Perilunate Fracture-Dislocation in Association with Dorsal Dislocation of the Thumb Carpometacarpal Joint: A Rare Injury Pattern.

We report a dorsal trans-scaphoid perilunate fracture-dislocation associated with dorsal dislocation of the thumb carpometacarpal joint in a 25-year-old man. This is a rare injury and we discuss a possible mechanism for the injury. Level of Evidence: Level V (Therapeutic).

The Prevalence and Risk Factors for Trigger Digits in a Random Sampling of a Japanese Population Registry between 50 and 89 Years of Age.

Background: Trigger digit(s) (TD) is one of the most common disorders of the hand in the elderly population. The aim of this study is to determine the prevalence and identify the risk factors for TD in an elderly Japanese population. Methods: We randomly sampled 1,297 subjects between the ages of 50 and 89 years from the population registry of a town in Japan. About 413 subjects agreed to participate in the study, and all were examined for the presence of TD. Subjects were divided into three groups namely history of treatment for TD in the past (PTD), current evidence of TD (CTD) or both (BTD). The prevalence of TD was weighted by age according to the composition of the Japanese population. Age, female gender, obesity, hard manual work, exposure to vibration tools, sports activity, smoking, alcohol, wrist fracture, hypertension, hypothyroidism, diabetes mellitus, rheumatoid arthritis and carpal tunnel syndrome were assessed as risk factors for TD using univariate and multivariate logistic regression analysis. Results: Forty subjects had TD. This included 18, 19 and 3 subjects with PTD, CTD and BTD, respectively. The weighted prevalence of TD was 9.7% (female, 14.3%; male, 4.4%) in the Japanese population aged 50-89 years. Age 70-79 and female gender were identified as risk factors for TD. Conclusions: The random sampling of a Japanese population registry between the ages of 50 and 89 years revealed the prevalence of TD as 9.7% and identified age between 70 and 79 and female gender as risk factors for developing TD. Level of Evidence: Level II (Therapeutic).

[Long-Term Survival by Low-Dose Imatinib after Recurrence of GIST].

A man in his 70s was observed to have GIST recurrence 19 months after surgery. Chemotherapy was initiated with imatinib 400 mg/day orally. The dose was eventually reduced to 100 mg/day to avoid side effects. Tumor reduction was confirmed 3 months after treatment initiation. Currently, 84 months after the onset of GIST, the patient survives with continuous intake of the same dose of oral imatinib. We were able to observe long-term survival in a patient with recurrent GIST after the administration of a small dose of imatinib.

Prevalence and associated factors of primary elbow osteoarthritis in the Japanese general elderly population: a Japanese cohort survey randomly sampled from a basic resident registry.

BACKGROUND: The epidemiology of primary elbow osteoarthritis (PEOA) remains unknown. We aimed to evaluate the prevalence and associated factors of PEOA in a cross-sectional resident cohort from a municipal registry of a Japanese town. METHODS: A total of 415 residents over 50 years of age were randomly sampled from a Japanese town and were adjusted for age and gender. Those with diseases that could potentially cause a secondary osteoarthritis of the elbow were excluded. The remaining 318 subjects (150 men and 168 women) underwent bidirectional radiography of the elbow. Subjects were diagnosed with PEOA if one of their elbows was Kellgren-Lawrence (KL) grade 2 or greater. In addition, motion pain and tenderness at the elbow were examined by orthopedic surgeons. Associated factors for the PEOA were statistically analyzed. RESULTS: The prevalence of PEOA was 25.2% (male, 27.3%; female, 23.2%), and the prevalence of symptomatic PEOA was 0.9%. The age-stratified prevalence of PEOA was as follows: 50-59, 6.2% (male, 5.0%; female, 7.3%); 60-69, 15.4% (male, 17.5%; female, 13.7%); 70-79, 29.5% (male, 35.3%; female, 25.0%); and 80-89, 55.9% (male, 55.6%; female, 56.3%). Age and body mass index were revealed as associated factors that increased the prevalence of PEOA with KL grade 2 or greater. The use of vibrating tools was demonstrated as an independent associated factor that increased the prevalence of PEOA with KL grade 4 in addition to the 2 aforementioned factors. CONCLUSIONS: The prevalence of PEOA in Japanese subjects was 25.2% for those aged 50-89 years with a mean age of 69.2 years, most of which was asymptomatic OA without motion pain or tenderness at the elbow. Age and body mass index increased the prevalence of PEOA with KL grade 2 or greater. The prevalence of PEOA increased with age, but the disease was self-accommodated by most people.

The Predictive Factors of Displacement of Adult Distal End Radius Fracture Treated with Casting.

Background: In the conservative management of distal radial fractures (DRFs), the optimal dorsi-volar angulation of the wrist at cast immobilization and proper cast molding to minimize the risk of redisplacement are unclear. This study identified the predictors of fracture redisplacement during cast immobilization for adult DRFs. Methods: We examined for dorsi-volar angulation, gap index, volar tilt (VT), radial inclination (RI), and radial length (RL) in lateral or posteroanterior radiographs of 90 DRFs. We investigated possible predisposition factors for redisplacement including patient age, sex, extra- or intra-articular fracture, metaphyseal comminution, original displacements, dorsi-volar angulation of the wrist at cast immobilization, restoration of the volar cortex at cast immobilization, and gap index of the cast. Results: Neither dorsi-volar angulation nor gap index had significant association with an unacceptable alignment nor decrease of VT, RI, and RL. In multivariate analysis, patient age, original displacement, and intra-articular fracture were the significant predictors of an unacceptable alignment or decrease of VT and RI. Conclusions: Our findings indicate dorsi-volar angulation and cast molding quality have no clinical effect on preventing fracture redisplacement. The predictive factors of the displacement were patient age, original displacement, and intra-articular fracture.