Identifying non-genetic factors associated with trigger finger.

BACKGROUND: The non-genetic factors predisposing to trigger finger (TF) have mostly been characterised in small studies from individual institutions. Here, we aimed to provide a more complete picture of TF and its associations. METHODOLOGY: This case-control study used cross-sectional data from the UK Biobank population-based cohort to identify and determine the strength of associations of phenotypic variables with TF. We performed multivariable logistic regression of a multitude of phenotypic factors associated with TF. RESULTS: We identified 2250 individuals with medical and surgical diagnostic codes for TF, and 398,495 controls. TF was found to be significantly associated with age (OR 1.04, 95% CI 1.03-1.04, P < 2.23×10-308), female sex (OR 1.22, 95% CI 1.08-1.39, P = 2.35×10-3), body mass index (OR 1.10, 95% CI 1.04-1.16, P = 5.52×10-4), carpal tunnel syndrome (OR 9.59, 95% CI 8.68-10.59, P < 2.23×10-308), Dupuytren's disease (OR 4.89, 95% CI 4.06-5.89, P < 2.23×10-308), diabetes mellitus without complications (OR 1.35, 95% CI 1.15-1.58, P = 2.03×10-4) and with complications (OR 2.46, 95% CI 1.90-3.17, P = 4.98×10-12), HbA1c (OR 1.01, 95% CI 1.01-1.02, P = 8.99×10-9), hypothyroidism (OR 1.24, 95% CI 1.07-1.43, P = 4.75×10-3) and rheumatoid arthritis (OR 1.33, 95% CI 1.06-1.68, P = 0.014). CONCLUSION: Our results provide evidence supporting the well-known risk factors such as diabetes mellitus, carpal tunnel syndrome, age and female sex. Furthermore, we can confirm putative associations such as hypothyroidism, obesity and rheumatoid arthritis, while providing evidence against others such as hypertension and hyperlipidaemia. A novel finding arising from this study is the strong association with Dupuytren's disease. Our study design allowed us to identify these associations as being independent from carpal tunnel syndrome, thereby indicating a shared pathophysiology between this disease and TF.

Higher densities of T-lymphocytes in the subsynovial connective tissue of people with carpal tunnel syndrome.

Symptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as "non-inflammatory" based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.

Mortality in patients with Dupuytren's disease in the first 5 years after diagnosis: a population-based survival analysis.

Previous studies suggest that Dupuytren's disease is associated with increased mortality, but most studies failed to account for important confounders. In this population-based cohort study, general practitioners' (GP) data were linked to Statistics Netherlands to register all-cause and disease-specific mortality. Patients with Dupuytren's disease were identified using the corresponding diagnosis code and assessing free-text fields from GP consultations. Multiple imputations were performed to estimate missing values of covariates, followed by 1:7 propensity score matching to balance cases with controls on confounding factors. A frailty proportional hazard model was used to compare mortality between both groups. Out of 209,966 individuals, 2561 patients with Dupuytren's disease were identified and matched to at least four controls. After a median follow-up of 5 years, mortality was found to be actually reduced in patients with Dupuytren's disease. There was no difference in mortality secondary to cancer or cardiovascular disease. Future studies with longer average follow-up using longitudinal data should clarify these associations in the longer term.Level of evidence: III.

A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.

Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.

Polygenic Risk Associations with Clinical Characteristics and Recurrence of Dupuytren Disease.

BACKGROUND: Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin. METHODS: The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine P value cutoffs for PRS generation explaining most variance. RESULTS: The PRS for DD was significantly associated with a positive family history for DD, age at onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI. CONCLUSIONS: Although GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in the future. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Modifiable Risk Factors for Prevention in Dupuytren Disease: A UK Biobank Case-Control Study.

BACKGROUND: Dupuytren disease is associated with significant comorbidity and mortality, and it has no existing prevention strategies. It is unclear which modifiable risk factors are most amenable for prevention. This study aimed to determine the strength of modifiable risk factors for Dupuytren disease, and to investigate associations with other diseases. METHODS: Using UK Biobank data, this case-control study analyzed the association between phenotypic variables and Dupuytren disease through multivariable logistic regression. Exposures assessed were age, sex, body mass index, waist-to-hip ratio, Townsend deprivation index, smoking status, alcohol intake, diabetes mellitus, hypertension, cancer, liver disease, respiratory disease, rheumatoid arthritis, epilepsy, psoriasis, and gout. RESULTS: There were 4148 cases and 397,425 controls. Male sex (OR, 3.23; 95% CI, 2.90 to 3.60; P = 1.07 × 10 -100 ), increasing age (OR, 1.08; 95% CI, 1.07 to 1.08; P = 6.78 × 10 -167 ), material deprivation (OR, 1.01; 95% CI, 1.00 to 1.02; P = 0.0305), high-density lipoprotein cholesterol (OR, 1.76; 95% CI, 1.58 to 1.96; P = 3.35 × 10 -24 ), smoking exposure, and alcohol intake were all associated with increased odds of Dupuytren disease. With increasing obesity class, there was approximately 25% decreased odds (OR, 0.774; 95% CI, 0.734 to 0.816; P = 4.71 × 10 -21 ). Diabetes with microvascular or end-organ complications was associated with more than 2.5 times increased odds of Dupuytren disease (OR, 2.59; 95% CI, 1.92 to 3.44; P = 1.92 × 10 -10 ). Within this group, increasing hemoglobin A1c values by 10 mmol/mol, or 0.9%, increased the odds by 31% (OR, 1.31; 95% CI, 1.13 to 1.51; P = 2.19 × 10 -4 ). CONCLUSION: Diabetes and poor glycemic control are major risk factors for Dupuytren disease, which present an opportunity for prevention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

The Hand and Wrist: AntImicrobials and Infection (HAWAII) trial.

BACKGROUND: Hand trauma, comprising injuries to both the hand and wrist, affects over five million people per year in the NHS, resulting in 250 000 operations each year. Surgical site infection (SSI) following hand trauma surgery leads to significant morbidity. Triclosan-coated sutures may reduce SSI in major abdominal surgery but have never been tested in hand trauma. Feasibility needs to be ascertained before a definitive trial can be delivered in hand trauma. METHODS: A multicentre feasibility RCT of antimicrobial sutures versus standard sutures involving adults undergoing surgery for hand trauma to evaluate feasibility for a definitive trial. Secondary objectives were incidence of SSI in both groups, hand function measured with patient-reported outcome measures, health-related quality of life and change in employment. Randomization was performed on a 1:1 basis, stratified by age of the patient and whether the injury was open or closed, using a secure, centralized, online randomization service. Participants were blinded to allocation. RESULTS: 116 participants were recruited and randomized (60 intervention, 56 control). Of 227 screened, most were eligible (89.5 per cent), and most who were approached agreed to be included in the study (84.7 per cent). Retention was low: 57.5 per cent at 30 days, 52 per cent at 90 days and 45.1 per cent at 6 months. Incidence of SSI was >20 per cent in both groups. Hand function deteriorated after injury but recovered to near pre-injury levels during the study period. CONCLUSIONS: Risk of SSI after hand trauma is high. A definitive RCT of antimicrobial sutures in hand trauma surgery is feasible, if retention is improved. TRIAL REGISTRATION: ISRCTN10771059.

Genetic correlations between migraine and carpal tunnel syndrome.

BACKGROUND: Surgical deactivation of extracranial nerve trigger sites is now well-established as an effective treatment for migraine headache. Parallels have been drawn to median nerve decompression for carpal tunnel syndrome (CTS), and two previous studies have demonstrated an association between migraine and CTS. We sought to: (1) substantiate these findings in a considerably larger UK cohort, and; (2) investigate potential genetic associations between the two disorders. METHODS: Nested case-control studies were conducted in the UK Biobank cohort of 401,656 individuals. Odds ratios were calculated for the association between migraine and CTS in the overall cohort and sex-stratified subsets. Genetic correlation between migraine and CTS was interrogated by linkage disequilibrium score regression (LDSC), leveraging data from published genome-wide association studies. Regions of genetic overlap were identified by Multi-Trait Analysis of GWAS (MTAG) and Cross-Phenotype Association (CPASSOC). RESULTS: Migraine and CTS show a significant epidemiological association within UK Biobank (OR=1.14, 95% CI: 1.04-1.25, p=0.0058), which is specific to females (OR=1.15; 95% CI: 1.04-1.28, p=0.0057) and not males (OR=1.07; 95% CI: 0.82-1.40, p=0.61). Genetic analysis demonstrated a significant positive genetic correlation between the two disorders (rg=0.13, p=0.0039), and implicated the TRIM32 locus on chromosome 9 as a region of genetic overlap. CONCLUSIONS: This study replicates past reports of an epidemiological association between CTS and migraine, albeit in females only. This association is underpinned by a genetic correlation, with shared genetic susceptibility at the TRIM32 locus. Our data adds credibility to the notion that an element of entrapment neuropathy underlies migraine pathophysiology.

The management of partial extensor tendon lacerations of the hand and forearm: A systematic review.

Injuries to the extensor mechanism of the hand and forearm are common and cause significant functional disability. Complete tendon lacerations are managed with surgical repair, whereas selected partial tendon injuries may be managed without repair but with splinting and physiotherapy alone. There is limited evidence to support the management of partial lacerations, in particular the decision of whether to repair or not. We aimed to systematically review the literature to determine the optimal management of partial extensor tendon lacerations in the hand and forearm. A protocol for the systematic review was developed prospectively and registered with PROSPERO (CRD42021250431). PubMed, EMBASE, clinicaltrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1990 to 27/05/2022. 4565 studies were screened, of which 88 underwent full text review. Five studies were included, one randomised control trial and four cohort studies. One study examined outcomes of partial lacerations treated without repair; the other four studies examined outcomes following repair. Pinch and grip strength and time to return to work were similar regardless of management. Adverse outcomes were reported for patients undergoing surgical repair; none were observed in those managed without repair. Meta-analysis was precluded by study heterogeneity and high risk of bias. There is limited evidence to support the management of partial extensor tendon lacerations, with some low-quality evidence that non-operative management of selected partial lacerations is safe. There is a pressing need for pragmatic, multicentre randomised trials to assess the cost-effectiveness of current treatments.

Reporting of scar outcomes in the hand and wrist; a state-of-the-art literature review.

OBJECTIVES: The aim of this literature review was to synthesise and report current practice in evaluation and reporting of scar outcomes in hand and wrist clinical research. METHODS: A systematic search from inception to 2022 was conducted using three electronic databases. English language randomized controlled trials and observational cohort studies reporting standardised scar outcome measures and/or scar symptoms, appearance, impairment, function, or mental health outcomes in patients with hand and wrist scars were included. Two independent reviewers determined study eligibility and performed data extraction of a priori identified scar outcome domains. Data analysis included descriptive statistics and identification of discordance in taxonomy. RESULTS: Fifty-nine studies were included. Elective surgery cohorts were the most frequently included clinical population (n = 28; 47%) followed by burns (n = 16; 27%). Six different standardised scar outcome measures were reported by 25% of studies however only 7% of studies utilised a patient-reported measure. Scar symptoms were the most frequently reported outcome domain (81%); but taxonomy was incongruous, constructs lacked working definitions required for generalisability and outcome measurement was variable and unreported. Nineteen different measures of scar appearance and structure were reported by 30 (51%) of studies however only nine (23%) were patient-reported. Seven different hand function PROMs were reported by 25 (43%) studies. Person-centred domains including scar acceptability (12%), mental health impact (5%), and social participation (4%) were rarely reported. CONCLUSIONS: This review highlights that evaluation and reporting of hand and wrist scar outcomes is not standardised, assessment methods and measures are under-reported and there is discordance in taxonomy. Evaluation is not person-centred, rather it is dependent on clinician assessment. Domains including scar acceptability, mental health, and social participation are rarely addressed. A stakeholder consensus derived hand and wrist scar core outcome measurement set will promote standardisation and underpin improvements in clinical research quality, transparency, and rigour.

The Development, Deployment, and Evaluation of the CLEFT-Q Computerized Adaptive Test: A Multimethods Approach Contributing to Personalized, Person-Centered Health Assessments in Plastic Surgery.

BACKGROUND: Routine use of patient-reported outcome measures (PROMs) and computerized adaptive tests (CATs) may improve care in a range of surgical conditions. However, most available CATs are neither condition-specific nor coproduced with patients and lack clinically relevant score interpretation. Recently, a PROM called the CLEFT-Q has been developed for use in the treatment of cleft lip or palate (CL/P), but the assessment burden may be limiting its uptake into clinical practice. OBJECTIVE: We aimed to develop a CAT for the CLEFT-Q, which could facilitate the uptake of the CLEFT-Q PROM internationally. We aimed to conduct this work with a novel patient-centered approach and make source code available as an open-source framework for CAT development in other surgical conditions. METHODS: CATs were developed with the Rasch measurement theory, using full-length CLEFT-Q responses collected during the CLEFT-Q field test (this included 2434 patients across 12 countries). These algorithms were validated in Monte Carlo simulations involving full-length CLEFT-Q responses collected from 536 patients. In these simulations, the CAT algorithms approximated full-length CLEFT-Q scores iteratively, using progressively fewer items from the full-length PROM. Agreement between full-length CLEFT-Q score and CAT score at different assessment lengths was measured using the Pearson correlation coefficient, root-mean-square error (RMSE), and 95% limits of agreement. CAT settings, including the number of items to be included in the final assessments, were determined in a multistakeholder workshop that included patients and health care professionals. A user interface was developed for the platform, and it was prospectively piloted in the United Kingdom and the Netherlands. Interviews were conducted with 6 patients and 4 clinicians to explore end-user experience. RESULTS: The length of all 8 CLEFT-Q scales in the International Consortium for Health Outcomes Measurement (ICHOM) Standard Set combined was reduced from 76 to 59 items, and at this length, CAT assessments reproduced full-length CLEFT-Q scores accurately (with correlations between full-length CLEFT-Q score and CAT score exceeding 0.97, and the RMSE ranging from 2 to 5 out of 100). Workshop stakeholders considered this the optimal balance between accuracy and assessment burden. The platform was perceived to improve clinical communication and facilitate shared decision-making. CONCLUSIONS: Our platform is likely to facilitate routine CLEFT-Q uptake, and this may have a positive impact on clinical care. Our free source code enables other researchers to rapidly and economically reproduce this work for other PROMs.

Dupuytren Disease: Prevalence, Incidence, and Lifetime Risk of Surgical Intervention. A Population-Based Cohort Analysis.

BACKGROUND: Health care burden attributable to Dupuytren disease (DD) is largely unknown. The authors determined (1) the prevalence and incidence of DD, (2) the incidence of first surgical intervention, and (3) the lifetime risk of surgical intervention in the United Kingdom National Healthcare Service. METHODS: In this population-based dynamic cohort analysis, data of the Clinical Practice Research Datalink was linked to Hospital Episode Statistics, to characterize the diagnosis and surgical treatment of DD. Secular trends of incidence of DD diagnosis and first surgical treatment were calculated for 2000 to 2013. A multistate Markov model was designed to estimate the lifetime risk of first surgical intervention. RESULTS: A total of 10,553,454 subjects were included in the analyses, 5,502,879 (52%) of whom were women. Of these, 38,707 DD patients were identified. Point prevalence in 2013 was 0.67% (99% CI, 0.66 to 0.68). The incidence of DD almost doubled from 0.30 (99% CI, 0.28 to 0.33) per 1000 person-years in 2000, to 0.59 (99% CI, 0.56 to 0.62) per 1000 person-years in 2013. The incidence of first surgical intervention similarly increased from 0.29 (99% CI, 0.23 to 0.37) to 0.88 (99% CI, 0.77 to 1.00) in the same period. A man or woman newly diagnosed with DD at age 65 has a lifetime risk of surgical intervention of 23% and 13%, respectively, showing only a very subtle decrease when diagnosed later in life. CONCLUSIONS: DD is an important health condition in the older population, because prevalence and incidence rates have almost doubled in the past decade. Estimated lifetime risk of surgical treatment is relatively low, but almost twice in men compared with women. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Dupuytren's disease is a work-related disorder: results of a population-based cohort study.

OBJECTIVES: Dupuytren's disease (DD) is a fibroproliferative disorder of the hands, characterised by the development of fibrous nodules and cords that may cause disabling contractures of the fingers. The role of manual work exposure in the aetiology of DD is controversial. We investigated whether current occupational exposure to manual work is associated with DD, and if there is a dose-response relationship. METHODS: In this population-based cohort analysis, we used data from the UK Biobank cohort. Our primary outcome was the presence of DD. The exposure of interest was manual work, measured for each participant in two different ways to allow two independent analyses to be undertaken: (1) the current manual work status of the occupation at the time of recruitment, and (2) a cumulative manual work exposure score, calculated based on the occupational history. We performed propensity score matching and applied a logistic regression model. RESULTS: We included 196 265 participants for the current manual work analysis, and 96 563 participants for the dose-response analysis. Participants whose current occupation usually/always involved manual work were more often affected with DD than participants whose occupation sometimes/never involved manual work (OR 1.29, 95% CI 1.12 to 1.49, p<0.001). There was a positive dose-response relationship between cumulative manual work exposure score and DD. Each increment in cumulative work exposure score increased the odds by 17% (OR 1.17, 95% CI 1.08 to 1.27, p<0.001). CONCLUSIONS: Manual work exposure is a risk factor for DD, with a clear dose-response relationship. Physicians treating patients should recognise DD as a work-related disorder and inform patients accordingly.

Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis.

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

Serious adverse event rates and reoperation after arthroscopic shoulder surgery: population based cohort study.

OBJECTIVE: To provide clinicians and patients with accurate risk estimates of serious adverse events after common elective shoulder arthroscopic procedures, including reoperation within one year. DESIGN: Population based cohort study. SETTING: Hospital Episode Statistics for NHS England, including civil registration mortality data from the Office for National Statistics. PARTICIPANTS: 288 250 arthroscopic shoulder procedures performed in 261 248 patients aged ≥16 years between 1 April 2009 and 31 March 2017. Elective procedures were grouped into subacromial decompression, rotator cuff repair, acromioclavicular joint excision, glenohumeral stabilisation, and frozen shoulder release. MAIN OUTCOME MEASURES: The primary outcomes were rates of serious adverse events (mortality, pulmonary embolism, pneumonia, myocardial infarction, acute kidney injury, stroke, and urinary tract infection) requiring inpatient care within 90 days post-surgery. Secondary outcomes were specific adverse event rates at 90 days, and reoperations (including for deep infection) within one year. RESULTS: The overall rate of complications within 90 days after arthroscopic shoulder surgery (including reoperation) was low at 1.2% (95% confidence interval 1.2% to 1.3%), with one in 81 patients at risk, and varied according to type of procedure, from 0.6% (0.5% to 0.8%) for glenohumeral stabilisation to 1.7% (1.5% to 1.8%) for frozen shoulder release. After adjustment for age, comorbidities, and sex, no effect of procedure type was observed. Pneumonia was the most common adverse event (0.3%, 0.3% to 0.4%), with one in 303 patients at risk. Pulmonary embolic events were rare, at 0.1% (0.1% to 0.1%), with one in 1428 patients at risk. At one year, the overall rate for reoperation was 3.8% (3.8% to 3.9%), with one in 26 patients at risk, ranging from 2.7% (2.5% to 3.0%) for glenohumeral stabilisation to 5.7% (5.4% to 6.1%) for frozen shoulder release. The overall rate of further surgery for deep infection was low, at 0.1% (0.1% to 0.1%), with one in 1111 patients at risk, but was higher after rotator cuff repair (0.2%, 0.2% to 0.2%), with one in 526 patients at risk. Over the study period the number of arthroscopic shoulder procedures increased, except for subacromial decompression, which decreased. CONCLUSIONS: The findings of this study suggest that risks of serious adverse events associated with common shoulder arthroscopy procedures are low. Nevertheless, serious complications do occur, and include the risk of reoperation in one in 26 patients within one year. STUDY REGISTRATION: Clinical. TRIALS: gov NCT03573765.

Genome-wide association analysis and replication in 810,625 individuals with varicose veins.

Varicose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery.

A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery.

ABSTRACT: The role that inflammation plays in human nerve injury and neuropathic pain is incompletely understood. Previous studies highlight the role of inflammation in the generation and maintenance of neuropathic pain, but the emerging evidence from the preclinical literature for its role in the resolution of neuropathic pain remains to be explored in humans. Here, we use carpal tunnel syndrome (CTS) as a human model system of nerve injury and neuropathic pain to determine changes in serum cytokine protein levels and gene expression levels before (active stage of disease) and after carpal tunnel decompression surgery (recovery). Fifty-five patients with CTS were studied, and 21 healthy age-matched and gender-matched participants served as controls. In the active stage of the disease (CTS before surgery vs healthy controls), PTGES2 mRNA was decreased in patients (adjusted P = 0.013), while transforming growth factor-ß and C-C motif chemokine ligand 5 protein levels were increased (adjusted P = 0.016 and P = 0.047, respectively). In the resolution phase (CTS before surgery vs after surgery), IL-9 mRNA was increased after surgery (adjusted P = 0.014) and expression of IL-6 mRNA and IL-4 protein levels were increased before surgery (adjusted P = 0.034 and P = 0.002, respectively). IL-9 mRNA expression negatively correlated with several (neuropathic) pain scores. By contrast, protein levels of IL-4 positively correlated with pain scores. In conclusion, we demonstrate specific dysregulation of systemic cytokine expression in both the active and resolution phases of nerve injury and neuropathic pain. IL-9 represents an interesting candidate associated with resolution of nerve injury and neuropathic pain.