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Clinical decision-support tools (DSTs) represent a valuable resource in healthcare. However, lack of Human Factors considerations and early design research has often limited their successful adoption. To complement previous technically focused work, we studied adoption opportunities of a future DST built on a predictive model of Alzheimer’s Disease (AD) progression. Our aim is two-fold: exploring adoption opportunities for DSTs in AD clinical care, and testing a novel combination of methods to support this process. We focused on understanding current clinical needs and practices, and the potential for such a tool to be integrated into the setting, prior to its development. Our user-centred approach was based on field observations and semi-structured interviews, analysed through workflow analysis, user profiles, and a design-reality gap model. The first two are common practice, whilst the latter provided added value in highlighting specific adoption needs. We identified the likely early adopters of the tool as being both psychiatrists and neurologists based in research-oriented clinical settings. We defined ten key requirements for the translation and adoption of DSTs for AD around IT, user, and contextual factors. Future works can use and build on these requirements to stand a greater chance to get adopted in the clinical setting.

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.

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.

We performed Mendelian randomization analyses of body mass index and waist–hip ratio adjusted for body mass index in Dupuytren’s disease using summary statistics from genome-wide association study meta-analyses. We found that adiposity is causally protective against Dupuytren’s disease, with the inverse-variance weighted Mendelian randomization analysis estimating that a 1 standard deviation increase in body mass index (equivalent to 4.8 kg/m2) leads to 28% (95% confidence interval: 18–37%) lower relative odds of developing Dupuytren’s disease, and a 1 standard deviation increase in waist–hip ratio adjusted for body mass index (equivalent to a waist–hip ratio of 0.09) leads to 26% (95% confidence interval: 6–42%) lower relative odds of developing Dupuytren’s disease. We conclude from this study that regardless of the well-established negative health effects of obesity, the raised body mass index is associated with a lower risk of Dupuytren’s disease and may be causally protective for the development of the disease.

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.

BackgroundPatients often carry medication lists to mitigate information loss across healthcare settings. We aimed to identify mechanisms by which these lists could be used to support safety, key supporting features, and barriers and facilitators to their use.MethodsWe used a mixed-methods design comprising two focus groups with patients and carers, 16 semistructured interviews with healthcare professionals, 60 semistructured interviews with people carrying medication lists, a quantitative features analysis of tools available for patients to record their medicines and usability testing of four tools. Findings were triangulated using thematic analysis. Distributed cognition for teamwork models were used as sensitising concepts.ResultsWe identified a wide range of mechanisms through which carrying medication lists can improve medication safety. These included improving the accuracy of medicines reconciliation, allowing identification of potential drug interactions, facilitating communication about medicines, acting as an aide-mémoire to patients during appointments, allowing patients to check their medicines for errors and reminding patients to take and reorder their medicines. Different tools for recording medicines met different needs. Of 103 tools examined, none met the core needs of all users. A key barrier to use was lack of awareness by patients and carers that healthcare information systems can be fragmented, a key facilitator was encouragement from healthcare professionals.ConclusionOur findings suggest that patients and healthcare professionals perceive patient-held medication lists to have a wide variety of benefits. Interventions are needed to raise awareness of the potential role of these lists in enhancing patient safety. Such interventions should empower patients and carers to identify a method that suits them best from a range of options and avoid a ‘one size fits all’ approach.

Background Upper limb arthroplasty is an increasingly used treatment modality for end-stage joint disease of the shoulder, elbow and wrist. Whilst complications have been reported, the risk of venous thromboembolism has received less attention when compared to the lower limb. Guidance to aid clinical decision-making remains limited. This review aims to ascertain whether venous thromboembolism prophylaxis is beneficial after upper limb major joint replacement surgery. Methods A systematic review was performed in April 2019, utilising EMBASE, MEDLINE, Cochrane and Google Scholar. All clinical studies reporting venous thromboembolism incidence and risk reduction (after prophylaxis) in upper limb joint replacement were included. Results Twenty-four observational studies were identified. The reported incidence of venous thromboembolism ranged from 0.2% to 16% (weighted mean 0.68%) and 0.2% to 0.8% (weighted mean 0.49%) in shoulder and elbow arthroplasty, respectively. No records for wrist arthroplasty were found. In the literature, baseline venous thromboembolism risk of patients without an operation is reported as 0.5%. Discussion There is a lack of good quality evidence regarding the risks and benefits of venous thromboembolism prophylaxis in upper limb major joint replacement surgery. We recommend further research, ideally formal randomised controlled trials to guide recommendations. Although venous thromboembolism is rare in upper limb surgery, surgeons should remain vigilant to this possibility.

BackgroundVaricose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.MethodsWe performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.ResultsWe discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.ConclusionsGenes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.

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 To elucidate the genetic architecture of haemorrhoids and identify genes and biological pathways central to their pathobiology. Method We report the first ever genome-wide association study of haemorrhoids in 31,652 cases and 369,931 controls from UK Biobank. Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for haemorrhoids was constructed to compare genetic susceptibility in surgical vs non-surgical haemorrhoids patients. Results Twelve novel genome-wide significant susceptibility loci were discovered to be associated with haemorrhoids. Seventeen genes were mapped to these loci, and gene sets in biological pathways relating to extracellular matrix regulation and TGF-β signalling were strongly implicated. Seven gene-products (41.2%) were predicted tractable to antibody and/or small molecule targeting, and three products (17.6%) have known pharmaceutical interactions (ACHE, ADRA2B, ELN). The wGRS analysis demonstrated that haemorrhoid patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 4.58 × 10-27). Conclusions This study has advanced our understanding of haemorrhoids pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to haemorrhoids.

Aim To elucidate the genetic architecture of varicose veins (VVs) and identify genes and biological pathways central to their pathobiology. Method We performed hitherto the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe, Inc (total 135,514 VVs cases and 675,111 controls). Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for VVs was constructed to compare genetic susceptibility in surgical vs non-surgical VVs patients. Results 109 genome-wide significant (P ≤ 5 × 10-8) loci were identified in UK Biobank, 46 of which successfully replicated in the 23andMe cohort. Twenty-eight loci have not been previously reported. We mapped 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis. The wGRS analysis demonstrated that VVs patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 2.46 × 10−13). Conclusions This study has advanced our understanding of VVs pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to VVs.

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.

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.

Background The aim of this systematic review was to synthesise peer-reviewed literature assessing the impact of electronic prescribing (eP) systems on the working practices of healthcare professionals (HCPs) in the inpatient setting and identify implications for practice and research. Methods We searched PubMed, Medline, Embase, Cochrane and the Cumulative Index to Nursing Allied Health Literature databases for studies published from inception to November 2018. We included controlled, uncontrolled, observational and descriptive studies that explored the effect of eP on HCPs’ working practices in an inpatient setting. Data on setting, eP system and impact on working practices were extracted. Methodological quality was assessed using the Mixed Methods Appraisal Tool. Emergent themes were identified and subjected to narrative synthesis. The protocol was registered with PROSPERO (registration CRD42017075804). Results Searches identified 1301 titles and abstracts after duplicate removal. 171 papers underwent full-text review. A total of 25 studies met the inclusion criteria, from nine different countries. Nineteen were of commercial eP systems. There were a range of study designs; most (n = 14) adopted quantitative methods such as cross-sectional surveys, ten adopted qualitative approaches and a further one used mixed methods. Fourteen of the 25 studies were deemed to be of high quality. Four key themes were identified: communication, time taken to complete tasks, clinical workflow, and workarounds. Within each theme, study findings differed as to whether the effects of eP on HCPs’ working practices were positive or negative. Conclusion There is a lack of consensus within the literature on the impact of eP on HCPs’ working practices. Future research should explore the strategies resulting in a positive impact on HCPs’ working practices and learn from those that have not been successful.

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.

Background: The administration of medication or fluids via the intravenous route is a common intervention for many hospital inpatients. However, little research has explored the safety and quality of intravenous therapy from the patient’s perspective, despite the role of the patient in patient safety receiving increased attention in recent years. Objective: To explore patients’ perspectives on the perceived quality and safety of intravenous infusions and identify implications for practice. Method: Qualitative semistructured interviews were conducted with 35 hospital patients receiving intravenous infusions in critical care, oncology day care, general medicine, and general surgery areas within 4 National Health Service hospitals in England. Data were analyzed thematically. Results: Four underlying and interlinked themes were identified: knowledge about intravenous infusions, challenges associated with receiving intravenous infusions, the role of health-care professionals, and patients’ attitudes toward receiving infusions. Conclusions: Patients were generally satisfied with receiving infusions; however, factors that contributed to decreased feelings of quality and safety were identified, suggesting areas for intervention. Issues to do with infusion pump alarms, reduced mobility, cannulation, and personal preferences for information, if given more attention, may improve patients’ experiences of receiving intravenous infusions.

ObjectivePrioritisation of important treatment uncertainties for ‘Common Conditions Affecting the Hand and Wrist’ via a UK-based James Lind Alliance Priority Setting Partnership.SettingThis process was funded by a national charitable organisation and based in the UK.ParticipantsAnyone with experience of common conditions affecting the adult hand and wrist, including patients, carers and healthcare professionals. All treatment modalities delivered by a hand specialist, including therapists, surgeons or other allied professionals, were considered.InterventionsEstablished James Lind Alliance Priority Setting Partnership methods were employed.Electronic and paper questionnaires identified potential uncertainties. These were subsequently confirmed using relevant, up-to-date systematic reviews. A final list of top 10 research uncertainties was developed via a face-to-face workshop with representation from patients and clinicians. Impact of research was sought by surveying hand clinicians electronically.Outcome measuresThe survey responses and prioritisation—both survey and workshop based.ResultsThere were 889 individually submitted questions from the initial survey, refined to 59 uncertainties across 32 themes. Eight additional uncertainties were added from published literature before prioritisation by 261 participants and the workshop allowed the final top 10 list to be finalised. The top 10 has so far contributed to the award of over £3.8 million of competitively awarded funding.ConclusionsThe Common Conditions in the Hand and Wrist Priority Setting Partnership identified important research questions and has allowed research funders to identify grant applications which are important to both patients and clinicians

Introduction Varicose veins (VV) impact a third of the UK adult population; 10% of patients develop lipodermatosclerosis and ulceration. VV often requires surgical management, however, there is a high-risk of recurrence. VV is a complex disease, where genetic and non-genetic components contribute to overall phenotypic expression. The genetic architecture of VV is poorly understood; we aimed to uncover its genetic basis. Method We conducted hitherto the largest genome-wide association study of VV. In stage one, using UK Biobank, we compared 22,473 VV patients and 379,183 controls. In stage two, replication and meta-analysis were performed in an independent cohort of 113,041 VV cases and 295,928 controls from 23&Me (California, USA). In-silico analysis was conducted in FUMA, MAGMA, and XGR. Result 109 genome-wide significant (P≤ 5×10-8) loci were identified in UK Biobank, 45 of which successfully replicated in the 23&Me cohort. Twenty-seven loci have not been previously reported. FUMA positionally-mapped 128 genes at the replicated loci, with 84 having a combined annotation-dependent depletion score (CADD) >12.37, suggesting functional, deleterious variants. MAGMA analysis implicated pathways involved in cardiovascular system development (P=1.57×10-08) and tube morphogenesis (P=9.35×10-08). Furthermore, XGR revealed enriched pathways in downstream signalling in naive CD8+ T cells (P=0.0017), and encoding structural and core extracellular glycoproteins (both P=0.007). Conclusion We identified 45 variants conferring risk of VV, which provide insights into disease biology. Implicated genes are enriched in pathways involved in vascular development, immune cell activity and extracellular matrix function, and provide new targets for therapeutic development. Take-home message Unravelling the genetic architecture of varicose veins may facilitate our understanding of the disease and guide therapeutic approaches.

Background: Several approaches to plate fixation of the proximal phalanx have been proposed, such as the dorsal extensor splitting approach and the lateral or dorso-lateral extensor sparing approach, which aims to minimise invasiveness to promote native extensor tendon glide. This study aimed to meta-analyse the outcomes of these two approaches. Methods: A systematic review of electronic databases was undertaken, and the outcomes of comparative studies meta-analysed. Results: Three studies were included for meta-analysis. Total active motion (TAM) was significantly greater in the extensor sparing group compared to the extensor splitting (Mean difference 8.52 degrees, 95%CI 0.8–16.36, p = 0.03). Conclusions: This study demonstrates that there is preliminary evidence favouring the use of extensor sparing approaches when fixing proximal phalanxes – however, this result requires validation with randomised controlled trials.

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.

Proximal phalangeal fractures have traditionally been fixed via either Kirschner wires or dorsal plating. Concerns regarding lack of compression and potential for infection with wire fixation, and adhesion formation and stiffness with plating, have lead to alternative fixation methods, such as intramedullary screw fixation. However, the literature regarding this modality is limited. Methods: A systematic review was performed to review the literature regarding intramedullary screw fixation for proximal phalangeal fractures. English language studies that reported original data and commented on at least one postoperative measure of function were eligible for inclusion. 4 studies were eligible for inclusion, with a further 3 studies assessing proximal and middle phalanges analysed separately. Total active motion was greater than 240° in all proximal phalangeal studies; mean post-operative DASH was 3.62. 6% of patients sustained a major complication. Intramedullary screw fixation of proximal phalangeal fractures is safe, providing stable fixation to allow early motion.

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.

Lymphoedema is the accumulation of protein-rich interstitial fluid within subcutaneous tissue and skin as a result of dysfunction of the lymphatic system. It is an underestimated, widely neglected and debilitating chronic condition. This article presents an overview of lymphoedema and recent advances in its management.

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

Background Computerised adaptive testing (CAT) has the potential to transform plastic surgery outcome measurement by making patient-reported outcome measures (PROMs) shorter, individualised and more accurate than pen-and-paper questionnaires. Objectives This paper reports the results of two optimisation studies for the CLEFT-Q CAT, a CAT intended for use in the field of cleft lip and/or palate. Specifically, we aimed to identify the optimal score estimation and item selection methods for using this CAT in clinical practice. These represent two major components of any CAT algorithm. Method Monte Carlo simulations were performed using simulated data in the R statistical computing environment and incorporated a range of score estimation and item selection techniques. The performance and accuracy of the CAT was assessed by mean items administered, correlation between CAT scores and paired linear assessment scores, and the root mean squared deviation (RMSD) of these score pairs. Results The accuracy of the CLEFT-Q CAT was not significantly affected by the choice of score estimation or item selection method. Sub-scales which originally contain more items were amenable to greater item reduction with CAT. Conclusion This study shows that score estimation and item selection methods that need minimal processing power can be used in the CLEFT-Q CAT without compromising accuracy. This means that the CLEFT-Q CAT could be administered quickly and efficiently with basic hardware demands. We recommend the use of less computationally intensive techniques in future CLEFT-Q CAT studies.

This study aimed to determine if having an overweight or obese range body mass index (BMI) at time of beginning school is associated with increased fracture incidence in childhood. A dynamic cohort was created from children presenting for routine preschool primary care screening, collected in the Information System for Research in Primary Care (SIDIAP) platform in Catalonia, Spain. Data were collected from 296 primary care centers representing 74% of the regional pediatric population. A total of 466,997 children (48.6% female) with a validated weight and height measurement within routine health care screening at age 4 years (±6 months) between 2006 and 2013 were included, and followed up to the age of 15, migration out of region, death, or until December 31, 2016. BMI was calculated at age 4 years and classified using WHO growth tables, and fractures were identified using previously validated ICD10 codes in electronic primary care records, divided by anatomical location. Actuarial lifetables were used to calculate cumulative incidence. Cox regression was used to investigate the association of BMI category and fracture risk with adjustment for socioeconomic status, age, sex, and nationality. Median follow-up was 4.90 years (interquartile range [IQR] 2.50 to 7.61). Cumulative incidence of any fracture during childhood was 9.20% (95% confidence interval [CI] 3.79% to 14.61%) for underweight, 10.06% (9.82% to 10.29%) for normal weight, 11.28% (10.22% to 12.35%) for overweight children, and 13.05% (10.69% to 15.41%) for children with obesity. Compared with children of normal range weight, having an overweight and obese range BMI was associated with an excess risk of lower limb fracture (adjusted hazard ratio [HR] = 1.42 [1.26 to 1.59]; 1.74 [1.46 to 2.06], respectively) and upper limb fracture (adjusted HR = 1.10 [1.03 to 1.17]; 1.19 [1.07 to 1.31]). Overall, preschool children with an overweight or obese range BMI had increased incidence of upper and lower limb fractures in childhood compared with contemporaries of normal weight. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Background and importance Studies suggest that in the hospital setting, prescribing errors are most common at admission, largely due to challenges of medication reconciliation. Problems are also common following transfer from hospital into the community and when attending outpatient appointments. Many patients who take medications use patient held information about medication (PHIMed) to improve transfer of medication related information across care settings. However, it is not known how PHIMed is used in practice and the extent to which PHIMed tools available meet the needs of patients and healthcare professionals. Discussion with patients and carers highlighted this as a priority for research. Aim and objectives To identify how PHIMed is used in practice, barriers and facilitators to its use, and its role in supporting medication safety. Material and methods We used a mixed methods design comprising two focus groups with patients and carers, 16 semi-structured interviews with healthcare professionals, 60 semi-structured interviews with PHIMed users, a quantitative features analysis of PHIMed solutions available in the UK and usability testing of four PHIMed tools. Participants were identified and recruited in Greater London in 2018, using advertisements on social media, our professional networks and face to face recruitment in outpatient clinics. Findings were triangulated using thematic analysis using distributed cognition for teamwork (DiCoT) models as sensitising concepts. NHS ethics approval was obtained. Results We found that PHIMed was viewed positively by patients and carers using it and healthcare professionals. We identified a wide range of mechanisms through PHIMed improved medication safety, such as identification of potential drug interactions. However, a key barrier to use was lack of awareness by patients and carers that healthcare information systems are often fragmented, which meant that they had not identified a need for PHIMed. Different PHIMed tools met different needs, with no ‘one size fits all’ solution. No tools currently meet the core needs of all users. Conclusion and relevance Healthcare professionals should raise awareness among patients and carers of the potential safety benefits of carrying and using PHIMed, encourage its use during consultations and be able to signpost to some of the tools and features available. PHIMed tool developers should modify their tools in order to meet all core user requirements. References and/or acknowledgements No conflict of interest.

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.).

Summary What is known and objectives The use of enteral tube feeding at home is becoming more widespread, with patients ranging in age and diseases. Dysphagia and swallowing difficulties can compromise nutritional intake and the administration of oral medications, affecting therapeutic outcomes negatively. Carers’ experiences of medicines administration and medicines optimization have not been explored fully. The objectives of this study were to identify issues carers experience in medicines administration; the strategies they have developed to cope; and suggestions to improve the medicines administration process. Methods An online survey was promoted nationally; 42 carers completed it. Descriptive statistical analysis was applied, as well as thematic analysis of open‐ended responses. Results were compared against the 4 principles of medicines optimization. Results and discussion 93% of respondents administered medications with enteral feeding tubes, but only 62% had received advice from healthcare professionals and only 8% had received written information on how to do so. Responses identified 5 medicines administration issues experienced by carers; 4 strategies they developed to cope; and 3 main areas of suggestions to improve medicines administration via enteral feeding at home. What is new and conclusion The 4 principles of medicines optimization have not previously been applied to enteral feeding. We present a novel account of carers’ experiences, for example coping with ill‐suited formulations and a lack of training and support, which should inform better practice (Principle 1). Carers sometimes experience suboptimal choice of medicines (Principle 2). Carers’ practices are not always well‐informed and may affect therapeutic outcomes and safety (Principle 3). There is scope for improvement in carer training, education and support to better support medicines optimization (Principle 4)., Carers of patients using enteral tube feeding experience a variety of issues when administering medications, such as coping with ill‐suited formulations and a lack of training and support. Carers’ practices are not always well‐informed and may affect therapeutic outcomes and safety. There is scope for improvement in carer training, education and support to better support medicines optimization.

Background:Hand osteoarthritis (OA) is a chronic, progressive disease, commonly affecting middle aged women. OA at the interphalangeal joints (IPJs) or the thumb base are considered different disease subsets (1). Few studies have investigated individual risk factors for IPJ OA progression (2). Prediction models can be used to calculate overall disease risk from multiple risk factors. This can guide prevention and treatment options.Objectives:Develop and internally validate a prediction model for IPJ OA progression.Methods:Data from the Chingford 1000 Women Study (Chingford Study), the largest population-based cohort worldwide assessing hand OA, was used. It is representative of the middle-aged female population in the United Kingdom (3). At baseline, 1,003 women aged 45 to 64 years’ old were recruited, and 693 measurements taken. Hand radiographs were taken at baseline and after ten years, read using the Kellgren-Lawrence (KL) atlas (inter-observer correlation: ≥0.7 (4)).For the current study, participants must have had OA (KL ≥2 in ≥1 IPJ) on baseline hand radiographs. Participants with KL 4 in all 16 IPJs at baseline were excluded. Risk factors from the Chingford Study at baseline were selected by biological plausibility, literature evidence (2), and hand surgeons‘ consensus (5): age (years), occupation (manual versus non manual), OA in ≥1 thumb base (KL ≥2 versus KL2), family history of hand OA (yes versus no). The outcome was defined on an ordinal scale for the number of IPJs (up to >5 IPJs) with OA progression (increase by KL ≥1), at ten years’.The prediction model was developed using a penalized proportional odds logistic regression. Odds ratios (95% confidence intervals) were reported for each risk factor. The model was internally validated using 2,000 bootstrap iterations. Model performance was assessed for discrimination (C-statistic), and calibration (C-slope). 3.5% of data was missing, and complete case analysis was used.Results:699 women had baseline hand radiographs: 38 were unreadable, 459 had no IPJ OA. Seven participants had missing data (occupation: 5, BMI: 1, family history: 1) and were excluded. 195 participants were included this study. Median age at baseline was 59 (interquartile range: 8) years.181 (92.8%) participants had OA progression at 10 years (Figure 1). Thumb base OA (odds ratio: 1.32 (0.93 to 1.88)) was most strongly associated with IPJ OA progression (Table 1). C-statistic was 0.57, and calibration slope was 1.38 for the optimism-corrected model.Table 1.Odds ratios for risk factorsRisk factorOdds ratio (95% confidence interval)Age (years)1.02 (0.99 to 1.06)Occupation (manual versus non manual)0.88 (0.60 to 1.29)Thumb base OA (Kellgren-Lawrence grade ≥2 versus 1.32 (0.93 to 1.88)Family history of hand OA (yes versus no)1.03 (0.72 to 1.45)Body mass index (kg/m2)1.04 (0.99 to 1.09)OA: OsteoarthritisConclusion:More stringent cut-offs for OA progression would be clinically useful. It was only weakly possible to predict which participants with IPJ OA would progress. This suggests that other risk factors, such as gender, ethnicity and genetics, may be predominant.Figure 1.Hand interphalangeal joints with osteoarthritis progression (Kellgren-Lawrence grade ≥1) at 10 years’ follow upReferences:[1]Kloppenburg M, et al. Research in hand osteoarthritis: time for reappraisal and demand for new strategies. Ann Rheum Dis. 2007;66(9):1157-61.[2]Shah K, et al. Risk factors for the progression of finger interphalangeal joint osteoarthritis: a systematic review. Rheumatol Int. 2020;40(11):1781-1792.[3]Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J Rheumatol. 1993;20:331-335.[4]Hart DJ, et al. Reliability and reproducibility of grading radiographs for osteoarthritis of the hand. Br J Rheum. 1993;32:S1.[5]Shah K, et al. Delphi consensus of risk factors for development and progression of finger interphalangeal joint osteoarthritis. J Hand Surg Eur Vol. 2019;44(10):1089-1090.Acknowledgements:We would like to thank all of the participants of The Chingford 1000 Women Study, Professor Tim Spector, Dr Deborah Hart, Dr Alan Hakim, Maxine Daniels, Alison Turner, James van Santen and Julie Damnjanovic for their time and dedication.Disclosure of Interests:Karishma Shah: None declared, Garrett Bullock: None declared, Alan Silman: None declared, Dominic Furniss: None declared, Nigel Arden Consultant of: Receives personal fees from Pfizer/Lily for consultancy outside the scope of this work, Grant/research support from: Receives grant from Merck outside the scope of this work, Gary Collins: None declared

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.

The exponential increase in the volume and complexity of healthcare data presents new challenges to researchers and clinicians in analysis and interpretation. The requirement for new strategies to extract meaningful information from large, noisy datasets has led to the development of the field of big data analytics. Artificial intelligence (AI) is a general-purpose technology in which machines carry out tasks traditionally thought to be only achievable by humans. Machine learning (ML) is an approach to AI in which machines can “learn” to perform tasks in an automated process, rather than being explicitly programmed by a human. Research aiming to apply ML techniques to classification, prediction and decision-making problems in healthcare has increased 61-fold from 2005 to 2019, mirroring this sense of early promise. The field of healthcare ML is relatively young, and many critical steps are needed before adoption into clinical practice, including transparent, unbiased development and reporting of algorithms. Articles claiming that machines can outperform, or replace, doctors in high-level tasks, such as diagnosis or prognostication, must be carefully appraised. It is critical that surgeons have an understanding of the principles and terminology of AI and ML to evaluate these claims and to take an active role in directing research. This article is an up-to-date review and primer for surgeons covering the core tenets of ML applied to surgical problems, including algorithm types and selection, model training and validation, interpretation of common outcome metrics, current and future reporting guidelines and discussion of the challenges and limitations in this field.

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.