A role for vessel-associated extracellular matrix proteins in multiple sclerosis pathology.

Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA-DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA-DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA-DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA-DRB*15-positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA-DRB1*15-positive and 23 HLA-DRB1*15-negative), and seven non-neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (-36.5%, p = 0.036 and - 24.7%, p = 0.039; respectively) in lesional and non-lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA-DRB1*15-positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro-inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.

Rapid evaluation of the Special Measures for Quality and challenged provider regimes: a mixed-methods study.

Background: Health-care organisations in England that are rated as inadequate for leadership and one other domain enter the Special Measures for Quality regime to receive support and oversight. A 'watch list' of challenged providers that are at risk of entering Special Measures for Quality also receive support. Knowledge is limited about whether or not the support interventions drive improvements in quality, the costs of the support interventions and whether or not the support interventions strike the right balance between support and scrutiny. Objective: To analyse the responses of trusts to the implementation of (1) interventions for Special Measures for Quality trusts and (2) interventions for challenged provider trusts to determine their impact on these organisations' capacity to achieve and sustain quality improvements. Design: This was rapid research comprising five interrelated workstreams: (1) a literature review using systematic methods; (2) an analysis of policy documents and interviews at the national level; (3) eight multisite, mixed-methods trust case studies; (4) an analysis of national performance and workforce indicators; and (5) an economic analysis. Results: The Special Measures for Quality/challenged provider regimes were intended to be 'support' programmes. Special Measures for Quality/challenged provider regimes had an emotional impact on staff. Perceptions of NHS Improvement interventions were mixed overall. Senior leadership teams were a key driver of change, with strong clinical input being vital. Local systems have a role in improvement. Trusts focus efforts to improve across multiple domains. Internal and external factors contribute to positive performance trajectories. Nationally, only 15.8% of Special Measures for Quality trusts exited the regime in 24 months. Entry into Special Measures for Quality/challenged provider regimes resulted in changes in quality indicators (such the number of patients waiting in emergency departments for more than 4 hours, mortality and the number of delayed transfers of care) that were more positive than national trends. The trends in staff sickness and absence improved after trusts left Special Measures for Quality/challenged provider regimes. There was some evidence that staff survey results improved. No association was found between Special Measures for Quality/challenged provider regimes and referral to treatment times or cancer treatment waiting times. NHS Improvement spending in case study trusts was mostly directed at interventions addressing 'training on cultural change' (33.6%), 'workforce quality and safety' (21.7%) and 'governance and assurance' (18.4%). The impact of Special Measures for Quality on financial stability was equivocal; most trusts exiting Special Measures for Quality experienced the same financial stability before and after exiting. Limitations: The rapid research design and 1-year time frame precludes longitudinal observations of trusts and local systems. The small number of indicators limited the quantitative analysis of impact. Measurement of workforce effects was limited by data availability. Conclusions: Empirical evidence of positive impacts of Special Measures for Quality/challenged provider regimes were identified; however, perceptions were mixed. Key lessons were that (1) time is needed to implement and embed changes; (2) ways to mitigate emotional costs and stigma are needed; (3) support strategies should be more trust specific; (4) poor organisational performance needs to be addressed within local systems; (5) senior leadership teams with stability, strong clinical input and previous Special Measures for Quality experience helped to enact change; (6) organisation-wide quality improvement strategies and capabilities are needed; (7) staff engagement and an open-listening culture promote continuous learning and a quality improvement 'mindset', which is critical for sustainable improvement; and (8) consideration of the level of sustainable funds required to improve patients' outcomes is needed. Future work: Future work could include evaluating recent changes to the regimes, the role of local systems and longitudinal approaches. Study registration: The review protocol is registered with PROSPERO (CRD42019131024). Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 11, No. 19. See the NIHR Journals Library website for further project information.

When health-care trusts in England have serious failings in the quality of care that they provide, they can be placed in 'Special Measures for Quality' and receive additional support from the NHS. There is also a list of 'challenged providers' at risk of entering Special Measures for Quality that receive support. In January 2019, of the 234 trusts in England, one-quarter had at some point been a challenged provider and/or entered Special Measures for Quality. We studied how trusts responded to entering the Special Measures for Quality or challenged provider regimes. We wanted to understand if the support that the trusts receive can help the trust to improve the quality of care provided to patients. We did this by reviewing the relevant literature; speaking to a range of staff in eight trusts and nearby health organisations; analysing costs; and observing meetings in four of these trusts. We also compared national performance information between Special Measures for Quality/challenged provider trusts and non-Special Measures for Quality/challenged provider trusts. We found that when a trust enters the Special Measures for Quality regime there is often an emotional impact on staff, who may experience low morale. Some staff thought that their trust received the right type of support, but others saw Special Measures for Quality as heavy-handed scrutiny or punishment. With hindsight, Special Measures for Quality was sometimes viewed more positively, as a pathway to make changes that were needed. Looking at all trusts in England, we found that when trusts entered Special Measures for Quality or became challenged providers they started to get better at seeing emergency department patients within 4 hours and reduced avoidable deaths. We also found that some parts of the staff survey results improved. We found that staff need time and space to make changes. Looking after staff and having a leadership and culture that supports continuous learning are important for making improvements. Regional health-care systems and local organisations have an important role to play in supporting trusts to make improvements.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.

AIMS: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields. METHODS: A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. RESULTS: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways. CONCLUSIONS: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.

Hidden influencesThe New Science of the Enchanted Universe Marshall Sahlins, with the assistance of Frederick B. Henry Jr. Princeton University Press, 2022. 208 pp.

Beliefs about the vital roles played by spirits and gods have long been underappreciated, argues an anthropologist.

The Special Measures for Quality and Challenged Provider Regimes in the English NHS: A Rapid Evaluation of a National Improvement Initiative for Failing Healthcare Organisations.

BACKGROUND: There is limited knowledge about interventions used for the improvement of low-performing healthcare organisations and their unintended consequences. Our evaluation sought to understand how healthcare organisations in the National Health Service (NHS) in England responded to a national improvement initiative (the Special Measures for Quality [SMQ] and challenged provider [CP] regimes) and its perceived impact on achieving quality improvements (QIs). METHODS: Our evaluation included national-level interviews with key stakeholders involved in the delivery of SMQ (n=6); documentary analysis (n=20); and a qualitative study based on interviews (n=60), observations (n=8) and documentary analysis (n=291) in eight NHS case study sites. The analysis was informed by literature on failure, turnaround and QI in organisations in the public sector. RESULTS: At the policy level, SMQ/CP regimes were intended to be "support" programmes, but perceptions of the interventions at hospital level were mixed. The SMQ/CP regimes tended to consider failure at an organisational level and turnaround was visualised as a linear process. There was a negative emotional impact reported by staff, especially in the short-term. Key drivers of change included: engaged senior leadership teams, strong clinical input and supportive external partnerships within local health systems. Trusts focused efforts to improve across multiple domains with particular investment in improving overall staff engagement, developing an open, listening organisational culture and better governance to ensure clinical safety and reporting. CONCLUSION: Organisational improvement in healthcare requires substantial time to embed and requires investment in staff to drive change and cultivate QI capabilities at different tiers. The time this takes may be underestimated by external 'turn-around' interventions and performance regimes designed to improve quality in the short-term and which come at an emotional cost for staff. Shifting an improvement focus to the health system or regional level may promote sustainable improvement across multiple organisations over the long-term.

Out with the old, in with the new: Could plasma exchange be used to fill a therapeutic gap in neurology?

The global tally of neurological disorders is exponentially rising and yet effective therapies for most remain evasive. There is a great deal of research into novel small molecules, immunotherapies and gene therapies to fill this therapeutic gap. We believe greater focus on plasma exchange as a research and clinical tool may provide useful insight into pathological mechanisms and effective treatment strategies. Plasma exchange has been traditionally used to treat antibody-mediated neurological diseases, such as myasthenia gravis and neuromyelitis optica, but there could be much wider future potential uses in neurology. Plasma exchange is not antibody specific, as it also removes a variety of other plasma-soluble factors, including age-related and disease-associated neurotoxic proteins, such as fibrinogen and amyloid. As research develops into the role of blood-brain barrier and immunological alterations in diseases not typically regarded as immune-driven, interest in neurotoxic plasma proteins grows. Here, we highlight that plasma exchange may have uses outside of antibody-mediated neurological diseases, by removing neurotoxic proteins from the systemic circulation.

The bicipital groove as a landmark for humeral version reference during shoulder arthroplasty: a computed tomography study of normal humeral rotation.

BACKGROUND: Accurate reproduction of humeral version is important in shoulder arthroplasty. Traditional referencing relative to the transepicondylar axis (TEA) is prone to error as it is absent on preoperative imaging and inaccurately reproduced intraoperatively. The bicipital groove is present on preoperative imaging and in the operative field and thus may be a useful landmark for accurate reproduction of humeral version. MATERIALS AND METHODS: Two trained observers analyzed 101 full-humerus computed tomography scans of patients undergoing a myeloma screening protocol. Measurements of humeral retroversion relative to the TEA (angle A), humeral articular axis retroversion relative to the bicipital groove (angle B), and the bicipital groove axis relative to the TEA (angle C) were made with comparison of the measurement properties of each. RESULTS: Humeral retroversion relative to the TEA was 23.7° ± 8° (range, 0.2°-48.7°; 95% confidence interval, 22°-26°). The humeral articular axis was retroverted to the bicipital groove axis (angle B) by 33.5° ± 9.4° (range, 15.5°-61.7°; 95% confidence interval, 32°-35°). Overall inter-rater reliability was 0.88. DISCUSSION: Measurement of humeral head retroversion relative to the bicipital groove is not inferior to the gold-standard measurement. The bicipital groove is present both on preoperative imaging and in the operative field, making it a potential reference landmark for accurate reproduction of humeral version in shoulder arthroplasty.

Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase δ.

A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.

Special Measures for Quality and Challenged Providers: Study Protocol for Evaluating the Impact of Improvement Interventions in NHS Trusts.

BACKGROUND: Healthcare organisations in England rated as inadequate in terms of leadership and one other domain enter the Special Measures for Quality (SMQ) regime to receive increased support and oversight. There is also a 'watch list' of challenged National Health Service (NHS) providers at risk of going into SMQ that receive support. There is limited knowledge about whether the interventions used to deliver this support drive improvements in quality, their costs, and whether they strike the right balance between support and scrutiny. The study will seek to determine how provider organisations respond to these interventions, and whether and how these interventions impact organisations' capacity to achieve and sustain quality improvements over time. METHODS: This is a multi-site, mixed methods study. We will carry out interviews at national level to understand the programme theory underpinning the interventions. We will conduct 8 NHS case studies to explore the impact and implementation of the interventions that form part of the SMQ and challenged providers programme. We will use a conceptual framework based on models of organisational readiness for change and draw on board maturity research for implementing quality improvement. We will also review the use of quantitative metrics and data for tracking the progress of improvements in quality of care and sustainability upon leaving SMQ, as well as the costs and benefits of the interventions through a cost-consequence analysis (CCA). DISCUSSION: High-quality interventions that successfully support struggling healthcare organisations are essential and an issue that is an international concern. Our study will allow a greater understanding of the programme theory, impact, and staff views and experiences of the SMQ and challenged providers regime. Formative feedback will be reported to key stakeholders.

A contingency management intervention to reduce cannabis use and time to relapse in early psychosis: the CIRCLE RCT.

BACKGROUND: Cannabis is the most prevalent illicit substance among people with psychosis, and its use is associated with poorer clinical and social outcomes. However, so far, there has been limited evidence that any treatment is effective for reducing use. Contingency management (CM) is an incentive-based intervention for substance misuse that has a substantial evidence base across a range of substances and cohorts. However, to date there have been no randomised controlled trials (RCTs) of CM as a treatment for cannabis use specifically in psychosis. OBJECTIVE: To conduct a RCT investigating the clinical effectiveness and cost-effectiveness of CM in reducing cannabis use among Early Intervention in Psychosis (EIP) service users. DESIGN: The CIRCLE (Contingency Intervention for Reduction of Cannabis in Early Psychosis) trial was a rater-blinded, multicentre RCT with two arms. Participants were randomised 1 : 1 to either an CM arm, in which participants received CM for cannabis use alongside an optimised treatment-as-usual programme including structured psychoeducation, or a control arm in which participants received the treatment as usual only. SETTING: EIP services across the Midlands and the south-east of England. PARTICIPANTS: The main eligibility criteria were EIP service users with a history of psychosis, aged 18-36 years, and having used cannabis at least once per week during 12 of the previous 24 weeks. INTERVENTION: The CM intervention offered financial incentives (i.e. shopping vouchers) for cannabis abstinence over 12 once-weekly sessions, confirmed using urinalysis. The maximum value in vouchers that participants could receive was £240. MAIN OUTCOME MEASURES: The main outcome was time to relapse, operationalised as admission to an acute mental health service or hospital. The primary outcome was assessed at 18 months post inclusion using electronic patient records. Secondary outcomes assessed the clinical effectiveness and cost-effectiveness of the intervention, for which data were collected at 3 and 18 months. RESULTS: A total of 278 participants were randomised to the CM arm and 273 were randomised to the control arm. In total, 530 (96%) participants were followed up for the primary outcome. There was no significant difference in time to admission between trial arms by 18 months following consent (hazard ratio 1.03, 95% confidence interval 0.76 to 1.40). There were no statistically significant differences in most secondary outcomes, including cannabis use, at either follow-up assessment. There were 58 serious adverse events, comprising 52 inpatient episodes, five deaths and one arrest. LIMITATIONS: Participant retention was low at 18 months, limiting the assessment of secondary outcomes. A different CM intervention design or reward level may have been effective. CONCLUSIONS: The CM intervention did not appear to be effective in reducing cannabis use and acute relapse among people with early psychosis and problematic cannabis use. FUTURE WORK: Cannabis use is still a significant clinical concern in this population. A pressing need remains to identify suitable treatments. A wider perspective on the social circumstances of young people with psychosis may be needed for a successful intervention to be found. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33576045. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 45. See the NIHR Journals Library website for further project information.

A large proportion of people with psychosis use cannabis, despite the negative impact that it has on their recovery. So far, a clearly effective way of helping young people in the early stages of psychosis to cut down their cannabis use has not been found. The CIRCLE trial investigated if an approach known as contingency management (CM) would be beneficial for this group. This approach involves offering voucher rewards for not using cannabis. It has been effective in addressing drug use problems in general, but there is not much evidence about its effects on cannabis use in those with psychosis. A total of 551 service users with psychosis who used cannabis agreed to enter the trial. Half of the sample group was chosen by a chance method to receive CM. The other half formed a comparison group. The CM group received shopping vouchers if urine samples showed that they had not used cannabis for the previous week, measured over 12 weekly sessions. Participants could obtain £240-worth of vouchers if they did not use cannabis during the treatment period. The participants in both groups were also offered a six-session psychoeducation programme about the pros and cons of cannabis use and ways to reduce use of it. The main comparison in the trial was the average length of time in each group before a relapse of psychosis occurred, which was recorded for each participant over 18 months after they joined the trial. The results found no difference between the two trial groups in this measure. Furthermore, there were no differences found between the groups in terms of the levels of cannabis use, clinical symptoms, or engagement with work or education. However, a cost-effectiveness analysis found an 85% chance of CM being more effective than the treatment-as-usual psychoeducation package, which appears to be because of the lower use of inpatient services by those receiving CM. However, it is difficult to understand why this was, because there was no drop in cannabis use. The results suggest that CM is unlikely to be clinically effective and that alternative treatments are still needed.

Clinical and cost-effectiveness of contingency management for cannabis use in early psychosis: the CIRCLE randomised clinical trial.

BACKGROUND: Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis. METHODS: CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045. RESULTS: Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group. CONCLUSIONS: Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered.

A high-throughput and rapid method for accurate identification of emerging multidrug-resistant Candida auris.

Candida auris is an emerging multidrug-resistant yeast associated with invasive infection in healthcare settings. Recently, C auris cases in the United States have been detected in 11 states with the majority of cases in New York, New Jersey and Illinois. Rapid and accurate identification of C auris is critical for patient care and the implementation of public health measures to control the spread of infection. Our aim was to develop and validate a rapid DNA extraction method using the Roche MagNA Pure 96 instrument and a TaqMan real-time PCR assay for reliable, high-throughput identification of C auris. We evaluated 247 patient dermal swab samples previously analysed by culture/MALDI-TOF. The diagnostic sensitivity and specificity were 93.6% and 97.2%, respectively. The assay was highly reproducible with a detection limit of 1 C auris CFU/10 µL. A receiver operating characteristic curve analysis of the real-time PCR data showed an area of 0.982 under the curve, with a CT cut-off value of ≤37.0. The turnaround time from DNA extraction to real-time PCR results was approximately 200 samples/day. In conclusion, we successfully validated a rapid and high-throughput method for accurate and reproducible identification of C auris with a significantly reduced turnaround time compared to culture/MALDI-TOF based methods.

Are Psychologic Factors Associated With Shoulder Scores After Rotator Cuff Surgery?

BACKGROUND: Psychologic factors are associated with pain and disability in patients with chronic shoulder pain. Recent research regarding the association of affective psychologic factors (emotions) with patients' pain and disability outcome after surgery disagrees; and the relationship between cognitive psychologic factors (thoughts and beliefs) and outcome after surgery is unknown. QUESTIONS/PURPOSES: (1) Are there identifiable clusters (based on psychologic functioning measures) in patients undergoing shoulder surgery? (2) Is poorer psychologic functioning associated with worse outcome (American Shoulder and Elbow Surgeons [ASES] score) after shoulder surgery? METHODS: This prospective cohort study investigated patients undergoing shoulder surgery for rotator cuff-related shoulder pain or rotator cuff tear by one of six surgeons between January 2014 and July 2015. Inclusion criteria were patients undergoing surgery for rotator cuff repair with or without subacromial decompression and arthroscopic subacromial decompression only. Of 153 patients who were recruited and consented to participate in the study, 16 withdrew before data collection, leaving 137 who underwent surgery and were included in analyses. Of these, 124 (46 of 124 [37%] female; median age, 54 years [range, 21-79 years]) had a complete set of four psychologic measures before surgery: Depression, Anxiety and Stress Scale; Pain Catastrophizing Scale; Pain Self-Efficacy Questionnaire; and Tampa Scale for Kinesiophobia. The existence of clusters of people with different profiles of affective and cognitive factors was investigated using latent class analysis, which grouped people according to their pattern of scores on the four psychologic measures. Resultant clusters were profiled on potential confounding variables. The ASES score was measured before surgery and 3 and 12 months after surgery. Linear mixed models assessed the association between psychologic cluster membership before surgery and trajectories of ASES score over time adjusting for potential confounding variables. RESULTS: Two clusters were identified: one cluster (84 of 124 [68%]) had lower scores indicating better psychologic functioning and a second cluster (40 of 124 [32%]) had higher scores indicating poorer psychologic functioning. Accounting for all variables, the cluster with poorer psychologic functioning was found to be independently associated with worse ASES score at all time points (regression coefficient for ASES: before surgery -9 [95% confidence interval {CI}, -16 to -2], p = 0.011); 3 months after surgery -15 [95% CI, -23 to -8], p < 0.001); and 12 months after surgery -9 [95% CI, -17 to -1], p = 0.023). However, both clusters showed improvement in ASES score from before to 12 months after surgery, and there was no difference in the amount of improvement between clusters (regression coefficient for ASES: cluster with poorer psychologic function 31 [95% CI, 26-36], p < 0.001); cluster with better psychologic function 31 [95% CI, 23-39], p < 0.001). CONCLUSIONS: Patients who scored poorly on a range of psychologic measures before shoulder surgery displayed worse ASES scores at 3 and 12 months after surgery. Screening of psychologic factors before surgery is recommended to identify patients with poor psychologic function. Such patients may warrant additional behavioral or psychologic management before proceeding to surgery. However, further research is needed to determine the optimal management for patients with poorer psychologic function to improve pain and disability levels before and after surgery. LEVEL OF EVIDENCE: Level II, therapeutic study.

Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier.

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

Physical Activity Preferences Among Older Adults: A Systematic Review.

The objective of this study was to identify preferences for physical activity among adults aged 65 years and over. A systematic review was conducted. A search strategy without language and date restriction (up until March 31, 2017) was developed for PubMed, CINAHL, PsycINFO, ERIC, and SPORTDiscus. Study selection and data extraction were performed independently by two reviewers. A total of 21 independent primary studies were included in the systematic review. Irrespective of the methodologies used and samples, a majority of older adults prefer to walk and engage in physical activity continuously for about 30 min. These findings are mainly generalizable to White females from the United States. Two-thirds of the studies were at high risk of selection bias, which suggests additional caution when interpreting the review findings. Nonetheless, policymakers, community organizations, and healthcare providers should consider walkability in their efforts to promote physical activity in older adults.

Tailored online cognitive behavioural therapy with or without therapist support calls to target psychological distress in adults receiving haemodialysis: A feasibility randomised controlled trial.

BACKGROUND: Psychological distress is prevalent in haemodialysis (HD) patients yet access to psychotherapy remains limited. This study assessed the feasibility and acceptability of online cognitive-behavioural therapy (CBT) tailored for HD patients, with or without therapist support, for managing psychological distress. METHODS: This feasibility randomised controlled trial recruited patients from a UK HD centre. Following psychological distress screens, patients with mild-moderate psychological distress (Patient Health Questionnaire PHQ-9; score: 5-19 and/or Generalised Anxiety Disorder; GAD-7 score: 5-14) who met remaining inclusion criteria were approached for consent. Consenters were individually randomised (1:1) to online-CBT or online-CBT plus three therapist support calls. Outcomes included recruitment, retention, and adherence rates. Exploratory change analyses were performed for: psychological distress, quality of life (QoL), illness perceptions, and costs. The statistician was blinded to allocation. RESULTS: 182 (44%) out of 410 patients approached completed psychological distress screens. 26% found screening unacceptable; a further 30% found it unfeasible. Psychological distress was detected in 101 (55%) patients, 60 of these met remaining inclusion criteria. The primary reason for ineligibility was poor computer literacy (N=17, 53%). Twenty-five patients were randomised to the supported (N=18) or unsupported arm (N=7); 92% were retained at follow-up. No differences in psychological distress or cost-effectiveness were observed. No trial adverse events occurred. CONCLUSION: Online CBT appears feasible but only for computer literate patients who identify with the label psychological distress. A definitive trial using the current methods for psychological distress screening and online care delivery is unfeasible. ClinicalTrials.gov Identifier: NCT02352870.