Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

[Neuropathology of Inflammatory and Autoimmune-Mediated Diseases].

Herein, the author summarize the basic findings on the neuropathology of inflammatory and autoimmune central nervous system (CNS) diseases. Current knowledge on infectious, demyelinating, and autoimmune diseases have also been reported. Further, I emphasize the importance of considering the neuropathology of meningitis, encephalitis, and abscesses as infectious diseases; multiple sclerosis and neuromyelitis optica as demyelinating diseases; and vasculitis, paraneoplastic neurological syndrome, and collagen diseases as autoimmune diseases.

Efficacy of the traction method for gastric endoscopic submucosal dissection: a randomized controlled trial (with videos).

BACKGROUND AND AIMS: To overcome the technical difficulties associated with gastric endoscopic submucosal dissection (ESD), a novel traction device that can alter the direction of traction was developed. This study compared the efficacy and safety of conventional ESD versus those of traction-assisted gastric ESD. METHODS: Patients with a single gastric epithelial neoplasm were randomized to receive conventional (n = 75) or traction-assisted (n = 73) gastric ESD. The primary outcome was ESD procedure time. RESULTS: There were no differences between the conventional and traction-assisted groups with respect to treatment results or adverse events. The mean procedure time was similar for both groups (78.9 vs 88.3 minutes, respectively; P = .3); however, times for the traction device tended to be shorter for lesions in the lesser curvature of the upper or middle stomach (84.6 vs 123.2 minutes; P = .057). CONCLUSIONS: Traction-assisted ESD for lesions in the lesser curvature of the upper or middle stomach were shorter, thereby reducing the procedure time of conventional ESD. (Clinical trial registration: University Hospital Medial Information Network Clinical Trials Registry, identifier 000044450.).

Automatic hip osteoarthritis grading with uncertainty estimation from computed tomography using digitally-reconstructed radiographs.

PURPOSE: Progression of hip osteoarthritis (hip OA) leads to pain and disability, likely leading to surgical treatment such as hip arthroplasty at the terminal stage. The severity of hip OA is often classified using the Crowe and Kellgren-Lawrence (KL) classifications. However, as the classification is subjective, we aimed to develop an automated approach to classify the disease severity based on the two grades using digitally-reconstructed radiographs from CT images. METHODS: Automatic grading of the hip OA severity was performed using deep learning-based models. The models were trained to predict the disease grade using two grading schemes, i.e., predicting the Crowe and KL grades separately, and predicting a new ordinal label combining both grades and representing the disease progression of hip OA. The models were trained in classification and regression settings. In addition, the model uncertainty was estimated and validated as a predictor of classification accuracy. The models were trained and validated on a database of 197 hip OA patients, and externally validated on 52 patients. The model accuracy was evaluated using exact class accuracy (ECA), one-neighbor class accuracy (ONCA), and balanced accuracy. RESULTS: The deep learning models produced a comparable accuracy of approximately 0.65 (ECA) and 0.95 (ONCA) in the classification and regression settings. The model uncertainty was significantly larger in cases with large classification errors ( P < 6 e - 3 ). CONCLUSIONS: In this study, an automatic approach for grading hip OA severity from CT images was developed. The models have shown comparable performance with high ONCA, which facilitates automated grading in large-scale CT databases and indicates the potential for further disease progression analysis. Classification accuracy was correlated with the model uncertainty, which would allow for the prediction of classification errors. The code will be made publicly available at https://github.com/NAIST-ICB/HipOA-Grading .

Hybrid representation-enhanced sampling for Bayesian active learning in musculoskeletal segmentation of lower extremities.

PURPOSE: Manual annotations for training deep learning models in auto-segmentation are time-intensive. This study introduces a hybrid representation-enhanced sampling strategy that integrates both density and diversity criteria within an uncertainty-based Bayesian active learning (BAL) framework to reduce annotation efforts by selecting the most informative training samples. METHODS: The experiments are performed on two lower extremity datasets of MRI and CT images, focusing on the segmentation of the femur, pelvis, sacrum, quadriceps femoris, hamstrings, adductors, sartorius, and iliopsoas, utilizing a U-net-based BAL framework. Our method selects uncertain samples with high density and diversity for manual revision, optimizing for maximal similarity to unlabeled instances and minimal similarity to existing training data. We assess the accuracy and efficiency using dice and a proposed metric called reduced annotation cost (RAC), respectively. We further evaluate the impact of various acquisition rules on BAL performance and design an ablation study for effectiveness estimation. RESULTS: In MRI and CT datasets, our method was superior or comparable to existing ones, achieving a 0.8% dice and 1.0% RAC increase in CT (statistically significant), and a 0.8% dice and 1.1% RAC increase in MRI (not statistically significant) in volume-wise acquisition. Our ablation study indicates that combining density and diversity criteria enhances the efficiency of BAL in musculoskeletal segmentation compared to using either criterion alone. CONCLUSION: Our sampling method is proven efficient in reducing annotation costs in image segmentation tasks. The combination of the proposed method and our BAL framework provides a semi-automatic way for efficient annotation of medical image datasets.

Leg length discrepancy should be assessed based on the whole length of the lower limb in patients with osteoarthritis secondary to developmental dysplasia of the hip.

Aims: This study aimed to investigate the incidence of ≥ 5 mm asymmetry in lower and whole leg lengths (LLs) in patients with unilateral osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH-OA) and primary hip osteoarthritis (PHOA), and the relationship between lower and whole LL asymmetries and femoral length asymmetry. Methods: In total, 116 patients who underwent unilateral total hip arthroplasty were included in this study. Of these, 93 had DDH-OA and 23 had PHOA. Patients with DDH-OA were categorized into three groups: Crowe grade I, II/III, and IV. Anatomical femoral length, femoral length greater trochanter (GT), femoral length lesser trochanter (LT), tibial length, foot height, lower LL, and whole LL were evaluated using preoperative CT data of the whole leg in the supine position. Asymmetry was evaluated in the Crowe I, II/III, IV, and PHOA groups. Results: The incidences of whole and lower LL asymmetries were 40%, 62.5%, 66.7%, and 26.1%, and 21.7%, 20.8%, 55.6%, and 8.7% in the Crowe I, II/III, and IV, and PHOA groups, respectively. The incidence of tibial length asymmetry was significantly higher in the Crowe IV group (44.4%) than that in the PHOA group (4.4%). In all, 50% of patients with DDH-OA with femoral length GT and LT asymmetries had lower LL asymmetry, and 75% had whole LL asymmetry. The incidences of lower and whole LL asymmetries were 20% and 42.9%, respectively, even in the absence of femoral length GT and LT asymmetries. Conclusion: Overall, 43% of patients with unilateral DDH-OA without femoral length asymmetry had whole LL asymmetry of ≥ 5 mm. Thus, both the femur length and whole LL should be measured to accurately assess LL discrepancy in patients with unilateral DDH-OA.

Patients With Subacute Sclerosing Panencephalitis in Japan: A 2022 Nationwide Survey.

BACKGROUND: In Japan, the incidence of subacute sclerosing panencephalitis (SSPE) has reduced; however, the medical conditions and factors associated with disease progression remain unclear. METHODS: A nationwide survey of SSPE was conducted using a questionnaire in 2022. We conducted a descriptive analysis of the patients with SSPE in 2022 and Cox proportional hazards analyses for disease progression. We compared the patients with SSPE with those in a 2007 survey. RESULTS: A total of 37 surviving patients with SSPE were enrolled [median age: 32 years (range: 16-52 years)]. No new cases have been identified since 2017 in the survey. Jabbour stage IV was the most common stage (66.7%). The hazard ratios (95% confidence intervals) of male sex and age at the time of measles infection (years) were 2.56 (1.13-5.76) and 0.57 (0.34-0.93), respectively. Compared with those in 2007, the proportion of patients in hospitals decreased from 13.7% to 2.7%, whereas that of patients in nursing facilities increased from 17.6% to 29.7%. The proportions of patients prescribed inosine pranobex, interferon and ribavirin at the time of the survey decreased from 96.1% to 79.4%, 74.8% to 14.3% and 25.3% to 0%, respectively. The proportions of patients with gastrostomy, tracheostomy and ventilator use increased from 5.9% to 69.7%, 23.3% to 60.0% and 10.8% to 32.4%, respectively. CONCLUSIONS: Decreased measles cases in Japan reduced new SSPE cases. However, surviving patients in 2022 had advanced disease stages and needed medical care. Male sex and early measles infection were significantly associated with disease progression.

Clinical characteristics of motor functional neurological disorder manifesting as limb weakness after vaccination against coronavirus disease 2019: A case series.

Background: The characteristics of functional limb weakness (FLW) as one of the manifestations of functional neurological disorder after vaccination against coronavirus disease 2019 (COVID-19) remain controversial. Methods: In this descriptive case series, we aimed to elucidate the characteristics of Japanese patients with FLW who claimed muscle weakness after COVID-19 vaccination among patients who visited our outpatient clinic between 1 June 2021 and 31 December 2022. Results: Nine patients were diagnosed with FLW (mean age: 30.8 years), including two men and seven women. Seven patients were vaccinated with the BioNTech/Pfizer vaccine and two with the mRNA-1273 Moderna vaccine. All patients demonstrated various positive signs for FLW. Magnetic resonance imaging or computed tomography indicated no abnormality that could explain their symptoms. At the time of the clinic visit, five patients were treated for psychiatric disorders, including depression, insomnia, attention-deficit hyperactivity disorder, and Asperger's syndrome. Muscle weakness spread to the limbs beyond the vaccinated arm in seven patients. Conclusions: We describe the basic characteristics of FLW in Japanese patients after COVID-19 vaccination. Further recognition of these characteristics could aid the diagnosis of FLW by physicians allowing them to support these patients effectively.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

[Eserine, in Crooked House and Curtain].

Eserine, well-known as physostigmine, is classified as an alkaloid. It is a cholinesterase inhibitor and appears in Agatha Christie's novel entitled, Crooked House and Curtain: Poirot's Last Case. In clinical medicine, eserine was used as an ophthalmic treatment for glaucoma and considered as a treatment for myasthenia gravis, Alzheimer's disease, and hereditary cerebellar ataxias. Currently, it is used as a treatment for anticholinergic poisoning.

Femoral head translation in borderline and definite dysplastic hips during weight-bearing: 2D/3D image registration analysis.

PURPOSE: The aims of this study were to 1) assess femoral head translation during weight-bearing in symptomatic developmental dysplasia of the hip (DDH) and 2) compare it between borderline DDH and definite DDH. METHODS: The study included four individuals with borderline DDH and nine with definite DDH, scheduled for periacetabular osteotomy. Anteroposterior X-ray images of the hip joint were obtained in the standing position, and computed tomography images of the pelvis were obtained in the supine position. Femoral head translation from the supine to a standing position was measured using 2D/3D X-ray image registration. RESULTS: From a supine to a standing position, the femoral head translated 0.3 mm laterally, 0.5 mm anteriorly, and 0.5 mm superiorly on average. The mean femoral head translation in 3D between the supine and standing positions was 1.5 mm. The 3D femoral head translation in the borderline DDH group was significantly greater than that in the definite DDH group. In the definite DDH group, there was a significant correlation between the center edge (CE) angle and 3D femoral head translation (ρ = -0.78, P = 0.012). CONCLUSIONS: Symptomatic DDH showed femoral head translation in the anterior, lateral, and superior directions during weight-bearing. In definite DDH, the amount of femoral head translation was negatively correlated with the CE angle. The amount of 3D translation in patients with borderline DDH was larger than that in definite DDH. Dynamic joint instability during weight-bearing was observed in borderline DDH as well as definite DDH. Treatment to enhance joint stability during weight-bearing is important in both cases.

First evidence of tick-borne encephalitis (TBE) outside of Hokkaido Island in Japan.

Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000 km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200 km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700 km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.

Imaging Features of Early Diffuse Idiopathic Skeletal Hyperostosis (pre-DISH): Analysis of Progression of Ligament Ossification over 5 Years by Computed Tomography.

Introduction: Some patients who have not been diagnosed with diffuse idiopathic skeletal hyperostosis (DISH) (patients in the preclinical stage of DISH [pre-DISH]) may develop DISH in the future. However, there are currently no clearly defined diagnostic criteria for pre-DISH. This study aims to define pre-DISH by analyzing the change in the ossification extent in each intervertebral space in the thoracic and lumbar spines over time using computed tomography (CT). Methods: Of the patients who underwent CT of the thoracic to pelvic region at least twice from 2009 to 2018, 188 who underwent CT at an interval of 5 years to 5 years and 2 months were enrolled. The prevalence of DISH during the first and second CT scans was investigated. The pre-DISH feature was defined, and the prevalence of pre-DISH on the first CT and the change after 5 years in patients with pre-DISH was investigated. Results: Of the 188 patients, 37 (19.7%) and 48 (25.5%) were diagnosed with DISH on the first and second CT scans, respectively. Pre-DISH was defined as the ossification characterized by the modified Mata score of three contiguous intervertebral spaces with a score of ≥2 points (222; 2 points, ligament ossification of half or more of the intervertebral disc height but incomplete fusion), and 52 patients were diagnosed with pre-DISH. Of the 52 patients with a score of ≥(222), 11 (21.2%) were diagnosed with DISH 5 years later. Conclusions: Patients who have three contiguous intervertebral spaces with a modified Mata score of 2 or 3 points should be considered pre-DISH.

Development and validation of an open-source tool for opportunistic screening of osteoporosis from hip CT images.

Aims: This study aimed to develop and validate a fully automated system that quantifies proximal femoral bone mineral density (BMD) from CT images. Methods: The study analyzed 978 pairs of hip CT and dual-energy X-ray absorptiometry (DXA) measurements of the proximal femur (DXA-BMD) collected from three institutions. From the CT images, the femur and a calibration phantom were automatically segmented using previously trained deep-learning models. The Hounsfield units of each voxel were converted into density (mg/cm3). Then, a deep-learning model trained by manual landmark selection of 315 cases was developed to select the landmarks at the proximal femur to rotate the CT volume to the neutral position. Finally, the CT volume of the femur was projected onto the coronal plane, and the areal BMD of the proximal femur (CT-aBMD) was quantified. CT-aBMD correlated to DXA-BMD, and a receiver operating characteristic (ROC) analysis quantified the accuracy in diagnosing osteoporosis. Results: CT-aBMD was successfully measured in 976/978 hips (99.8%). A significant correlation was found between CT-aBMD and DXA-BMD (r = 0.941; p < 0.001). In the ROC analysis, the area under the curve to diagnose osteoporosis was 0.976. The diagnostic sensitivity and specificity were 88.9% and 96%, respectively, with the cutoff set at 0.625 g/cm2. Conclusion: Accurate DXA-BMD measurements and diagnosis of osteoporosis were performed from CT images using the system developed herein. As the models are open-source, clinicians can use the proposed system to screen osteoporosis and determine the surgical strategy for hip surgery.

Bone mineral density estimation from a plain X-ray image by learning decomposition into projections of bone-segmented computed tomography.

Osteoporosis is a prevalent bone disease that causes fractures in fragile bones, leading to a decline in daily living activities. Dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) are highly accurate for diagnosing osteoporosis; however, these modalities require special equipment and scan protocols. To frequently monitor bone health, low-cost, low-dose, and ubiquitously available diagnostic methods are highly anticipated. In this study, we aim to perform bone mineral density (BMD) estimation from a plain X-ray image for opportunistic screening, which is potentially useful for early diagnosis. Existing methods have used multi-stage approaches consisting of extraction of the region of interest and simple regression to estimate BMD, which require a large amount of training data. Therefore, we propose an efficient method that learns decomposition into projections of bone-segmented QCT for BMD estimation under limited datasets. The proposed method achieved high accuracy in BMD estimation, where Pearson correlation coefficients of 0.880 and 0.920 were observed for DXA-measured BMD and QCT-measured BMD estimation tasks, respectively, and the root mean square of the coefficient of variation values were 3.27 to 3.79% for four measurements with different poses. Furthermore, we conducted extensive validation experiments, including multi-pose, uncalibrated-CT, and compression experiments toward actual application in routine clinical practice.

Establishment of a uniform histological evaluation method for early stage osteophytes in the destabilization of the medial meniscus mouse model.

Background: Osteophyte formation is attracting attention as an early-stage pathology of knee osteoarthritis (OA). Although osteophyte formation is understood as a defense response to joint instability, its role and impact on OA remain largely unknown. Many studies have been conducted using the surgical destabilization of the medial meniscus (DMM) mouse model, but there are few standard evaluation methods, especially in the histological evaluation of early-stage osteophytes. The purpose of this study was to establish a reproducible and uniform method for histological evaluation of characteristics of early osteophyte formation in the DMM mouse model. Methods: Male mice were operated with DMM at 12 weeks old and histologically evaluated at 4 days and 1, 2 and 4 weeks after DMM. Osteophyte Width, Osteophyte Area, and Original and Modified Maturity Scores were used to evaluate osteophytes for all sections. Results: Osteophyte Width, Osteophyte Area and Maturity Scores were all greater anteriorly than posteriorly in the knee joint. The Modified Maturity Score was more strongly correlated with position than the Original Maturity Score, and could be used to evaluate early-stage osteophyte formation. Conclusion: The Modified Maturity Score as well as Osteophyte Width and Area at the section of the anterior cruciate ligament (ACL) attachment site can provide a reproducible evaluation method to histologically assess the early-stage osteophyte formation in the DMM mouse model.

Functional Neurological Disorder Overlapping Paroxysmal Kinesigenic Dyskinesia Confirmed by Genetic Diagnosis.

Functional neurological disorder (FND) may mimic various kinds of neurologic diseases and may coexist with other neurologic disorders. In cases overlapped by FND, it might be challenging to distinguish symptoms induced by FND and those induced by other underlying neurological disorders, especially when patients show no positive signs indicative of FND. Here, we present the case of a patient who was genetically diagnosed with paroxysmal kinesigenic dyskinesia (PKD). However, most of the patient's symptoms were considered to indicate FND. To our knowledge, there are no reports of FND overlapping PKD. This case illustrates the possibility that FND can coexist with and mimic symptoms of other diseases. It is necessary to rule out coexisting FND symptoms that may modify clinical presentations that cannot simply be explained by a recognized neurological disease.

Difference in implant design affects midflexion rotational laxity in cruciate-retaining total knee arthroplasty: a computer navigation study.

PURPOSE: This study aimed to compare midflexion rotational laxity between two different design concept models of cruciate-retaining total knee arthroplasty: symmetrical surface design of neutral joint line obliquity and asymmetrical surface design of varus joint line obliquity. METHODS: Sixty-three knees that underwent cruciate-retaining total knee arthroplasty were evaluated. Manual maximum passive rotational stress without acceleration was applied to the knees under navigation monitoring. Pre-operative and post-operative internal and external rotational angles were measured at 30°, 45°, 60°, and 90° knee flexion. RESULTS: The post-operative internal rotational laxity was significantly increased compared with pre-operative levels at 30°, 45°, 60°, and 90° flexion among all subjects (mean 9.7° vs 11.1°, 10.6° vs 11.6°, 11.2° vs 12.9°, and 13.2° vs 14.9°; p = 0.01, 0.04, 0.001, and 0.008, respectively). The post-operative external rotational laxity was significantly decreased compared to pre-operative levels at 30°, 45°, 60°, and 90° flexion among all subjects (mean 10.8° vs 6.8°, 12.5° vs 9.4°, 12.8° vs 10.0°, and 11.3° vs 9.5°; p < 0.0001, < 0.0001, < 0.0001, and 0.0008, respectively). The post-operative total rotational laxity significantly decreased, compared with pre-operative levels, at 30° and 45° flexion among all subjects (mean 20.4° vs 17.9°, and 23.1° vs 21.1°; p = 0.002 and 0.04, respectively). The post-operative total rotational laxity was significantly smaller in asymmetrically designed total knee arthroplasty than in symmetrically designed total knee arthroplasty at 30°, 45°, and 60° flexion (mean 19.3° vs 15.8°, 22.8° vs 18.7°, and 24.4° vs 20.8°; p = 0.03, 0.03, and 0.02, respectively), whereas no significant difference was observed at 90° flexion. CONCLUSION: Compared to symmetrical surface design, asymmetrical surface design resulted in lower rotational laxity at the midflexion range in cruciate-retaining total knee arthroplasty. LEVEL OF EVIDENCE: III.

Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery.

iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.

Decomposition of musculoskeletal structures from radiographs using an improved CycleGAN framework.

This paper presents methods of decomposition of musculoskeletal structures from radiographs into multiple individual muscle and bone structures. While existing solutions require dual-energy scan for the training dataset and are mainly applied to structures with high-intensity contrast, such as bones, we focused on multiple superimposed muscles with subtle contrast in addition to bones. The decomposition problem is formulated as an image translation problem between (1) a real X-ray image and (2) multiple digitally reconstructed radiographs, each of which contains a single muscle or bone structure, and solved using unpaired training based on the CycleGAN framework. The training dataset was created via automatic computed tomography (CT) segmentation of muscle/bone regions and virtually projecting them with geometric parameters similar to the real X-ray images. Two additional features were incorporated into the CycleGAN framework to achieve a high-resolution and accurate decomposition: hierarchical learning and reconstruction loss with the gradient correlation similarity metric. Furthermore, we introduced a new diagnostic metric for muscle asymmetry directly measured from a plain X-ray image to validate the proposed method. Our simulation and real-image experiments using real X-ray and CT images of 475 patients with hip diseases suggested that each additional feature significantly enhanced the decomposition accuracy. The experiments also evaluated the accuracy of muscle volume ratio measurement, which suggested a potential application to muscle asymmetry assessment from an X-ray image for diagnostic and therapeutic assistance. The improved CycleGAN framework can be applied for investigating the decomposition of musculoskeletal structures from single radiographs.