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A patient developed fever, raised inflammatory markers and a maculopapular rash following commencement of clozapine for treatment of his schizoaffective disorder. Skin biopsy confirmed Sweet's syndrome. Identification of the cause was challenging, with a number of possible considerations including infection, malignancy and various potential drug triggers. This case highlights the difficulties in the diagnosis of Sweet's syndrome, as well as in identifying the original trigger, which can have significant consequences for management. Withdrawal of potentially causative drugs must be balanced with their benefits, and decisions must be made in the best interests of the patient. Following two courses of prednisolone and withdrawal of clozapine, the patient's rash and systemic symptoms resolved. This confirmed the diagnosis of drug-induced Sweet's syndrome, with clozapine as the offending agent. His mental state stabilised on an alternative antipsychotic.

Background Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder involving inattention, hyperactivity and impulsivity, which starts in childhood and frequently persists into adulthood. Stimulant and non-stimulant medication are the mainstay of treatment in adults. ADHD in adults is commonly comorbid in people with severe mental illness (SMI) such as bipolar disorder (bipolar) and psychosis. There is substantial uncertainty over the effectiveness of stimulant and non-stimulant medication in adult ADHD comorbid with SMI. There is also concern that they could trigger or worsen psychotic or manic symptoms. Whilst National Institute of Health and Care Evidence (NICE) ADHD guidelines indicate available evidence does not justify a deviation from their main recommendations of using stimulants first line, this is based on limited studies within this comorbid population. A randomised controlled trial (RCT) is needed to address this evidence gap. We present a protocol for a pragmatic, observer-blind, multi-centre, two-arm, RCT called SNAPPER that aims to investigate the clinical and cost-effectiveness of stimulant compared with non-stimulant medication for adults with ADHD and a history of SMI. Methods The recruitment target is 244 participants, aged 18 years or above, who have a history of SMI (either bipolar disorder or psychosis) with ADHD. Having provided informed consent for screening, participants will undergo validated diagnostic screening assessments to re-confirm the diagnosis of bipolar or psychosis and confirm an ADHD diagnosis. Those with confirmed diagnoses will provide informed consent for entry to the main trial and will then be randomised to receive either stimulant (lisdexamfetamine) or non-stimulant (atomoxetine) medication. The primary outcome measure is observer-rated ADHD symptom severity at 6 months. Secondary outcomes include ADHD symptom severity at 12 months, emergence of symptoms of bipolar or psychosis, health-related quality of life, occupational, daily functioning, substance misuse, cost-effectiveness, adherence, concomitant medication and process outcomes at 6 and 12 months. Discussion Given that untreated ADHD is associated with poor clinical outcomes, unemployment and criminal justice system involvement, clear evidence in this area is likely to improve recovery for individuals with ADHD and a history of SMI, reducing costs for the individual, the NHS and society. Trial registration ISRCTN79796233. Registered on 19/05/2022.  https://www.isrctn.com/ISRCTN79796233 .

The Maudsley 3-item visual analogue scale (M3VAS) was developed as a novel and intuitive patient-reported measure for depression, focusing on core symptoms and suicidality. To evaluate the longitudinal validity of M3VAS for capturing symptom change over time. Both M3VAS and the Patient Health Questionnaire (PHQ-9, as reference standard) were administered in an observational study (RHAPSODY, no. NCT04939818) at weeks 0, 2 and 4 to both depressed patients ( = 50) and matched controls ( = 24). We serially tested factor structure, internal consistency and convergence (correlation) over time, assessing responsiveness by both correlation of change in score and effect of time across scales (analysis of variance and effect size). M3VAS exhibited strong factor loadings and high item interrelatedness (Cronbach's alpha 0.78-0.83) at all time points. Total scores correlated strongly with PHQ-9 at each time point ( > 0.8, < 0.001). Correlation of score change over the study period ( = 0.65, < 0.001) also confirmed responsiveness. In the depressed group, an effect of time on score was seen for both M3VAS ( = 4.942, = 0.010) and PHQ-9 ( = 12.505, < 0.001), with standard response mean (Cohen's ) of 0.58 and 0.74, respectively. No effect of time was seen in the control group. Following previous cross-sectional validation against the Quick Inventory of Depressive Symptomatology-Self-report, this present study demonstrated appropriate longitudinal measurement properties for M3VAS as a measure of depression, including responsiveness. Evaluating the ability of M3VAS to discern responses with a variety of treatments is a key future goal.

Determining the optimum next-step treatment for the numerous patients with depression who do not adequately respond to an initial trial of medication remains a source of uncertainty in clinical practice. Although a number of psychological treatments are known to be effective for depression, their relative merits in the treatment-resistant group have not been ascertained. The Cochrane Collaboration has recently published a meta-analysis of the evidence available for the use of various psychotherapies as an adjunct to antidepressants compared with antidepressants alone in treatment-resistant depression. This article provides a commentary and appraisal of the clinical utility of these findings.

Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans. This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578. Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66–81]) of 124 solicited adverse events were mild, 31 (25% [18–33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11–17·42], p<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% [95% CI 19–73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58–93]) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay. ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials. UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.

We have just witnessed the largest and most devastating outbreak of Ebola virus disease, which highlighted the urgent need for development of an efficacious vaccine that could be used to curtail future outbreaks. Prior to 2014, there had been limited impetus worldwide to develop a vaccine since the virus was first discovered in 1976. Though too many lives were lost during this outbreak, it resulted in the significantly accelerated clinical development of a number of candidate vaccines through an extraordinary collaborative global effort coordinated by the World Health Organisation (WHO) and involving a number of companies, trial centres, funders, global stakeholders and agencies. We have acquired substantial safety and immunogenicity data on a number of vaccines in Caucasian and African populations. The rapid pace of events led to the initiation of the landmark efficacy trial testing the rVSV-vectored vaccine, which showed high level efficacy in an outbreak setting when deployed using an innovative ring vaccination strategy. Though the Public Health Emergency of International Concern (PHEIC) declared by the WHO has now been lifted, the global scientific community faces numerous challenges ahead to ensure that there is a licensed, deployable vaccine available for use in future outbreaks for at least the Zaire and Sudan strains of Ebola virus. There remain several unanswered questions on the durability of protection, mechanistic immunological correlates and preferred deployment strategies. This review outlines a brief history of the development of Ebola vaccines, the significant progress made since the scale of the outbreak became apparent, some lessons learnt and how they could shape future development of vaccines and the management of similar outbreaks.

ObjectivesTo measure changes in length of stay following total knee and hip replacement (TKR and THR) between 1997 and 2014 and estimate the impact on hospital reimbursement, all else being equal. Further, to assess the degree to which observed trends can be explained by improved efficiency or changes in patient profiles.DesignCross-sectional study using routinely collected data.SettingNational Health Service primary care records from 1995 to 2014 in the Clinical Practice Research Datalink were linked to hospital inpatient data from 1997 to 2014 in Hospital Episode Statistics Admitted Patient Care.ParticipantsStudy participants had a diagnosis of osteoarthritis or rheumatoid arthritis.InterventionsPrimary TKR, primary THR, revision TKR and revision THR.Primary outcome measuresLength of stay and hospital reimbursement.Results10 260 primary TKR, 10 961 primary THR, 505 revision TKR and 633 revision THR were included. Expected length of stay fell from 16.0 days (95% CI 14.9 to 17.2) in 1997 to 5.4 (5.2 to 5.6) in 2014 for primary TKR and from 14.4 (13.7 to 15.0) to 5.6 (5.4 to 5.8) for primary THR, leading to savings of £1537 and £1412, respectively. Length of stay fell from 29.8 (17.5 to 50.5) to 11.0 (8.3 to 14.6) for revision TKR and from 18.3 (11.6 to 28.9) to 12.5 (9.3 to 16.8) for revision THR, but no significant reduction in reimbursement was estimated. The estimated effect of year of surgery remained similar when patient characteristics were included.ConclusionsLength of stay for joint replacement fell substantially from 1997 to 2014. These reductions have translated into substantial savings. While patient characteristics affect length of stay and reimbursement, patient profiles have remained broadly stable over time. The observed reductions appear to be mostly explained by improved efficiency.

Background The serious adverse events associated with metal on metal hip replacements have highlighted the importance of improving methods for monitoring surgical implants. The new European Union (EU) device regulation will enforce post-marketing surveillance based on registries among other surveillance tools. Europe has a common regulatory environment, a common market for medical devices, and extensive experience with joint replacement registries. In this context, we elaborate how joint replacement registries, while building on existing structure and data, can better ensure safety and balance risks and benefits. Main text Actions to improve registry-based implant surveillance include: enriching baseline and diversifying outcomes data collection; improving methodology to limit bias; speeding-up failure detection by active real-time monitoring; implementing risk-benefit analysis; coordinating collaboration between registries; and translating knowledge gained from the data into clinical decision-making and public health policy. Conclusions The changes proposed here will improve patient safety, enforce the application of the new legal EU requirements, augment evidence, improve clinical decision-making, facilitate value-based health-care delivery, and provide up-to-date guidance for public health.

Assessing the impacts of anthropogenic degradation and climate change on global carbon cycling is hindered by a lack of clear, flexible and easy‐to‐use productivity models along with scarce trait and productivity data for parameterizing and testing those models. We provide a simple solution: a mechanistic framework (RS‐CFM) that combines remotely‐sensed foliar‐trait and canopy‐structural data with trait‐based metabolic theory to efficiently map productivity at large spatial scales. We test this framework by quantifying net primary productivity (NPP) at high‐resolution (0.01‐ha) in hyper‐diverse Peruvian tropical forests (30040 hectares) along a 3322‐m elevation gradient. Our analysis captures hotspots and elevational shifts in productivity more accurately and in greater detail than alternative empirical‐ and process‐based models that use plant functional types. This result exposes how high‐resolution, location‐specific variation in traits and light competition drive variability in productivity, opening up possibilities to fully harness remote sensing data and reliably scale up from traits to map global productivity in a more direct, efficient and cost‐effective manner.

Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of deterioration. The objective of this study was to evaluate the application of joint latent class model in identifying trajectories of frailty progression over time and their group-specific risk of death in older people. The primary care records of UK patients, aged over 65 as of January 1, 2010, included in the Clinical Practice Research Datalink: GOLD and AURUM databases, were analyzed and linked to mortality data. The electronic frailty index (eFI) scores were calculated at baseline and annually in subsequent years (2010-2013). Joint latent class model was used to divide the population into clusters with different trajectories and associated mortality hazard ratios. The model was built in GOLD and validated in AURUM. Five trajectory clusters were identified and characterized based on baseline and speed of progression: low–slow, low–moderate, low–rapid, high–slow, and high–rapid. The high–rapid cluster had the highest average starting eFI score; 7.9, while the low–rapid cluster had the steepest rate of eFI progression; 1.7. Taking the low–slow cluster as reference, low–rapid and high–rapid had the highest hazard ratios: 3.73 (95% CI 3.71, 3.76) and 3.63 (3.57-3.69), respectively. Good validation was found in the AURUM population. Our research found that there are vulnerable subgroups of the older population who are currently frail or have rapid frailty progression. Such groups may be targeted for greater healthcare monitoring.