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Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

Real-world systems that involve some non-smooth change are often well-modeled by piecewise-smooth systems. However there still remain many gaps in the mathematical theory of such systems. This doctoral thesis presents new results regarding bifurcations of piecewise-smooth, continuous, autonomous systems of ordinary differential equations and maps. Various codimension-two, discontinuity induced bifurcations are unfolded in a rigorous manner. Several of these unfoldings are applied to a mathematical model of the growth of Saccharomyces cerevisiae (a common yeast). The nature of resonance near border-collision bifurcations is described; in particular, the curious geometry of resonance tongues in piecewise-smooth continuous maps is explained in detail.

Objectives The aim of this systematic review was to provide an overview of time to return to work (RTW) after carpal tunnel release (CTR), including return to different occupations and working patterns. Methods A systematic search from inception to 2016 was conducted using nine electronic databases, trial registries and grey literature repositories. Randomized controlled trials and observational studies reporting RTW times after CTR were included. Study risk of bias was assessed using Cochrane risk of bias assessment tools. Time to RTW was summarized using median and range. Results A total of 56 relevant studies were identified: 18 randomized controlled trials and 38 observational studies. Only 4 studies were rated as having a low risk of bias. Reported RTW times ranged from 4-168 days. Few studies reported occupational information. Among 6 studies, median time to return to non-manual work was 21 days (range 7-41), compared with 39 days for manual work (range 18-101). Median time to return to modified or full duties was 23 days (ranges 12-50 and 17-64, respectively), as reported by 3 studies. There was no common method of defining, collecting or reporting RTW data. Conclusions This review highlights wide variation in reported RTW times after CTR. Whilst occupational factors may play a role, these were poorly reported, and there is currently limited evidence to inform individual patients of their expected duration of work absence after CTR. A standardized definition of RTW is needed, as well as an agreed method of collecting and reporting related data.

Background Carpal tunnel syndrome is a common nerve compression disorder which affects hand sensation and function. Carpal tunnel release surgery (CTR) is frequently performed to alleviate these symptoms. For many CTR patients, surgery occurs during their working lifetime, but there is currently no evidence-based guidance to inform clinicians or patients when it might be safe to return to different types of work afterwards. The aim of this qualitative study was to explore the return to work experiences of patients who had recently undergone CTR. Methods Semi-structured 1:1 interviews were conducted with a subgroup of participants recruited to a multi-centre prospective cohort study. Interviewees were purposely selected to represent a range of demographic, clinical and occupational characteristics. All had recently undergone CTR and had returned to work. Interviews were audio recorded, transcribed verbatim and analysed using the framework method. Participants were recruited until data saturation was achieved. Results Fourteen participants were interviewed: 11 women (median age 49 years, range 27–61) and 3 men (age range 51–68 years). Three key themes were identified. Theme 1 centred on the level of functional disability experienced immediately after surgery. There was an expectation that CTR would be a ‘minor’ procedure, but this did not match the participants’ experiences. Theme 2 explored the desire for validation for the time away from work, with participants recalling a need to justify their work absence to themselves as well as to their employers. Theme 3 focused on the participants’ reflections of handing their return to work and function, with many reporting uncertainties about what constituted appropriate activity loads and durations. There was a desire for specific information relating to individual work roles. Conclusion Individual return to work decision-making was largely influenced by the recommendations received. According to the views of participants, clinicians may be able to prepare patients better pre-operatively, especially with respect to function in the immediate post-operative period and by providing return to work guidance that can be tailored for individual work roles.

Background The ubiquitous use of dental amalgam for over 180 years has resulted in the exposure of millions of dental workers to mercury. Dental amalgam contains approximately 50% mercury. Dental workers, including dentists, dental assistants, and dental hygienists, have been shown to have increased levels of mercury and suffer more from health issues related to mercury exposure than the general public. Mercury is known to be absorbed via inhalation or through the skin. There are many routine dental procedures that require the removal of dental amalgam by using the dental high-speed drill, which we suspected generates an occupational mercury exposure that is not sufficiently recognized. Results We showed that drilling dental amalgam generates particulate that volatilizes significant amounts of mercury vapor generally for more than an hour after removal. The levels of mercury vapor created by this procedure frequently exceed the safety thresholds of several jurisdictions and agencies. Conclusions A significant, underrecognized source of localized exposure to mercury vapor was identified in this study. The vapor was created by microgram levels of particulate generated from dental amalgam removal with a high-speed dental drill, even when all feasible engineering controls were used to reduce mercury exposure. This exposure may explain why dental workers incur health effects when safety thresholds are not breached. The dispersion patterns for the particulate are not known, so the use of effective skin barriers and inhalation protection are required during amalgam removal to protect the dental worker from this form of occupational mercury exposure. Standard methodologies for occupational mercury exposure assessment appear to be inadequate when assessing mercury exposure during amalgam removal.

IntroductionHospital-acquired thrombosis (HAT) is defined as any venous thromboembolism (VTE)-related event during a hospital admission or occurring up to 90 days post discharge, and is associated with significant morbidity, mortality and healthcare-associated costs. Although surgery is an established risk factor for VTE, operations with a short hospital stay (<48 hours) and that permit early ambulation are associated with a low risk of VTE. Many patients undergoing short-stay surgical procedures and who are at low risk of VTE are treated with graduated compression stockings (GCS). However, evidence for the use of GCS in VTE prevention for this cohort is poor.Methods and analysisA multicentre, cluster randomised controlled trial which aims to determine whether GCS are superior in comparison to no GCS in the prevention of VTE for surgical patients undergoing short-stay procedures assessed to be at low risk of VTE. A total of 50 sites (21 472 participants) will be randomised to either intervention (GCS) or control (no GCS). Adult participants (18–59 years) who undergo short-stay surgical procedures and are assessed as low risk of VTE will be included in the study. Participants will provide consent to be contacted for follow-up at 7-days and 90-days postsurgical procedure. The primary outcome is the rate of symptomatic VTE, that is, deep vein thrombosis or pulmonary embolism during admission or within 90 days. Secondary outcomes include healthcare costs and changes in quality of life. The main analysis will be according to the intention-to-treat principle and will compare the rates of VTE at 90 days, measured at an individual level, using hierarchical (multilevel) logistic regression.Ethics and disseminationEthical approval was granted by the Camden and Kings Cross Research Ethics Committee (22/LO/0390). Findings will be published in a peer-reviewed journal and presented at national and international conferences.Trial registration numberISRCTN13908683.

ObjectivesTo describe when patients return to different types of work after elective carpal tunnel release (CTR) surgery and identify the factors associated with the duration of sickness absence.DesignMulticentre prospective observational cohort study.Setting and participantsParticipants were recruited preoperatively from 16 UK centres and clinical, occupational and demographic information were collected. Participants completed a weekly diary and questionnaires at four and 12 weeks postoperatively.OutcomesThe main outcome was duration of work absence from date of surgery to date of first return to work.Results254 participants were enrolled in the study and 201 provided the follow-up data. Median duration of sickness absence was 20 days (range 1–99). Earlier return to work was associated with having surgery in primary care and a self-reported work role involving more than 4 hours of daily computer use. Being female and entitlement to more than a month of paid sick leave were both associated with longer work absences. The duration of work absence was strongly associated with the expected duration of leave, as reported by participants before surgery. Earlier return to work was not associated with poorer clinical outcomes reported 12 weeks after CTR.ConclusionsThere was wide variation in the duration of work absence after CTR across all occupational categories. A combination of occupational, demographic and clinical factors was associated with the duration of work absence, illustrating the complexity of return to work decision making. However, preoperative expectations were strongly associated with the actual duration of leave. We found no evidence that earlier return to work was harmful. Clear, consistent advice from clinicians preoperatively setting expectations of a prompt return to work could reduce unnecessary sickness absence after CTR. To enable this, clinicians need evidence-informed guidance about appropriate timescales for the safe return to different types of work.

Background Dupuytren’s contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment; however, recent studies have indicated that an alternative to surgery—collagenase clostridium histolyticum (collagenase)—is better than a placebo in the treatment of Dupuytren’s contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of collagenase compared with limited fasciectomy surgery. Dupuytren’s intervention surgery vs collagenase trial (DISC) trial was therefore designed to fill this evidence gap. Methods/design The DISC trial is a multi-centre pragmatic two-arm parallel-group, randomised controlled trial. Participants will be assigned 1:1 to receive either collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren’s contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported patient evaluation measure assessed 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost-effectiveness of treatments, and a qualitative sub-study will assess participants’ experiences and preferences of the treatments. Discussion The DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost-effectiveness of collagenase compared to limited fasciectomy surgery for patients with Dupuytren’s contracture. Trial registration Clinical.Trials.gov ISRCTN18254597 . Registered on April 11, 2017.

Isolated pisiform dislocation is rare. We present one such case in a 20-year-old man occurring after a direct injury to the wrist. After an initial delay in diagnosis and unsuccessful closed reduction, he underwent resection of the pisiform. At 12-month follow-up, he had full range of movement of the wrist and no residual pain.

AbstractObjectivesTo investigate whether the use of graduated compression stockings (GCS) offers any adjuvant benefit when pharmaco-thromboprophylaxis is used for venous thromboembolism prophylaxis in patients undergoing elective surgery.DesignOpen, multicentre, randomised, controlled, non-inferiority trial.SettingSeven National Health Service tertiary hospitals in the United Kingdom.Participants1905 elective surgical inpatients (≥18 years) assessed as being at moderate or high risk of venous thromboembolism were eligible and consented to participate.InterventionParticipants were randomly assigned (1:1) to receive low molecular weight heparin (LMWH) pharmaco-thromboprophylaxis alone or LMWH pharmaco-thromboprophylaxis and GCS.Outcome measuresThe primary outcome was imaging confirmed lower limb deep vein thrombosis with or without symptoms, or pulmonary embolism with symptoms within 90 days of surgery. Secondary outcome measures were quality of life, compliance with stockings and LMWH, lower limb complications related to GCS, bleeding complications, adverse reactions to LMWH, and all cause mortality.ResultsBetween May 2016 and January 2019, 1905 participants were randomised. 1858 were included in the intention to treat analysis (17 were identified as ineligible after randomisation and 30 did not undergo surgery). A primary outcome event occurred in 16 of 937 (1.7%) patients in the LMWH alone group compared with 13 of 921 (1.4%) in the LMWH and GCS group. The risk difference between the two groups was 0.30% (95% confidence interval −0.65% to 1.26%). Because the 95% confidence interval did not cross the non-inferiority margin of 3.5% (P<0.001 for non-inferiority), LMWH alone was confirmed to be non-inferior.ConclusionsFor patients who have elective surgery and are at moderate or high risk of venous thromboembolism, administration of pharmaco-thromboprophylaxis alone is non-inferior to a combination of pharmaco-thromboprophylaxis and GCS. These findings indicate that GCS might be unnecessary in most patients undergoing elective surgery.Trial registrationISRCTN13911492.