Complement factor I deficiency: a potentially treatable cause of fulminant cerebral inflammation

Objective To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation. Methods Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature. Results We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function. Conclusions Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role

Project WISH: The Emerald City

Phase 3 of Project WISH saw the evolution of the Emerald City (E-City) from a collection of specialized independent analyses and ideas to a working structural design integrated with major support systems and analyses. Emphasis was placed on comparing and contrasting the closed and open cycle gas core nuclear rocket engines to further determine the optimum propulsive system for the E-City. Power and thermal control requirements were then defined and the question of how to meet these requirements was addressed. Software was developed to automate the mission/system/configuration analysis so changes dictated by various subsystem constraints could be managed efficiently and analyzed interactively. In addition, the liquid hydrogen propellant tank was statically designed for minimum mass and shape optimization using a finite element modeling package called SDRC I-DEAS. Spoke and shaft cross-sectional areas were optimized on ASTROS (Automated Structural Optimization System) for mass minimization. A structural dynamic analysis of the optimal structure also conducted using ASTROS enabled a study of the modes, frequencies, displacements, and accelerations of the E-City. Finally, the attitude control system design began with an initial mass moment of inertia analysis and was then designed and optimized using linear quadratic regulator control theory

Which doctors and with what problems contact a specialist service for doctors? A cross sectional investigation

Background: In the United Kingdom, specialist treatment and intervention services for doctors are underdeveloped. The MedNet programme, created in 1997 and funded by the London Deanery, aims to fill this gap by providing a self-referral, face-to-face, psychotherapeutic assessment service for doctors in London and South-East England. MedNet was designed to be a low-threshold service, targeting doctors without formal psychiatric problems. The aim of this study was to delineate the characteristics of doctors utilising the service, to describe their psychological morbidity, and to determine if early intervention is achieved. Methods: A cross-sectional study including all consecutive self-referred doctors (n = 121, 50% male) presenting in 2002–2004 was conducted. Measures included standardised and bespoke questionnaires both self-report and clinician completed. The multi-dimensional evaluation included: demographics, CORE (CORE-OM, CORE-Workplace and CORE-A) an instrument designed to evaluate the psychological difficulties of patients referred to outpatient services, Brief Symptom Inventory to quantify caseness and formal psychiatric illness, and Maslach Burnout Inventory. Results: The most prevalent presenting problems included depression, anxiety, interpersonal, self-esteem and work-related issues. However, only 9% of the cohort were identified as severely distressed psychiatrically using this measure. In approximately 50% of the sample, problems first presented in the preceding year. About 25% were on sick leave at the time of consultation, while 50% took little or no leave in the prior 12 months. A total of 42% were considered to be at some risk of suicide, with more than 25% considered to have a moderate to severe risk. There were no significant gender differences in type of morbidity, severity or days off sick. Conclusion: Doctors displayed high levels of distress as reflected in the significant proportion of those who were at some risk of suicide; however, low rates of severe psychiatric illness were detected. These findings suggest that MedNet clients represent both ends of the spectrum of severity, enabling early clinical engagement for a significant proportion of cases that is of importance both in terms of personal health and protecting patient care, and providing a timely intervention for those who are at risk, a group for whom rapid intervention services are in need and an area that requires further investigation in the UK

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Interrogating intervention delivery and participants’ emotional states to improve engagement and implementation: A realist informed multiple case study evaluation of Engager

BACKGROUND: 'Engager' is an innovative 'through-the-gate' complex care intervention for male prison-leavers with common mental health problems. In parallel to the randomised-controlled trial of Engager (Trial registration number: ISRCTN11707331), a set of process evaluation analyses were undertaken. This paper reports on the depth multiple case study analysis part of the process evaluation, exploring how a sub-sample of prison-leavers engaged and responded to the intervention offer of one-to-one support during their re-integration into the community. METHODS: To understand intervention delivery and what response it elicited in individuals, we used a realist-informed qualitative multiple 'case' studies approach. We scrutinised how intervention component delivery lead to outcomes by examining underlying causal pathways or 'mechanisms' that promoted or hindered progress towards personal outcomes. 'Cases' (n = 24) were prison-leavers from the intervention arm of the trial. We collected practitioner activity logs and conducted semi-structured interviews with prison-leavers and Engager/other service practitioners. We mapped data for each case against the intervention logic model and then used Bhaskar's (2016) 'DREIC' analytic process to categorise cases according to extent of intervention delivery, outcomes evidenced, and contributing factors behind engagement or disengagement and progress achieved. RESULTS: There were variations in the dose and session focus of the intervention delivery, and how different participants responded. Participants sustaining long-term engagement and sustained change reached a state of 'crises but coping'. We found evidence that several components of the intervention were key to achieving this: trusting relationships, therapeutic work delivered well and over time; and an in-depth shared understanding of needs, concerns, and goals between the practitioner and participants. Those who disengaged were in one of the following states: 'Crises and chaos', 'Resigned acceptance', 'Honeymoon' or 'Wilful withdrawal'. CONCLUSIONS: We demonstrate that the 'implementability' of an intervention can be explained by examining the delivery of core intervention components in relation to the responses elicited in the participants. Core delivery mechanisms often had to be 'triggered' numerous times to produce sustained change. The improvements achieved, sustained, and valued by participants were not always reflected in the quantitative measures recorded in the RCT. The compatibility between the practitioner, participant and setting were continually at risk of being undermined by implementation failure as well as changing external circumstances and participants' own weaknesses. TRIAL REGISTRATION NUMBER: ISRCTN11707331, Wales Research Ethics Committee, Registered 02-04-2016-Retrospectively registered https://doi.org/10.1186/ISRCTN11707331

Superior outcomes of nodal metastases compared to visceral sites in oligometastatic colorectal cancer treated with stereotactic ablative radiotherapy

Background: Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases. Methods: A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0–2, ≤3 sites of disease, a disease free interval of >6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS). Results: 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2–22.85). The LC at 1 year was 83.8% (CI 76.4%−91.9%) with a PFS of 55% (CI 47%−64.7%) respectively. LC at 1 year was 90% (CI 83%−99%) for nodal metastases (NM), 75% (63%−90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38–0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18–0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor. Conclusion: Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis

Development and evaluation of a collaborative care intervention for male prison leavers with mental health problems: the Engager research programme

BackgroundMany male prison leavers have significant mental health problems. Prison leavers often have a history of trauma, ongoing substance misuse and housing insecurity. Only a minority of prison leavers receive mental health care on release from prison.ObjectivesThe aim of the Engager research programme was to develop and evaluate a theory- and evidence-informed complex intervention designed to support individuals with common mental health problems (e.g. anxiety, depression) and other complex needs, including mental health comorbidity, before and after release from prison.MethodsIn phase 1, the intervention was developed through a set of realist-informed substudies, including a realist review of psychosocial care for individuals with complex needs, case studies within services demonstrating promising intervention features, focus groups with individuals from under-represented groups, a rapid realist review of the intervention implementation literature and a formative process evaluation of the prototype intervention. In a parallel randomised trial, methodological development included selecting outcome measures through reviewing literature, piloting measures and a consensus process, developing ways to quantify intervention receipt, piloting trial procedures and modelling economic outcomes. In phase 2, we conducted an individually randomised superiority trial of the Engager intervention, cost-effectiveness and cost–consequence analyses and an in-depth mixed-methods process evaluation. Patient and public involvement influenced the programme throughout, primarily through a Peer Researcher Group.ResultsIn phase 1, the Engager intervention included multiple components. A practitioner offered participants practical support, emotional help (including mentalisation-based approaches) and liaison with other services in prison on the day of the participant’s release and for 3–5 months post release. An intervention delivery platform (i.e. training, manual, supervision) supported implementation. Outcome measures were selected through testing and stakeholder consensus to represent a broad range of domains, with a general mental health outcome as the primary measure for the trial. Procedures for recruitment and follow-up were tested and included flexible approaches to engagement and retention. In phase 2, the trial was conducted in three prison settings, with 280 participants randomised in a 1 : 1 ratio to receive either Engager plus usual care (n = 140) or usual care only (n = 140). We achieved a follow-up rate of 65% at 6 months post release from prison. We found no difference between the two groups for the Clinical Outcomes in Routine Evaluation – Outcome Measure at 6 months. No differences in secondary measures and sensitivity analyses were found beyond those expected by chance. The cost-effectiveness analysis showed that Engager cost significantly more at £2133 (95% of iterations between £997 and £3374) with no difference in quality-adjusted life-years (–0.017, 95% of iterations between –0.042 and 0.007). The mixed-methods process evaluation demonstrated implementation barriers. These barriers included problems with retention of the intervention team, and the adverse health and criminal justice system context. Seventy-seven per cent (108/140) of individuals had at least one community contact. Significant proportions of participants engaging received day release work and practical support. In contrast, there was evidence that the psychological components, mentalisation and developing a shared understanding were used less consistently. When engagement was positive, these components were associated with positive achievement of goals for individuals. We were also able to identify how to improve the intervention programme theory, including how to support individuals who were unrealistic in their perception of their ability to cope with challenges post release.Strengths and limitationsOur development work provides a worked example of the development of a complex intervention, particularly given little prior evidence or theory specific to male offenders to build on. Our trial methodological development enabled the completion of, to the best of our knowledge, the first fully powered trial of a mental health intervention for prison leavers with common mental health problems. There were potential weaknesses in the trial methodology in terms of follow-up rates and outcome measures, with the latter potentially being insufficiently sensitive to important but highly individual changes in participants who responded to the intervention.ConclusionsDelivering a randomised controlled trial for prison leavers with acceptable levels of follow-up is possible, despite adverse conditions. Full intervention implementation was challenging, but this is to be expected. Some individuals did respond well to the intervention when both practical and psychological support were flexibly deployed as intended, with evidence that most components were experienced as helpful for some individuals. It is recommended that several key components be developed further and tested, along with improved training and supervision, to support delivery of the Engager intervention within existing teams working with prison leavers

Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high-risk patients, but does not reduce the incidence of delirium

Background: Delirium in patients with hip fractures lead to higher morbidity and mortality. Prevention in high-risk patients by prescribing low dose haloperidol is currently under investigation. Methods. This prospective cohort surveillance assessed hip fracture patients for risk of developing a delirium with the Risk Model for Delirium (RD) score. High-risk patients (score ≥5 points) were treated with a prophylactic low-dose of haloperidol according to hospital protocol. Primary outcome was delirium incidence. Secondary outcomes were differences between high- and low-risk patients in delirium, length of stay (LOS), return to pre-fracture living situation and mortality. Logistic regression analysis was performed with age, ASA-classification, known dementia, having a partner, type of fracture, institutional residence and psychotropic drug use as possible confounders. Results: 445 hip fracture patients aged 65 years and older were admitted from January 2008 to December 2009. The RD-score was completed in 378 patients, 173 (45.8%) high-risk patients were treated with prophylactic medication. Sensitivity was 71.6%, specificity 63.8% and the negative predictive value (NPV) of a score < 5 was 85.9%. Delirium incidence (27.0%) was not significantly different compared to 2007 (27.8%) 2006 (23.9%) and 2005 (29.0%) prior to implementation of the RD- protocol. Logistic regression analysis showed that high-risk patients did have a significant higher delirium incidence (42.2% vs. 14.1%, OR 4.1, CI 2.43-7.02). They were more likely to be residing at an alternative living situation after 3 months (62.3% vs. 17.0%, OR 6.57, CI 3.23-13.37) and less likely to be discharged from hospital before 10 days (34.9% vs. 55.9%, OR 1.63, CI 1.03-2.59). Significant independent risk factors for a delirium were a RD-score 5 (OR 4.13, CI 2.43-7.02), male gender (OR 1.93, CI 0.99-1.07) and age (OR 1.03, CI 0.99-1.07). Conclusions: Introducing the delirium prevention protocol did not reduce delirium incidence. The RD-score did identify patients with a high risk to develop a delirium. This high-risk group had a longer LOS and returned to pre-fracture living situation less often. The NPV of a score < 5 was high, as it should be for a screening instrument. Concluding, the RD-score is a useful tool to identify patients with poorer outcome

Risk factors for failure to return to the pre-fracture place of residence after hip fracture: a prospective longitudinal study of 444 patients

Introduction: Long-term place of residence after hip fracture is not often described in literature. The goal of this study was to identify risk factors, known at admission, for failure to return to the pre-fracture place of residence of hip fracture patients in the Wrst year after a hip fracture. Methods: This is a prospective longitudinal study of 444 consecutive admissions of hip fracture patients aged ≥65 years. Place of residence prior to admission, at discharge, after 3 and 12 months was registered. Patients admitted from a nursing home (n = 49) were excluded from statistical analysis. Multivariable logistic regression analysis was performed, using age, gender, presence of a partner, ASAscore, dementia, anaemia at admission, type of fracture, pre-fracture level of mobility and level of activities of daily living (ADL) as possible risk factors. Results: Two hundred eighty-nine patients lived in their own home, 31.8% returned at discharge, 72.9% at 3 months and 72.8% at 12 months. Age, absence of a partner, dementia, and a lower pre-fracture level of ADL or mobility were independent contributors to failure to return to their own home at discharge, 3 or 12 months. 106 patients lived in a residential home; 33.3% returned at discharge, 68.4% at 3 months and 64.4% at 12 months. Age was an independent contributor to failure to return to a residential home. Conclusions: Age, dementia and a lower pre-fracture level of ADL were the main signiWcant risk factors for failure to return to the pre-fracture residence. As the 3- and 12-month return-rates were similar, 3-month follow-up might be used as an endpoint in future research