SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

A KLHL40 3' UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism.

Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). Common features include fetal akinesia, fractures, contractures, dysphagia, respiratory failure and neonatal death. Here, we describe a 26-year-old man with relatively mild NEM8. He presented with hypotonia and bilateral femur fractures at birth, later developing bilateral Achilles' contractures, scoliosis, and elbow and knee contractures. He had walking difficulties throughout childhood and became wheelchair bound from age 13 after prolonged immobilization. Muscle magnetic resonance imaging at age 13 indicated prominent fat replacement in his pelvic girdle, posterior compartments of thighs and vastus intermedius. Muscle biopsy revealed nemaline bodies and intranuclear rods. RNA sequencing and western blotting of patient skeletal muscle indicated significant reduction in KLHL40 mRNA and protein, respectively. Using gene panel screening, exome sequencing and RNA sequencing, we identified compound heterozygous variants in KLHL40; a truncating 10.9 kb deletion in trans with a likely pathogenic variant (c.*152G > T) in the 3' untranslated region (UTR). Computational tools SpliceAI and Introme predicted the c.*152G > T variant created a cryptic donor splice site. RNA-seq and in vitro analyses indicated that the c.*152G > T variant induces multiple de novo splicing events that likely provoke nonsense mediated decay of KLHL40 mRNA explaining the loss of mRNA expression and protein abundance in the patient. Analysis of 3' UTR variants in ClinVar suggests variants that introduce aberrant 3' UTR splicing may be underrecognized in Mendelian disease. We encourage consideration of this mechanism during variant curation.

Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma.

Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.

Dual effects of TGF-ß inhibitor in ALS - inhibit contracture and neurodegeneration.

As persistent elevation of transforming growth factor-ß (TGF-ß) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-ß would be effective against both exacerbations. The effects of TGF-ß and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-ß inhibitor in ameliorating the pathogenic role of TGF-ß in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-ß causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-ß in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-ß inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-ß inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.

Early Elbow Flexion Contracture Predicts Shoulder Contracture in Infants with Brachial Plexus Birth Injury.

OBJECTIVE: To determine if children who present with an elbow flexion contracture (EFC) from brachial plexus birth injury (BPBI) are more likely to develop shoulder contracture and undergo surgical treatment. STUDY DESIGN: Retrospective review of children <2 years of age with BPBI who presented to a single children's hospital from 1993 to 2020. Age, elbow and shoulder range of motion (ROM), imaging measurements, and surgical treatment and outcome were analyzed. Patients with an EFC of ≥10° were included in the study sample. Data from 2445 clinical evaluations (1190 patients) were assessed. The final study cohort included 72 EFC cases matched with 230 non-EFC controls. Three patients lacked sufficient follow-up data. RESULTS: There were 299 included patients who showed no differences between study and control groups with respect to age, sex, race, ethnicity, or functional score. Patients with EFC had 12° less shoulder range of motion (95% CI, 5°-20°; P < .001) and had 2.5 times the odds of shoulder contracture (OR, 2.5; 95% CI, 1.3-4.7; P = .006). For each additional 5° of EFC, the odds of shoulder contracture increased by 50% (OR, 1.5; 95% CI, 1.2-1.8; P < .001) and odds of shoulder procedure increased by 62% (OR, 1.62; 95% CI, 1.04-2.53; P = .03). Sensitivity of EFC for predicting shoulder contracture was 49% and specificity was 82%. CONCLUSIONS: In patients with BPBI <2 years of age, presence of EFC can be used as a screening tool in identifying shoulder contractures that may otherwise be difficult to assess. Prompt referral should be arranged for evaluation at a BPBI specialty clinic, because delayed presentation risks worsening shoulder contracture and potentially more complicated surgery.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

ERBB3 deficiency causes a multisystemic syndrome in human patient and zebrafish.

The Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598), while a recent study reported six additional patients carrying ERBB3 variants which exhibited distinct clinical features with evident intestinal dysmotility (OMIM 243180). The potential connection between these phenotypes remains unknown, and the ERBB3-related phenotype spectrum needs to be better characterized. Here, we described a patient presenting with a multisystemic syndrome including skip segment Hirschsprung disease, bilateral clubfoot deformity, and cardiac defect. Trio-whole exome sequencing revealed a novel compound heterozygous variant (c.1914-7C>G; c.2942_2945del) in the patient's ERBB3 gene. RT-PCR and in vitro minigene analysis demonstrated that variant c.1914-7C>G caused aberrant mRNA splicing. Both variants resulted in premature termination codon and complete loss of ERBB3 function. erbb3b knockdown in zebrafish simultaneously caused a reduction in enteric neurons in the distal intestine, craniofacial cartilage defects, and micrognathia, which phenotypically mimics ERBB3-related intestinal dysmotility and some features of lethal congenital contracture syndrome in human patients. These findings provide further patient and animal evidence supporting that ERBB3 deficiency causes a complex syndrome involving multiple systems with phenotypic variability among distinct individuals.

Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy.

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.

Bone marrow-derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization.

Joint contracture causes distressing permanent mobility disorder due to trauma, arthritis, and aging, with no effective treatment available. A principal and irreversible cause of joint contracture has been regarded as the development of joint capsule fibrosis. However, the molecular mechanisms underlying contracture remain unclear. We established a mouse model of knee joint contracture, revealing that fibrosis in joint capsules causes irreversible contracture. RNA-sequencing of contracture capsules demonstrated a marked enrichment of the genes involved in the extracellular region, particularly periostin (Postn). Three-dimensional magnetic resonance imaging and immunohistological analysis of contracture patients revealed posterior joint capsule thickening with abundant type I collagen (Col1a2) and POSTN in humans. Col1a2-GFPTG ; Postn-/- mice and chimeric mice with Col1a2-GFPTG ; tdTomatoTG bone marrow showed fibrosis in joint capsules caused by bone marrow-derived fibroblasts, and POSTN promoted the migration of bone marrow-derived fibroblasts, contributing to fibrosis and contracture. Conversely, POSTN-neutralizing antibody attenuated contracture exacerbation. Our findings identified POSTN as a key inducer of fibroblast migration that exacerbates capsule fibrosis, providing a potential therapeutic strategy for joint contracture.

Association of Knee Osteoarthritis and Flexion Contracture With Localized Tibial Articular Cartilage Loss: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether a knee flexion contracture (FC) was associated with localized tibial articular cartilage loss over a 1-year period using Osteoarthritis Initiative quantitative data. METHODS: Five hundred seventy-eight participants from a previously established nested case-control study of people with radiographic knee OA with or without progression, based on radiographs and symptoms, had their knee range of extension measured at baseline and received magnetic resonance imaging (MRI) at baseline and 1 year. The tibial articular cartilage of the medial and lateral condyles was segmented into anterior, center, and posterior regions. We tested for associations between knee FC (defined as lack of extension to 0°), and localized changes in tibial articular cartilage thickness or percent of denuded bone (0 mm thickness) after 1 year relative to baseline using ANOVA, controlling for baseline MRI outcomes and clinical factors. RESULTS: Knee FC was associated with denuded bone in the medial condyle center (ß 0.44, 95% CI 0.02-0.86) and preserved cartilage thickness in the medial condyle posterior (ß 0.01, 95% CI 0.002-0.03) regions. CONCLUSION: Knee FC unloading the tibial center region and loading the posterior region was associated with localized articular cartilage loss centrally and preserved articular cartilage posteriorly. These findings are consistent with knee FC negatively affecting unloaded tibial articular cartilage.

Expanding the phenotypic spectrum for CDK8-related disease: A case report.

BACKGROUND: Cyclin-dependent kinase 8 (CDK8) is part of a regulatory kinase module that regulates the activity of the Mediator complex. The Mediator, a large conformationally flexible protein complex, goes on to regulate RNA polymerase II activity, consequently affecting transcriptional regulation. Thus, inactivating mutations of the genes within the kinase module cause aberrant transcriptional regulation and disease, namely, CDK8-related intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA). CASE PRESENTATION: We describe, for the first time, a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother. The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA; however, undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child. This phenotype was not found in the mother, highlighting a heterogenous presentation for the same variant within the same family. Furthermore, the described clinical presentation may further support the notion of a module- or Mediator-related syndrome with varying clinical presentation. CONCLUSION: This case report documents the first inherited case of IDDHBA and expands the phenotypic spectrum for CDK8-related disease to include undocumented progressive contractures of the hips and knees as well as scoliosis, which may support the notion of a module- or Mediator-related syndrome with varying clinical presentation.

Joint contractures is a recurrent clinical feature of individuals with neurodevelopmental disorder due to FOXP1 likely gene disruptive variants.

Haploinsufficiency of FOXP1 gene is responsible for a neurodevelopmental disorder presenting with intellectual disability (ID), autism spectrum disorder (ASD), hypotonia, mild dysmorphic features, and multiple congenital anomalies. Joint contractures are not listed as a major feature of FOXP1-related disorder. We report five unrelated individuals, each harboring likely gene disruptive de novo FOXP1 variants or whole gene microdeletion, who showed multiple joint contractures affecting at least two proximal and/or distal joints. Consistent with the phenotype of FOXP1-related disorder, all five patients showed developmental delay with moderate-to-severe speech delay, ID, ASD, and facial dysmorphic features. FOXP1 is implicated in neuronal differentiation and in organizing motor axon projections, thus providing a potential developmental basis for the joint contractures. The combination of joint contractures and neurodevelopmental disorders supports the clinical suspicion of FOXP1-related phenotype.

FBN2 pathogenic variants in congenital contractural arachnodactyly with severe cardiovascular manifestations.

PURPOSE: Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears, but rarely with lethal cardiovascular manifestations as in Marfan syndrome. It is imperative to conduct a comprehensive analysis and review of the pathogenesis of CCA resulting from pathogenic variants in FBN2 gene. MATERIALS AND METHODS: Using whole-exome sequencing and Sanger sequencing, we identified a novel pathogenic splice-altering variant (c.4472-3C>A) in intron 34 of FBN2 gene in a CCA pedigree. The transcriptional result of the splicing-altering variant was analyzed by RNA sequencing. We systematically analyzed the clinical manifestations of all reported cases of CCA caused by splicing-altering pathogenic variants and focused on all the pathogenic variants in FBN2 gene that are associated with severe cardiovascular manifestations. RESULTS: The splice-altering variant (c.4472-3C>A) in FBN2 was demonstrated to result in the exon 35 skipping and cause an in-frame deletion. Furthermore, we identified exons 31 to 35 may be a hotspot region in FBN2 gene associated with severe cardiovascular phenotype. CONCLUSIONS: This study enriched the pathogenic spectrum of CCA and identified a hotspot region in FBN2 gene associated with severe cardiovascular manifestations. We recommend that patients carrying pathogenic variants in exons 31 to 35 of FBN2 pay more attention to cardiac evaluation.

Long-term effects of non-weight bearing and immobilization after anterior cruciate ligament reconstruction on joint contracture formation in rats.

PURPOSE: Non-weight bearing improves and immobilization worsens contracture induced by anterior cruciate ligament reconstruction (ACLR), but effect persistence after reloading and remobilization remains unclear, and the combined effects of these factors on ACLR-induced contracture are unknown. We aimed to determine 1) whether the effects of short-term (2-week) non-weight bearing or immobilization after ACLR on contracture would be sustained by reloading or remobilization during a 10-week observation period, and 2) how the combination of both interventions compared to the outcome of either alone. METHODS: We divided 88 ACL-reconstructed male rats into four groups: non-intervention, non-weight bearing, joint immobilization, and both interventions. Interventions were performed for 2 weeks, followed by rearing without intervention. Twelve untreated rats were used as controls. At 2, 4, and 12 weeks post-surgery, we assessed range of motion (ROM) and histological changes. RESULTS: ACLR resulted in persistent loss of ROM, accompanied by synovial shortening, capsule thickening, and osteophyte formation. Two weeks of non-weight bearing increased ROM and reduced osteophyte size, but the beneficial effects disappeared within 10 weeks after reloading. Two-week immobilization decreased ROM and facilitated synovial shortening. After remobilization, ROM partially recovered but remained below non-intervention levels at 12 weeks. When both interventions were combined, ROM was similar to immobilization alone. CONCLUSIONS: The beneficial effects of 2-week non-weight bearing on contracture diminished within 10 weeks after reloading. The adverse effects of 2-week immobilization on contracture persisted after 10 weeks of remobilization. The effects of the combined use of both interventions on contracture were primarily determined by immobilization.

Bladder neck contracture following transurethral surgery of prostate: a retrospective single-center study.

PURPOSE: Bladder neck contracture (BNC) is a rare but intolerant complication after transurethral surgery of prostate. The present study aims to investigate the incidence and risk factors of BNC in patients diagnosed benign prostate hyperplasia (BPH) and following transurethral resection or enucleation of the prostate (TURP/TUEP). METHODS: This retrospective study included 1008 BPH individuals who underwent transurethral surgery of the prostate between January 2017 and January 2022. Patients' demographics, medical comorbidities, urologic characteristics, perioperative parameters, and the presence of BNC were documented. Univariate and multivariate analyses were conducted to identify the risk factors. RESULTS: A total of 2% (20/1008) BPH patients developed BNC postoperatively and the median occurring time was 5.8 months. Particularly, the incidences of BNC were 4.7% and 1.3% in patients underwent Bipolar-TURP and TUEP respectively. Preoperative urinary tract infection (UTI), elevated PSA, smaller prostate volume (PV), bladder diverticulum (BD), and B-TURP were significantly associated with BNC in the univariate analysis. Further multivariate logistic regression demonstrated preoperative UTI (OR 4.04, 95% CI 2.25 to 17.42, p < 0.001), BD (OR 7.40, 95% CI 1.83 to 31.66, p < 0.001), and B-TURP (OR 3.97, 95% CI 1.55 to 10.18, p = 0.004) as independent risk factors. All BNC patients were treated with transurethral incision of the bladder neck (TUIBN) combined with local multisite injection of betamethasone. During a median follow-up of 35.8 months, 35% (7/20) of BNC patients recurred at a median time of 1.8 months. CONCLUSION: BNC was a low-frequency complication following transurethral surgery of prostate. Preoperative UTI, BD, and B-TURP were likely independent risk factors of BNC. TUIBN combined with local multisite injection of betamethasone may be promising choice for BNC treatment.

Iatrogenic or recurrent bladder neck contracture treated by the Palminteri-Ferrari technique: a new way to approach a frustrating condition.

PURPOSE: Bladder neck stricture (BNS) is a bothersome disease which may affect patients after trauma or prostatic surgery. It is frustrating due to the low durable success rate of currently available surgical techniques. The aim of the study is to explore the efficacy of a novel technique. MATERIALS & METHODS: The surgical protocol was developed by two high case-volume surgeons. The technique consists of Holmium laser incisions at 3-6-9-12 o'clock. Subsequently, triamcinolone acetonide 40 mg is injected. Two months later, the BNS is endoscopically checked in operatory room and re-procedure take place, if necessary (max 3 times). Failure was defined as the need of definitive urinary diversion. Subjective satisfaction was measured through PGI-I Questionnaire. RESULTS: A total of 45 patients were enrolled. Median age was 63 (IQR 59-69) years and BNS developed by different causes. Naïve BNS procedure patients were 12 (26.7%), others 33 (73.3%) underwent median 2 (IQR 1-4) previous urethrotomies, including 16 other surgeries. Suprapubic bladder catheter was present in 34 patients (75.6%). No complications were registered. Re-procedure at control was necessary in 24 patients (53.3%) for a median of 1 (IQR 1-3) procedures. At median follow-up of 18 months, failures were 4 (8.9%) and urinary incontinence was reported in 2 patients (4.5%) who required incontinence surgery. Median PGI-I was 2. CONCLUSIONS: Our technique of BNS treatment allows good outcomes and high rate of subjective improvement amongst patients. Moreover, naïve patients seem to have better results. However, longer follow-up and higher sample size are mandatory to further assess these data.

Robotic YV plasty outcomes for bladder neck contracture vs. vesico-urethral anastomotic stricture.

PURPOSE: To compare the outcomes of patients undergoing robotic YV plasty for bladder neck contracture (BNC) vs. vesico-urethral anastomotic stricture (VUAS). METHODS: A retrospective study included male patients who underwent robotic YV plasty for BNC after endoscopic treatment of BPH or VUAS between August 2019 and March 2023 at a single academic center. The primary assessed was the patency rate at 1 month post-YV plasty and during the last follow-up visit. RESULTS: A total of 21 patients were analyzed, comprising 6 in the VUAS group and 15 in the BNC group. Patients with VUAS had significantly longer operative times (277.5 vs. 146.7 min; p = 0.008) and hospital stay (3.2 vs. 1.7 days; p = 0.03). Postoperative complications were more common in the VUAS group (66.7% vs. 26.7%; p = 0.14). All patients resumed spontaneous voiding postoperatively. Five patients (23.8%) who developed de novo stress urinary incontinence had already an AUS (n = 1) or required concomitant AUS implantation (n = 3), all of whom were in the VUAS group (83.3% vs. 0%; p < 0.0001). The proportion of patients improved was similar in both groups (PGII = 1 or 2: 83.3% vs. 80%; p = 0.31). Stricture recurrence occurred in 9.5% of patients in the whole cohort, with no significant difference between the groups (p = 0.50). Long-term reoperation was required in three VUAS patients, showing a statistically significant difference between the groups (p = 0.05). CONCLUSION: Robotic YV plasty is feasible for both VUAS and BNC. While functional outcomes and stricture-free survival may be similar for both conditions, the perioperative outcomes were less favorable for VUAS patients.

Assistive technologies, including orthotic devices, for the management of contractures in adults after a stroke.

BACKGROUND: Contractures (reduced range of motion and increased stiffness of a joint) are a frequent complication of stroke. Contractures can interfere with function and cause cosmetic and hygiene problems. Preventing and managing contractures might improve rehabilitation and recovery after stroke. OBJECTIVES: To assess the effects of assistive technologies for the management of contractures in adults after a stroke. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases, and three trials registers in May 2022. We also searched for reference lists of relevant studies, contacted experts in the field, and ran forward citation searches. SELECTION CRITERIA: Randomised controlled studies (RCTs) that used electrical, mechanical, or electromechanical devices to manage contractures in adults with stroke were eligible for inclusion in this review. We planned to include studies that compared assistive technologies against no treatment, routine therapy, or another assistive technology. DATA COLLECTION AND ANALYSIS: Three review authors (working in pairs) selected all studies, extracted data, and assessed risk of bias. The primary outcomes were passive joint range of motion (PROM) with and without standardised force, and indirect measures of PROM. The secondary outcomes included hygiene. We also wanted to evaluate the adverse effects of assistive technology. Effects were expressed as mean differences (MDs) or standardised mean differences (SMDs) with 95% confidence intervals (CIs). MAIN RESULTS: Seven studies fulfilled the inclusion criteria. Five of these were meta-analysed; they included 252 adults treated in acute and subacute rehabilitation settings. All studies compared assistive technology with routine therapy; one study also compared assistive technology with no treatment, but we were unable to obtain separate data for stroke participants. The assistive technologies used in the studies were electrical stimulation, splinting, positioning using a hinged board, and active repetitive motor training using a non-robotic device with electrical stimulation. Only one study applied stretching to end range. Treatment duration ranged from four to 12 weeks. The overall risk of bias was high for all studies. We are uncertain whether: • electrical stimulation to wrist extensors improves passive range of wrist extension (MD -7.30°, 95% CI -18.26° to 3.66°; 1 study, 81 participants; very low-certainty evidence); • a non-robotic device with electrical stimulation to shoulder flexors improves passive range of shoulder flexion (MD -9.00°, 95% CI -25.71° to 7.71°; 1 study; 50 participants; very low-certainty evidence); • assistive technology improves passive range of wrist extension with standardised force (SMD -0.05, 95% CI -0.39 to 0.29; four studies, 145 participants; very low-certainty evidence): • a non-robotic device with electrical stimulation to elbow extensors improves passive range of elbow extension (MD 0.41°, 95% CI -0.15° to 0.97°; 1 study, 50 participants; very low-certainty evidence). One study reported the adverse outcome of pain when using a hinged board to apply stretch to wrist and finger flexors, and another study reported skin breakdown when using a thumb splint. No studies reported hygiene or indirect measures of PROM. AUTHORS' CONCLUSIONS: Only seven small RCTs met the eligibility criteria of this review, and all provided very low-certainty evidence. Consequently, we cannot draw firm conclusions on the effects of assistive technology compared with routine therapy or no therapy. It was also difficult to confirm whether there is a risk of harm associated with treatment using assistive technology. Future studies should apply adequate treatment intensity (i.e. magnitude and the duration of stretch) and use valid and reliable outcome measures. Such studies might better identify the role of assistive technology in the management of contractures in adults after a stroke.

Clinical Outcomes of Arthroscopic Surgery in Patients with Gluteal Muscle Contracture: Single-Institution Results from a High-Volume Cohort.

BACKGROUND The aim of this study was to assess clinical outcomes of arthroscopic surgery for gluteal muscle contracture (GMC) with at least 2 years of follow-up in a large sample. MATERIAL AND METHODS A total of 665 patients who underwent arthroscopic release procedure at our institution between March 2014 and December 2018 and met the inclusion criteria were included in this study. All the patients were operated on by the same surgeon and the surgeon released the contracture band from anterior to posterior starting from the anterior edge of the ITB, the contracture band of the gluteus maximus, and vastus medialis tensor. After exclusion, 544 patients (218 males and 326 females) were finally included. Clinical outcomes at 2 years of postoperative follow-up were evaluated by a combination of several methods, including a new criterion we proposed for postoperative assessment, which included the cross-leg test, difficulty in squatting with legs together, and abnormal gait, the visual analogue scale (VAS), the modified Harris hip score (mHHS), and the satisfaction of patients. RESULTS The average follow-up time was 48.2±14.9 months. Based on the new criteria, 513 (94.3%) patients were evaluated as good, 25 (4.6%) as fair, and 6 (1.1%) as poor. The mHHS increased from 72.1±6.0 (range, 56.0-81.3) to 97.3±2.2 (range, 92.3-100.0) (P<0.001). The VAS decreased from 3.3±1.1 (range, 0-5) to 0.062±0.13 (range, 0-1) (P<0.001). For subjective satisfaction, 526 (96.7%) patients were satisfied, 14 (2.6%) patients were neutral, and 4 (0.7%) patients were dissatisfied. CONCLUSIONS In a large sample, favorable and durable clinical outcomes were observed after the arthroscopic procedure. Clinical symptoms and mHHS showed significant improvement with a minimum 2-year follow-up.

Factors affecting anophthalmic socket reconstruction outcomes using autologous oral mucosal graft.

BACKGROUND: Limited studies have reported surgical outcomes that are defined by strict criteria following grade 2 or 3 socket reconstruction using an oral mucosal graft (OMG). We aimed to determine factors influencing surgical outcomes of anophthalmic socket reconstruction using OMG in patients with grade 2 or 3 socket contractures. METHODS: Thirty-seven patients who underwent socket reconstruction with autologous OMG between January 2007 and December 2017 were retrospectively analyzed. The successful outcome was defined as an eye prosthesis wearing without experiencing displacement and the absence of any re-operations or additional surgeries following socket reconstruction. Factors affecting surgical outcomes were identified using multivariate analysis. RESULTS: A total of 15 male and 22 female patients (mean age: 40.2 ± 17.2 years) were included. The median duration of socket contracture was 21.5 years. Grade 2 and 3 socket contractures, based on Tawfik's classification, were reported in 20 and 17 patients, respectively. Twenty-eight and eight patients underwent socket reconstruction using OMG alone and OMG combined with a hard palate graft, respectively. The success rates of grades 2 and 3 socket contracture reconstruction were 80.0% and 52.9%, respectively. Multivariate analysis demonstrated that only grade 3 contractures were predictive of worse outcomes. At the final visit (mean follow-up: 6.3 years), 34 patients (91.9%) could wear their eye prostheses. CONCLUSIONS: Socket reconstruction using autologous OMG can provide acceptable results in grade 2 and 3 contractures; however, satisfactory results were more significantly reported in grade 2 than in grade 3 contractures.