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.

Central Adiposity Increases Risk of Kidney Stone Disease through Effects on Serum Calcium Concentrations.

SIGNIFICANCE STATEMENT: Kidney stone disease is a common disorder with poorly understood pathophysiology. Observational and genetic studies indicate that adiposity is associated with an increased risk of kidney stone disease. However, the relative contribution of general and central adipose depots and the mechanisms by which effects of adiposity on kidney stone disease are mediated have not been defined. Using conventional and genetic epidemiological techniques, we demonstrate that general and central adiposity are independently associated with kidney stone disease. In addition, one mechanism by which central adiposity increases risk of kidney stone disease is by increasing serum calcium concentration. Therapies targeting adipose depots may affect calcium homeostasis and help to prevent kidney stone disease. BACKGROUND: Kidney stone disease affects approximately 10% of individuals in their lifetime and is frequently recurrent. The disease is linked to obesity, but the mechanisms mediating this association are uncertain. METHODS: Associations of adiposity and incident kidney stone disease were assessed in the UK Biobank over a mean of 11.6 years/person. Genome-wide association studies and Mendelian randomization (MR) analyses were undertaken in the UK Biobank, FinnGen, and in meta-analyzed cohorts to identify factors that affect kidney stone disease risk. RESULTS: Observational analyses on UK Biobank data demonstrated that increasing central and general adiposity is independently associated with incident kidney stone formation. Multivariable MR, using meta-analyzed UK Biobank and FinnGen data, established that risk of kidney stone disease increases by approximately 21% per one standard deviation increase in body mass index (BMI, a marker of general adiposity) independent of waist-to-hip ratio (WHR, a marker of central adiposity) and approximately 24% per one standard deviation increase of WHR independent of BMI. Genetic analyses indicate that higher WHR, but not higher BMI, increases risk of kidney stone disease by elevating adjusted serum calcium concentrations (ß=0.12 mmol/L); WHR mediates 12%-15% of its effect on kidney stone risk in this way. CONCLUSIONS: Our study indicates that visceral adipose depots elevate serum calcium concentrations, resulting in increased risk of kidney stone disease. These findings highlight the importance of weight loss in individuals with recurrent kidney stones and suggest that therapies targeting adipose depots may affect calcium homeostasis and contribute to prevention of kidney stone disease.

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.

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.

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.

Relative motion orthoses for early active motion after finger extensor and flexor tendon repairs: A systematic review.

BACKGROUND: The relative motion (RM) orthosis was introduced over 40 years ago for extensor tendon rehabilitation and more recently applied to flexor tendon repairs. PURPOSE: We systematically reviewed the evidence for RM orthoses following surgical repair of finger extensor and flexor tendon injuries including indications for use, configuration and schedule of orthosis wear, and clinical outcomes. STUDY DESIGN: Systematic review. METHODS: A PRISMA-compliant systematic review searched eight databases and five trial registries, from database inception to January 7, 2022. The protocol was registered prospectively (CRD42020211579). We identified studies describing patients undergoing rehabilitation using RM orthoses after surgical repair of acute tendon injuries of the finger and hand. RESULTS: For extensor tendon repairs, ten studies, one trial registry and five conference abstracts met inclusion criteria, reporting outcomes of 521 patients with injuries in zones IV-VII. Miller's criteria were predominantly used to report range of motion; with 89.6% and 86.9% reporting good or excellent outcomes for extension lag and flexion deficit, respectively. For flexor tendon repairs, one retrospective case series was included reporting outcomes in eight patients following zones I-II repairs. Mean total active motion was 86%. No tendon ruptures were reported due to the orthosis not protecting the repair for either the RME or RMF approaches. DISCUSSION: Variation was seen in use of RME plus or only, use of night orthoses and orthotic wear schedules, which may be the result of evolution of the RM approach. Since Hirth et al's 2016 scoping review, there are five additional studies, including two RCTs reporting the use of the RM orthosis in extensor tendon rehabilitation. CONCLUSIONS: There is now good evidence that the RM approach is safe in zones V-VI extensor tendon repairs. Limited evidence currently exists for zones IV and VII extensor and for flexor tendon repairs. Further high-quality clinical studies are needed to demonstrate its safety and efficacy.

Artificial Intelligence in Fracture Detection: A Systematic Review and Meta-Analysis.

Background Patients with fractures are a common emergency presentation and may be misdiagnosed at radiologic imaging. An increasing number of studies apply artificial intelligence (AI) techniques to fracture detection as an adjunct to clinician diagnosis. Purpose To perform a systematic review and meta-analysis comparing the diagnostic performance in fracture detection between AI and clinicians in peer-reviewed publications and the gray literature (ie, articles published on preprint repositories). Materials and Methods A search of multiple electronic databases between January 2018 and July 2020 (updated June 2021) was performed that included any primary research studies that developed and/or validated AI for the purposes of fracture detection at any imaging modality and excluded studies that evaluated image segmentation algorithms. Meta-analysis with a hierarchical model to calculate pooled sensitivity and specificity was used. Risk of bias was assessed by using a modified Prediction Model Study Risk of Bias Assessment Tool, or PROBAST, checklist. Results Included for analysis were 42 studies, with 115 contingency tables extracted from 32 studies (55 061 images). Thirty-seven studies identified fractures on radiographs and five studies identified fractures on CT images. For internal validation test sets, the pooled sensitivity was 92% (95% CI: 88, 93) for AI and 91% (95% CI: 85, 95) for clinicians, and the pooled specificity was 91% (95% CI: 88, 93) for AI and 92% (95% CI: 89, 92) for clinicians. For external validation test sets, the pooled sensitivity was 91% (95% CI: 84, 95) for AI and 94% (95% CI: 90, 96) for clinicians, and the pooled specificity was 91% (95% CI: 81, 95) for AI and 94% (95% CI: 91, 95) for clinicians. There were no statistically significant differences between clinician and AI performance. There were 22 of 42 (52%) studies that were judged to have high risk of bias. Meta-regression identified multiple sources of heterogeneity in the data, including risk of bias and fracture type. Conclusion Artificial intelligence (AI) and clinicians had comparable reported diagnostic performance in fracture detection, suggesting that AI technology holds promise as a diagnostic adjunct in future clinical practice. Clinical trial registration no. CRD42020186641 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Cohen and McInnes in this issue.

Prognostic factors for finger interphalangeal joint osteoarthritis: a systematic review.

OBJECTIVE: Radiographic hand OA affects one in five adults. Symptomatic hand OA can result in functional impairment, pain and reduced quality of life. A prevalent form of hand OA is IP joint OA, however prognostic factors for IP joint OA remain poorly understood. This systematic review aimed to identify prognostic factors for IP joint OA, and to summarize the diagnostic criteria for IP joint OA in prognostic studies. METHODS: EMBASE, MEDLINE, Scopus and The Cochrane Library were searched from inception until 19 February 2020 (PROSPERO CRD42019116782). Eligible studies described diagnostic criteria defining IP joint OA, and assessed potential prognostic factors for IP joint OA. Risk of bias was assessed using a modified Quality in Prognosis Studies (QUIPS) tool and a best evidence synthesis was used. RESULTS: Eighteen studies were included (risk of bias: eight high, three moderate, seven low). All defined OA radiographically, and three studies incorporated clinical symptoms into their definition of OA. Forty-nine potential prognostic factors were assessed. Eight were prognostic: older age in women, female gender (both moderate evidence); family history of Heberden's nodes, Kashin-Beck disease, older age in men, dental occupation in men, finger fracture, parity (all limited evidence). Higher BMI in women (limited evidence) was prognostic for symptomatic radiographic OA. No prognostic factors for symptomatic OA were identified. CONCLUSION: IP joint OA is most commonly defined radiographically, yet criteria were heterogeneous. Eight prognostic factors for radiographic IP joint OA and one for symptomatic radiographic IP joint OA were identified, all with limited or moderate evidence. Further studies on causality and on prognostic pathways are needed.

Low rate of subsequent surgery and serious complications following intra-articular steroid injection for base of thumb osteoarthritis: national cohort analysis.

OBJECTIVES: Intra-articular steroid injection is commonly used to treat base of thumb osteoarthritis (BTOA), despite a lack of large-scale data on safety and effectiveness. We estimate the incidence of serious complications and further procedures following BTOA injection, including the risk of post-operative serious surgical site infection for subsequent operative intervention. METHODS: Hospital Episode Statistics data linked to mortality records from 1 April 1998 to 31 March 2017 were used to identify all BTOA injections undertaken in adults in the National Health Service secondary care in England. Patients were followed up longitudinally until death or 31 March 2017. A multivariable regression with a Fine and Gray model adjusting for the competing risk of mortality in addition to age, sex and socioeconomic deprivation was used to identify factors associated with progression to further procedure. Secondary outcomes included serious complications after injection and subsequent surgical site infection. RESULTS: A total of 19 120 primary injections were performed during the 19-year period in 18 356 patients. Of these 76.5% were female; mean age 62 years (s.d. 10.6); 50.48% underwent further procedure; 22.40% underwent surgery. Median time to further intervention was 412 days (IQR 110-1945). Female sex was associated with increased risk of proceeding to surgery. Serious complication rate following injection was 0.04% (0.01-0.08) within 90 days. Of those proceeding to surgery 0.16% (0.06-0.34) presented with a wound infection within 30 days and 90 days, compared with an overall post-operative wound infection rate of 0.03% (0.02-0.05). CONCLUSIONS: Very low rates of serious complications were identified following BTOA injections performed in secondary care; only one in five patients proceeded to subsequent surgery. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03573765.

Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth.

We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 µm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.

Human factors: the pharmaceutical supply chain as a complex sociotechnical system.

BACKGROUND: The COVID-19 pandemic has exacerbated preexisting weaknesses in the global supply chain. Regional assessments by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and independent consultants, have demonstrated various contributory causal factors requiring changes in policy, relationships, and incentives within the dynamic and developing networks. Human factors and ergonomics (HFE) is an approach that encourages sociotechnical systems thinking to optimize the performance of systems that involve human activity. The global supply chain can be considered such a system. However, it has neither been systematically examined from this perspective. METHODS: In 2015, the UK Chartered Institute of Ergonomics and Human Factors established the Pharmaceutical Sector Group. This unique group is open to all who work in the pharmaceutical sector at any level and in any discipline who share the vision of a pharmaceutical system that places an understanding of HFE at the heart of improving the use of healthcare products throughout their life cycles including their supply chains. RESULTS: For this complex system to work efficiently, it is paramount that we have effective coordination and integration between the different elements in the supply chain. HFE can give valuable insights and solutions for developing these complex social-technical systems effectively. CONCLUSION: By partnering with international groups such as Biophorum and Bio Supply Chain Management Alliance, we wish to stimulate discussion about how sociotechnical thinking about HFE may help develop better monitoring and investigative techniques to strengthen global supply chains.

Recursive Partitioning vs Computerized Adaptive Testing to Reduce the Burden of Health Assessments in Cleft Lip and/or Palate: Comparative Simulation Study.

BACKGROUND: Computerized adaptive testing (CAT) has been shown to deliver short, accurate, and personalized versions of the CLEFT-Q patient-reported outcome measure for children and young adults born with a cleft lip and/or palate. Decision trees may integrate clinician-reported data (eg, age, gender, cleft type, and planned treatments) to make these assessments even shorter and more accurate. OBJECTIVE: We aimed to create decision tree models incorporating clinician-reported data into adaptive CLEFT-Q assessments and compare their accuracy to traditional CAT models. METHODS: We used relevant clinician-reported data and patient-reported item responses from the CLEFT-Q field test to train and test decision tree models using recursive partitioning. We compared the prediction accuracy of decision trees to CAT assessments of similar length. Participant scores from the full-length questionnaire were used as ground truth. Accuracy was assessed through Pearson's correlation coefficient of predicted and ground truth scores, mean absolute error, root mean squared error, and a two-tailed Wilcoxon signed-rank test comparing squared error. RESULTS: Decision trees demonstrated poorer accuracy than CAT comparators and generally made data splits based on item responses rather than clinician-reported data. CONCLUSIONS: When predicting CLEFT-Q scores, individual item responses are generally more informative than clinician-reported data. Decision trees that make binary splits are at risk of underfitting polytomous patient-reported outcome measure data and demonstrated poorer performance than CATs in this study.

Temporal Trends and Geographical Variation in Dupuytren Disease Surgery in England: A Population-Based Cohort Study.

BACKGROUND: Dupuytren disease (DD) is a common fibroproliferative disease of the palmar fascia. The mainstay of DD treatment in England is surgery with either percutaneous needle fasciotomy, limited fasciectomy, or dermofasciectomy. This study aimed to investigate the temporal trends and geographical variation of primary DD surgery in England. METHODS: A longitudinal population-based cohort study was perfomed using the Hospital Episode Statistics database from April 1, 2007, to March 31, 2017. Directly standarized rates were estimated over time (between financial years 2007-2008 and 2016-2017) and by geographic region (by clinical commissioning groups [CCGs]; financial years 2010-2011, 2013-2014, and 2016-2017). The Office for National Statistics midyear population estimates were used as the reference population. MAIN FINDINGS: Primary DD surgery was undertaken at a steadily increasing rate from financial year 2007 to 2008, to 2016 to 2017 in England. There was a striking 3.6-fold variation in the rates of primary DD surgery among National Health Service CCGs in England place of residence. CONCLUSIONS: This significant variation in DD surgical treatment in England suggests a need for the development of standardized surgical practice across all CCGs and National Health Service hospitals, promoting equality of access to cost-effective health care.

Integrative analysis of Dupuytren's disease identifies novel risk locus and reveals a shared genetic etiology with BMI.

Dupuytren's disease is a common inherited tissue-specific fibrotic disorder, characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand. Although genome-wide association study (GWAS) have identified 24 genomic regions associated with Dupuytrens risk, the biological mechanisms driving signal at these regions remain elusive. We identify potential biological mechanisms for Dupuytren's disease by integrating the most recent, largest GWAS (3,871 cases and 4,686 controls) with eQTLs (47 tissue panels from five consortia, total n = 3,975) to perform a transcriptome-wide association study. We identify 43 tissue-specific gene associations with Dupuytren's risk, including one in a novel risk region. We also estimate the genome-wide genetic correlation between Dupuytren's disease and 45 complex traits and find significant genetic correlations between Dupuytren's disease and body mass index (BMI), type II diabetes, triglycerides, and high-density lipoprotein (HDL), suggesting a shared genetic etiology between these traits. We further examine local genetic correlation to identify 8 and 3 novel regions significantly correlated with BMI and HDL respectively. Our results are consistent with previous epidemiological findings showing that lower BMI increases risk for Dupuytren's disease. These 12 novel risk regions provide new insight into the biological mechanisms of Dupuytren's disease and serve as a starting point for functional validation.

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.

Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10-8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.

Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics.

Ninety per cent of the human population has been right-handed since the Paleolithic, yet the brain signature and genetic basis of handedness remain poorly characterized. Here, we correlated brain imaging phenotypes from ∼9000 UK Biobank participants with handedness, and with loci found significantly associated with handedness after we performed genome-wide association studies (GWAS) in ∼400 000 of these participants. Our imaging-handedness analysis revealed an increase in functional connectivity between left and right language networks in left-handers. GWAS of handedness uncovered four significant loci (rs199512, rs45608532, rs13017199, and rs3094128), three of which are in-or expression quantitative trait loci of-genes encoding proteins involved in brain development and patterning. These included microtubule-related MAP2 and MAPT, as well as WNT3 and MICB, all implicated in the pathogenesis of diseases such as Parkinson's, Alzheimer's and schizophrenia. In particular, with rs199512, we identified a common genetic influence on handedness, psychiatric phenotypes, Parkinson's disease, and the integrity of white matter tracts connecting the same language-related regions identified in the handedness-imaging analysis. This study has identified in the general population genome-wide significant loci for human handedness in, and expression quantitative trait loci of, genes associated with brain development, microtubules and patterning. We suggest that these genetic variants contribute to neurodevelopmental lateralization of brain organization, which in turn influences both the handedness phenotype and the predisposition to develop certain neurological and psychiatric diseases.

Risk factors for the progression of finger interphalangeal joint osteoarthritis: a systematic review.

Progressive hand interphalangeal joint (IPJ) osteoarthritis is associated with pain, reduced function and impaired quality of life. However, the evidence surrounding risk factors for IPJ osteoarthritis progression is unclear. Identifying risk factors for IPJ osteoarthritis progression may inform preventative strategies and early interventions to improve long-term outcomes for individuals at risk of IPJ osteoarthritis progression. The objectives of the study were to describe methods used to measure the progression of IPJ osteoarthritis and identify risk factors for IPJ osteoarthritis progression. MEDLINE, EMBASE, Scopus, and The Cochrane Library were searched from inception to 19th February 2020 (PROSPERO CRD42019121034). Eligible studies assessed potential risk factor/s associated with IPJ osteoarthritis progression. Risk of bias was assessed using a modified QUIPS Tool, and a best evidence synthesis was performed. Of eight eligible studies, all measured osteoarthritis progression radiographically, and none considered symptoms. Eighteen potential risk factors were assessed. Diabetes (adjusted mean difference between 2.06 and 7.78), and larger finger epiphyseal index in males (regression coefficient ß = 0.202) and females (ß = 0.325) were identified as risk factors (limited evidence). Older age in men and women showed mixed results; 13 variables were not risk factors (all limited evidence). Patients with diabetes and larger finger epiphyseal index might be at higher risk of radiographic IPJ osteoarthritis progression, though evidence is limited and studies are biased. Studies assessing symptomatic IPJ osteoarthritis progression are lacking.

Surgical interventions for the prevention or treatment of lymphoedema after breast cancer treatment.

BACKGROUND: Breast cancer is the most common type of cancer amongst women worldwide, and one distressing complication of breast cancer treatment is breast and upper-limb lymphoedema. There is uncertainty regarding the effectiveness of surgical interventions in both the prevention and management of lymphoedema affecting the arm after breast cancer treatment. OBJECTIVES: 1. To assess and compare the efficacy of surgical interventions for the prevention of the development of lymphoedema (LE) in the arm after breast cancer treatment.2. To assess and compare the efficacy of surgical interventions for the treatment of established LE in the arm after breast cancer treatment. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for all prospectively registered and ongoing trials on 2 November 2017. Reference lists of included studies were also handsearched by three review authors for additional eligible trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing a surgical intervention for the prevention or treatment of lymphoedema of the arm after breast cancer treatment to either standard intervention, placebo intervention, or another surgical intervention were included. Patients of both sexes and all ages who have had treatment for their breast cancer were considered. No limits were applied to language or study location. Three authors independently determined the eligibility of each study. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data for each included study using a pre-designed data extraction pro forma and used Cochrane's 'risk of bias' tool for assessing risk of bias. Dichotomous variables were analysed using the Mantel-Haenszel method to estimate risk ratios (RRs). Differences in continuous variables were expressed as mean differences (MDs). GRADE was used to assess the certainty of the evidence provided by the included studies. MAIN RESULTS: Two studies involving 95 participants examined surgical interventions for preventing breast cancer-related lymphoedema. Both studies evaluated the efficacy of the lymphaticovenular anastomosis technique as part of a preventative management protocol. Both studies were deemed to be at unclear risk of bias overall. Statistical variation between the studies was low, which increases the reliability of the evidence. However, the two studies were conducted in the same centre. Lymphaticovenular anastomosis appears to result in a reduction in the incidence of lymphoedema compared to nonoperative management with a risk ratio of 0.20 (95% CI 0.06 to 0.63, P = 0.006; 95 participants; low-certainty evidence). The RCTs did not evaluate any of the secondary outcomes.One study involving 36 participants evaluated the effectiveness of vascularised lymph node transfer for treating breast cancer-related lymphoedema. The trial was deemed to be at unclear risk of bias. For participants suffering from stage 2 lymphoedema, the evidence suggested reductions in limb volume (MD -39.00%, 95% CI -47.37% to -30.63%, very low-certainty evidence), pain scores (MD -4.16, 95% CI -5.17 to -3.15, very low-certainty evidence), heaviness sensation (MD -4.27, 95% CI -5.74 to -2.80, very low-certainty evidence), mean number of infections/year (MD -1.22, 95% CI -2.00 to -0.44, very low-certainty evidence), and an improvement in overall function scores (MD -3.77, 95% CI -4.89 to -2.65, very low-certainty evidence) for those who had undergone vascularised lymph node transfer compared to those who had undergone no treatment. AUTHORS' CONCLUSIONS: There is low-certainty evidence that lymphaticovenular anastomosis is effective in preventing the development of lymphoedema after breast cancer treatment based on the findings from two studies. One study providing very low-certainty evidence found that vascularised lymph node transfer is an efficacious option in the treatment of established stage 2 lymphoedema related to breast cancer. Important secondary outcomes in this review were rarely reported in the included studies. More high-quality RCTs are required to further elucidate the effectiveness of surgical interventions in the prevention and treatment of lymphoedema after breast cancer treatment. At the time of this review, no ongoing trials on this topic were identified.

Lymphaticovenular anastomosis improves quality of life and limb volume in patients with secondary lymphedema after breast cancer treatment.

Secondary lymphedema is a common side effect of breast cancer treatment, with significant impact on patients' physical and psychological well-being. Conservative therapies are the gold standard treatment, however surgical options are becoming more popular. Lymphaticovenular anastomosis (LVA) is a supermicrosurgical procedure that aims to restore lymphatic flow by anastomosing damaged lymphatics to subcutaneous venules. We aimed to assess the effects of LVA on patients' limb volume and quality of life. Pre- and postoperative limb volumes and LYMQOL scores were collected for patients undergoing LVA for lymphedema secondary to breast cancer. Thirty-seven patients underwent LVA. A significant reduction was seen in median excess limb volume postoperatively (13.3%-6.6%, P < 0.005), with volumetric improvement seen in 78% of patients. Thirteen patients were able to discontinue compression garment use. Eighty-six percent of patients reported improved quality of life postoperatively with median LYMQOL score increasing from 90 to 104 points (P < 0.005). LVA is a minimally invasive surgical option for patients with early stage lymphedema. It can lead to significant volumetric improvements and in select patients, freedom from compression therapy. LVA can also lead to significant improvements in quality of life, in particular patients' mood and perception of their appearance.