Objective: Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. Method: Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. Results: A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI -0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. Conclusion: The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use.

Referrals to mental health services, and mental health-related presentations to emergency departments (EDs), among children and young people (CYP) have increased over the last decade. In the UK, national guidelines and standards recommend that CYP who present to an ED with mental health issues should receive a psychosocial assessment, while evidence suggests that the use of a psychosocial assessment tool can enhance the management of this patient cohort. However, it can be challenging for ED healthcare professionals to undertake a formal psychosocial assessment due to a range of factors. This article reports the results of a service evaluation, undertaken in two children's EDs in a large NHS trust in England. The evaluation involved a review of 308 ED clinical records of CYP who presented to the EDs with mental health issues, to assess the extent to which this cohort was receiving a structured psychosocial assessment. The results showed that only a small proportion (34%, n=104) of the clinical records contained evidence of some form of psychosocial assessment, while the use of a psychosocial assessment tool was documented in only 22 (7%) of these 104 clinical records. The results have informed a wider quality improvement project to enhance practice in this area.

Background: Treatment resistance (TR) in schizophrenia may be defined by the persistence of positive and/or negative symptoms despite adequate treatment. Whilst previous investigations have focused on positive symptoms, negative symptoms are highly prevalent, impactful, and difficult to treat. In the current study we aimed to develop easily employable prediction models to predict TR in positive and negative symptom domains from first episode psychosis (FEP). Methods: Longitudinal cohort data from 1027 individuals with FEP was utilised. Using a robust definition of TR, n = 51 (4.97 %) participants were treatment resistant in the positive domain and n = 56 (5.46 %) treatment resistant in the negative domain 12 months after first presentation. 20 predictor variables, selected by existing evidence and availability in clinical practice, were entered into two LASSO regression models. We estimated the models using repeated nested cross-validation (NCV) and assessed performance using discrimination and calibration measures. Results: The prediction model for TR in the positive domain showed good discrimination (AUC = 0.72). Twelve predictor variables (male gender, cannabis use, age, positive symptom severity, depression and academic and social functioning) were retained by each outer fold of the NCV procedure, indicating importance in prediction of the outcome. However, our negative domain model failed to discriminate those with and without TR, with results only just over chance (AUC = 0.56). Conclusions: Treatment resistance of positive symptoms can be accurately predicted from FEP using routinely collected baseline data, however prediction of negative domain-TR remains a challenge. Detailed negative symptom domains, clinical data, and biomarkers should be considered in future longitudinal studies.

Alzheimer's disease is a chronic, neurological condition that faces many challenges in its management and therapy nowadays highlighting the importance and urgent need of researching new ways of approaching this disease. Retinoic acid and its derivatives, collectively known as the retinoids, are considered promising agents that have disease-modifying properties in affecting Alzheimer's disease. This thesis aims to address the research questions of what the role of retinoids is in Alzheimer's disease, and whether they can be used as a novel drug candidate for treating this condition. Retinoids' properties and agonistic actions on the nuclear receptors retinoic acid receptor (RAR) and retinoic X receptor (RXR) affect various pathways as well as their underlying genetic factors that compose important pathophysiological hallmarks causing the progression of Alzheimer's disease as amyloid β (Aβ) production and deposition, neurofibrillary tangle (NFT) formation and phosphorylation, and inflammatory and autoimmune responses. Retinoic acid inhibits the amplification of these pathways and modifies the disease progression in animal models, proposing a solid basis for human trials. Hence, investigating retinoids as pharmacological agents in human trials has been conducted, and several synthetic analogues have been developed to address issues concerning retinoic acid's instability and short half-life, as well as adverse drug reactions. The most prominent of these analogues is tamibarotene, a stable retinoic acid derivative with a higher half-life, higher specificity to target receptors, and fewer adverse reactions. A number of criteria that explain what a novel drug candidate should have when managing Alzheimer's disease have been formulated, and which also explain why most novel drug candidates other than retinoic acid have failed in achieving clinical results. Most of these candidates share one common trait which is a single-target approach in targeting disease pathways. This means that when administering these agents, their actions are to target a single disease-causing pathway at a time but do not affect other pathways. On the other hand, tamibarotene is a novel drug candidate that targets a range of pathways at once and provides a more comprehensive approach in its pharmacological actions.

Background: Newly-qualified doctors in the United Kingdom experience a great deal of stress and have poor wellbeing when compared to more senior counterparts. A number of interventions have been put in place to boost healthcare professionals' wellbeing, but little is known about interventions aimed to improve the wellbeing of newly-qualified doctors in the United Kingdom. This study aims to systematically review current evidence of interventions which improved the wellbeing of newly-qualified junior doctors in the United Kingdom. Methods: Five key electronic databases were searched. Subsequently, reference scanning and citation search was performed. Studies were included if they were conducted from the commencement of the Foundation Programme in 2004, until 2019. In addition, studies had to be performed on junior doctors: working in the United Kingdom and within their first five years post-qualification and have a quantitative outcome. Studies which did not meet these criteria were excluded. Quality was assessed using the modified Newcastle-Ottawa scale. Bias was not formally assessed using a standardised tool. Results: Seven papers met the inclusion criteria and identified three main types of interventions: mentorship, mindfulness and clinical preparation interventions. The majority of included studies reported a positive result from the performed intervention, suggesting these to be beneficial in improving junior doctor wellbeing, and thereby reducing anxiety and stress levels. However, most of the studies used small sample sizes. Conclusions: This review reveals that there is dearth of evidence on the effectiveness of intervention to improve the wellbeing of newly-qualified doctors in the United Kingdom. Most of the identified interventions focused on relieving stress and anxiety inherent within newly-qualified doctors' training programmes. However, wellbeing interventions need to take into cognisance all the factors which impact on wellbeing, particularly job-related factors. We recommend that future researchers implement large-scale holistic interventions using appropriate research methods.

Most clinic attenders with chronic hepatitis B (CHB) are serum HBeAg-negative, and a minority will require suppressive antiviral treatment. Expert guidelines propose schedules for the monitoring of untreated patients, but the recommended frequency of patient review does not reflect recognised demographic determinants of HBeAg-negative chronic hepatitis. Also, the impact of patient ethnicity on risk has not been defined. The aim of our study was to determine the rates and determinants of antiviral treatment initiation in a large multi-ethnic cohort of CHB patients attending a single centre. We undertook a retrospective study using entirely electronic sources of patient information. Treatment initiation dates were identified from electronic pharmacy records. Crude and time-dependent statistical analyses were undertaken to identify rate and risk factors for treatment initiation. Treatment was initiated for 232/1256 (18.5%) patients with rates of 23.2% and 33.2% at 5 and 10 years. An increased risk of treatment was associated with male sex (RR 1.803), older age at presentation (RR 1.027 per year increase) and with non-Black ethnicity (RR 1.654). Patient sex, baseline age and ethnicity also determined risk for treatment in the subset of patients with normal serum ALT and low HBV DNA at baseline, though overall treatment rate in this group was low (only 2% per annum). Thus, patient demographics permit risk stratification for treatment initiation and could determine to a significant extent the frequency of review required for untreated HBeAg-negative patients. Black ethnicity is associated with a significant reduction in risk of treatment initiation.