Assessing the outcome of surgery for Dupuytren's disease of the hand

Dupuytren’s disease (DD) is a fibroproliferative disorder causing deformity of fingers and disability. Different treatments exist ranging from dividing cords (needle aponeurotomy) through disease excision (fasciectomy) to disease excision with resurfacing with a skin graft (dermofasciectomy). A range of outcome measurements has been used in DD, including angular measurements of finger joints and patient-reported outcome measures (PROMs). This thesis hypothesised that the leading candidate outcome measures are inadequate (subject to bias, invalid, and/or uninterpretable) and that currently there is insufficient evidence to inform patient-centred treatment choice in DD. To investigate this, existing evidence was appraised and studies of validity and interpretability of outcomes were conducted. This comprised a systematic review and meta-analysis of surgical trials, a systematic review of interpretability of outcome measures, cross sectional studies of the validity of leading candidate outcome measures (joint angles, the Disabilities of the Arm, Shoulder and Hand tool (DASH), and the Unité Rhumatologique des Affections de la Main scale (URAM)), and a prospective cohort study of outcome interpretability and variables associated with functional outcome. Key findings: • There were too few trials comparing treatments to inform practice in DD, and methodological quality was generally poor. • There were limited interpretability data to guide the design of future studies. • Dynamism was present in 89% of digits, with mean MCPJ dynamism of 6o and PIPJ dynamism of 14o; 11% of digits exhibited over 30 degrees of dynamism. • Patients had virtually unique goals for surgery, with 26% captured by the URAM • The DASH and the URAM were not structurally valid in factor analysis • The DASH was uninterpretable; the URAM’s minimal important change was 10.5 • The factors associated with poor functional outcome differ from those associated with recurrence. Future work should examine validity for other outcome measures; qualitative investigation of patients’ experiences; and patient-centred high quality randomised controlled trials

Assessing the outcome of surgery for Dupuytren's disease of the hand

Dupuytren’s disease (DD) is a fibroproliferative disorder causing deformity of fingers and disability. Different treatments exist ranging from dividing cords (needle aponeurotomy) through disease excision (fasciectomy) to disease excision with resurfacing with a skin graft (dermofasciectomy). A range of outcome measurements has been used in DD, including angular measurements of finger joints and patient-reported outcome measures (PROMs). This thesis hypothesised that the leading candidate outcome measures are inadequate (subject to bias, invalid, and/or uninterpretable) and that currently there is insufficient evidence to inform patient-centred treatment choice in DD. To investigate this, existing evidence was appraised and studies of validity and interpretability of outcomes were conducted. This comprised a systematic review and meta-analysis of surgical trials, a systematic review of interpretability of outcome measures, cross sectional studies of the validity of leading candidate outcome measures (joint angles, the Disabilities of the Arm, Shoulder and Hand tool (DASH), and the Unité Rhumatologique des Affections de la Main scale (URAM)), and a prospective cohort study of outcome interpretability and variables associated with functional outcome. Key findings: • There were too few trials comparing treatments to inform practice in DD, and methodological quality was generally poor. • There were limited interpretability data to guide the design of future studies. • Dynamism was present in 89% of digits, with mean MCPJ dynamism of 6o and PIPJ dynamism of 14o; 11% of digits exhibited over 30 degrees of dynamism. • Patients had virtually unique goals for surgery, with 26% captured by the URAM • The DASH and the URAM were not structurally valid in factor analysis • The DASH was uninterpretable; the URAM’s minimal important change was 10.5 • The factors associated with poor functional outcome differ from those associated with recurrence. Future work should examine validity for other outcome measures; qualitative investigation of patients’ experiences; and patient-centred high quality randomised controlled trials

Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin

AbstractHuman islet amyloid polypeptide (hIAPP) forms amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). Pre-fibrillar hIAPP oligomers (in contrast to monomeric IAPP or mature fibrils) increase membrane permeability, suggesting an important role in the disease. In the first structural study of membrane-associated hIAPP, lamellar neutron diffraction shows that oligomeric hIAPP inserts into phospholipid bilayers, and extends across the membrane. Rifampicin, which inhibits hIAPP-induced membrane permeabilisation in functional studies, prevents membrane insertion. In contrast, rat IAPP (84% identical to hIAPP, but non-amyloidogenic) does not insert into bilayers. Our findings are consistent with the hypothesis that membrane-active pre-fibrillar hIAPP oligomers insert into beta cell membranes in NIDDM

The use of Botulinum toxin in the management of Hidradenitis Suppurativa : a systematic review

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by suppurative infection, sinus tract, and abscess formation. International management guidelines are largely consensus-based. Botulinum toxin (BTX) has been widely used in the treatment of apocrine and eccrine gland disorders, such as hyperhidrosis, although the effectiveness of BTX in the treatment of HS remains unknown. The aim of this systematic review was to understand the published evidence of BTX safety and effectiveness in the management of HS. Methods: We conducted a PRISMA-compliant, prospectively registered (PROSPERO, CRD42021228732), systematic review. We devised bespoke search strategy and applied it to the Cochrane Central Register of Controlled Trials, Medline, Embase, and OpenGrey up until March 2022. We included all clinical studies that reported outcomes following BTX treatment in patients diagnosed with HS (both adult and pediatric). Results: A total of 4658 studies were identified, of which six met full inclusion criteria reporting data on 26 patients. The six identified studies included one randomized control trial, one case series, and four case studies. The one included randomized control trial demonstrated a significant reduction in the Dermatology Life Quality Index score at 3 months following treatment with BTX. Conclusions: The effectiveness and safety of BTX in the treatment of HS remain unknown. This systematic review identified a paucity of high-quality clinical data. Evidence of treatment effectiveness is likely to come from registry-based cohort studies using established core outcome sets in the first instance

Imaging Biomarkers and Prevalence of Complex Aortic Plaque in Cryptogenic Stroke: A Systematic Review

Atherosclerosis; Imaging; StrokeAterosclerosis; Imágenes; IctusAterosclerosi; Imatges; IctusBackground Complex aortic plaque (CAP) is a potential embolic source in patients with cryptogenic stroke (CS). We review CAP imaging criteria for transesophageal echocardiogram (TEE), computed tomography angiography (CTA), and magnetic resonance imaging and calculate CAP prevalence in patients with acute CS. Methods and Results PubMed and EMBASE databases were searched up to December 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guideline. Two independent reviewers extracted data on study design, imaging techniques, CAP criteria, and prevalence. The Cochrane Collaboration tool and Guideline for Reporting Reliability and Agreement Studies were used to assess risk of bias and reporting completeness, respectively. From 2293 studies, 45 were reviewed for CAP imaging biomarker criteria in patients with acute CS (N=37 TEE; N=9 CTA; N=6 magnetic resonance imaging). Most studies (74%) used ≥4 mm plaque thickness as the imaging criterion for CAP although ≥1 mm (N=1, CTA), ≥5 mm (N=5, TEE), and ≥6 mm (N=2, CTA) were also reported. Additional features included mobility, ulceration, thrombus, protrusions, and assessment of plaque composition. From 23 prospective studies, CAP was detected in 960 of 2778 patients with CS (0.32 [95% CI, 0.24–0.41], I2=94%). By modality, prevalence estimates were 0.29 (95% CI, 0.20–0.40; I2=95%) for TEE; 0.23 (95% CI, 0.15–0.34; I2=87%) for CTA and 0.22 (95% CI, 0.06–0.54; I2=92%) for magnetic resonance imaging. Conclusions TEE was commonly used to assess CAP in patients with CS. The most common CAP imaging biomarker was ≥4 mm plaque thickness. CAP was observed in one‐third of patients with acute CS. However, high study heterogeneity suggests a need for reproducible imaging methods.The work is supported by the National Heart, Lung, and Blood Institute (R01 HL147355, Z.F.), American Heart Association Career Development Awards (938082 to J.W.S.; 23CDA1053561 to J.W.), Vice Provost for University Research Foundation (J.W.S.), and Institute of Translational Medicine and Therapeutics (J.W.S.)

Microscopic simulation of membrane molecule diffusion on corralled membrane surfaces

The current understanding of how receptors diffuse and cluster in the plasma membrane is limited. Data from single-particle tracking and laser tweezer experiments have suggested that membrane molecule diffusion is affected by the presence of barriers dividing the membrane into corrals. Here, we have developed a stochastic spatial model to simulate the effect of corrals on the diffusion of molecules in the plasma membrane. The results of this simulation confirm that a fence barrier (the ratio of the transition probability for diffusion across a boundary to that within a corral) on the order of 103–104 recreates the experimentally measured difference in diffusivity between artificial and natural plasma membranes. An expression for the macroscopic diffusivity of receptors on corralled membranes is derived to analyze the effects of the corral parameters on diffusion rate. We also examine whether the lattice model is an appropriate description of the plasma membrane and look at three different sets of boundary conditions that describe diffusion over the barriers and whether diffusion events on the plasma membrane may occur with a physically relevant length scale. Finally, we show that to observe anomalous (two-timescale) diffusion, one needs high temporal (microsecond) resolution along with sufficiently long (more than milliseconds) trajectories

Psychometric sensitivity analyses can identify bias related to measurement properties in trials that use patient-reported outcome measures : a secondary analysis of a clinical trial using the disabilities of the arm, shoulder and hand questionnaire

Objectives Demonstrate psychometric sensitivity analyses for testing the stability of study findings to assumptions made about patient-reported outcome measures. Study Design and Setting We performed secondary analyses of Disability of Arm, Shoulder, and Hand (DASH) data collected within the Prevention of Shoulder Problems clinical trial, which compared upper limb function scores in women who had undergone breast cancer surgery, randomized to either an exercise program or usual care. We repeated the principal trial analyses after grouping DASH items into subscales suggested by factorial analyses in this dataset and applied item response theory to account for unequal item weighting. We checked for measurement invariance by participant age and response shift bias using established techniques. Results Our analyses suggested that the DASH measured two constructs: motor function and sensory symptoms. The majority of the six-month difference in DASH score was driven by motor function. With item response theory scoring, we found differences in both constructs at 12 months (P = 0.019 and P = 0.007), but in neither construct at 6 months, contrary to the original trial results. We found no differential item function by age or between baseline and 12-month measurements. Conclusions Psychometric sensitivity analyses aid in the interpretation of the Prevention of Shoulder Problems trial’s results

Experimental evidence for limited in vivo virulence of Mycobacterium africanum

Funding Information: The authors thank the excellent support from the i3S scientific platforms, namely Animal Facility and Translational Cytometry. Funding. This work was supported by Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 ? Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through Funda??o para a Ci?ncia e a Tecnologia, Minist?rio da Ci?ncia, Tecnologia e Inova??o in the framework of the project ?Institute for Research and Innovation in Health Sciences? (POCI-01-0145-FEDER-007274), and by grants FCT ? Aga Khan Development Network (ref 333197025), POCI-01-0145-FEDER-028955 (to MS), PTDC/BIA-MIC/30692/2017, and UID/Multi/04413/2013 (to DM and MV). BC and KF were funded by FCT Ph.D. scholarships SFRH/BD/114403/2016 and SFRH/BD/114405/2016, respectively. The Gulbenkian Foundation is acknowledged for a field work research grant to BC, Bolsas de apoio ? investiga??o para estudantes de doutoramento dos PALOP, Ref. P-146397. DM and MS were supported by FCT through Estimulo Individual ao Emprego Cient?fico. Publisher Copyright: © Copyright © 2019 Cá, Fonseca, Sousa, Maceiras, Machado, Sanca, Rabna, Rodrigues, Viveiros and Saraiva.Tuberculosis remains a public health problem and a main cause of death to humans. Both Mycobacterium tuberculosis and Mycobacterium africanum cause tuberculosis. In contrast to M. tuberculosis, which is geographically spread, M. africanum is restricted to West Africa. Differences have also been found in the growth rate and type of disease caused by M. africanum, globally suggesting an attenuation of this bacteria. In this study, we used the mouse model of infection to follow the dynamics of M. africanum infection in terms of bacterial burdens and tissue pathology, as well as the immune response triggered. Our findings support a lower virulence of M. africanum as compared to M. tuberculosis, including in mice lacking IFN-γ, a major protective cytokine in tuberculosis. Furthermore, the lung immune response triggered by M. africanum infection in wild-type animals was characterized by a discrete influx of leukocytes and a modest transcriptional upregulation of inflammatory mediators. Our findings contribute to elucidate the pathogenesis of M. africanum, supporting the hypothesis that this is an attenuated member of the tuberculosis-causing bacteria. Understanding the biology of M. africanum and how it interacts with the host to establish infection will have implications for our knowledge of TB and for the development of novel and better tools to control this devastating disease.publishersversionpublishe

The surgical management of hidradenitis suppurativa in the United Kingdom: a national survey of care pathways informing the THESEUS study

Background The evidence-base underpinning treatment efficacy and effectiveness for hidradenitis suppurativa (HS) is limited, as has been highlighted in the wide-ranging research priorities established by a James Lind Alliance priority-setting partnership (PSP). Understanding the landscape of surgical practice is a key step towards tackling undesired variation in care and resolving treatment uncertainties. This survey of current surgical practice aimed to describe care pathways involving surgeons for the management of HS and surgical approaches to management. Methods In the development of the prospective cohort Treatment of Hidradenitis Suppurativa Evaluation Study (THESEUS), a bespoke electronic surgeon survey was conducted to describe variation in care pathways and surgical preferences in the management of HS. This was disseminated to a pre-defined denominator list of surgeons using local collaborators through the reconstructive surgery trials network (RSTN). Results Key results were small numbers of surgeons working in formal multidisciplinary teams (MDTs) (8/198, 4%), heterogeneity of first-line intervention, low rates of guideline endorsed treatments (laser and deroofing in particular), variation in wound closure methods and follow-up length, and that over half of respondents do not use well-validated outcome instruments to determine treatment success/failure (110/198, 56%). Conclusions This survey demonstrated variation in care, which is likely to be undesirable. Surgeons treating HS patients might consider developing MDTs or referring patients to those with an interest in HS and considering routine outcome measurement. Such steps might reduce variation, increase standardisation of care and improve access to specific treatments

Primary care management of hidradenitis suppurativa: a cross-sectional survey of UK GPs

Background Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that causes painful discharging nodules and skin tunnels. HS has associations with several systemic diseases, including cardiovascular disease (CVD), anxiety, and depression. High levels of chronic morbidity suggest an important role for primary care. However, little evidence exists regarding current management of HS and its comorbidities in UK general practice.Aim To describe current practice among UK GPs in treating and referring people with HS.Design & setting A web-based survey was circulated to UK Primary Care Dermatology Society (PCDS) members and GPs in Forth Valley, Scotland.Method Survey responses were analysed with descriptive statistics.Results A total of 134 UK GPs completed the survey. Seventy per cent (n = 94) saw at least one patient with HS in the previous month. Ninety-four per cent (n = 125/133) reported confidence in diagnosis, and 89% (n = 120/134) in initial treatment of HS. Most GPs initiated topical treatments and extended courses of oral antibiotic for HS, and many gave advice on adverse lifestyle factors. A minority provided analgesia, or screening for CVD risk factors, and depression. Most GPs referred to dermatology if secondary care input was required, with few referrals to specialised multidisciplinary services.Conclusion GPs regularly diagnose and manage uncomplicated HS, but screening for important comorbidities associated with HS is not common practice