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PurposeMultiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making.ParticipantsEstablished with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019.Findings to dateThe study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up.Future plansA third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology. Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia. Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography. Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29–79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic “shutdown”. The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6). Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.

Fatigue is common and disabling in multiple sclerosis, yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. A clearer understanding of relationships between fatigue and key clinical, neuropsychiatric and imaging variables including depression could yield clinically relevant mechanistic insight. We applied a data-driven multivariate network approach to quantify relationships between fatigue and other variables in early multiple sclerosis.Data were collected from Scottish patients with newly diagnosed, immunotherapy-naïve, relapsing-remitting multiple sclerosis at baseline and month 12 follow-up in FutureMS, a nationally representative multicentre cohort. Subjective fatigue was assessed using the validated Fatigue Severity Scale. Detailed phenotyping included measures assessing physical disability, affective disorders, objective cognitive performance, subjective sleep quality, and structural brain imaging. Bivariate correlations between fatigue and other variables were calculated. Network analysis was then conducted to estimate partial correlations between variables, after accounting for all other included variables. Secondary networks included individual depressive symptoms, to control for overlapping symptom items in measures of fatigue and depression.Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 49.5% of the cohort reported clinically significant fatigue. Bivariate correlations confirmed that fatigue severity was significantly correlated with all included measures of physical disability, affective disturbance (anxiety and depression), cognitive performance (processing speed and memory/attention), and sleep quality, but not with structural brain imaging variables including normalized lesion and grey matter volumes. In the network analysis, fatigue showed strong correlations with depression, followed by Expanded Disability Status Scale. Weak connections with walking speed, subjective sleep quality and anxiety were identified. After separately controlling for measurement of “tiredness” in our measure of depression, some key depressive symptoms (anhedonia, subjective concentration deficits, subjectively altered speed of movement, and appetite) remained linked to fatigue. Conversely, fatigue was not linked to objective cognitive performance, white matter lesion volume, or grey matter volumes (cortical, subcortical or thalamic). Results were consistent at baseline and month 12. Depression was identified as the most central variable in the networks. Correlation stability coefficients and bootstrapped confidence intervals of the edge weights supported stability of the estimated networks.Our findings support robust links between subjective fatigue and depression in early relapsing-remitting multiple sclerosis, despite absence of links between fatigue and either objective cognitive performance, or structural brain imaging variables. Depression, including specific depressive symptoms, could be a key target of treatment and research in multiple sclerosis-related fatigue.

Fatigue is common and disabling in multiple sclerosis (MS), yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. We applied a multivariate network approach to quantify relationships between fatigue and other variables in early MS.Data were collected from patients with newly diagnosed immunotherapy-naïve relapsing-remitting MS at baseline and month 12 follow-up in FutureMS, a Scottish nationally representative cohort. Subjective fatigue was assessed by Fatigue Severity Scale. Detailed phenotyping included measures assessing each of physical disability, affective disorders, cognitive performance, sleep quality, and structural brain imaging. Network analysis was conducted to estimate partial correlations between variables. Baseline networks were compared between those with persistent and remitted fatigue at one-year follow up.Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 154 patients (47.8%) reported clinically significant fatigue. In the network analysis, fatigue severity showed strongest connections with depression, followed by Expanded Disability Status Scale. Conversely, fatigue severity was not linked to objective cognitive performance or brain imaging variables. Even after controlling for measurement of "tiredness" in our measure of depression, four specific depressive symptoms remained linked to fatigue. Results were consistent at baseline and month 12. Overall network strength was not significantly different between groups with persistent and remitted fatigue (4.89 vs 2.90, p = 0.11).Our findings support robust links between subjective fatigue and depression in early relapsing-remitting MS. Shared mechanisms between specific depressive symptoms and fatigue could be key targets of treatment and research in MS-related fatigue.

Background: The management of pain, agitation and sedation for ventilated patients who are admitted to intensive care is an essential part of their care. The introduction of sedation protocols is associated with improved patient outcomes. Methods: We conducted an observational cohort study among mechanically ventilated patients in a 16-bed ICU over a two-year period. We retrospectively examined data from two patient populations, namely those before and after the introduction of a new sedation protocol in July 2015. The primary outcome was the duration of mechanical ventilation in both groups. Results: After the implementation of the new sedation protocol, there was a significant decrease in the mean duration of mechanical ventilation (1.45 days). Furthermore, we observed a non-significant reduction in the mean duration of ICU stay. Conclusion : The new protocol was associated with outcome improvements including: decreased mean duration of mechanical ventilation and a reduced number of ventilated days; and increased patient throughput with a slight increase in the length of vasopressor support. Moreover, the use of a structure-process-outcome model of quality improvement was associated with significant improvements in process measures of quality.

ObjectiveMultiple sclerosis (MS) is an inflammatory degenerative condition of central nervous system. The disease course and presentation of MS is highly heterogeneous. Advanced retinal imaging techniques such as optic coherence tomography (OCT) can capture abnormalities of anterior visual pathway with high resolution, which may contribute greater insights into the pathophysiology of MS.MethodsPeople with newly diagnosed relapsing-remitting MS were recruited for FutureMS retinal imaging study from two study centres in Scotland. The baseline visit was completed within 6 months of diagnosis with initial follow-up 12 months after the baseline visit. The assessments included in FutureMS retinal imaging study were visual acuity test, self-reported eye questionnaire and OCT scan.ResultsA total of 196 FutureMS participants completed the retinal imaging study of FutureMS with 185 participants at M0 and 155 at M12. A total of 144 participants completed both M0 and M12 visits. At the whole cohort level, the distribution of retinal measures is generally consistent between baseline and follow-up.ConclusionThe FutureMS retinal imaging study aims to demonstrate that patient with MS present with different extent of retinal abnormalities that can be captured by retinal imaging modalities such as OCT soon after diagnosis. These changes may sensitively mirror the brain atrophy or serve as predictors for disease activity. By developing sensitive, quantifiable and objective retinal biomarkers, FutureMS retinal imaging study will provide an opportunity to stratify patient with MS at an early stage and support future therapeutic strategies for a better outcome.

Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. However, there is significant inter-individual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate, or aggressive disease course is very limited. There is therefore a need for integrated predictive tools to inform individualised treatment decision-making. FutureMS is a nationally representative, prospective observation cohort study comprising of 440 participants with a new diagnosis of relapsing remitting MS living in Scotland between May 2016 and March 2019. Established with the aim of addressing this need for individualised predictive tools, the cohort is designed to combine detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow up at year one is complete and longer term follow up is planned, beginning at five years after first visit. The study aims to explore the pathobiology and determinants of disease heterogeneity in MS. Here we describe the cohort design and present a profile of the participants at baseline and one year of follow up.

IntroductionMultiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. MRI can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression. This paper provides an overview of MRI data acquisition, management and processing in FutureMS.Methods and analysisMRI is acquired at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures.Ethics and disseminationThe study received ethical approval from the South East Scotland Research Ethics Committee 02 (reference 15/SS/0233). Results will be made available to study participants and funders.STRENGTHS AND LIMITATIONS OF THE STUDYBrain imaging acquired within six months after relapsing-remitting multiple sclerosis (RRMS) diagnosis allows for detection of abnormalities at a very early stage of disease.Longitudinal structural and microstructural brain MRI are integrated with multi-modal clinical, blood biomarker, genetic and retinal imaging data to allow comprehensive evaluation of early RRMS stratifiers.MR protocol optimization was implemented mid-study to improved image quality and protocol harmonization, resulting in some between-subject protocol variation.Multiplatform MRI acquisition required to allow access for a large MS population across Scotland introduces inevitable inter-site data variance.Contrast enhanced MRI was not acquired, limiting imaging evaluation of active inflammatory lesions.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis., Wong et al. reviewed historical approaches to clinical trials in amyotrophic lateral sclerosis. Lack of sensitive outcome measures, limitations in resources and barriers to trial participation were challenges for timely and definitive evaluation of drugs in two-arm trials. They concluded that future trials should be more flexible, scalable and efficient., Graphical Abstract Graphical Abstract

Persistence of HIV through integration into host DNA in CD4(+) T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8(+) T cells are triggered to kill infected CD4(+) T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial'' HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A*02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8(+) T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4(+) T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

Neurologic conditions represent some of the most confusing, challenging, and frustrating cases to treat. Because of this, it is not surprising that many pet owners turn to alternative therapies, including cannabis, to treat their pets. This chapter provides information on the use of cannabinoid compounds for the treatment or management of common neurologic diseases and disorders of dogs and cats.

Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing—termed kick and kill regimens—have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18–60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI −0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.

Introduction Globally, Traditional Medicine (TM) plays an important role in healthcare. In South Africa, attempts at regulation of Traditional Health Practitioners (THPs) began in 2007. Implementation efforts include the interim THP Council and proposed regulations. Amidst wide criticism, progress at ground-level is slow. To date, no THPs are registered. The aim of the study was to explore the perspectives of stakeholders on the local realities in relation to the regulation of THPs in order to capitalize on the challenges and opportunities both nationally and internationally. Methods Stakeholders were selected based on a prior stakeholder mapping study to participate in in-depth interviews. The stakeholders belonged to one of the following broad groups: 1) local government, 2) academic experts 3) traditional health practitioner associations or organisations 4) non-government organisations or consumer groups and 5) international organisation or donors. A framework analysis approach was used to arrive at four overarching themes. Results Perceptions of key challenges and opportunities linked to the implementation of the THP Act are common across stakeholder groups, though with varied explanation. The four overarching themes within which challenges and opportunities were described are: 1) risk-benefit of regulation, 2) understanding, awareness, and paradigmatic opposition, 3) THP-centred research for sustained progress and coexistence, and 4) systemic disadvantage, stigma, and conflict. Conclusion Global recommendations are clear. However, a more comprehensive understanding of this landscape would lend itself to regulation and policy, truly compatible with the contextual realities. The researchers recommend THP-centred research and capacity-building for implementation and wider health-system benefit.

Background: The World Health Organization recommends efavirenz 400 mg (EFV400) as first-line antiretroviral therapy, with a disclaimer that no data with anti-tuberculosis (TB) treatment exist. Many people living with human immunodeficiency virus (PLWH) require TB treatment with isoniazid (INH) and rifampicin (RIF), which affect cytochrome P450 and antiretroviral exposure. Methods: PLWH receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/EFV 600 mg with a viral load (VL)

Neuropsychological (NP) performance is a consistent correlate of everyday functioning in schizophrenia, but it is unclear whether relationships between individual NP ability areas and domains of everyday functioning are general or specific. Assessments of real-world everyday functioning may be influenced by environmental and social factors (e.g., social security, disability status, opportunities and restrictions in living situations). This study examined the specificity of the relationships between different NP abilities and performance-based measures of social and living skills.181 ambulatory older (age50) patients with schizophrenia were examined with NP tests measuring episodic and working memory, executive functioning, verbal fluency, and processing speed. All subjects performed tasks examining social (Social Skills Performance Assessment: SSPA) and everyday living (UCSD Performance Based Skills Assessment: UPSA) skills.Using canonical analysis, the NP variables were used to predict the functional capacity measures. The analysis found that 37% of the variance in the functional capacity and NP measures was shared, X(2) (54)=106.29, p.001. Two canonical roots described the cognitive variables and the roots were differentially associated with everyday living and social skills. The root loading on processing speed, episodic memory, and executive functions were associated with UPSA scores, while the root loading on working and episodic memory and verbal fluency were associated most strongly with social competence.Social and everyday living skills deficits in patients with schizophrenia may reflect generally independent domains of functional outcome, linked through cognitive performance. The data suggest that somewhat different cognitive processes are associated with these two domains of functional capacity, although there appears to be some overlap, which may be due to the nature of the NP tests employed.

Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P .001), cognitive (P .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P .001 for all); behavioral domain scores did not diverge significantly between groups.Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

The Berkeley Group for non-violent male sex offenders has been operating since February 1977. An account of the early period appeared in Probation Journal (September, 1978). The leaders of this highly consistent project now offer a review of its effectiveness and the response from members past and present.