EBF1 Limits the Numbers of Cochlear Hair and Supporting Cells and Forms the Scala Tympani and Spiral Limbus during Inner Ear Development.

Early B-cell factor 1 (EBF1) is a basic helix-loop-helix transcription factor essential for the differentiation of various tissues. Our single-cell RNA sequencing data suggest that Ebf1 is expressed in the sensory epithelium of the mouse inner ear. Here, we found that the murine Ebf1 gene and its protein are expressed in the prosensory domain of the inner ear, medial region of the cochlear duct floor, otic mesenchyme, and cochleovestibular ganglion. Ebf1 deletion in mice results in incomplete formation of the spiral limbus and scala tympani, increased number of cells in the organ of Corti and Kölliker's organ, and aberrant course of the spiral ganglion axons. Ebf1 deletion in the mouse cochlear epithelia caused the proliferation of SOX2-positive cochlear cells at E13.5, indicating that EBF1 suppresses the proliferation of the prosensory domain and cells of Kölliker's organ to facilitate the development of appropriate numbers of hair and supporting cells. Furthermore, mice with deletion of cochlear epithelium-specific Ebf1 showed poor postnatal hearing function. Our results suggest that Ebf1 is essential for normal auditory function in mammals.

Comparison of Postoperative outcomes Among Patients Treated by Male Versus Female Surgeons: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare clinical outcomes of patients treated by female surgeons versus those treated by male surgeons. SUMMARY BACKGROUND DATA: It remains unclear as to whether surgical performance and outcomes differ between female and male surgeons. METHODS: We conducted a meta-analysis to compare patients' clinical outcomes-including patients' postoperative mortality, readmission, and complication rates-between female versus male surgeons. MEDLINE, Embase, CENTRAL, ICTRP, and ClinicalTrials.gov were searched from inception to September 8, 2022. The update search was conducted on July 19, 2023. We used random-effects models to synthesize data and GRADE to evaluate the certainty. RESULTS: A total of 15 retrospective cohort studies provided data on 5,448,121 participants. We found that patients treated by female surgeons experienced a lower post-operative mortality compared with patients treated by male surgeons (8 studies; adjusted odds ratio [aOR], 0.93; 95%CI, 0.88 - 0.97; I2=27%; moderate certainty of the evidence). We found a similar pattern for both elective and non-elective (emergent or urgent) surgeries, although the difference was larger for elective surgeries (test for subgroup difference P=0.003). We found no evidence that female and male surgeons differed for patient readmission (3 studies; aOR, 1.20; 95%CI, 0.83 - 1.74; I2=92%; very low certainty of the evidence) or complication rates (8 studies; aOR, 0.94; 95%CI, 0.88 - 1.01: I2=38%; very low certainty of the evidence). CONCLUSIONS: This systematic review and meta-analysis suggests that patients treated by female surgeons have a lower mortality compared with those treated by male surgeons.

Mutations in the SARS-CoV-2 spike proteins affected the ACE2-binding affinity during the development of Omicron pandemic variants.

Mutations in SARS-CoV-2 caused multiple waves of pandemics. To identify the function of such mutations, we investigated the binding affinity of the S protein with its receptor, ACE2. Omicron BA.1 showed significantly lower binding affinity with human ACE2 than prototype SARS-CoV-2 and Alpha strain, indicating that pre-Omicron to Omicron transition was not mediated by increasing the ACE2-binding affinity. Meanwhile, the later Omicron variants, BA.5 and XBB.1.5, showed significantly higher ACE2-binding affinity, suggesting that the increased ACE2-binding could be involved in the variant transition within Omicron strains. Furthermore, Alpha and Omicron variants, but not prototype SARS-CoV-2, bound mouse ACE2, which lead to a hypothesis that early Omicron strains evolved from Alpha strain by acquiring multiple mutations in mice.

Clinical features of patients with carcinoma soft tissue metastases as surgical indications: a retrospective cohort study.

BACKGROUND: Soft-tissue metastasis of carcinoma is rare. In the present study, we investigated the surgical indications and clinical features of patients with soft tissue metastases of carcinoma. METHODS: In this retrospective cohort study, we enrolled 26 patients with soft tissue carcinoma metastasis referred to our department for treatment. Sex, age, location, size, depth, pain due to the tumor, primary origin, serum C-reactive protein (CRP) level, MRI examinations, diagnosis by a previous physician, carcinoma markers from blood, history of carcinoma, other metastases, performance status (PS), and surgical procedures were documented. Associations between variables and surgery were statistically analyzed. RESULTS: The primary cancer origin was found to be the lung (n = 10), kidney (n = 7), esophagus (n = 2), stomach (n = 1), breast (n = 1), liver (n = 1), ureter (n = 1), anus (n = 1), and unknown (n = 2). The mean CRP level of all patients was 2.3 mg/dL. Seven tumors (26.9%) were originally suspected to be soft tissue metastases of carcinoma, while 19 tumors (73.1%) were considered soft tissue sarcomas or inflammatory lesions by the previous treating physician. Twenty patients (76.9%) had other metastases. The PS of the 12 patients (46.2%) was zero. Eleven patients (42.3%) underwent surgery for soft tissue metastases. Diagnosis of soft tissue metastasis by a previous physician and good PS (p < 0.05) were significantly associated with surgery. CONCLUSION: Overall, the present results show that surgical indications for soft tissue metastasis of carcinoma include diagnosis by the referring physician or good PS of the patients.

Midline invasion predicts poor prognosis in diffuse hemispheric glioma, H3 G34-mutant: an individual participant data review.

INTRODUCTION: Diffuse hemispheric glioma, H3 G34-mutant (DHGs), is a newly categorized tumor in pediatric-type diffuse high-grade gliomas, World Health Organization grade 4, with a poor prognosis. Although prognostic factors associated with genetic abnormalities have been reported, few reports have examined the clinical presentation of DHGs, especially from the viewpoint of imaging findings. In this study, we investigated the relationship between clinical factors, including imaging findings, and prognosis in patients with DHGs. METHODS: We searched Medline through the PubMed database using two search terms: "G34" and "glioma", between 1 April 2012 and 1 July 2023. We retrieved articles that described imaging findings and overall survival (OS), and added one DHG case from our institution. We defined midline invasion (MI) as invasion to the contralateral cerebrum, brainstem, corpus callosum, thalamus, and basal ganglia on magnetic resonance imaging. The primary outcome was 12-month survival, estimated using Kaplan-Meier curves and logistic regression. RESULTS: A total of 96 patients were included in this study. The median age was 22 years, and the proportion of male patients was 48.4%. Lesions were most frequently located in the frontal lobe (52.6%). MI was positive in 39.6% of all patients. The median OS was 14.4 months. Univariate logistic regression analysis revealed that OS was significantly worse in the MI-positive group compared with the MI-negative group. Multivariate logistic regression analysis revealed that MI was an independent prognostic factor in DHGs. CONCLUSIONS: In this study, MI-positive cases had a worse prognosis compared with MI-negative cases. PREVIOUS PRESENTATIONS: No portion of this study has been presented or published previously.

Peripheral Nerve Blocks in the Preoperative Management of Hip Fractures: A Systematic Review and Network Meta-Analysis.

STUDY OBJECTIVE: We conducted a systematic review and network meta-analysis to evaluate the comparative efficacy of peripheral nerve block types for preoperative pain management of hip fractures. METHODS: We searched Cochrane, Central Register of Controlled Trials, MEDLINE, EMBASE, ICTRP, ClinicalTrials.gov, and Google Scholar for randomized clinical trials. We included participants aged more than 16 years with hip fractures who received peripheral nerve blocks or analgesics for preoperative pain management. The primary outcomes were defined as absolute pain score 2 hours after block placement, preoperative consumption of morphine equivalents, and length of hospital stay. We used a random-effects network meta-analysis conceptualized in the Bayesian framework. Confidence of evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 63 randomized controlled studies (4,778 participants), of which only a few had a low risk of bias. The femoral nerve block, 3-in-1 block, fascia iliaca compartment block, and pericapsular nerve group block yielded significantly lowered pain scores at 2 hours after block placement compared with those with no block (standardized mean differences [SMD]: -1.1; 95% credible interval [CrI]: -1.7 to -0.48, [confidence of evidence: low]; SMD: -1.8; 95% CrI: -3.0 to -0.55, [low]; SMD: -1.4; 95% CrI: -2.0 to -0.72, [low]; SMD: -2.3; 95% CrI: -3.2 to -1.4, [moderate], respectively). The pericapsular nerve group block, 3-in-1 block, fascia iliaca compartment block, and femoral nerve block resulted in lower pain scores than the no-block group. Additionally, the pericapsular nerve group block yielded a lower pain score than femoral nerve block or fascia iliaca compartment block (SMD: -1.21; 95% CrI: -2.18 to -0.23, [very low]: SMD: -0.92; 95% CrI: -1.70 to -0.16, [low]). However, both the fascia iliaca compartment block and femoral nerve block did not show a reduction in morphine consumption compared with no block. To our knowledge, no studies have compared the pericapsular nerve group block with other methods regarding morphine consumption. Furthermore, no significant difference was observed between peripheral nerve blocks and no block in terms of the length of hospital stay. CONCLUSIONS: Compared with no block, preoperative peripheral nerve blocks for hip fractures appear to reduce pain 2 hours after block placement. Comparing different blocks, pericapsular nerve group block might be superior to fascia iliaca compartment block and femoral nerve block for pain relief, though the confidence evidence was low in most comparisons because of the moderate to high risk of bias in many of the included studies and the high heterogeneity of treatment strategies across studies. Therefore, further high-quality research is needed.

Comparative efficacy of ultrasound guidance or conventional anatomical landmarks for neuraxial puncture in adult patients: a systematic review and network meta-analysis.

BACKGROUND: Preprocedural, real-time, and computer-aided three-dimensional ultrasound has been widely used for neuraxial puncture; however, the optimal guidance is unclear. We examined the comparative efficacy of three ultrasound guidance and anatomical landmarks for neuraxial puncture in adults. METHODS: We searched for randomised controlled studies comparing the efficacy of ultrasound guidance and anatomical landmarks for neuraxial puncture in adults using electronic databases and unpublished studies. The primary outcomes were first-pass success and patient satisfaction. A random-effects network meta-analysis (NMA) was used. RESULTS: We identified 74 eligible studies (7090 patients). Preprocedural ultrasound and real-time ultrasound-guided neuraxial puncture improved first-pass success compared with anatomical landmarks (risk ratio [RR] 1.6; 95% credible interval [CrI] 1.3-1.9; RR 1.9; 95% CrI 1.3-2.9, respectively, moderate confidence). Computer-aided ultrasound-guided neuraxial puncture also increased first-pass success (RR 1.8; 95% CrI 0.97-3.3, low confidence), although estimates were imprecise. However, real-time ultrasound-guided neuraxial puncture resulted in minimal difference in first-pass success compared with preprocedural ultrasound (RR 1.2; 95% CrI 0.8-1.8, moderate confidence). Preprocedural ultrasound improved patient satisfaction slightly compared with anatomical landmark use (standardised mean differences 0.28; 95% CrI 0.092-0.47, low confidence). CONCLUSIONS: This NMA provides evidence supporting ultrasound-guided neuraxial puncture compared with use of anatomical landmarks, including indirect comparisons. Among the three ultrasound guidance methods, preprocedural ultrasound appears to be a better adjunctive option.

Anti-osteoporotic drug efficacy for periprosthetic bone loss after total hip arthroplasty: A systematic review and network meta-analysis.

BACKGROUND: Periprosthetic bone loss following total hip arthroplasty (THA) threatens prosthesis stability. This systematic review and network meta-analysis aimed to compare the efficacy of anti-osteoporotic drugs for measures of hip function according to functional outcomes, periprosthetic femoral bone mineral density loss in each Gruen zone, and revision surgery after THA. METHODS: The systematic search of six literature databases was conducted in December 2021 in accordance with PRISMA guidelines. Adult participants who underwent primary THA were included. A random-effects network meta-analysis was performed within a frequentist framework, and the confidence in the evidence for each outcome was evaluated using the CINeMA tool, which assessed the credibility of results from the network meta-analysis. We included 22 randomized controlled trials (1243 participants) comparing the efficacy and safety of bisphosphonates (including etidronate, clodronate, alendronate, risedronate, pamidronate, and zoledronate), denosumab, selective estrogen receptor modulator, teriparatide, calcium + vitamin D, calcium, and vitamin D. We defined the period for revision surgery as the final follow-up period. RESULTS: Raloxifene, bisphosphonate, calcium + vitamin D, and denosumab for prosthetic hip function might have minimal differences when compared with placebos. The magnitude of the anti-osteoporotic drug effect on periprosthetic femoral bone loss varied across different Gruen zones. Bisphosphonate, denosumab, teriparatide might be more effective than placebo in Gruen zone 1 at 12 months after THA. Additionally, bisphosphonate might be more effective than placebo in Gruen zones 2, 5, 6, and 7 at 12 months after THA. Denosumab was efficacious in preventing bone loss in Gruen zones 6 and 7 at 12 months after THA. Teriparatide was likely to be efficacious in preventing bone loss in Gruen zone 7 at 12 months after THA. Raloxifene was slightly efficacious in preventing bone loss in Gruen zones 2 and 3 at 12 months after THA. Calcium was slightly efficacious in preventing bone loss in Gruen zone 5 at 12 months after THA. None of the studies reported revision surgery. CONCLUSIONS: Bisphosphonate and denosumab may be effective anti-osteoporotic drugs for preventing periprosthetic proximal femoral bone loss due to stress shielding after THA, particularly in cementless proximal fixation stems, which are the most commonly used prostheses worldwide.

Endosteal strut using a hydroxyapatite/poly-L-lactide mesh tube with a proximal humeral locking plate for the treatment of proximal humeral fractures.

PURPOSE: Proximal humeral fractures cause large intramedullary bone defects after humeral-head reduction. Hydroxyapatite/poly-L-lactide (HA/PLLA) materials are widely used for various fractures. However, the efficacy of endosteal strut using a HA/PLLA mesh tube (ES-HA/PLLA) with a locking plate for treating proximal humeral fractures was not reported. The purpose of this study is to examine the efficacy of ES-HA/PLLA with a proximal humeral locking plate in proximal humeral fractures. METHODS: Seventeen patients with proximal humeral fractures treated using ES-HA/PLLA with a locking plate from November 2017 to November 2021 were evaluated. The range of motion of the shoulder and postoperative complications were assessed at the final follow-up. Radiographs were evaluated to assess bone union and loss of reduction by measuring humeral-head height (HHH) and humeral neck-shaft angle (NSA). RESULTS: The average flexion and external rotation of the shoulder at the final follow-up were 137° (range, 90-180°) and 39° (range, - 10 to 60°), respectively. All fractures were united. The average HHH and NSA just after the surgery and final follow-up were 12.5 mm and 11.6 mm and 129.9° and 127.4°, respectively. Two patients presented screw perforation of the humeral head. One patient underwent implant removal due to infection. Avascular necrosis of the humeral head was observed in one patient with arthritis mutilans. CONCLUSIONS: The use of ES-HA/PLLA with a proximal humeral locking plate resulted in bone union in all patients and prevented postoperative loss of reduction. ES-HA/PLLA is one of the treatment options for proximal humeral fractures.

Joint-preservation surgery for bone sarcoma in adolescents and young adults.

Bone sarcoma often occurs in childhood, as well as in adolescents and young adults (AYAs). AYAs differ from pediatric patients in that their bone is skeletally mature and the physis has almost disappeared with the completion of growth. Although AYAs spend less time outside, they often participate in sports activities, as well as driving, working, and raising a family, which are natural activities in daily living. Multidisciplinary approaches involving imaging, multi-agent chemotherapy, surgical procedures, and careful postoperative care has facilitated an increase in limb-sparing surgery for bone sarcoma. In addition, recent advances in imaging modalities and surgical techniques enables joint-preservation surgery, preserving the adjacent epiphysis, for selected patients following the careful assessment of the tumor margins and precise tumor excision. An advantage of this type of surgery is that it retains the native function of the adjacent joint, which differs from joint-prosthesis replacement, and provides excellent limb function. Various reconstruction procedures are available for joint-preserving surgery, including allograft, vascularized fibula graft, distraction osteogenesis, and tumor-devitalized autografts. However, procedure-related complications may occur, including non-union, infection, fracture, and implant failure, and surgeons should fully understand the advantages and disadvantages of these procedures. The longevity of the normal limb function for natural activities and the curative treatment without debilitation from late toxicities should be considered as a treatment goal for AYA patients. This review discusses the concept of joint-preservation surgery, types of reconstruction procedures associated with joint-preservation surgery, and current treatment outcomes.

Comparative efficacy of ultrasound guidance and fluoroscopy or computed tomography guidance in spinal nerve injections: a systematic review and meta-analysis.

PURPOSE: Spinal nerve injections have traditionally been performed under fluoroscopic (FL) and computed tomography (CT) guidance. Recently, ultrasound (US)-guided procedures have provided an alternative guidance approach that does not expose the patient and operator to radiation. The aim of this study was to compare the efficacy and safety of US-guided spinal nerve injections compared with FL- or CT-guided spinal nerve injections. METHODS: MEDLINE, Cochrane Library, EMBASE, international clinical trials registry platform (ICTRP) and ClinicalTrials.gov database searches for inclusion until February 2023 were independently performed by two authors using predefined criteria. Randomized controlled trials (RCTs) were included. Primary outcomes were change in pain score (numeric rating scale or visual analogue scale) and major adverse events. Secondary outcomes were procedure time, change in functional disability score and minor adverse events. Meta-analysis was performed using random-effect model. We evaluated the certainty of evidence based on the Grading of Recommendations, Assessment and Development (GRADE) approach. RESULTS: Eight RCTs involving 962 patients were included. There might be little to no difference in the mean score of the pain change between the US-guided methods and the FL- or CT-guided injections (standard mean difference -0.06; 95% confidence interval [CI] -0.26 to 0.15). US guidance probably reduced major adverse events (0.7% [3/433] and 6.5% [28/433], respectively), reduced procedure time (mean difference -4.19 min; 95% CI -5.09 to -3.30), and probably reduced minor adverse events (2.1% [9/433] and 4.2% [18/433], respectively) compared with FL or CT guidance. There was probably little to no difference in the change in functional disability score with either method. CONCLUSION: US-guided spinal nerve injections remained effective and reduced adverse events compared with conventional FL- or CT-guided spinal nerve injections. Further RCTs are required to verify our results. STUDY REGISTRATION: Open Science Forum (Available from: https://osf.io/vt92w/ ).

Needle tract seeding of a sclerosing epithelioid fibrosarcoma in a biopsy tract: a case report.

BACKGROUND: A sclerosing epithelioid fibrosarcoma (SEF) is an uncommon tumor of the deep soft tissue. An SEF has been described as a low-grade tumor with high local recurrence and metastatic rates. Generally, in bone and soft tissue tumors, a resection of the biopsy route is recommended; however, there is limited evidence with respect to the dissemination of the tumor tissue during a needle biopsy. CASE PRESENTATION: A mass in the right pelvic cavity, with no symptoms, was observed in a 45-year-old woman during a gynecological examination. Computed tomography (CT) revealed a multilocular mass with calcification in the pelvic cavity. The magnetic resonance imaging (MRI) showed an iso-signal intensity on T1 weighted images and hypo- and iso-signal intensity on T2 weighted images. The CT-guided core needle biopsy was performed using a dorsal approach, and the biopsy diagnosis was a low-grade spindle cell tumor. The tumor was excised using an anterior approach. The tumor tissue comprised spindle cells and epithelioid cells with irregular nuclei, and the immunohistological analysis was positive for vimentin and epithelial membrane antigen, which was consistent with a diagnosis of sclerosing epithelioid fibrosarcoma. Five years after the surgery, the MRI showed a tumor recurrence in the subcutaneous tissue of the right buttock, which was consistent with the needle biopsy tract. The patient underwent a tumor excision, and the resected tumor was similar to the primary tumor. CONCLUSIONS: The recurrent tumor was excised with a surgical margin, and the tumor specimen had the histological features of a sclerosing epithelioid fibrosarcoma. It was difficult to investigate the association of the core needle biopsy with the tumor recurrence because the approach of the biopsy tract is usually same as that used in a tumor excision. However, the present case indicated the tumor may recur in the biopsy tract of a soft tissue sarcoma. Surgeons should be aware of the possibility of disseminating tumor tissues in a needle biopsy.

The impact and prevention of systemic and diagnostic errors in surgical malpractice claims in Japan: a retrospective cohort study.

The Surgical Patient Safety System (SURPASS) has been proven to improve patient outcomes. However, few studies have evaluated the details of litigation and its prevention in terms of systemic and diagnostic errors as potentially preventable problems. The present study explored factors associated with accepted claims (surgeon-loss). We retrospectively searched the national Japanese malpractice claims database between 1961 and 2017. Using multivariable logistic regression models, we assessed the association between medical malpractice variables (systemic and diagnostic errors, facility size, time, place, and clinical outcomes) and litigation outcomes (acceptance). We evaluated whether or not the factors associated with litigation could have been prevented with the SURPASS checklist. We identified 339 malpractice claims made against general surgeons. There were 159 (56.3%) accepted claims, and the median compensation paid was 164,381 USD. In multivariable analyses, system (odds ratio, 27.2 95% confidence interval 13.8-53.5) and diagnostic errors (odds ratio 5.3, 95% confidence interval 2.7-10.5) had a significant statistical association with accepted claims. The SURPASS checklist may have prevented 7% and 10% of the accepted claims and systemic errors, respectively. It is unclear what proportion of accepted claims indicated that general surgeon loses should be prevented from performing surgery if the SURPASS checklist were used. In conclusion, systemic and diagnostic errors were associated with accepted claims. Surgical teams should adhere to the SURPASS checklist to enhance patient safety and reduce surgeon risk.

Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals.

Computational screening is one of the fundamental techniques in drug discovery. Each compound in a chemical database is bound to the target protein in virtual, and candidate compounds are selected from the binding scores. In this work, we carried out combinational computation of docking simulation to generate binding poses and molecular mechanics calculation to estimate binding scores. The coronavirus infectious disease has spread worldwide, and effective chemotherapy is strongly required. The viral 3-chymotrypsin-like (3CL) protease is a good target of low molecular-weight inhibitors. Hence, computational screening was performed to search for inhibitory compounds acting on the 3CL protease. As a preliminary assessment of the performance of this approach, we used 51 compounds for which inhibitory activity had already been confirmed. Docking simulations and molecular mechanics calculations were performed to evaluate binding scores. The preliminary evaluation suggested that our approach successfully selected the inhibitory compounds identified by the experiments. The same approach was applied to 8820 compounds in a database consisting of approved and investigational chemicals. Hence, docking simulations, molecular mechanics calculations, and re-evaluation of binding scores including solvation effects were performed, and the top 200 poses were selected as candidates for experimental assays. Consequently, 25 compounds were chosen for in vitro measurement of the enzymatic inhibitory activity. From the enzymatic assay, 5 compounds were identified to have inhibitory activities against the 3CL protease. The present work demonstrated the feasibility of a combination of docking simulation and molecular mechanics calculation for practical use in computational virtual screening.

In Silico Identification of Inhibitory Compounds for SARS-Cov-2 Papain-Like Protease.

Virtual screening with high-performance computers is a powerful and cost-effective technique in drug discovery. A chemical database is searched to find candidate compounds firmly bound to a target protein, judging from the binding poses and/or binding scores. The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infectious disease has spread worldwide for the last three years, causing severe slumps in economic and social activities. SARS-Cov-2 has two viral proteases: 3-chymotrypsin-like (3CL) and papain-like (PL) protease. While approved drugs have already been released for the 3CL protease, no approved agent is available for PL protease. In this work, we carried out in silico screening for the PL protease inhibitors, combining docking simulation and molecular mechanics calculation. Docking simulations were applied to 8,820 molecules in a chemical database of approved and investigational compounds. Based on the binding poses generated by the docking simulations, molecular mechanics calculations were performed to optimize the binding structures and to obtain the binding scores. Based on the binding scores, 57 compounds were selected for in vitro assay of the inhibitory activity. Five inhibitory compounds were identified from the in vitro measurement. The predicted binding structures of the identified five compounds were examined, and the significant interaction between the individual compound and the protease catalytic site was clarified. This work demonstrates that computational virtual screening by combining docking simulation with molecular mechanics calculation is effective for searching candidate compounds in drug discovery.

The impact of system and diagnostic errors for medical litigation outcomes in orthopedic surgery.

BACKGROUND: Medical litigation resulting from medical errors has a negative impact on health economics for both patients and medical practitioners. In medical litigation involving orthopedic surgeons, we aimed to identify factors contributing to plaintiff victory (orthopedic surgeon loss) through a comprehensive assessment. METHODS: This retrospective study included 166 litigation claims against orthopedic surgeons using a litigation database in Japan. We evaluated the sex and age of the patient (plaintiff), initial diagnosis, diagnostic error, system error, the time and place of each claim that led to malpractice litigation, the institution's size, and clinical outcomes. The main outcome was the litigation outcome (acceptance or rejection) in the final judgment. Acceptance meant that the orthopedic surgeon lost the malpractice lawsuit. We conducted multivariable logistic regression analyses to examine the association of factors with an accepted claim. RESULTS: The median age of the patients was 42 years, and 65.7% were male. The litigation outcome of 85 (51.2%) claims was acceptance. The adjusted median indemnity paid was $151,818. The multivariable analysis showed that diagnostic error, system error, sequelae, inadequate medical procedure, and follow-up observation were significantly associated with the orthopedic surgeon losing the lawsuit. In particular, claims involving diagnostic errors were more likely to be acceptance claims, in which the orthopedic surgeon lost (adjusted odds ratio 16.7, 95% confidence intervals: 4.7 to 58.0, p < 0.001). All of the claims in which the orthopedic surgeon lost were associated with a diagnostic or system error, with the most common one being system error. CONCLUSIONS: System errors and diagnostic errors were significantly associated with acceptance claims (orthopedic surgeon losses). Since these are modifiable factors, it is necessary to take measures not only for individual physicians but also for the overall medical management system to enhance patient safety and reduce the litigation risk of orthopedic surgeons.

Sarcoma: Molecular Pathology, Diagnostics, and Therapeutics.

Although the incidence of sarcomas accounts for less than 1% of all malignancies, they are classified into more than 50 different subtypes with different biological behaviours [...].

Cumulated ambulation score as predictor of postoperative mobility in patients with proximal femur fractures.

INTRODUCTION: The cumulated ambulation score (CAS) has been developed as an index for evaluating mobility in the early postoperative period. This study aimed to estimate the association between CAS and independent ambulation after surgery for proximal femur fractures. MATERIALS AND METHODS: This retrospective cohort study included 223 elderly patients who underwent surgery for proximal femur fractures and had independent ambulation before the injury. Multivariable logistic regression analyses with cognitive impairment, pre-injury Barthel index, and CAS as the test variables were used to predict independent ambulation at 2 weeks (model 1) and 3 months (model 2) postoperatively. We established scoring systems based on the modeling results. RESULTS: The number of patients with independent ambulation at 2 weeks and 3 months postoperatively was 115 and 169, respectively. Univariate analysis showed that the CAS was significantly associated with independent ambulation at 2 weeks and 3 months postoperatively. Multivariable analysis showed that models 1 and 2 had good predictive accuracies, with areas under the receiver-operating characteristic curve of 0.855 and 0.868, respectively. Among the explanatory variables, only the CAS in model 2 was not significantly associated with the postoperative ambulatory ability. Scoring systems for both models 1 and 2 also had good predictive accuracies, with cut-off scores of 3.5 for model 1 and 9.5 for model 2. CONCLUSIONS: The CAS predicted independent ambulation at 2 weeks postoperatively; however, this relationship was limited at 3 months postoperatively. Therefore, the CAS may help estimate independent ambulation at discharge from an acute-care hospital.

In silico analysis of inner ear development using public whole embryonic body single-cell RNA-sequencing data.

The inner ear comprises four epithelial domains: the cochlea, vestibule, semicircular canals, and endolymphatic duct/sac. These structures are segregated at embryonic day 13.5 (E13.5). However, these four anatomical structures remain undefined at E10.5. Here, we aimed to identify lineage-specific genes in the early developing inner ear using published data obtained from single-cell RNA-sequencing (scRNA-seq) of embryonic mice. We downloaded 5000 single-cell transcriptome data, named 'auditory epithelial trajectory', from the Mouse Organogenesis Cell Atlas. The dataset was supposed to include otic epithelial cells at E9.5-13.5. We projected the 5000 â€‹cells onto a two-dimensional space encoding the transcriptional state and visualised the pattern of otic epithelial cell differentiation. We identified 15 clusters, which were annotated as one of the four components of the inner ear epithelium using known genes that characterise the four different tissues. Additionally, we classified 15 clusters into sub-regions of the four inner ear components. By comparing transcriptomes between these 15 clusters, we identified several candidates of lineage-specific genes. Characterising these new candidate genes will help future studies about inner ear development.

Inhibition of EGFR and MEK surmounts entrectinib resistance in a brain metastasis model of NTRK1-rearranged tumor cells.

Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.