SPG20 protein spartin is recruited to midbodies by ESCRT-III protein Ist1 and participates in cytokinesis.

Hereditary spastic paraplegias (HSPs, SPG1-46) are inherited neurological disorders characterized by lower extremity spastic weakness. Loss-of-function SPG20 gene mutations cause an autosomal recessive HSP known as Troyer syndrome. The SPG20 protein spartin localizes to lipid droplets and endosomes, and it interacts with tail interacting protein 47 (TIP47) as well as the ubiquitin E3 ligases atrophin-1-interacting protein (AIP)4 and AIP5. Spartin harbors a domain contained within microtubule-interacting and trafficking molecules (MIT) at its N-terminus, and most proteins with MIT domains interact with specific ESCRT-III proteins. Using yeast two-hybrid and in vitro surface plasmon resonance assays, we demonstrate that the spartin MIT domain binds with micromolar affinity to the endosomal sorting complex required for transport (ESCRT)-III protein increased sodium tolerance (Ist)1 but not to ESCRT-III proteins charged multivesicular body proteins 1-7. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells by small interfering RNA significantly decreases the number of cells where spartin is present at midbodies. Depletion of spartin does not affect Ist1 localization to midbodies but markedly impairs cytokinesis. A structure-based amino acid substitution in the spartin MIT domain (F24D) blocks the spartin-Ist1 interaction. Spartin F24D does not localize to the midbody and acts in a dominant-negative manner to impair cytokinesis. These data suggest that Ist1 interaction is important for spartin recruitment to the midbody and that spartin participates in cytokinesis

A qualitative process evaluation using the behaviour change wheel approach: Did a whole genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 within UK hospitals operate as anticipated?

PURPOSE: The aim of this study was to conduct a process evaluation of a whole-genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 through changing infection prevention and control (IPC) behaviours within the COVID-19 pandemic. METHODS: We used a three-staged design. Firstly, we described and theorized the purported content of the SRF using the behaviour change wheel (BCW). Secondly, we used inductive thematic analysis of one-to-one interviews (n = 39) to explore contextual accounts of using the SRF. Thirdly, further deductive analysis gauged support for the intervention working as earlier anticipated. RESULTS: It was possible to theorize the SRF using the BCW approach and visualize it within a simple logic model. Inductive thematic analyses identified the SRF's acceptability, ease of use and perceived effectiveness. However, major challenges to embedding it in routine practice during the unfolding COVID-19 crisis were reported. Notwithstanding this insight, deductive analysis showed support for the putative intervention functions 'Education', 'Persuasion' and 'Enablement'; behaviour change techniques '1.2 Problem solving', '2.6 Biofeedback', '2.7 Feedback on outcomes of behaviour' and '7.1 Prompts and cues'; and theoretical domains framework domains 'Knowledge' and 'Behavioural regulation'. CONCLUSIONS: Our process evaluation of the SRF, using the BCW approach to describe and theorize its content, provided granular support for the SRF working to change IPC behaviours as anticipated. However, our complementary inductive thematic analysis highlighted the importance of the local context in constraining its routine use. For SRFs to reach their full potential in reducing nosocomial infections, further implementation research is needed

Analysis of morbid events and risk factors for death after cardiac transplantation

AbstractRisk factors for death after cardiac transplantation performed at the University of Alabana at Birmingham from January 1981 to July 1985 included (by multivariate analysis) higher calculated preoperative pulmonary vascular resistance (early and constant phases), murphology of cardiomyopathy (versus ischemic heart disease) (constant phase only) and black race (constant phase). overall actuarial survival was 71% at 1 year and 48% at 3 years (including azalhioprine and cyclosporine eras). The hazard function for death was highest immediately after operation and declined rapidly thereafter, merging with a constant phase of risk at about 3 months.The most favorable group for long-term survival was the group of white patients with ischemic heart disease and low pulmonary vascular resistance. When such patients had a pulmonary vascular resistance < 3 units m2, the 3 year survival rate exceeded 85%; The most common causes of death were acute rejection (24%) and infection (17%) The risk of infection remained highest during the first several months after any period of augmented immunosuppression

Protocol for the COG-UK hospital-onset COVID-19 infection (HOCI) multicentre interventional clinical study: evaluating the efficacy of rapid genome sequencing of SARS-CoV-2 in limiting the spread of COVID-19 in UK NHS hospitals

OBJECTIVES: Nosocomial transmission of SARS-CoV-2 has been a significant cause of mortality in National Health Service (NHS) hospitals during the COVID-19 pandemic. The COG-UK Consortium Hospital-Onset COVID-19 Infections (COG-UK HOCI) study aims to evaluate whether the use of rapid whole-genome sequencing of SARS-CoV-2, supported by a novel probabilistic reporting methodology, can inform infection prevention and control (IPC) practice within NHS hospital settings. DESIGN: Multicentre, prospective, interventional, superiority study. SETTING: 14 participating NHS hospitals over winter–spring 2020/2021 in the UK. PARTICIPANTS: Eligible patients must be admitted to hospital with first-confirmed SARS-CoV-2 PCR-positive test result &gt;48 hour from time of admission, where COVID-19 diagnosis not suspected on admission. The projected sample size is 2380 patients. INTERVENTION: The intervention is the return of a sequence report, within 48 hours in one phase (rapid local lab processing) and within 5–10 days in a second phase (mimicking central lab), comparing the viral genome from an eligible study participant with others within and outside the hospital site. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes are incidence of Public Health England (PHE)/IPC-defined SARS-CoV-2 hospital-acquired infection during the baseline and two interventional phases, and proportion of hospital-onset cases with genomic evidence of transmission linkage following implementation of the intervention where such linkage was not suspected by initial IPC investigation. Secondary outcomes include incidence of hospital outbreaks, with and without sequencing data; actual and desirable changes to IPC actions; periods of healthcare worker (HCW) absence. Health economic analysis will be conducted to determine cost benefit of the intervention. A process evaluation using qualitative interviews with HCWs will be conducted alongside the study. TRIAL REGISTRATION NUMBER: ISRCTN50212645. Pre-results stage. This manuscript is based on protocol V.6.0. 2 September 2021

Total ankle replacement versus ankle arthrodesis for patients aged 50-85 years with end-stage ankle osteoarthritis: the TARVA RCT

BACKGROUND: We aimed to compare the clinical effectiveness, cost-effectiveness and complication rates of total ankle replacement with those of arthrodesis (i.e. ankle fusion) in the treatment of end-stage ankle osteoarthritis. METHODS: This was a pragmatic, multicentre, parallel-group, non-blinded randomised controlled trial. Patients with end-stage ankle osteoarthritis who were aged 50-85 years and were suitable for both procedures were recruited from 17 UK hospitals and randomised using minimisation. The primary outcome was the change in the Manchester-Oxford Foot Questionnaire walking/standing domain scores between the preoperative baseline and 52 weeks post surgery. RESULTS: Between March 2015 and January 2019, 303 participants were randomised using a minimisation algorithm: 152 to total ankle replacement and 151 to ankle fusion. At 52 weeks, the mean (standard deviation) Manchester-Oxford Foot Questionnaire walking/standing domain score was 31.4 (30.4) in the total ankle replacement arm (n = 136) and 36.8 (30.6) in the ankle fusion arm (n = 140); the adjusted difference in the change was -5.6 (95% confidence interval -12.5 to 1.4; p = 0.12) in the intention-to-treat analysis. By week 52, one patient in the total ankle replacement arm required revision. Rates of wound-healing issues (13.4% vs. 5.7%) and nerve injuries (4.2% vs. < 1%) were higher and the rate of thromboembolic events was lower (2.9% vs. 4.9%) in the total ankle replacement arm than in the ankle fusion arm. The bone non-union rate (based on plain radiographs) in the ankle fusion arm was 12.1%, but only 7.1% of patients had symptoms. A post hoc analysis of fixed-bearing total ankle replacement showed a statistically significant improvement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score (-11.1, 95% confidence interval -19.3 to -2.9; p = 0.008). We estimate a 69% likelihood that total ankle replacement is cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over the patient's lifetime. LIMITATIONS: This initial report contains only 52-week data, which must therefore be interpreted with caution. In addition, the pragmatic nature of the study means that there was heterogeneity between surgical implants and techniques. The trial was run across 17 NHS centres to ensure that decision-making streams reflected the standard of care in the NHS as closely as possible. CONCLUSIONS: Both total ankle replacement and ankle fusion improved patients' quality of life at 1 year, and both appear to be safe. When total ankle replacement was compared with ankle fusion overall, we were unable to show a statistically significant difference between the two arms in terms of our primary outcome measure. The total ankle replacement versus ankle arthrodesis (TARVA) trial is inconclusive in terms of superiority of total ankle replacement, as the 95% confidence interval for the adjusted treatment effect includes both a difference of zero and the minimal important difference of 12, but it can rule out the superiority of ankle fusion. A post hoc analysis comparing fixed-bearing total ankle replacement with ankle fusion showed a statistically significant improvement of total ankle replacement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score. Total ankle replacement appears to be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime based on long-term economic modelling. FUTURE WORK: We recommend long-term follow-up of this important cohort, in particular radiological and clinical progress. We also recommend studies to explore the sensitivity of clinical scores to detect clinically important differences between arms when both have already achieved a significant improvement from baseline. TRIAL REGISTRATION: This trial is registered as ISRCTN60672307 and ClinicalTrials.gov NCT02128555. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 5. See the NIHR Journals Library website for further project information

Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials

BACKGROUND: Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease. METHODS: Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015-2016 and 2018-2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment. RESULTS: In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility. In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART. CONCLUSIONS: Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design. TRIAL REGISTRATION: MS-SMART: NCT01910259 ; registered July 2013 and MS-STAT2: NCT03387670 ; registered Jan 2018

A qualitative process evaluation using the behaviour change wheel approach: did a whole genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 within UK hospitals operate as anticipated?

Purpose: The aim of this study was to conduct a process evaluation of a whole-genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 through changing infection prevention and control (IPC) behaviours within the COVID-19 pandemic. Methods: We used a three-staged design. Firstly, we described and theorized the purported content of the SRF using the behaviour change wheel (BCW). Secondly, we used inductive thematic analysis of one-to-one interviews (n = 39) to explore contextual accounts of using the SRF. Thirdly, further deductive analysis gauged support for the intervention working as earlier anticipated. Results: It was possible to theorize the SRF using the BCW approach and visualize it within a simple logic model. Inductive thematic analyses identified the SRF's acceptability, ease of use and perceived effectiveness. However, major challenges to embedding it in routine practice during the unfolding COVID-19 crisis were reported. Notwithstanding this insight, deductive analysis showed support for the putative intervention functions ‘Education’, ‘Persuasion’ and ‘Enablement’; behaviour change techniques ‘1.2 Problem solving’, ‘2.6 Biofeedback’, ‘2.7 Feedback on outcomes of behaviour’ and ‘7.1 Prompts and cues’; and theoretical domains framework domains ‘Knowledge’ and ‘Behavioural regulation’. Conclusions: Our process evaluation of the SRF, using the BCW approach to describe and theorize its content, provided granular support for the SRF working to change IPC behaviours as anticipated. However, our complementary inductive thematic analysis highlighted the importance of the local context in constraining its routine use. For SRFs to reach their full potential in reducing nosocomial infections, further implementation research is needed

A qualitative process evaluation using the behaviour change wheel approach : did a whole genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 within UK hospitals operate as anticipated?

Purpose The aim of this study was to conduct a process evaluation of a whole-genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 through changing infection prevention and control (IPC) behaviours within the COVID-19 pandemic. Methods We used a three-staged design. Firstly, we described and theorized the purported content of the SRF using the behaviour change wheel (BCW). Secondly, we used inductive thematic analysis of one-to-one interviews (n = 39) to explore contextual accounts of using the SRF. Thirdly, further deductive analysis gauged support for the intervention working as earlier anticipated. Results It was possible to theorize the SRF using the BCW approach and visualize it within a simple logic model. Inductive thematic analyses identified the SRF's acceptability, ease of use and perceived effectiveness. However, major challenges to embedding it in routine practice during the unfolding COVID-19 crisis were reported. Notwithstanding this insight, deductive analysis showed support for the putative intervention functions ‘Education’, ‘Persuasion’ and ‘Enablement’; behaviour change techniques ‘1.2 Problem solving’, ‘2.6 Biofeedback’, ‘2.7 Feedback on outcomes of behaviour’ and ‘7.1 Prompts and cues’; and theoretical domains framework domains ‘Knowledge’ and ‘Behavioural regulation’. Conclusions Our process evaluation of the SRF, using the BCW approach to describe and theorize its content, provided granular support for the SRF working to change IPC behaviours as anticipated. However, our complementary inductive thematic analysis highlighted the importance of the local context in constraining its routine use. For SRFs to reach their full potential in reducing nosocomial infections, further implementation research is needed

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)

Objective: Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype–phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious. Methods: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1. Results: In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material. Conclusions: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders