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Medial arterial calcification (MAC) is a chronic systemic vascular disorder distinct from atherosclerosis that is frequently but not always associated with diabetes mellitus, chronic kidne...

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-β 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.

This study assesses the diagnostic accuracy of ultrasound and magnetic resonance imaging (MRI) in diagnosing Stener lesions of the thumb. MEDLINE, PubMed, Embase and Cochrane CENTRAL were searched for studies using ultrasound or MRI to detect Stener lesions following suspected thumb ulnar collateral ligament injuries. The reference standard was surgical exploration or clinical joint stability. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. A random-effects bivariate meta-analysis was used to estimate pooled sensitivity and specificity. Forest plots were generated. Nine ultrasound (315 thumbs) and six MRI (107 thumbs) studies were included in meta-analysis (all high risk of bias). Pooled sensitivity and specificity for ultrasound were 95% and 94%, and for MRI were 93% and 98%. Both ultrasound and MRI demonstrate high diagnostic accuracy in detecting Stener lesions. Ultrasound is an appropriate first-line imaging modality.

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

Background Carpal tunnel decompression surgery to treat carpal tunnel syndrome is a common procedure, yet data on safety and effectiveness of the operation in the general population remain scarce. We aimed to estimate the incidence of reoperation and serious postoperative complications (requiring admission to hospital or further surgery) following carpal tunnel decompression in routine clinical practice and to identify the patient factors associated with these adverse outcomes. Methods We did a nationwide cohort analysis including all carpal tunnel decompression surgeries in patients aged 18 years or older, done in the National Health Service in England between April 1, 1998, and March 31, 2017, using the Hospital Episode Statistics dataset linked to mortality records. Patients were followed-up until death or until the end of the study (March 31, 2017). Primary outcomes were the overall incidence of carpal tunnel decompression reoperation and serious postoperative complications (surgical site infection or dehiscence, or neurovascular or tendon injury, requiring admission to hospital or further surgery) within 30 days and 90 days after surgery. Multivariable Cox regression analysis was used to identify factors influencing complications and reoperation, and the Fine and Gray method was used to adjust for the competing risk of mortality. This study is registered with ClinicalTrials.gov, NCT03573765. Findings 855 832 carpal tunnel decompression surgeries were done between April 1, 1998, and March 31, 2017 (incidence rate 1·10 per 1000 person-years [95% CI 1·02–1·17]). 29 288 procedures (3·42%) led to carpal tunnel decompression reoperation (incidence rate 3·18 per 1000 person-years [95% CI 3·12–3·23]). Of the 855 832 initial surgeries, 620 procedures (0·070% [95% CI 0·067–0·078]) led to a serious complication within 30 days after surgery, and 698 procedures (0·082% [0·076–0·088]) within 90 days. Local complications within 90 days after surgery were associated with male sex (adjusted hazard ratio 2·32 [95% CI 1·74–3·09]) and age category 18–29 years (2·25 [1·10–4·62]). Male sex (adjusted subhazard ratio 1·09 [95% CI 1·06–1·13]), old age (>80 years vs 50–59 years: 1·09 [1·03–1·15]), and greater levels of comorbidity (Charlson score ≥5 vs 0: 1·25 [1·19–1·32]) and socioeconomic deprivation (most deprived 10% vs least deprived 10%: 1·18 [1·10–1·27]) were associated with increased reoperation risk. Interpretation To our knowledge, this is the largest national study on carpal tunnel decompression to date, providing strong evidence on serious postoperative complication and reoperation rates. Carpal tunnel decompression appears to be a safe operation in most patients, with an overall serious complication rate (requiring admission to hospital or further surgery) of less than 0·1%. Funding Versus Arthritis; Medical Research Council; Royal College of Surgeons of England and National Joint Registry research fellowship; University of Oxford; National Institute for Health Research; and National Institute for Health Research Biomedical Research Centre, Oxford.

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 β = 0.202) and females (β = 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. Electronic supplementary material The online version of this article (10.1007/s00296-020-04687-1) contains supplementary material, which is available to authorized users.

Objectives: Errors in medication administration are common, with many interventions suggested to reduce them. For intravenous infusion–related errors, “smart infusion devices” incorporating dose error reduction software are widely advocated. Our aim was to explore the role of smart infusion devices in preventing or contributing to medication administration errors using retrospective review of 2 complementary data sets that collectively included a wide range of errors with different levels of actual or potential harm. Methods: We reviewed 216 medication administration errors identified from an observational study in clinical practice and 123 medication incidents involving infusion devices reported to a national reporting system. The impact of smart infusion devices in preventing or contributing to these errors was assessed by the research team and an expert panel. Results: The data suggest that use of any infusion device rather than gravitational administration may have prevented 13% of observed errors and 8% of reported incidents; additional reductions may be possible with standalone smart infusion devices, and further potential reductions with smart infusion devices integrated with electronic prescribing and barcode administration systems. An estimated 52% to 73% of errors that occurred with traditional infusion pumps could be prevented with such integrated smart infusion devices. In the few cases where smart infusion devices were used, these contributed to errors in 2 of 58 observed errors and 7 of 8 reported incidents. Conclusions: Smart infusion devices not only prevent some medication administration errors but can also contribute to them. Further evaluation of such systems is required to make recommendations for policy and practice.

Background Intravenous (IV) medication administration has traditionally been regarded to be error-prone with high potential for harm. A recent US multisite study revealed surprisingly few potentially harmful errors despite a high overall error rate. However, there is limited evidence about infusion practices in England and how they relate to prevalence and types of error. Objectives To determine the prevalence, types and severity of errors and discrepancies in infusion administration in English hospitals, and to explore sources of variation in errors, discrepancies and practices, including the contribution of smart pumps. Design Phase 1 comprised an observational point-prevalence study of IV infusions, with debrief interviews and focus groups. Observers compared each infusion against the medication order and local policy. Deviations were classified as either errors or discrepancies based on their potential for patient harm. Contextual issues and reasons for deviations were explored qualitatively during observer debriefs, and analytically in supplementary analyses. Phase 2 comprised in-depth observational studies at five of the participating sites to better understand causes of error and how safety is maintained. Workshops were held with key stakeholder groups, including health professionals and policy-makers, the public and industry. Setting Sixteen English NHS hospital trusts. Results Point-prevalence data were collected from 1326 patients and 2008 infusions. In total, 240 errors were observed in 231 infusions and 1489 discrepancies were observed in 1065 infusions. Twenty-three errors (1.1% of all infusions) were considered potentially harmful; one might have resulted in short-term patient harm had it not been intercepted, but none was judged likely to prolong hospital stay or result in long-term harm. Types and prevalence of deviations varied widely among trusts, as did local policies. Deviations from medication orders and local policies were sometimes made for efficiency or to respond to patient need. Smart pumps, as currently implemented, had little effect. Staff had developed practices to manage efficiency and safety pragmatically by working around systemic challenges. Limitations Local observers may have assessed errors differently across sites, although steps were taken to minimise differences through observer training, debriefs, and review and cleaning of data. Each in-depth study involved a single researcher, and these were limited in scale and scope. Conclusions Errors and discrepancies are common in everyday infusion administration but most have low potential for patient harm. Findings are best understood by viewing IV infusion administration as a complex adaptive system. Better understanding of performance variability to strategically manage risk may be more helpful for improving patient safety than striving to eliminate all deviations. Future work There is potential value in reviewing policy around IV infusion administration to reduce unnecessary variability, manage staff workload and engage patients, while retaining the principle that policy has to be fit for purpose, contextualised to the particular ward situation and treatment protocol, and sensitive to the risks of different medications. Further work on understanding infusion administration as a complex adaptive system might deliver new insights into managing patient safety. Funding This project was funded by the NIHR Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 7. See the NIHR Journals Library website for further project information.

We aimed to assess the association between bariatric surgery and incident Dupuytren's disease (DD) using propensity score-matched cohort studies among Swedish nationwide healthcare registries. Patients aged 30-79 years who underwent bariatric surgery 2006-2019 were matched on their propensity scores, up to two obese bariatric surgery-free (unexposed) patients. We applied Cox proportional hazard regression to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the risk of DD overall, in subgroups of age, sex, bariatric surgery type and duration of follow-up. Among 34,959 bariatric surgery patients and 54,769 propensity score-matched obese patients, the risk of DD was increased in bariatric surgery patients compared with obese unexposed patients (HR 1.30, 95% CI 1.02-1.65), among women (HR 1.36; 1.00-1.84); those undergoing gastric bypass (HR 1.33; 1.04-1.71) and those with >5 years follow-up (HR 1.63; 1.14-2.34). Our results suggest that substantial weight loss is associated with an increased risk of DD in an obese population., Journal of Hand Surgery (European Volume), 47 (3), ISSN:1753-1934, ISSN:2043-6289

Trigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.

Over 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, that encodes the key enzyme in the synthesis of all-trans retinoic acid (atRA), have been associated with severe hand OA. In this study, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in UK Biobank. Articular cartilage was acquired from 33 consenting individuals with hand OA at the time of routine hand OA surgery. They were stratified by genotype and RNA sequencing performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulates similar inflammatory genes by a process that we have previously termed mechanoflammation, and which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-dependent genes, indicative of cellular atRA levels, and 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 (PPAR)-γ dependent mechanism. Talarozole, delivered by minipump, was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6h after mouse knee joint destabilization, and reduced cartilage degradation and osteophyte formation after 4 weeks. 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 in OA.One Sentence SummaryAnalysis of hand OA cartilage stratified by ALDH1A2 polymorphic variants reveals a targetable, anti-inflammatory role for retinoic acid in OA.

Aim Develop a prediction model for incident radiographic IPJ osteoarthritis when multiple clinical risk factors are present. Methods This study used secondary analysis from the Chingford 1000 Women Study, a prospective cohort of women aged 45 to 64 years. At baseline, anthropometric, clinical, and lifestyle measured had been collected. Hand radiographs had been taken at baseline and 10 years, read using the Kellgren-Lawrence atlas. For the current study, participants with osteoarthritis (Kellgren-Lawrence ≥2) in any IPJ at baseline were excluded. Risk factors were selected from baseline based on biological plausibility, a published systematic review, and a Delphi study of Hand Surgeons. Incident osteoarthritis was diagnosed at 10 years if ≥ 1 IPJ was Kellgren-Lawrence ≥2. The model was built with logistic regression and elastic net penalisation, and performance assessed through discrimination (c-statistic) and calibration (c-slope). Complete case analysis was used. Results Of 1,003 participants, 459 participants were included in this study (median age: 51 years, 202 (44%) with IPJ osteoarthritis at follow-up). Manual occupation (P Conclusions Osteoarthritis at the base of thumb and IPJs might be a continuum of the same disease. Knowledge of these modifiable and non-modifiable risk factors can inform prevention strategies.

Background Hand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design. Methods This is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60–90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study. Discussion Identifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference. Trial registration ISRCTN12196200 registered on 15 January 2019.

The brain signature and genetic basis of handedness are unclear. Wiberg et al. show that left-handers have higher functional connectivity between language networks, and identify four genomic regions associated with handedness. Variants within these regions appear, by influencing brain architecture, to predispose both to left-handedness and to certain neuropsychiatric diseases., 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.

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.

Radiographic osteoarthritis (OA) is most prevalent in the hand. The association of hand injury with pain or OA is unclear. The objective was to describe the relationship between hand injury and ipsilateral pain and OA in cricketers. Data from former and current cricketers aged ≥ 30 years was used. Data included history of cricket-related hand/finger injury leading to > 4 weeks of reduced exercise, hand/finger joint pain on most days of the last month, self-reported history of physician-diagnosed hand/finger OA. Logistic regression assessed the relationship between injury with hand pain (in former cricketers) and with OA (in all cricketers), adjusted for age, seasons played, playing standard. Of 1893 participants (844 former cricketers), 16.9% reported hand pain, 4.3% reported OA. A history of hand injury increased the odds of hand pain (OR (95% CI) 2.2, 1.4 to 3.6). A history of hand injury also had increased odds of hand OA (3.1, 2.1 to 4.7). Cricket-related hand injury was related to an increased odds of hand pain and OA. This highlights the importance of hand injury prevention strategies within cricket. The high prevalence of hand pain is concerning, and further research is needed to determine the impacts of hand pain.

Dupuytren’s disease (DD) is a common fibro-proliferative disorder of the palm. We estimated the risk of serious local and systemic complications and re-operation after DD surgery. We queried England’s Hospital Episode Statistics database and included all adult DD patients who were surgically treated. A longitudinal cohort study and self-controlled case series were conducted. Between 1 April 2007 and 31 March 2017, 121,488 adults underwent 158,119 operations for DD. The cumulative incidence of 90-day serious local complications was low at 1.2% (95% CI 1.1–1.2). However, the amputation rate for re-operation by limited fasciectomy following dermofasciectomy was 8%. 90-day systemic complications were also uncommon at 0.78% (95% CI 0.74–0.83), however operations routinely performed under general or regional anaesthesia carried an increased risk of serious systemic complications such as myocardial infarction. Re-operation was lower than previous reports (33.7% for percutaneous needle fasciotomy, 19.5% for limited fasciectomy, and 18.2% for dermofasciectomy). Overall, DD surgery performed in England was safe; however, re-operation by after dermofasciectomy carries a high risk of amputation. Furthermore, whilst serious systemic complications were unusual, the data suggest that high-risk patients should undergo treatment under local anaesthesia. These data will inform better shared decision-making regarding this common condition.

Background Dupuytren's disease is a common complex disease caused by genetic and nongenetic factors. The role of many nongenetic risk factors is still unclear and debatable. This study aimed to systematically review the association between Dupuytren's disease and nongenetic risk factors. Methods A search strategy was developed based on the Population, Exposure, Comparison, Outcomes and Study framework. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature search was conducted in MEDLINE, Embase, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to November of 2018. Title and abstract and then full-text screening against eligibility criteria was performed independently by two reviewers, and consensus was achieved by a third reviewer. The Effective Public Health Practice Project and the Oxford Centre for Evidence Based Medicine tools were used to assess study quality and to evaluate the level of evidence of included studies, respectively. Results Reviewers identified 4434 studies, of which 54 were included in the analysis. There was strong evidence for the association between Dupuytren's disease and advanced age, male sex, family history of Dupuytren's disease, and diabetes mellitus. Furthermore, heavy alcohol drinking, cigarette smoking, and manual work exposure showed a significant dose-response relationship. The quality of the included studies was mainly low or moderate, and most studies were level 3 or 4 on the Oxford Centre for Evidence Based Medicine scale. Conclusions The study results show a strong association between Dupuytren's disease and advanced age, male sex, family history of Dupuytren's disease, diabetes mellitus, heavy alcohol drinking, cigarette smoking, and manual work exposure. Further studies are required to explain the causal relationship of these associations.

Summary Background The prevalence of chronic wrist pain and subsequent functional decline is increasing. Diagnosis is challenging, with non-surgical treatment frequently failing. Recently, partial wrist denervation (PWD) has gained popularity as a procedure to alleviate chronic pain. Methods A systematic review was performed in April 2019. Inclusion criteria involved clinical studies with a minimum of ten wrists, focusing on PROMs, objective measures of function and complications. Papers investigating complete or mixed denervation procedures were excluded. Results Nine studies were included (292 wrists), all of which were observational in study design and limited in patient numbers, evaluation techniques and follow-up length. PWD appears to be associated with a reduction in pain, and functional improvement. Further surgery was required in 54 (24%) wrists at an average follow-up of 18 months. PWD was not found to complicate further surgery. Conclusion PWD is associated with improvement in short-term pain relief and functional status, yet carries a high re-operation rate without contraindicating further salvage surgery. Further research is required to evaluate the benefits, duration of relief and long-term complications of PWD.

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.

Systems contradictions present challenges that need to be effectively managed, e.g. due to conflicting rules and advice, goal conflicts, and mismatches between demand and capacity. We apply FRAM (Functional Resonance Analysis Method) to intravenous infusion practices in an intensive care unit (ICU) to explore how tensions and contradictions are managed by people. A multi-disciplinary team including individuals from nursing, medical, pharmacy, safety, IT and human factors backgrounds contributed to this analysis. A FRAM model investigation resulting in seven functional areas are described. A tabular analysis highlights significant areas of performance variability, e.g. administering medication before a prescription, prioritising drugs, different degrees of double checking and using sites showing early signs of infection for intravenous access. Our FRAM analysis has been non-normative: performance variability is not necessarily wanted or unwanted, it is merely necessary where system contradictions cannot be easily resolved and so adaptive capacity is required to cope.

Carpal tunnel release provides an opportunity to study sensory nerve regeneration in humans. Schmid et al. show that cutaneous reinnervation correlates with symptom improvement after surgery. ADCYAP1 (encoding PACAP) expression is associated with sensory reinnervation in vivo and facilitates neuron outgrowth in vitro., 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

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren’s disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis., New anti-fibrotics aided by a better understanding of fibrotic cell subsets and their functions are needed. Here the authors perform single-cell RNA-seq and CyTOF on nodules from patients with Dupuytren’s disease to map subsets and the state of mesenchymal cells during pathogenic fibrogenesis.

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren’s disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis. New anti-fibrotics aided by a better understanding of fibrotic cell subsets and their functions are needed. Here the authors perform single-cell RNA-seq and CyTOF on nodules from patients with Dupuytren’s disease to map subsets and the state of mesenchymal cells during pathogenic fibrogenesis.

Mechanical force is a fundamental regulator of cell phenotype. Myofibroblasts are central mediators of fibrosis, a major unmet clinical need characterised by the deposition of excessive matrix proteins. Traction forces of myofibroblasts play a key role in remodelling the matrix and modulate the activities of embedded stromal cells. Here, we employ a combination of unsupervised computational analysis, cytoskeletal profiling and single cell traction force microscopy as a functional readout to uncover how the complex spatiotemporal dynamics and mechanics of living human myofibroblast shape sub-cellular profiling of traction forces in fibrosis. We resolve distinct biophysical communities of myofibroblasts, and our results provide a new paradigm for studying functional heterogeneity in human stromal cells., Summary: High resolution traction force microscopy at single-cell level reveals the biophysical landscape of primary human myofibroblasts.

Publisher's version (útgefin grein), Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P, R.J.A. is an Action for Pulmonary Fibrosis Research Fellow. L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. R.G.J. is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). I.N. is supported by the NHLBI (R01HL130796). B.G.-G. is funded by Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) cofunded by European Social Fund. J.M.O. is supported by the NHLBI (K23HL138190). C.F. is supported by the Spanish Ministry of Science, Innovation and Universities (grant RTC-2017-6471-1; Ministerio de Ciencia e Innovacion/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea) cofinanced by the European Regional Development Funds “A way of making Europe” from the European Union and by agreement OA17/008 with Instituto Tecnológico y de Energías Renovables to strengthen scientific and technological education, training, research, development and innovation in Genomics, Personalized Medicine and Biotechnology. The Spain Biobank array genotyping service was performed at CEGEN-PRB3-ISCIII, which is supported by PT17/0019, of the PE I+D+i 2013–2016, funded by Instituto de Salud Carlos III, and cofinanced by the European Regional Development Funds. P.L.M. is an Action for Pulmonary Fibrosis Research Fellow. M.O. is a fellow of the Parker B. Francis Foundation and a Scholar of the Michael Smith Foundation for Health Research. B.D.H. is supported by NIH K08 HL136928, Parker B. Francis Research Opportunity Award. M.H.C. and G.M.H. are supported by NHLBI grants R01HL113264 (M.H.C.), R01HL137927 (M.H.C.), R01HL135142 (M.H.C. and G.M.H.), R01111024 (G.M.H.), and R01130974 (G.M.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. T.M.M. is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017) and a British Lung Foundation Chair in Respiratory Research (C17-3). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health. I.P.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. I.S. is supported by Medical Research Council (G1000861) and Asthma UK (AUK-PG-2013-188). D.F. was supported by an Intermediate Fellowship from the Wellcome Trust (097152/Z/11/Z). This work was partially supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. V.N. is funded by an NIHR Clinical Lectureship. G.G. is supported by project grant 141513-051 from the Icelandic Research Fund and Landspitali Scientific Fund A-2016-023, A-2017-029, and A-2018-025. D.J.L. and A.M. are supported by Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, Massachusetts) using the Affymetrix Genome-Wide Human SNP Array 6.0. This work was supported by NIH grants R01 HL131565 (A.M.), R01 HL103676 (D.J.L.), and R01 HL137234 (D.J.L.).

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 β = 0.202) and females (β = 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.

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45–60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted., Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca2+ concentration and excretion.

Background One of the complications of lymphoedema is recurrent cellulitis. The aim was to determine whether lymphaticovenous anastomosis (LVA) was effective at reducing cellulitis in patients with lymphoedema. Methods This was a retrospective review of patients with arm/leg lymphoedema who underwent LVA. The frequency of cellulitis was compared before and after surgery. The diagnostic criteria for cellulitis were a fever of 38·5°C or higher, and warmth/redness in the affected limb(s). Results A total of 95 patients were included. The mean number of episodes of cellulitis in the year preceding surgery was 1·46, compared with 0·18 in the year after surgery (P < 0·001). Conclusion LVA reduced the rate of cellulitis in these patients with lymphoedema.

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.ObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.Methods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Main resultsWe identified and replicated three new genome-wide significant (P-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.ConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Many studies have highlighted the patient safety risks in intravenous medication administration, and various technological solutions have been proposed to mitigate those risks, including ‘smart pumps’ and closed-loop systems. Few studies describe these implementations in detail. In this article, we report on a sociotechnical investigation of a closed-loop documentation system linked with smart pumps for intravenous infusion administration on an intensive care unit. The smart pumps are ‘mapped’ to an electronic prescribing and medication administration system, allowing infusion rates, volumes and boluses of intravenous medication to be monitored in real time. Ethnographic observations were conducted over 37 h, including direct observation of infusion administration (n = 23 infusions), discussions with clinical staff and semi-structured interviews with intensive care unit managers (n = 2). Analysis was based on the Distributed Cognition for Teamwork (DiCoT) method to understand how information is processed across individuals, teams and technologies. We report on how the system works in context, and identify contributions and compromises to patient safety with new risks that need to be managed at bedside and intensive care unit level.

Objective As survival from cancer continues to improve, greater importance is placed on quality of life after surgery.Lymphoedemais a common and disabling complication of cancer treatment. Lymphaticovenularanastomosis(LVA) is a supermicrosurgical treatment option for lower limb lymphoedema. The aim of this study was to assess the effectiveness of LVA in reducing limb volume and its effect on quality of life of patients with secondary leg lymphoedema following treatment for cancer, includinggynaecological cancers. Methods Limb volume and patient rated quality of life were collected prospectively pre-operatively and at every post-operative appointment in this case series. All patients presenting to the clinic with stable or progressive leg lymphoedema despiteconservative therapywho were suitable candidates for LVA over a three-year period were included. Results Twenty-nine patients were treated with LVA, 19 for unilateral lymphoedema and 10 for bilateral. In unilateral cases median limb excess volume reduced from 27% to 16% post-operatively (pp Conclusions In selected patients with early stagelymphoedema secondaryto cancer treatment, LVA offers a minimally invasive surgical option that can achieve significant volumetric and quality of life improvements.

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.

ObjectivesTo provide accurate risk estimates of serious adverse events after elective shoulder replacement surgery for arthritis, including age and sex specific estimates of the lifetime risk of revision surgery.DesignPopulation based cohort study.SettingHospital episode statistics for NHS England, including civil registration mortality data.Participants58 054 elective shoulder replacements in 51 895 adults (aged ≥50 years) between April 1998 and April 2017.Main outcome measuresThe lifetime risk of revision surgery, calculated using an actuarial life table approach and the cumulative probability method. Rates of serious adverse events at 30 and 90 days post-surgery: pulmonary embolism, myocardial infarction, lower respiratory tract infection, acute kidney injury, urinary tract infection, cerebrovascular events, and all cause death. Secondary outcome measures were the number of surgeries performed each year and Kaplan-Meier estimates of revision risk at 3, 5, 10, and 15 years.ResultsThe number of shoulder replacements performed each year increased 5.6-fold between 1998 and 2017. Lifetime risks of revision surgery ranged from 1 in 37 (2.7%, 95% confidence interval 2.6% to 2.8%) in women aged 85 years and older to 1 in 4 (23.6%, 23.2% to 24.0%) in men aged 55-59 years. The risks of revision were highest during the first five years after surgery. The risk of any serious adverse event at 30 days post-surgery was 1 in 28 (3.5%, 3.4% to 3.7%), and at 90 days post-surgery was 1 in 22 (4.6%, 4.4% to 4.8%). At 30 days, the relative risk of pulmonary embolism compared with baseline population risk was 61 (95% confidence interval 50 to 73) for women aged 50-64. Serious adverse events were associated with increasing age, comorbidity, and male sex. 1 in 5 (21.2%, 17.9% to 25.1%) men aged 85 years and older experienced at least one serious adverse event within 90 days.ConclusionsYounger patients, particularly men, need to be aware of a higher likelihood of early failure of shoulder replacement and the need for further and more complex revision replacement surgery. All patients should be counselled about the risks of serious adverse events. These risks are higher than previously considered, and for some could outweigh any potential benefits. Our findings caution against unchecked expansion of shoulder replacement surgery in both younger and older patients. The more accurate age and sex specific estimates of risk from this study are long overdue and should improve shared decision making between patients and clinicians.Study registrationClinicalTrials.govNCT03573765.

BACKGROUND Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a multifactorial etiology and heritability of ~45-60%. To identify common genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations. METHODS GWAS and trans-ethnic meta-analysis of 12,123 kidney stone cases and 416,928 controls was performed. Genotype-phenotype correlations were established in a validation cohort of kidney stone patients. Biological pathways were studied in vitro in HEK293 cells. RESULTS Twenty loci associated with nephrolithiasis were identified, ten of which are novel. One such locus is associated with CYP24A1 and is predicted to affect vitamin D metabolism. Five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. The CYP24A1-associated locus, correlated with serum calcium concentration and number of kidney stone episodes in a validation cohort of nephrolithiasis patients. In addition, the DGKD-associated locus correlated with urinary calcium excretion in the validation cohort. Moreover, DGKD knockdown was shown to impair CaSR-signal transduction in vitro, an effect that was rectified by the calcimimetic cinacalcet, thereby supporting the role of DGKD in CaSR signaling. CONCLUSIONS Our study identified ten novel loci associated with kidney stone disease; six loci are predicted to influence calcium-sensing receptor and vitamin D metabolism pathways. These findings indicate that genotyping may help to inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR signaling or vitamin D activation pathways in patients with recurrent kidney stones.

Background: Healthcare related costs for carpal tunnel decompression surgery (CTD) to treat carpal tunnel syndrome (CTS) exceed two billion dollars per year, despite a scarcity of data on safety and effectiveness. We estimated the incidence of revision surgery and complications following CTD, and the patient factors associated with adverse outcomes. Methods: We included all CTD surgeries undertaken in England using the Hospital Episode Statistics dataset linked to mortality records from 01/04/1998 until 31/03/2017. Patients were followed up until death or 31/03/2017. Primary outcomes were the overall incidence of revision CTD and postoperative complications (surgical site infection or dehiscence requiring surgery, neurovascular or tendon injury) within 30 and 90 days of surgery. Multivariable Cox regression analysis was used to identify factors influencing complications and revision surgery. The Fine and Gray method was used to adjust for the competing risk of mortality. Findings: 855 838 CTDs were performed during the 19-year period (incidence rate 1.10 per 1000 person years [95% CI 1·02 to 1·17]). Complication rates were 0·07% (95% CI 0·067 to 0·078) within 30 days, 0·08% (95% CI 0·073 to 0·085) within 90 days. 90-day local complications were associated with male sex and age category 18-29 years (adjusted hazard ratios 2·32 [1·74 to 3·09], 2·25 [1·10 to 4·62] respectively). 3·4% underwent revision CTD (incidence rate 3·18 per 1000 person years [95% CI 3·12 to 3·23]). Male sex, increasing age, greater levels of comorbidity, and increasing socioeconomic deprivation were associated with increased revision risk (adjusted subhazard ratios 1·09 [95% CI 1·05 to 1·13]; 1·09 [1·03 to 1·15]; 1·25 [1·19 to 1·32] and 1·18 [1·10 to 1·27]). Interpretation: This is the largest national study on CTD to date, providing the best available evidence on complication and revision rates. CTD is a safe operation, with an overall complication rate of less than 0.1%. Funding: Versus Arthritis; Medical Research Council; RCS England/ NJR research fellowship; University of Oxford; National Institute for Health Research; NIHR Biomedical Research Centre, Oxford. Declaration of Interest: All authors have completed the ICMJE uniform disclosure and declare: no support from any organization for the submitted work; D P-A has received research grants from Amgen, Servier, UCB; departmental fees for speaker services from Amgen, departmental fees for consultancy from UCB. No other relationships or activities could appear to have influenced the submitted work. Ethical Approval: This study was approved by the University of Oxford Research Services Clinical Trials Research Group (project ID 12787), and the NHS Data Access Advisory Group (DAAG). It was carried out in accordance with the NHS Digital Data Sharing Agreement (DARS-NIC-29827-Q8Z7Q) and registered at clinicaltrials.gov (NCT03573765). Studies using non-identifiable records from Hospital Episode Statistics are exempt from research ethics committee approval.

Background:Carpal tunnel syndrome (CTS) is a chronic compression neuropathy caused by entrapment of the median nerve in the wrist causing pain and sensory loss. Prior observational research suggested that obesity increased the risk of CTS. However, the impact of weight loss among obese patients on CTS has not been assessed to date.Objectives:To assess the association between bariatric surgery and CTS in a secondary care setting.Methods:We performed a propensity score (PS)-matched cohort study using data from Swedish nationwide healthcare registries (patient registry [secondary care], causes of death registry, prescribed drug registry). Patients aged 18-79 years who underwent bariatric surgery between 2006 and 2019 were matched to up to 2 obese bariatric surgery-free patients (called unexposed patients) based on their PS. PS-matching was carried out in risk set sampling to reduce selection bias, within 4 sequential cohort entry blocks to account for time trend biases. The outcome CTS was defined as a diagnosis of CTS in secondary care or carpal tunnel decompression surgery. After a 1-year run-in period, patients were followed in an “as-treated” approach. We applied Cox proportional hazard regression to calculate hazard ratios (HR) with 95% confidence intervals (CIs) of CTS among bariatric surgery patients when compared to obese unexposed patients overall, and in subgroups of age, sex, bariatric surgery type, and by duration of follow-up.Results:A total of 40 619 bariatric surgery patients were PS-matched to 63 540 obese unexposed patients. A total of 72.3% of bariatric surgery patients were women. Bariatric surgery patients had a mean age of 41.7 years and a mean follow-up of 6.8 years. All patient characteristics in obese unexposed patients were highly similar. We observed 1 356 and 1 938 severe CTS cases among bariatric surgery and obese unexposed patients, respectively. Bariatric surgery was not associated overall with CTS (HR of 0.98, 95% CI 0.91-1.05). However, the risk of CTS seemed to decrease with age at bariatric surgery – the lowest CTS risk was observed among bariatric surgery patients aged 18-34 years (HR of 0.87, 95% CI 0.74-1.01), when compared to obese unexposed patients. Sex did not modify the risk of CTS among bariatric surgery patients compared to obese unexposed patients. Restrictive bariatric surgery yielded lower risks of CTS (HRs of 0.81, 95% CI 0.69-0.88) than did malabsorptive bariatric surgery (HR of 0.95, 95% CI 0.88-1.02) when compared to obese unexposed patients. The risk of CTS increased with duration of follow-up. The lowest risk was observed 1-3 years after bariatric surgery (HR of 0.77, 95% CI 0.68-0.88) and the highest risk 6-13 years after bariatric surgery (HR of 1.20, 95% CI 1.05-1.36) when compared to obese unexposed patients.Conclusion:Our results suggest that substantial weight loss is not overall associated with severe CTS in an obese patient population. However, bariatric surgery was associated with an initial decreased risk of CTS after bariatric surgery followed by an increased risk in later follow-up. Furthermore, restrictive bariatric surgery but not malapsorptive bariatric surgery was associated with a decreased risk of CTS.Acknowledgements:We thank Prof. Dr. Jesper Lagergren (Karolinksa Institutet, Stockholm, Sweden) for hosting Dr. Theresa Burkard for a research stay at the Upper Gastrointestinal Surgery Group and making the data available for use. Furthermore, we thank Dr. Giola Santoni (Karolinksa Institutet, Stockholm, Sweden) for her technical support.Disclosure of Interests:None declared.

Introduction Recurrent cellulitis is a frequent and challenging complication of lymphoedema. British Lymphology Society cellulitis guidelines state that decongestive lymphatic therapy reduces the frequency of cellulitis attacks, but do not mention the effect of surgical interventions. This systematic review aims to assess whether surgical interventions for lymphoedema reduce the frequency of attacks of cellulitis. Materials and methods Embase, Medline, and the Cochrane database were searched for relevant articles from database inception to January 2016. Four hundred and thirty-six abstracts were retrieved. Studies were included which contained quantitative data on cellulitis incidence before and after a surgical intervention. Two independent reviewers applied selection criteria, selecting 27 papers for full text review. Two were unavailable in the UK from any source. Results A variety of surgical techniques were utilized in the 25 papers included: lymphaticovenous anastomosis, superficial-to-deep lymphaticolymphatic anastomosis, lymph node transfer, Charles procedure, muscle flap transfer, Homan's procedure, and subcutaneous tissue excision below skin flaps. Five studies combined techniques. One study compared the intervention to a control group (physical therapy). Cellulitis incidence was decreased following surgical intervention in 24/25 studies included. Eight had quantifiable reductions in cellulitis over a set follow-up period; in the other 16 preoperative incidence was not precisely defined. Conclusion Surgery appears effective at reducing cellulitis incidence in lymphoedema. However, high quality evidence from randomized controlled trials is lacking. Future research should concentrate on comparison with control groups, for example compression alone versus compression with surgical intervention, in patients with lymphoedema and greater than two attacks of cellulitis per year.

Objective To determine the evidence-based optimal strategy for management of drains following axillary dissection. Background Despite randomised control trials addressing the issue over the past 20–30 years, there is no widely accepted consensus as to when drains should be removed post axillary dissection. Methods We searched the electronic databases Medline, Embase, Cinahl, Cochrane Library of Systematic Reviews and Web of Science Citation Index. References within identified studies were also searched. Studies were independently identified and data extracted according to a pre-determined proforma based on the Cochrane Collaboration data extraction template by two independent researchers. Validity was determined according to a published standard. Discrepancies were corrected by consensus. Results There was no difference in infection rates between early and late drain removal, hospital stay was reduced when drains were removed earlier, and higher total volume drainage prior to drain removal predicted subsequent seroma formation. The optimal timing of drain removal post axillary dissection could not be determined from the literature. Conclusion Optimal timing of drain removal following axillary dissection remains unknown after this systematic review due to heterogeneity between included studies leading to an inability to provide evidence-based consensus guidance.

Background Despite numerous studies over the past few decades, the optimum strategy for deciding when to remove drains following axillary lymphadenectomy remains unknown. This meta-analysis aims to compare time-limited and volume-controlled strategies for drain removal. Methods A total of 584 titles were identified following a systematic literature search of EMBASE, MEDLINE, Cinahl and the Cochrane library; 6 titles met our eligibility criteria. Data were extracted and independently verified by two authors. Time-limited drain removal was defined as drain removal at Results In all the studies, the time-limited approach resulted in earlier drain removal. Development of a seroma is 2.54 times more likely with early drain removal (Mantel-Haenszel Fixed Odds Ratio (OR) 2.54, p < 0.00001). However, there is no difference in infection rates between early and late drain removal (OR Z 1.07, p Z 0.76). Conclusions This meta-analysis demonstrates that a strategy of early drain removal following axillary lymphadenectomy is safe, with no difference in infection rates; however, the incidence of seroma is significantly higher, which may necessitate more demanding outpatient care. There is a need for further well-designed clinical trials to address the clinical equipoise in this common area of surgical practice.