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BackgroundThe value of continuity in primary care has been demonstrated for multiple positive outcomes. However, little is known about how the expansion of remote and digital care models in primary care have impacted continuity.AimTo explore the impact of the expansion of remote and digital care models on continuity in primary care.Design and settingA systematic review of continuity in primary care.MethodA keyword search of Embase, MEDLINE, and CINAHL databases was used along with snowball sampling to identify relevant English-language qualitative and quantitative studies from any country between 2000 and 2022, which explored remote or digital approaches in primary care and continuity. Relevant data were extracted, analysed using GRADE-CERQual, and narratively synthesised.ResultsFifteen studies were included in the review. The specific impact of remote approaches on continuity was rarely overtly addressed. Some patients expressed a preference for relational continuity depending on circumstance, problem, and context; others prioritised access. Clinicians valued continuity, with some viewing remote consultations more suitable where there was high episodic or relational continuity. With lower continuity, patients and clinicians considered remote consultations harder, higher risk, and poorer quality. Some evidence suggested that remote approaches and/or their implementation risked worsening inequalities and causing harm by reducing continuity where it was valuable. However, if deployed strategically and flexibly, remote approaches could improve continuity.ConclusionWhile the value of continuity in primary care has previously been well demonstrated, the dearth of evidence around continuity in a remote and digital context is troubling. Further research is, therefore, needed to explore the links between the shift to remote care, continuity and equity, using real-world evaluation frameworks to ascertain when and for whom continuity adds most value, and how this can be enabled or maintained.

Persistent symptoms lasting longer than 3 weeks are thought to affect 10-20% of patients following SARS-CoV-2 infection. No formal guidelines exist in the UK for treating patients with long COVID and services are sporadic and variable, although additional funding is promised for their development.In this study, narrative interviews and focus groups are used to explore the lived experience of 43 healthcare professionals with long COVID. These individuals see the healthcare system from both professional and patient perspectives, thus represent an important wealth of expertise to inform service design.We present a set of co-designed quality standards, highlighting equity and ease of access, minimal patient care burden, clinical responsibility, a multidisciplinary and evidence-based approach, and patient involvement; and we apply these to propose a potential care pathway model that could be adapted and translated to improve care of patients long COVID.

Background Approximately 10% of patients with Covid-19 experience symptoms beyond 3–4 weeks. Patients call this “long Covid”. We sought to document such patients’ lived experience, including accessing and receiving healthcare and ideas for improving services. Methods We held 55 individual interviews and 8 focus groups (n = 59) with people recruited from UK-based long Covid patient support groups, social media and snowballing. We restricted some focus groups to health professionals since they had already self-organised into online communities. Participants were invited to tell their stories and comment on others’ stories. Data were audiotaped, transcribed, anonymised and coded using NVIVO. Analysis incorporated sociological theories of illness, healing, peer support, clinical relationships, access, and service redesign. Results Of 114 participants aged 27–73 years, 80 were female. Eighty-four were White British, 13 Asian, 8 White Other, 5 Black, and 4 mixed ethnicity. Thirty-two were doctors and 19 other health professionals. Thirty-one had attended hospital, of whom 8 had been admitted. Analysis revealed a confusing illness with many, varied and often relapsing-remitting symptoms and uncertain prognosis; a heavy sense of loss and stigma; difficulty accessing and navigating services; difficulty being taken seriously and achieving a diagnosis; disjointed and siloed care (including inability to access specialist services); variation in standards (e.g. inconsistent criteria for seeing, investigating and referring patients); variable quality of the therapeutic relationship (some participants felt well supported while others felt “fobbed off”); and possible critical events (e.g. deterioration after being unable to access services). Emotionally significant aspects of participants’ experiences informed ideas for improving services. Conclusion Suggested quality principles for a long Covid service include ensuring access to care, reducing burden of illness, taking clinical responsibility and providing continuity of care, multi-disciplinary rehabilitation, evidence-based investigation and management, and further development of the knowledge base and clinical services. Trial registration NCT04435041.

BackgroundFewer than 1% of UK general practice consultations occur by video.AimTo explain why video consultations are not more widely used in general practice.Design and settingAnalysis of a sub-sample of data from three mixed-method case studies of remote consultation services in various UK settings from 2019–2021.MethodThe dataset included interviews and focus groups with 121 participants from primary care (33 patients, 55 GPs, 11 other clinicians, nine managers, four support staff, four national policymakers, five technology industry). Data were transcribed, coded thematically, and then analysed using the Planning and Evaluating Remote Consultation Services (PERCS) framework.ResultsWith few exceptions, video consultations were either never adopted or soon abandoned in general practice despite a strong policy push, short-term removal of regulatory and financial barriers, and advances in functionality, dependability, and usability of video technologies (though some products remained ‘fiddly’ and unreliable). The relative advantage of video was perceived as minimal for most of the caseload of general practice, since many presenting problems could be sorted adequately and safely by telephone and in-person assessment was considered necessary for the remainder. Some patients found video appointments convenient, appropriate, and reassuring but others found a therapeutic presence was only achieved in person. Video sometimes added value for out-of-hours and nursing home consultations and statutory functions (for example, death certification).ConclusionEfforts to introduce video consultations in general practice should focus on situations where this modality has a clear relative advantage (for example, strong patient or clinician preference, remote localities, out-of-hours services, nursing homes).

Background: Accessing and receiving care remotely (by telephone, video or online) became the default option during the coronavirus disease 2019 (COVID-19) pandemic, but in-person care has unique benefits in some circumstances. We are studying UK general practices as they try to balance remote and in-person care, with recurrent waves of COVID-19 and various post-pandemic backlogs. Methods: Mixed-methods (mostly qualitative) case study across 11 general practices. Researchers-in-residence have built relationships with practices and become familiar with their contexts and activities; they are following their progress for two years via staff and patient interviews, documents and ethnography, and supporting improvement efforts through co-design. In this paper, we report baseline data. Results: Reflecting our maximum-variety sampling strategy, the 11 practices vary in size, setting, ethos, staffing, population demographics and digital maturity, but share common contextual features—notably system-level stressors such as high workload and staff shortages, and UK’s technical and regulatory infrastructure. We have identified both commonalities and differences between practices in terms of how they: 1] manage the ‘digital front door’ (access and triage) and balance demand and capacity; 2] strive for high standards of quality and safety; 3] ensure digital inclusion and mitigate wider inequalities; 4] support and train their staff (clinical and non-clinical), students and trainees; 5] select, install, pilot and use technologies and the digital infrastructure which support them; and 6] involve patients in their improvement efforts. Conclusions: General practices’ responses to pandemic-induced disruptive innovation appear unique and situated. We anticipate that by focusing on depth and detail, this longitudinal study will throw light on why a solution that works well in one practice does not work at all in another. As the study unfolds, we will explore how practices achieve timely diagnosis of urgent or serious illness and manage continuity of care, long-term conditions and complex needs.

Callard and Perego depict long Covid as the first illness to be defined by patients who came together on social media. Responding to their call to address why patients were so effective in making long Covid visible and igniting action to improve its care, we use narrative inquiry - a field of research that investigates the place and power of stories and storytelling. We analyse a large dataset of narrative interviews and focus groups with 114 people with long Covid (45 of whom were healthcare professionals) from the United Kingdom, drawing on socio-narratology (Frank), therapeutic emplotment (Mattingly) and polyphonia (Bakhtin). We describe how storytelling devices including chronology, metaphor, characterisation, suspense and imagination were used to create persuasive accounts of a strange and frightening new condition that was beset with setbacks and overlooked or dismissed by health professionals. The most unique feature of long Covid narratives (in most but not all cases) was the absence, for various pandemic-related reasons, of a professional witness to them. Instead of sharing their narratives in therapeutic dialogue with their own clinician, people struggled with a fragmented inner monologue before finding an empathetic audience and other resonant narratives in the online community. Individually, the stories seemed to make little sense. Collectively, they provided a rich description of the diverse manifestations of a grave new illness, a shared account of rejection by the healthcare system, and a powerful call for action to fix the broken story. Evolving from individual narrative postings to collective narrative drama, long Covid communities challenged the prevailing model of Covid-19 as a short-lived respiratory illness which invariably delivers a classic triad of symptoms; undertook and published peer-reviewed research to substantiate its diverse and protracted manifestations; and gained positions as experts by experience on guideline development groups and policy taskforces.

ObjectiveTo explore the lived experience of ‘brain fog’—the wide variety of neurocognitive symptoms that can follow Covid-19.Design and settingUK-wide longitudinal qualitative study comprising online interviews and focus groups with email follow-up.Method50 participants were recruited from a previous qualitative study of the lived experience of long Covid (n = 23) and online support groups for people with persistent neurological problems following Covid-19 (n = 27). In remotely-held focus groups, participants were invited to describe their cognitive symptoms and comment on others’ accounts. Individuals were followed up by email 4-6 months later. Data were audiotaped, transcribed, anonymised and coded in NVIVO. They were analysed by an interdisciplinary team with expertise in general practice, clinical neuroscience, the sociology of chronic illness and service delivery, and checked by three people with lived experience of brain fog.Results84% of participants were female and 60% were White British ethnicity. Most had never been hospitalised for Covid-19. Qualitative analysis revealed the following themes: mixed views on the appropriateness of the term ‘brain fog’; rich descriptions of the experience of neurocognitive impairments (especially executive function, attention, memory and language), accounts of how the illness fluctuated—and in some but not all cases, resolved—over time; the profound psychosocial impact of the condition on relationships, personal and professional identity; self-perceptions of guilt, shame and stigma; strategies used for self-management; challenges accessing and navigating the healthcare system; and participants’ search for physical mechanisms to explain their symptoms.ConclusionThese qualitative findings complement research into the epidemiology and underlying pathophysiological mechanisms for neurological symptoms after Covid-19. Services for such patients should include: an ongoing therapeutic relationship with a clinician who engages with the illness in its personal, social and occupational context as well as specialist services that are accessible, easily navigable, comprehensive, and interdisciplinary.SummaryStrengths and Limitations of StudyTo our knowledge, this is the largest and most in-depth qualitative study of the lived experience of brain fog in survivors of Covid-19.The research team was interdisciplinary and interprofessional, and included consultation with patient experts by experience, who helped with data interpretation and peer review.Oversampling from men and non-white ethnic groups allowed partial correction of an initially skewed sample.The sample was drawn entirely from the UKResidual skews in the samples, particularly regarding minority ethnic groups and occupational classes, limited our ability to capture the full range of experiencesFunding statementThis research is funded from the following sources: National Institute for Health Research (BRC-1215-20008), ESRC (ES/V010069/1), and Wellcome Trust (WT104830MA). Funders had no say in the planning and execution of the study or writing up of the paper. KTSP is supported by the National Institute for Health Research Biomedical Research Centre based at Oxford University Hospitals NHS Foundation Trust and the University of Oxford.Competing Interests StatementEL and TG provided evidence on long Covid for House of Lords Select Committee TG was on the oversight group for the long Covid guideline at the National Institute for Health and Clinical Excellence, and at the time of writing is on the UK’s National Long Covid Task Force.KP and CC have no competing interests to declare.

Background: Following a pandemic-driven shift to remote service provision, UK general practices offer telephone, video or online consultation options alongside face-to-face. This study explores practices’ varied experiences over time as they seek to establish remote forms of accessing and delivering care. Methods: This protocol is for a mixed-methods multi-site case study with co-design and national stakeholder engagement. 11 general practices were selected for diversity in geographical location, size, demographics, ethos, and digital maturity. Each practice has a researcher-in-residence whose role is to become familiar with its context and activity, follow it longitudinally for two years using interviews, public-domain documents and ethnography, and support improvement efforts. Research team members meet regularly to compare and contrast across cases. Practice staff are invited to join online learning events. Patient representatives work locally within their practice patient involvement groups as well as joining an online patient learning set or linking via a non-digital buddy system. NHS Research Ethics Approval has been granted. Governance includes a diverse independent advisory group with lay chair. We also have policy in-reach (national stakeholders sit on our advisory group) and outreach (research team members sit on national policy working groups). Results (anticipated): We expect to produce rich narratives of contingent change over time, addressing cross-cutting themes including access, triage and capacity; digital and wider inequities; quality and safety of care (e.g. continuity, long-term condition management, timely diagnosis, complex needs); workforce and staff wellbeing (including non-clinical staff, students and trainees); technologies and digital infrastructure; patient perspectives; and sustainability (e.g. carbon footprint). Conclusion: By using case study methods focusing on depth and detail, we hope to explain why digital solutions that work well in one practice do not work at all in another. We plan to inform policy and service development through inter-sectoral network-building, stakeholder workshops and topic-focused policy briefings.

The majority of health outcomes are determined by socioeconomic factors, which traditional healthcare systems are ill-prepared to address. Social prescribing offers a means of increasing the nonmedical options available to practitioners to better target these issues. Interventions are diverse but frequently involve signposting to community resources or referral to a ‘link worker’ who can support an individual in utilising these to deal with challenging situations. Some schemes also involve an element of community development. Theoretic rationale and qualitative data support social prescribing interventions; however, definitive evidence of efficacy is lacking. This is largely due to the inadequacy of current evaluation attempts and the framework of evidence valuation among policymakers. Specific challenges for social prescribing include defining the remit of interventions, issues around the link worker role, ensuring adequate funding, cross-sector working and stakeholder relationships and ensuring high-quality evaluation. Social prescribing is gaining global popularity; thus, practitioners and policymakers have a responsibility to promote high-quality, evidence-based interventions and the research required to identify these.

BackgroundApproximately 10% of patients with Covid-19 experience symptoms beyond 3-4 weeks. Patients call this “long Covid”. We sought to document the lived experience of such patients, their accounts of accessing and receiving healthcare, and their ideas for improving services.MethodWe held 55 individual interviews and 8 focus groups (n = 59) with people recruited from UK-based long Covid patient support groups, social media and snowballing. We restricted some focus groups to health professionals since they had already self-organised into online communities. Participants were invited to tell their personal stories and comment on others’ stories. Data were audiotaped, transcribed, anonymised and coded using NVIVO. Analysis incorporated sociological theories of illness, healing, peer support, the clinical relationship, access to care, and service redesign.ResultsThe sample was 70% female, aged 27-73 years, and comprised White British (74%), Asian (11%), White Other (7%), Black (4%), and Mixed (4%). 27 were doctors and 23 other health professionals. 10% had been hospitalised. Analysis revealed a confusing illness with many, varied and often relapsing-remitting symptoms and uncertain prognosis; a heavy sense of loss and stigma; difficulty accessing and navigating services; difficulty being taken seriously and achieving a diagnosis; disjointed and siloed care (including inability to access specialist services); variation in standards (e.g. inconsistent criteria for seeing, investigating and referring patients); variable quality of the therapeutic relationship (some participants felt well supported while others felt “fobbed off”); and possible critical events (e.g. deterioration after being unable to access services). Emotional touch points in participants’ experiences informed ideas for improving services.ConclusionQuality principles for a long Covid service should include ensuring access to care, reducing burden of illness, taking clinical responsibility and providing continuity of care, multi-disciplinary rehabilitation, evidence-based investigation and management, and further development of the knowledge base and clinical services.Study registrationNCT04435041

Background The coronavirus pandemic has exerted significant impacts on primary care, causing rapid digital transformation, exacerbating social isolation, and disrupting medical student and General Practice [GP] trainee education. Here we report on a medical student telephone initiative set-up by a final year GP trainee (the equivalent of a family medicine resident), which aimed to support patients at high risk and vulnerable to the Coronavirus Disease of 2019 [Covid-19]. In addition, it was hoped the project would mitigate a digital divide, enable proactive anticipatory planning, and provide an active learning environment to compensate for the pandemic’s impact on medical education. Methods Thirty-three medical students conducted daily telephone conversations with high risk and vulnerable patients as specified by the initial NHSE published lists. They confirmed public health messages, offered details for voluntary support groups, established need for medication delivery, explored levels of digital connectivity, and prompted discussions around end-of-life choices. Students had access to online reflective resources and daily remote debriefing sessions with the GP trainee. A convergent mixed-methods evaluation was subsequently undertaken, using quantitative process and descriptive data and individual qualitative interviews were conducted according to a maximal variation sampling strategy with students, General Practitioners [GPs], and the GP trainee. Inductive thematic analysis was then applied with cross-validation, respondent validation, and rich evidential illustration aiding integrity. Results Ninety-seven ‘high risk’ and 781 ‘vulnerable’ calls were made. Individuals were generally aware of public heath information, but some struggled to interpret and apply it within their own lives. Therefore respondents felt students provided additional practical and psychological benefits, particularly with regard to strengthening the links with the community voluntary groups. The project was widely liked by students who reported high levels of skill development and widened awareness, particularly valuing the active learning environment and reflective feedback sessions. Conclusion This study demonstrates utilization of medical students as wider assets within the primary health care team, with an initiative that enables support for vulnerable patients whilst promoting active medical education. Ongoing integration of students within ‘normal’ primary health care roles, such as chronic disease or mental health reviews, could provide similar opportunities for supported active and reflective learning.

Background: The coronavirus pandemic has exerted significant impacts on primary care, causing rapid digital transformation, exacerbating social isolation, and disrupting medical student and General Practitioner [GP] trainee education. Here we report on a medical student telephone initiative set-up by a GP trainee, which aimed to support patients at high risk and vulnerable to the Coronavirus Disease of 2019 [Covid-19]. In addition, it was hoped the project would mitigate a digital divide, enable proactive anticipatory planning, and provide an active learning environment to compensate for the pandemic’s impact on medical education. Methods:33 medical students conducted daily telephone conversations with high risk and vulnerable patients. They confirmed public health messages, offered details for voluntary support groups, established need for medication delivery, explored levels of digital connectivity, and prompted discussions around end-of-life choices. Students had access to online reflective resources and daily remote debriefing sessions with the GP trainee. A convergent mixed-methods evaluation was subsequently undertaken, using quantitative process and descriptive data and individual qualitative interviews were conducted according to a maximal variation sampling strategy with students, GPs, and the GP trainee. Inductive thematic analysis was then applied with cross-validation, respondent validation, and rich evidential illustration aiding integrity. Results:97 ‘high risk’ and 781 ‘vulnerable’ calls were made. Individuals were generally aware of public heath information, but some struggled to interpret and apply it within their own lives. Therefore respondents felt students provided additional practical and psychological benefits, particularly with regard to strengthening the links with the community voluntary groups. The project was widely liked by students who reported high levels of skill development and widened awareness, particularly valuing the active learning environment and reflective feedback sessions. Conclusion:This study demonstrates utilization of medical students as wider assets within the primary health care team, with an initiative that enables support for vulnerable patients whilst promoting active medical education. Ongoing integration of students within ‘normal’ primary health care roles, such as chronic disease or mental health reviews, could provide similar opportunities for supported active and reflective learning.

BackgroundThe introduction of remote triage and assessment early in the pandemic raised questions about patient safety. We sought to capture patients and clinicians’ experiences of the management of suspected acute COVID-19 and generate wider lessons to inform safer care.Setting and sampleUK primary healthcare. A subset of relevant data was drawn from five linked in-pandemic qualitative studies. The data set, on a total of 87 participants recruited via social media, patient groups and snowballing, comprised free text excerpts from narrative interviews (10 survivors of acute COVID-19), online focus groups (20 patients and 30 clinicians), contributions to a Delphi panel (12 clinicians) and fieldnotes from an online workshop (15 patients, clinicians and stakeholders).MethodsData were uploaded onto NVivo. Coding was initially deductive and informed by WHO and Institute of Medicine frameworks of quality and safety. Further inductive analysis refined our theorisation using a wider range of theories—including those of risk, resilience, crisis management and social justice.ResultsIn the early weeks of the pandemic, patient safety was compromised by the driving logic of ‘stay home’ and ‘protect the NHS’, in which both patients and clinicians were encouraged to act in a way that helped reduce pressure on an overloaded system facing a novel pathogen with insufficient staff, tools, processes and systems. Furthermore, patients and clinicians observed a shift to a more transactional approach characterised by overuse of algorithms and decision support tools, limited empathy and lack of holistic assessment.ConclusionLessons from the pandemic suggest three key strategies are needed to prevent avoidable deaths and inequalities in the next crisis: (1) strengthen system resilience (including improved resourcing and staffing; support of new tools and processes; and recognising primary care’s role as the ‘risk sink’ of the healthcare system); (2) develop evidence-based triage and scoring systems; and (3) address social vulnerability.

ObjectiveTo explore the lived experience of ‘brain fog’—the wide variety of neurocognitive symptoms that can follow COVID-19.Design and settingA UK-wide longitudinal qualitative study comprising online focus groups with email follow-up.Method50 participants were recruited from a previous qualitative study of the lived experience of long COVID-19 (n=23) and online support groups for people with persistent neurocognitive symptoms following COVID-19 (n=27). In remotely held focus groups, participants were invited to describe their neurocognitive symptoms and comment on others’ accounts. Individuals were followed up by email 4–6 months later. Data were audiotaped, transcribed, anonymised and coded in NVIVO. They were analysed by an interdisciplinary team with expertise in general practice, clinical neuroscience, the sociology of chronic illness and service delivery, and checked by people with lived experience of brain fog.ResultsOf the 50 participants, 42 were female and 32 white British. Most had never been hospitalised for COVID-19. Qualitative analysis revealed the following themes: mixed views on the appropriateness of the term ‘brain fog’; rich descriptions of the experience of neurocognitive symptoms (especially executive function, attention, memory and language), accounts of how the illness fluctuated—and progressed over time; the profound psychosocial impact of the condition on relationships, personal and professional identity; self-perceptions of guilt, shame and stigma; strategies used for self-management; challenges accessing and navigating the healthcare system; and participants’ search for physical mechanisms to explain their symptoms.ConclusionThese qualitative findings complement research into the epidemiology and mechanisms of neurocognitive symptoms after COVID-19. Services for such patients should include: an ongoing therapeutic relationship with a clinician who engages with their experience of neurocognitive symptoms in its personal, social and occupational context as well as specialist services that include provision for neurocognitive symptoms, are accessible, easily navigable, comprehensive and interdisciplinary.

Study Design Systematic review. Introduction and Purpose of the Study After traumatic hand injury, extensive physical and psychological adaptation is required following surgical reconstruction. Recovery from injury can understandably be emotionally challenging, which may result in impaired quality of life and delayed physical recovery. However, the evidence base for identifying high-risk patients is limited. Methods A PROSPERO-registered literature search of MEDLINE (1946-present), EMBASE (1980-present), PsychInfo, and CINAHL electronic databases identified 5156 results for studies reporting psychological outcomes after acute hand trauma. Subsequent review and selection by 2 independent reviewers identified 19 studies for inclusion. These were poor quality level 2 prognostic studies, cross sectional or cohort in design, and varied widely in methodology, sample sizes, diagnostic methods, and cutoff values used to identify psychological symptoms. Data regarding symptoms, predisposing factors, and questionnaires used to identify them were extracted and analyzed. Results Patients with amputations or a tendency to catastrophize suffered highest pain ratings. Persisting symptom presence at 3 months was the best predictor of chronicity. Many different questionnaires were used for symptom detection, but none had been specifically validated in a hand trauma population of patients. Few studies assessed the ability of selection tools to predict patients at high risk of developing adverse psychological outcomes. Discussion and Conclusion Despite a limited evidence base, screening at 3 months may detect post-traumatic stress disorder, anxiety, depression, and chronic pain, potentially allowing for early intervention and improved treatment outcomes. Level of Evidence Level 4.

> > ‘When I am an old woman I shall wear > > > > purple; > > > > With a red hat which doesn’t go, > > > > and doesn’t suit me. > > > > And I shall spend my pension on brandy and > > > > summer gloves; > > > > And satin sandals, > > > > and say we’ve no money for butter.’ > > 1 Jenny Joseph’s words echoed around the small room. Although I read them loudly, the frail form in the bed strained to hear them. The weak sunlight streamed through dusty windows and chintz curtains, highlighting her skinny arms and wizened face, and illuminating some early daffodils on the bedside table. It was my first home visit as a GP trainee. Predictably, my 6 months in emergency medicine had ended with a run of night shifts. The harsh surrealism of that environment, which, even at 3 am, heaved with the mentally disturbed, intoxicated, or frightened elderly, could not have formed a greater contrast …

Background Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS. Methods Mice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed. Results Compared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions. Conclusions The APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse.

Background Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. However, it displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. Experimentally induced brain injury has been shown to elicit a hepatic acute phase response that modulates leukocyte recruitment to the injured brain. Here, we sought to discover whether one effect of fenofibrate might include the suppression of the acute phase response (APR) following brain injury. Methods A 1-h intraluminal thread middle cerebral artery occlusion (MCAO) model followed by a 6-h reperfusion was performed in C57/BL6 mice. Quantitative reverse transcriptase-polymerase chain reaction was then used to measure hepatic expression of chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine ligand 10 (CXCL10) and serum amyloid A-1 (SAA-1), and immunohistochemical analysis was used to quantify brain and hepatic neutrophil infiltration following stroke. Results The MCAO and sham surgery induced the expression of all three acute phase reactants. A 14-day fenofibrate pre-treatment decreased reactant production, infarct volume, and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. Conclusions The data highlight a novel mechanism of action for fenofibrate and lend further evidence towards the promotion of its use as a prophylactic therapy in patients at risk of cerebral ischaemia. Further research is required to elucidate the mechanistic explanation underlying its actions.

IL-17 is argued to play an important role in the multiple sclerosis-like disease experimental autoimmune encephalitis (EAE). We investigated the therapeutic effects of anti-IL-17A in a chronic relapsing EAE ABH mouse model using conventional scoring, quantitative behavioral outcomes, and a novel vascular cell adhesion molecule 1 (VCAM-1)-targeted magnetic resonance imaging (MRI) contrast agent [anti-VCAM-microparticles of iron oxide (MPIO)] to identify conventionally undetectable neuropathology. Mice were administered prophylactic or treatment regimens of anti-IL-17A or IgG and two injections of anti-VCAM-MPIO before undergoing T2*-weighted three-dimensional and gadolinium-diethylenetriamine pentaacetic acid T1-weighted MRI. Rotarod, inverted screen, and open field motor function tests were performed, conventional clinical scores calculated, and central IL-17A mRNA expression quantified during acute disease, remission, and relapse. Prophylactic anti-IL-17A prevents acute disease and relapse and is associated with reduced clinical and functional severity. Treatment regimens delay relapse, improve functional scores, and are associated with reduced VCAM-MPIO lesions during remission. No significant alteration was detectable in levels of gadolinium-diethylenetriamine pentaacetic acid- or VCAM-MPIO-positive lesions during relapse. Prophylactic and treatment anti-IL-17A were therapeutically effective in chronic relapsing EAE, improving clinical and quantifiable functional outcomes. IL-17A expression seems significant during acute disease but less important chronically. Disease-related immunoneuropathology is more sensitively detected using VCAM-MPIO MRI, which may, therefore, be used to monitor therapy meaningfully.

BACKGROUND: Although recent diagnostic criteria for Alzheimer's disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta-analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies. METHODS: A MEDLINE search was performed in August 2011 to identify all potentially relevant publications relating to the biomarkers β-amyloid, tau, positron emission tomography ((18)F-fluorodeoxyglucose or ligands for amyloid), or magnetic resonance imaging (MRI). The reporting and methodology were assessed using the Standards for Reporting of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies assessment tools, respectively. Because clinical progression to dementia is the most commonly used reference standard, this review focuses on participants with objective cognitive impairment but no dementia at baseline. RESULTS: Of the 19,104 published references identified by the search, 142 longitudinal studies relating to the biomarkers of interest were identified, which included subjects who had objective cognitive impairment but no dementia at baseline. The highest number of studies (n = 70) and of participants (n = 4722) related to structural MRI. MRI also yielded the highest number of studies with extractable data for meta-analysis (n = 32 [46% of all structural MRI studies]), followed by cerebrospinal fluid tau (n = 24 [73%]). There were few studies on positron emission tomography ligands for amyloid having suitable data for meta-analysis (n = 4). There was considerable variation across studies in reporting outcomes, methods of blinding and selection, means of accounting for indeterminate or missing values, the interval between the test and assessments, and the determination of test thresholds. CONCLUSIONS: The body of evidence for biomarkers is not large and is variable across the different types of biomarkers. Important information is missing from many study reports, highlighting the need for standardization of methodology and reporting to improve the rigor of biomarker validation.

Catastrophic epileptic encephalopathy of unclear etiology following a mild metabolic insult generally has a poor outcome. Here, we present 2 such unrelated individuals in whom whole-exome sequencing identified the same de novo recurrent mutation (c.1207C>T p.Arg403Cys) in the gene encoding the guanosine triphosphatase (GTPase) Dynamin-1 like Protein (DNM1L) (reference sequence NM_012062.4).

Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. However, it displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. Experimentally induced brain injury has been shown to elicit a hepatic acute phase response that modulates leukocyte recruitment to the injured brain. Here, we sought to discover whether one effect of fenofibrate might include the suppression of the acute phase response (APR) following brain injury. A 1-h intraluminal thread middle cerebral artery occlusion (MCAO) model followed by a 6-h reperfusion was performed in C57/BL6 mice. Quantitative reverse transcriptase-polymerase chain reaction was then used to measure hepatic expression of chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine ligand 10 (CXCL10) and serum amyloid A-1 (SAA-1), and immunohistochemical analysis was used to quantify brain and hepatic neutrophil infiltration following stroke. The MCAO and sham surgery induced the expression of all three acute phase reactants. A 14-day fenofibrate pre-treatment decreased reactant production, infarct volume, and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. The data highlight a novel mechanism of action for fenofibrate and lend further evidence towards the promotion of its use as a prophylactic therapy in patients at risk of cerebral ischaemia. Further research is required to elucidate the mechanistic explanation underlying its actions.

Background Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer’s disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities. Objectives To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer’s disease dementia or other forms of dementia at follow-up. Search methods The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall. Selection criteria We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing those biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's disease dementia diagnosis, for example, the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Data collection and analysis We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies, and the full papers for eligibility. Two independent assessors performed data extraction and quality assessment. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve. Main results In total, 1282 participants with MCI at baseline were identified in the 15 included studies of which 1172 had analysable data; 430 participants converted to Alzheimer’s disease dementia and 130 participants to other forms of dementia. Follow-up ranged from less than one year to over four years for some participants, but in the majority of studies was in the range one to three years. Conversion to Alzheimer’s disease dementia The accuracy of the CSF t-tau was evaluated in seven studies (291 cases and 418 non-cases).The sensitivity values ranged from 51% to 90% while the specificity values ranged from 48% to 88%. At the median specificity of 72%, the estimated sensitivity was 75% (95% CI 67 to 85), the positive likelihood ratio was 2.72 (95% CI 2.43 to 3.04), and the negative likelihood ratio was 0.32 (95% CI 0.22 to 0.47). Six studies (164 cases and 328 non-cases) evaluated the accuracy of the CSF p-tau. The sensitivities were between 40% and 100% while the specificities were between 22% and 86%. At the median specificity of 47.5%, the estimated sensitivity was 81% (95% CI: 64 to 91), the positive likelihood ratio was 1.55 (CI 1.31 to 1.84), and the negative likelihood ratio was 0.39 (CI: 0.19 to 0.82). Five studies (140 cases and 293 non-cases) evaluated the accuracy of the CSF p-tau/ABeta ratio. The sensitivities were between 80% and 96% while the specificities were between 33% and 95%. We did not conduct a meta-analysis because the studies were few and small. Only one study reported the accuracy of CSF t-tau/ABeta ratio. Our findings are based on studies with poor reporting. A significant number of studies had unclear risk of bias for the reference standard, participant selection and flow and timing domains. According to the assessment of index test domain, eight of 15 studies were of poor methodological quality. The accuracy of these CSF biomarkers for ‘other dementias’ had not been investigated in the included primary studies. Investigation of heterogeneity The main sources of heterogeneity were thought likely to be reference standards used for the target disorders, sources of recruitment, participant sampling, index test methodology and aspects of study quality (particularly, inadequate blinding). We were not able to formally assess the effect of each potential source of heterogeneity as planned, due to the small number of studies available to be included. Authors' conclusions The insufficiency and heterogeneity of research to date primarily leads to a state of uncertainty regarding the value of CSF testing of t-tau, p-tau or p-tau/ABeta ratio for the diagnosis of Alzheimer's disease in current clinical practice. Particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore over-treatment) in clinical practice. These tests, like other biomarker tests which have been subject to Cochrane DTA reviews, appear to have better sensitivity than specificity and therefore might have greater utility in ruling out Alzheimer's disease as the aetiology to the individual's evident cognitive impairment, as opposed to ruling it in. The heterogeneity observed in the few studies awaiting classification suggests our initial summary will remain valid. However, these tests may have limited clinical value until uncertainties have been addressed. Future studies with more uniformed approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified.

Background: The United Kingdom [UK] and Denmark have similarly-structured health systems utilizing GPs as the access point to care. In both countries, National Dementia Strategies emphasize the importance of GPs in early diagnosis and management of dementia. A comparison of experiences could identify similarities and differences in the approach to identifying dementia, imparting the diagnosis to the patient and management strategies. These themes could then aid future service development. Method: A defined population-sampling frame and purposive sampling strategy was used to identify 12 UK and Danish GPs. In depth, one-on-one interviews were conducted to ascertain their current practice around diagnosing dementia, informing the patient and managing the condition and their general views towards the disease itself. These were transcribed verbatim and analysed thematically for similarities and contrasting opinions. Results: The lack of sensitive, specific tests for early dementia presents a diagnostic challenge for GPs. UK GPs expressed ambivalence towards the principle of diagnosis. Service coordination and communication were identified as major challenges to management in both countries and dementia was unequivocally viewed as stigmatizing. Conclusion: This study demonstrates heuristic significance, highlighting the need for a diagnostic framework that empowers GPs to make the best use of imperfect diagnostic tests for early dementia, whilst encouraging the continual improvement of such cognitive assessments and further work exploring how best a proactive coordination of care services may be facilitated. A deeper analysis is required to understand the ambivalence of UK GP to early diagnosis of dementia, along with an exploration of factors in both countries that may contribute to stigma associated with the condition and how this impacts on help-seeking behaviour and service provision.

Following elective surgical procedures, hospital discharge summaries are essential in the handover to primary care. The information provided varies between institutions and is highly user-dependent. Various interventions have focused on improving information transfer to patients and primary care physicians including the development of electronic templates, electronic transmission to primary care, and training initiatives for junior doctors. An evaluation of the urological patient’s journey at Southmead Hospital revealed a need for improved discharge summary advice. Urology specialists developed "gold standard" templates for elective urological procedures. Following a new rotation of junior doctors, discharge summaries were audited for one week. The templates were then made available on the urology ward, a teaching session was employed to encourage compliance, and the hospital electronic discharge summary template was edited. Following each intervention, summaries for one week of urology procedures were audited to assess the quality of advice provided to patients. At baseline, 18% of discharge summaries contained sufficient patient advice, this reduced to 10% after templates were made available on the wards, increasing to 45% following the education session and 84% once the electronic discharge summary proforma was edited. We conclude that discharge summaries are an effective time point for intervening to provide patients with specific post-operative information and this may be optimised for different elective procedures via the introduction of electronically-distributed standardised templates.

Four years after an orthoptic liver transplant for hepatocellular carcinoma secondary to alcoholic liver disease, the patient presented in a crescendo manner with skin infections and finally a septic right arm wound. The abscess was drained and cultures grew Mycobacterium tuberculosis. The patient reported a previous episode of ‘pneumonia’ and subsequent hospitalisations for recurrent chest infections, and following further investigation, he was diagnosed with disseminated tuberculosis. The infection responded to triple therapy, but primary closure of the arm wound was unsuccessful and it was treated conservatively with negative pressure wound therapy. The patient remains an inpatient 3 months after his presentation, responding well to therapy and anticipating imminent discharge. The patient's case serves as a reminder that infections are common in solid organ transplant recipients and clinicians should be aware of unusual or recurrent presentations in these patients, to allow for early diagnosis and timely management.