Exploring the effects of socio-economic inequalities on health and disability in Northern Irish adolescents: evidence from a nationally representative longitudinal study.

Although a negative association between socio-economic inequalities and health has been established, there is a dearth of robust longitudinal studies examining this relationship in adolescents. This study used a large, nationally representative longitudinal data set to investigate the association between socio-economic inequality, subjective health status and disabilities among young people in Northern Ireland over a ten-year period. Data were from the Northern Ireland Longitudinal Study, a census-based record linkage study (N = 46,535). Logistic regression models were estimated in which health and disability variables from the 2011 census were predicted by household deprivation in education, housing quality, housing tenure and employment from the 2001 census. Models were adjusted for health and disability status in 2001. Deprivation in employment, housing tenure and coming from a single-parent household in 2001 independently predicted poorer subjective health and disability status ten years later [ORs = 1.28-1.93]. Deprivation in education in 2001 was also associated with increased risk of disability in 2011 [OR = 1.15; 95% CI = 1.06-1.25]. These results show that there is a need to dedicate more resources and support for economically disadvantaged children and young people in Northern Ireland, where child health outcomes are poorer than in the rest of the UK.

Minding the gap-an examination of a pharmacist case management medicines optimisation intervention for older people in intermediate care settings.

BACKGROUND: Whilst attention has been paid within the literature to examining potentially inappropriate prescribing (PIP) for older adults in a variety of care settings, less is known about the extent within intermediate care. Furthermore, few studies have examined the utility of clinical pharmacist involvement in this care context. OBJECTIVE(S): Determine the prevalence of PIP in intermediate care (IC) settings in Northern Ireland (NI), explore the utility of a novel pharmacist case management model at reducing PIP and to examine the association with subsequent healthcare utilisation. METHODS: Secondary analysis of prospective data (N = 532) collected during a medicines optimisation pharmacist case management model in three intermediate care sites in NI. Independent prescriber pharmacists delivered the intervention. Variability in Medication Appropriateness Index score change (ΔMAI) from admission to discharge was examined using multivariate linear regression analysis. Multivariate logistic and Poisson regressions were used to examine the association between ΔMAI and likelihood and numbers of unplanned hospital readmissions within 30 and 90 days of IC discharge. RESULTS: PIP was highly prevalent (89.5%) at baseline with significant reductions in MAI score achieved from admission (Median = 14) to discharge (Median = 0) (Z = -18.28, p < .001). The prevalence of PIP at discharge was 7.8%. No relationship was observed between ΔMAI score and unplanned hospital readmission. Those who received at least one educational intervention were less likely to be readmitted within 30 days of IC discharge (OR = 0.15, 95% CI 0.03, 0.71, p < .001). Baseline healthcare utilisation consistently predicted healthcare utilisation post-IC discharge. CONCLUSIONS: Drug-related problems persist for many older adults following acute care discharge and intermediate care may provide an ideal location for medicines optimisation interventions.

Heterogeneity in Longitudinal Healthcare Utilisation by Older Adults: A Latent Transition Analysis of the Irish Longitudinal Study on Ageing.

BACKGROUND: Older adults likely exhibit considerable differences in healthcare need and usage. Identifying differences in healthcare utilisation both between and within individuals over time may support future service development. OBJECTIVES: To characterise temporal changes in healthcare utilisation among a nationally representative sample of community-dwelling older adults. METHODS: A latent transition analysis of the first three waves of The Irish Longitudinal Study on Ageing (TILDA) (N = 6128) was conducted. RESULTS: Three latent classes of healthcare utilisation were identified, 'primary care only'; 'primary care and outpatient visits' and 'multiple utilisation'. The classes were invariant across all three waves. Transition probabilities indicated dynamic changes over time, particularly for the 'primary care and outpatient visits' and 'multiple utilisation' statuses. DISCUSSION: Older adults exhibit temporal changes in healthcare utilisation which may reflect changes in healthcare need and disease progression. Further research is required to identify the factors which influence movement between healthcare utilisation patterns.

Depression trajectories among older community dwelling adults: Results from the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: This study investigated the role of a large range psychological, attitudinal and health related variables as predictors of depression trajectories amongst older adults over a 4-year time period. METHODS: Data from three consecutive waves of the TILDA survey of older community dwelling adults aged 50+ in Ireland were combined for analysis. Depression symptom scores were assessed using the Center for Epidemiological Studies- Depression scale (CES-D). Changes in depression scores over three time points were modelled as distinct trajectory classes using group-based trajectory modelling, whilst simultaneously controlling for demographic, attitudinal and health related predictors of these trajectory classes using multinomial regression. RESULTS: Four distinct depression trajectories were identified as (1) a stable low symptom level group (79%), (2) a moderate but deteriorating symptoms group (7.6%), (3) a moderate but improving group (10.1%) and (4) a vulnerable group with consistently high symptoms (3.1%). Multinomial logistic regression indicated that limiting pain, mobility impairments, perceived stress and loneliness predicted membership of the moderate and higher depressive symptom classes. Retirement status and higher reported levels of worry were associated with a greater likelihood of membership of the moderate symptom classes only. LIMITATIONS: Use of the CES-D is open to bias due to subjective nature of respondent reporting. CONCLUSIONS: Results concur with previous studies on the development of depression among older people and highlight the key health related and psychological variables that may inform interventions aimed at mitigating risks of developing depression among older adults.

Using a generic definition of cachexia in patients with kidney disease receiving haemodialysis: a longitudinal (pilot) study.

BACKGROUND: Research indicates that cachexia is common among persons with chronic illnesses and is associated with increased morbidity and mortality. However, there continues to be an absence of a uniformed disease-specific definition for cachexia in chronic kidney disease (CKD) patient populations. OBJECTIVE: The primary objective was to identify cachexia in patients receiving haemodialysis (HD) using a generic definition and then follow up on these patients for 12 months. METHOD: This was a longitudinal study of adult chronic HD patients attending two hospital HD units in the UK. Multiple measures relevant to cachexia, including body mass index (BMI), muscle mass [mid-upper arm muscle circumference (MUAMC)], handgrip strength (HGS), fatigue [Functional Assessment of Chronic Illness Therapy (FACIT)], appetite [Functional Assessment of Anorexia/Cachexia Therapy (FAACT)] and biomarkers [C-reactive protein (CRP), serum albumin, haemoglobin and erythropoietin resistance index (ERI)] were recorded. Baseline analysis included group differences analysed using an independent t-test, dichotomized values using the χ2 test and prevalence were reported using the Statistical Package for the Social Sciences 24 (IBM, Armonk, NY, USA). Longitudinal analysis was conducted using repeated measures analysis. RESULTS: A total of 106 patients (30 females and 76 males) were recruited with a mean age of 67.6 years [standard deviation (SD) 13.18] and dialysis vintage of 4.92 years (SD 6.12). At baseline, 17 patients were identified as cachectic, having had reported weight loss (e.g. >5% for >6 months) or BMI <20 kg/m2 and three or more clinical characteristics of cachexia. Seventy patients were available for analysis at 12 months (11 cachectic versus 59 not cachectic). FAACT and urea reduction ratio statistically distinguished cachectic patients (P = 0.001). However, measures of weight, BMI, MUAMC, HGS, CRP, ERI and FACIT tended to worsen in cachectic patients. CONCLUSION: Globally, cachexia is a severe but frequently underrecognized problem. This is the first study to apply the defined characteristics of cachexia to a representative sample of patients receiving HD. Further, more extensive studies are required to establish a phenotype of cachexia in advanced CKD.

Axial growth and refractive change in white European children and young adults: predictive factors for myopia.

This report describes development of spherical equivalent refraction (SER) and axial length (AL) in two population-based cohorts of white, European children. Predictive factors for myopic growth were explored. Participants were aged 6-7- (n = 390) and 12-13-years (n = 657) at baseline. SER and AL were assessed at baseline and 3, 6 and 9 years prospectively. Between 6 and 16 years: latent growth mixture modelling identified four SER classes (Persistent Emmetropes-PEMM, Persistent Moderate Hyperopes-PMHYP, Persistent High Hyperopes-PHHYP and Emerging Myopes-EMYO) as optimal to characterise refractive progression and two classes to characterise AL. Between 12 and 22-years: five SER classes (PHHYP, PMHYP, PEMM, Low Progressing Myopes-LPMYO and High Progressing Myopes-HPMYO) and four AL classes were identified. EMYO had significantly longer baseline AL (≥ 23.19 mm) (OR 2.5, CI 1.05-5.97) and at least one myopic parent (OR 6.28, CI 1.01-38.93). More myopic SER at 6-7 years (≤ + 0.19D) signalled risk for earlier myopia onset by 10-years in comparison to baseline SER of those who became myopic by 13 or 16 years (p ≤ 0.02). SER and AL progressed more slowly in myopes aged 12-22-years (- 0.16D, 0.15 mm) compared to 6-16-years (- 0.41D, 0.30 mm). These growth trajectories and risk criteria allow prediction of abnormal myopigenic growth and constitute an important resource for developing and testing anti-myopia interventions.

Esotropia Outcomes and the Influence of Delay to Wearing Full Hypermetropic Correction.

PURPOSE: To assess whether delay to full hypermetropic correction wear in children might influence the outcome of a diagnosis of full versus partially accommodative esotropia. METHODS: All children younger than 7 years who were referred with possible strabismus over a 1-year period were assessed. A standard set of details were documented: age at which esotropia was first noticed, age at which esotropia was confirmed by an orthoptist, age at which glasses were prescribed, and age at which full refractive error was constantly worn. When full-time hypermetropic correction was worn, the type of esotropia was determined. RESULTS: There were 430 children referred. Of these, 117 had a concomitant esotropia (62 males and 55 females). Esotropia was confirmed at 35.47 ± 16.67 months of age (range: 4 to 78 months). There were 51 children (43.6%) with full accommodative esotropia, 57 (48.7%) with partially accommodative esotropia, and 9 (7.7%) with nonaccommodative esotropia. Longer delays between the time at which esotropia was identified and the time at which glasses were prescribed were associated with a reduced likelihood of an outcome of full versus partially accommodative esotropia (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.58 to 0.93). Delay to glasses wear for full and partially accommodative esotropia was 1.94 ± 6.4 and 6.24 ± 8.36 months, respectively. Higher average spherical correction scores were associated with a higher likelihood of being in the full accommodative esotropia group (OR = 1.35, 95% CI = 1.07 to 1.69). CONCLUSIONS: A child with recent onset concomitant esotropia is more likely to achieve full versus partially accommodative esotropia if the delay to full hypermetropic corrective glasses wear is minimized. [J Pediatr Ophthalmol Strabismus. 2020;57(2):85-89.].

Estimating the Prevalence of Muscle Wasting, Weakness, and Sarcopenia in Hemodialysis Patients.

OBJECTIVES: Haemodialysis (HD) patients suffer from nutritional problems, which include muscle wasting, weakness, and cachexia, and are associated with poor clinical outcomes. The European Working Group for Sarcopenia in Older People (EWGSOP) and Foundations for the National Institute of Health (FNIH) have developed criteria for the assessment of sarcopenia, including the use of non-invasive techniques such as bioelectrical impedance assessment (BIA), anthropometry, and hand grip strength (HGS) dynamometry. This study investigated the prevalence of muscle wasting, weakness, and sarcopenia using the EWGSOP and FNIH criteria. METHODS: BIA was performed in 24 females (f) and 63 males (m) in the post-dialysis period. Total skeletal muscle mass and appendicular skeletal muscle mass were estimated and index values (i.e., muscle mass divided by height2 [kg/m2]) were calculated (Total Skeletal Muscle Index (TSMI) and Appendicular Skeletal Muscle Index (ASMI)). Mid-arm circumference and triceps skin-fold thickness were measured and mid-upper arm muscle circumference (MUAMC) calculated. HGS was measured using a standard protocol and Jamar dynamometer. Suggested cut-points for low muscle mass and grip strength were utilized using the EWGSOP and FNIH criteria with prevalence estimated, including sarcopenia. RESULTS: The prevalence varied depending on methodology: low TSMI (moderate and severe sarcopenia combined) was 55% for whole group: 21% (f) and 68% (m). Low ASMI was 32% for whole group: 25% (f) and 35% (m). Low MUAMC was 25% for whole group: 0% (f) and 30% (m). ASMI highly correlated with Body Mass Index (r = 0.78, P < .001) and MUAMC (r = 0.68, P < .001). Muscle weakness was high regardless of cut-points used (50-71% (f); 60-79% (m)). CONCLUSIONS: Internationally, this is the first study comparing measures of muscle mass (TSMM and ASMM by BIA and MUAMC) and muscle strength (HGS) using this specific methodology in a hemodialysis population. Future work is required to confirm findings.

Suppression of cathepsin K biomarker in synovial fluid as a free-drug-driven process.

Cathepsin K (CatK) inhibitors exhibited chondroprotective and pain-reducing effects in animal models, however, improvements were relatively modest at dose levels achieving maximal suppression of CatK biomarkers in urine. In this report, a previously characterized CatK inhibitor (MK-1256) is utilized to explore the potential of reduced target engagement and/or suboptimal exposure (free drug) as limiting factors to the pharmacological potential of CatK inhibitors in the knee joint. Following oral administration of MK-1256 at a dose level achieving maximal inhibition of urinary biomarker (helical peptide) in dogs, full suppression of the biomarker in synovial fluid was observed. Subsequent tissue distribution studies conducted in dogs and rabbits revealed that MK-1256 levels in synovial fluid and cartilage were consistent with the free-drug hypothesis. Reasonable projection (within twofold) of drug levels in these tissues can be made based on plasma drug concentration with adjustments for binding factors. These results indicate that the previously observed efficacies in the animal models were not limited by compound distribution or target engagement in the knee tissues.

Profiles of childhood trauma and psychopathology: US National Epidemiologic Survey.

PURPOSE: Childhood trauma may increase vulnerability to numerous specific psychiatric disorders, or a generalised liability to experience dimensions of internalising or externalising psychopathology. We use a nationally representative sample (N = 34,653) to examine the long-term consequences of childhood trauma and their combined effect as predictors of subsequent psychopathology. METHODS: Data from the US National Epidemiologic Survey on Alcohol and Related Conditions were used. Latent class analysis was used to identify childhood trauma profiles and multinomial logistic regression to validate and explore these profiles with a range of associated demographic and household characteristics. We used Structural Equation Modelling to substantiate initial latent class analysis findings by investigating a range of mental health diagnoses. Internalising and externalising domains of psychopathology were regressed on trauma profiles and associated demographic and household characteristics. We used Differential Item Functioning to examine associations between the trauma groups and a number of psychiatric disorders within internalising and externalising dimensions of mental health. RESULTS: We found a 3-class model of childhood trauma in which 85% of participants were allocated to a low trauma class; 6% to a multi-type victimization class (reporting exposures for all the child maltreatment criteria); and 9% to a situational trauma class (exposed to a range of traumas). Confirmatory Factor Analysis revealed an internalising-externalising spectrum was used to represent lifetime reporting patterns of mental health disorders. Both trauma groups showed specific gender and race/ethnicity differences, related family discord and increased psychopathology. Additionally, we found significant associations between the trauma groups and specific diagnoses within the internalising-externalising spectrum of mental health. CONCLUSIONS: The underlying patterns in the exposure to types of interpersonal and non-interpersonal traumas and associated mental health highlight the need to screen for particular types of childhood traumas when individuals present with symptoms of psychiatric disorders.

Establishing a clinical phenotype for cachexia in end stage kidney disease - study protocol.

BACKGROUND: Surveys using traditional measures of nutritional status indicate that muscle wasting is common among persons with end-stage kidney disease (ESKD). Up to 75% of adults undergoing maintenance dialysis show some evidence of muscle wasting. ESKD is associated with an increase in inflammatory cytokines and can result in cachexia, with the loss of muscle and fat stores. At present, only limited data are available on the classification of wasting experienced by persons with ESKD. Individuals with ESKD often exhibit symptoms of anorexia, loss of lean muscle mass and altered energy expenditure. These symptoms are consistent with the syndrome of cachexia observed in other chronic diseases, such as cancer, heart failure, and acquired immune deficiency syndrome. While definitions of cachexia have been developed for some diseases, such as cardiac failure and cancer, no specific cachexia definition has been established for chronic kidney disease. The importance of developing a definition of cachexia in a population with ESKD is underscored by the negative impact that symptoms of cachexia have on quality of life and the association of cachexia with a substantially increased risk of premature mortality. The aim of this study is to determine the clinical phenotype of cachexia specific to individuals with ESKD. METHODS: A longitudinal study which will recruit adult patients with ESKD receiving haemodialysis attending a Regional Nephrology Unit within the United Kingdom. Patients will be followed 2 monthly over 12 months and measurements of weight; lean muscle mass (bioelectrical impedance, mid upper arm muscle circumference and tricep skin fold thickness); muscle strength (hand held dynamometer), fatigue, anorexia and quality of life collected. We will determine if they experience (and to what degree) the known characteristics associated with cachexia. DISCUSSION: Cachexia is a debilitating condition associated with an extremely poor outcome. Definitions of cachexia in chronic illnesses are required to reflect specific nuances associated with each disease. These discrete cachexia definitions help with the precision of research and the subsequent clinical interventions to improve outcomes for patients suffering from cachexia. The absence of a definition for cachexia in an ESKD population makes it particularly difficult to study the incidence of cachexia or potential treatments, as there are no standardised inclusion criteria for patients with ESKD who have cachexia. Outcomes from this study will provide much needed data to inform development and testing of potential treatment modalities, aimed at enhancing current clinical practice, policy and education.

Methods for Molecular Diagnosis of Human Prion Disease.

Human prion diseases are associated with a range of clinical presentations, and they are classified by both clinicopathological syndrome and etiology, with subclassification according to molecular criteria. Here, we describe updated procedures that are currently used within the MRC Prion Unit at UCL to determine a molecular diagnosis of human prion disease. Sequencing of the PRNP open reading frame to establish the presence of pathogenic mutations is described, together with detailed methods for immunoblot or immunohistochemical determination of the presence of abnormal prion protein in the brain or peripheral tissues.

Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.

BACKGROUND: The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). METHODS: We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. FINDINGS: Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs. INTERPRETATION: ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. FUNDING: Medical Research Council and National Institute for Health Research.

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

BACKGROUND: Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. METHODS: A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. RESULTS: Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. CONCLUSION: The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

Severity of mental illness as a result of multiple childhood adversities: US National Epidemiologic Survey.

PURPOSE: To examine patterns of childhood adversity, their long-term consequences and the combined effect of different childhood adversity patterns as predictors of subsequent psychopathology. METHODS: Secondary analysis of data from the US National Epidemiologic Survey on alcohol and related conditions. Using latent class analysis to identify childhood adversity profiles; and using multinomial logistic regression to validate and further explore these profiles with a range of associated demographic and household characteristics. Finally, confirmatory factor analysis substantiated initial latent class analysis findings by investigating a range of mental health diagnoses. RESULTS: Latent class analysis generated a three-class model of childhood adversity in which 60 % of participants were allocated to a low adversity class; 14 % to a global adversities class (reporting exposures for all the derived latent classes); and 26 % to a domestic emotional and physical abuse class (exposed to a range of childhood adversities). Confirmatory Factor analysis defined an internalising-externalising spectrum to represent lifetime reporting patterns of mental health disorders. Using logistic regression, both adversity groups showed specific gender and race/ethnicity differences, related family discord and increased psychopathology. CONCLUSIONS: We identified underlying patterns in the exposure to childhood adversity and associated mental health. These findings are informative in their description of the configuration of adversities, rather than focusing solely on the cumulative aspect of experience. Amelioration of longer-term negative consequences requires early identification of psychopathology risk factors that can inform protective and preventive interventions. This study highlights the utility of screening for childhood adversities when individuals present with symptoms of psychiatric disorders.

A latent class analysis of trauma based on a nationally representative sample of US adolescents.

PURPOSE: Traumatic events in adolescence rarely occur in isolation. Multiple traumatic experiences are prevalent, diverse and a well-established risk factor for mental health disorders. The aim of this study was to explore and explain the heterogeneity in trauma profiles in a nationally representative sample of US adolescents. METHOD: Using latent class analysis, data on 10,123 adolescents aged between 13 and 18 from the National Comorbidity Survey Adolescent Supplement were examined. In addition, the relationships between the emergent classes and demographic and clinical variables were explored. RESULTS: A four-class solution was the best fit of adolescent trauma patterns, with classes labelled as low risk, sexual assault risk, non-sexual risk and high risk. When compared to the low risk class, those in the other classes were significantly more likely not to live with either biological parent, display symptoms indicative of mood and anxiety disorders, and to have higher rates of disorder comorbidity. CONCLUSIONS: This provides evidence of four distinct groups of adolescents who have experienced a variety of traumas. Evidence demonstrates the increased risk of adolescents with a history of trauma meeting the diagnostic criteria for not only individual disorders but also comorbidity across disorder categories.