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Background The treatment gap for epilepsy is large in low- and middle-income countries (LMICs) and the effectiveness and safety of the available anti-seizure medication (ASMs) is not fully understood. We systematically reviewed available evidence on therapeutic drug monitoring (TDM) of ASM in LMIC. Methods We searched four main databases (PubMed, Psych-Info, CINAHL and Embase) up to 31st December 2020, with eligible articles screened using a PRISMA checklist and a set of exclusion and inclusion criteria. Full texts were examined to evaluate the extent and practice of TDM in LMICs. Analyses were performed using Stata 13 and descriptive statistics were used to pool median distribution of TDM across studies. Results Of the 6,309 articles identified in the initial search, 65 (1.0%) met the eligibility criteria. TDM of ASMs was mostly done to assess toxicity (42.8%), but rarely to monitor adherence (9.0%). TDM differed by economic status and infrastructural status with majority of the studies coming from Europe (53.8%) and upper-middle-income countries (87.6%). First generation ASMs (82.3%) were more likely to be monitored than second generation ASMs (17.6%) and carbamazepine was the most frequently monitored drug. Fluorescence Polarization Immunoassay (FPIA) was the most common technique used for TDM (41.5%) followed by High-Performance Liquid Chromatography (HPLC) (16.9%). In addition, FPIA was the cheapest method of TDM based on approximated costs ($1000, TDx system). Assay validation and quality control were reported variably, and reference ranges used during TDM of ASMs were relatively uniform. Conclusions TDM is mostly done to evaluate ASM toxicity, but rarely for other reasons such as evaluating adherence or assessing clinical efficacy. There is a need for more investment in comprehensive and targeted TDM in LMICs when initiating treatment, switching therapies, adding or removing ASM and evaluating treatment response and safety of both first generation and second generation ASMs.
\n \n\n \n \nMental illness within Christian communities may be subject to stigmatization, with some attributing it to demonic possession, lack of faith, personal sin, or other negative spiritual influences. Contrasting research, however, suggests a potentially supportive role, in that Christian faith and community may aid recovery from mental illness and/or act as a buffer against onset or relapse. The aim of this qualitative review was to systematically collate and characterize published qualitative evidence that explores the experiences of adult Christians with mental illness in relation to their faith and community. An electronic search of 15 databases was conducted, alongside the manual review of notable journals in the area and expert consultation. Twentytwo studies were included from 12,607 reviewed articles. A thematic synthesis identified four higher level themes: positive experiences of Christian communities (subthemes: congregational support; faith leaders and pastoral care), positive coping through Christian meaning systems (subthemes: religious meaningmaking; positive coping through relationship with God), negative experiences of Christian communities (subthemes: imposed spiritualization of mental illness; stigma, exclusion, and marginalization), difficulties navigating faith amid suffering (subthemes: dissonance: mental illness and faith; negative affect). This qualitative systematic review provides support to the vital importance of Christian faith and community for Christians who experience mental illness. It categorizes the idiographic and often diverse ways in which Christians living with mental illness may experience their faith and church community and explores how Christian religious systems and communities may function to support or hinder experiences of mental illness.
\n \n\n \n \nBACKGROUND: The rising number of dementia diagnoses and imminent adoption of disease-modifying treatments necessitate innovative approaches to identify individuals at risk, monitor disease course and intervene non-pharmacologically earlier in the disease course. Digital assessments of dementia risk and cognitive function have the potential to outperform traditional in-person assessments in terms of their affordability, accuracy and longitudinal tracking abilities. However, their accessibility and reliability in older adults is unclear. AIMS: To evaluate the usability and reliability of a smartphone assessment of lifestyle and cognitive factors relevant to dementia risk in a group of UK-based older adults. METHOD: Cognitively healthy adults (n = 756) recruited through the Dementias Platform UK Great Minds volunteer register completed three assessments of cognitive function and dementia risk over a 3-month period and provided usability feedback on the Five Lives smartphone application (app). We evaluated cognitive test scores for age, gender and higher education effects, normality distributions, test-retest reliability and their relationship with participants' lifestyle dementia risk factors. RESULTS: Participants found the app 'easy to use', 'quick to complete' and 'enjoyable'. The cognitive tests showed normal or near-to-normal distributions, variable test-retest reliabilities and age-related effects. Only tests of verbal ability showed gender and education effects. The cognitive tests did not correlate with lifestyle dementia risk scores. CONCLUSIONS: The Five Lives assessment demonstrates high usability and reliability among older adults. These findings highlight the potential of digital assessments in dementia research and clinical practice, enabling improved accessibility and better monitoring of cognitive health on a larger scale than traditional in-person assessments.
\n \n\n \n \nINTRODUCTION: Ethnic minorities (also called racialised groups) are more likely to experience severe mental illness (SMI). People with SMI are more likely to experience multimorbidity (MM), making psychosis among racialised groups more likely to lead to MM, poor outcomes, disability and premature mortality. METHODS AND ANALYSIS: This National Institute for Health and Care Research-funded study (151887) seeks to use innovative participatory methods including photovoice and biographical narrative interviews in urban and rural areas of England to assemble experience data. These data will be subjected to polytextual thematic analysis, and alongside pictures and captions, will inform an experienced-based co-design of interventions, the implementation of which will be evaluated. There will be an economic analysis and a process evaluation of the implementation. ETHICS AND DISSEMINATION: This programme of work has received ethical (IRAS 322421; Newcastle North Tyneside Research Ethics Committee 23/NE/0143) and sponsor approval. The findings will be disseminated in galleries showing the creative work, as lay and academic summaries and infographics; as practice briefings for practitioners, commissioners and policy makers; peer-reviewed publications. TRIAL REGISTRATION NUMBER: https://www.researchregistry.com/browse-the-registry%23home/registrationdetails/649c08111c037d0027b17d17/.
\n \n\n \n \nBACKGROUND: Post-traumatic stress disorder (PTSD) has been linked to violent crime in veteran populations. However, whether there is a link between PTSD and violent crime in the general population is not known. This study aimed to investigate the hypothesised association between PTSD and violent crime in the Swedish general population and to investigate the extent to which familial factors might explain this association using unaffected sibling control individuals. METHODS: This nationwide, register-based cohort study assessed individuals born in Sweden in 1958-93 for eligibility for inclusion. Individuals who died or emigrated before their 15th birthday, were adopted, were twins, or whose biological parents could not be identified were excluded. Participants were identified and included from the National Patient Register (1973-2013), the Multi-Generation Register (1932-2013), the Total Population Register (1947-2013), and the National Crime Register (1973-2013). Participants with PTSD were matched (1:10) with randomly selected control individuals from the population without PTSD by birth year, sex, and county of residence in the year of PTSD diagnosis for the matched individual. Each participant was followed up from the date of matching (ie, the index person's first PTSD diagnosis) until violent crime conviction or until being censored at emigration, death, or Dec 31, 2013, whichever occurred first. Stratified Cox regressions were used to estimate the hazard ratio of time to violent crime conviction ascertained from national registers in individuals with PTSD compared with control individuals. To account for familial confounding, sibling analyses were conducted, comparing the risk of violent crime in a subsample of individuals with PTSD with their unaffected full biological siblings. FINDINGS: Of 3\u2008890\u2008765 eligible individuals, 13\u2008119 had a PTSD diagnosis (9856 [75\u00b71%] of whom were female and 3263 [24\u00b79%] of whom were male), were matched with 131\u2008190 individuals who did not, and were included in the matched cohort. 9114 individuals with PTSD and 14\u2008613 full biological siblings without PTSD were also included in the sibling cohort. In the sibling cohort, 6956 (76\u00b73%) of 9114 participants were female and 2158 (23\u00b77%) were male. Cumulative incidence of violent crime convictions after 5 years was 5\u00b70% (95% CI 4\u00b76-5\u00b75) in individuals diagnosed with PTSD versus 0\u00b77% (0\u00b76-0\u00b77) in individuals without PTSD. At the end of follow-up (median follow-up time 4\u00b72 years, IQR 2\u00b70-7\u00b76), cumulative incidence was 13\u00b75% (11\u00b73-16\u00b76) versus 2\u00b73% (1\u00b79-2\u00b76). Individuals with PTSD had a significantly higher risk of violent crime than the matched control population in the fully-adjusted model (hazard ratio [HR] 6\u00b74, 95% CI 5\u00b77-7\u00b72). In the sibling cohort, the risk of violent crime was also significantly higher in the siblings with PTSD (3\u00b72, 2\u00b76-4\u00b70). INTERPRETATION: PTSD was associated with increased risk of violent crime conviction, even after controlling for familial effects shared by siblings and in the absence of SUD or a history of violent crime. Although our results might not be generalisable to less severe or undetected PTSD, our study could inform interventions that aim to reduce violent crime in this vulnerable population. FUNDING: None.
\n \n\n \n \nBACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0\u00b733 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9\u00b720 years (SD 1\u00b779). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0\u00b701, 95% CI -0\u00b715 to 0\u00b717; p<0\u00b70001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.
\n \n\n \n \nOBJECTIVES: To examine the association between the Life Simple 7 cardiovascular health score at age 50 and incidence of dementia. DESIGN: Prospective cohort study. SETTING: Civil service departments in London (Whitehall II study; study inception 1985-88). PARTICIPANTS: 7899 participants with data on the cardiovascular health score at age 50. EXPOSURES: The cardiovascular health score included four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three point scale (0, 1, 2). The cardiovascular health score was the sum of seven metrics (score range 0-14) and was categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health. MAIN OUTCOME MEASURE: Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. RESULTS: 347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0) per 1000 person years among the group with poor cardiovascular health, the absolute rate differences per 1000 person years were -1.5 (95% confidence interval -2.3 to -0.7) for the group with intermediate cardiovascular health and -1.9 (-2.8 to -1.1) for the group with optimal cardiovascular health. Higher cardiovascular health score was associated with a lower risk of dementia (hazard ratio 0.89 (0.85 to 0.95) per 1 point increment in the cardiovascular health score). Similar associations with dementia were observed for the behavioural and biological subscales (hazard ratios per 1 point increment in the subscores 0.87 (0.81 to 0.93) and 0.91 (0.83 to 1.00), respectively). The association between cardiovascular health at age 50 and dementia was also seen in people who remained free of cardiovascular disease over the follow-up (hazard ratio 0.89 (0.84 to 0.95) per 1 point increment in the cardiovascular health score). CONCLUSION: Adherence to the Life Simple 7 ideal cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.
\n \n\n \n \nAlthough several dierent image modalities will be described, neuroimaging studies of brain function in dementia largely fall into two categories: (1) the study of resting blood ow and (2) measurement of brain changes due to a specic task. is chapter starts with a brief description of methods of emission tomography, functional magnetic resonance imaging (fMRI) and diusion tensor imaging (DTI) before describing applications in patients.
\n \n\n \n \nBACKGROUND: Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. METHODS: We included 3838 participants aged 18-90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. RESULTS: High alcohol use was associated with lower hippocampal volume (r\u00a0=\u00a0-0.10, p\u00a0=\u00a00.021), and overweight/obesity with lower total GMV (r\u00a0=\u00a0-0.09, p\u00a0=\u00a00.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r\u00a0=\u00a0-0.08, p\u00a0=\u00a00.001), but not hippocampal volume (r\u00a0=\u00a0-0.01, p\u00a0=\u00a00.625). CONCLUSIONS: This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.
\n \n\n \n \nThe sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age\u00a0=\u00a069.52 \u00b1 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age\u00a0=\u00a053.2 \u00b14.9 years) and late-life (mean age\u00a0=\u00a067.7 \u00b1 4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age\u00a0=\u00a070.87 \u00b1 4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with markers of cortical structure.
\n \n\n \n \nThe inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.
\n \n\n \n \nCumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d=0.54, p<0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d=0.47, p<0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-\u03b1 levels and major depression (d=0.40, p=0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1\u03b2 levels and major depression (d=-0.05, p=0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-\u03b1, interleukin-1\u03b2 and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
\n \n\n \n \nPsychoanalytical methodology has been described as causal explanation or hermeneutic understanding. This methodological dichotomy has been introduced into psychopathology by Karl Jaspers. Contemporary authors' contributions in the area are discussed. Although these authors accept a role for both methods, they agree with Jaspers that psychoanalysis should be subjected to the logical limitations of hermeneutic analysis. A logical framework for the interaction of explaining with understanding is presented and discussed in relation to psychiatric research.
\n \n\n \n \nBACKGROUND: Pre-morbid intelligence level is routinely assessed in Alzheimer's disease using the National Adult Reading Test (NART). This practice is based on the assumption that pronunciation of irregular words remains unaffected by the disease process. Recent reports have suggested that reading ability may become compromised in moderately demented subjects. METHOD: Sixty-eight probably Alzheimer patients were classified into stages of severity (minimal, mild and moderate) using the Mini-Mental State Examination (MMSE). NART and demographic equations were used to estimate pre-morbid ability. RESULTS: A significant correlation emerged between dementia severity and reading ability, NART v. MMSE scores, r = 0.46, P < 0.01. When the total sample was subdivided into moderate, mild and minimal subgroups, significant between-group differences emerged, despite the groups being well matched for age, sex, and years of full-time education. Pre-morbid IQ, as estimated by demographic regression equations, did not correlate with dementia severity. CONCLUSION: NART performance is compromised in moderate Alzheimer disease, and the measure provides a serious underestimate of pre-morbid IQ in patients with an MMSE of 13 or less.
\n \n\n \n \nBACKGROUND: Imaging studies in depression of the elderly are often small and highly selective. AIMS: To investigate a large group of elderly depressed patients in order to assess changes in clinical, imaging and neuropsychological variables at follow-up. METHOD: Patients (n = 175, age range 65-91 years) with clinical depression were identified from consecutive local referrals. Clinical interviews, neuropsychological tests and SPECT scans were carried out at referral and at two-year follow-up. RESULTS: Of 84 re-examined patients, 46.5% were well, 9.5% were ill, 33% partially recovered and 11% had developed dementia. Duration of illness before index assessment was the only factor to predict outcome. Thirty-nine patients could be scanned and followed up. There were no differences between patients with good or poor depressive outcome on SPECT. Ten clinically improved patients could be re-examined with SPECT. There were relative increases in right cingulate gyrus and right cerebellum at follow-up. CONCLUSIONS: The patients group was comparable with other studies showing high levels of residual depressive symptoms. Activity changes in limbic cortex are implicated in depression of old age.
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