Understanding risk factors for herpes zoster and postherpetic neuralgia in UK primary care: investigations to inform vaccine policy.

Background: Herpes zoster affects millions of people worldwide each year and many go on to suffer long-term pain, called postherpetic neuralgia (PHN). As zoster is common and PHN is difficult to treat, preventing zoster through vaccination is important. This thesis aims to better understand risk factors for zoster and PHN, in order to inform vaccination policy. Methods: Three large observational studies were carried out using primary care data from the UK Clinical Practice Research Datalink and linked secondary care data from the Hospital Episodes Statistics. First, a matched case-control study quantified the effects of possible risk factors for zoster and explored whether their effects differed by age group. Second, a descriptive study looked at antiviral prescription patterns and patient characteristics associated with antiviral receipt after zoster diagnosis. Third, a cohort study assessed risk factors for PHN and investigated whether their effects were modified by antiviral use. Results: The case-control study of zoster risk factors included 144,959 zoster patients and 549,336 controls and found an increased risk of zoster among patients with rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, chronic kidney disease, depression and type 1 diabetes; odds ratios ranged from 1.14 to 1.72. In general, the relative effects of these risk factors on zoster decreased with increasing age. In the descriptive study of antiviral use, of 142,216 zoster cases, only 58.1% received an antiviral prescription at zoster diagnosis. Antivirals were even under-prescribed among the immunosuppressed and older individuals, for whom guidelines recommend routine treatment. The cohort study of PHN risk factors identified 119,413 zoster patients, 5.8% of whom developed PHN. An increased risk of PHN was found among patients with rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, depression, type 2 diabetes, lower socioeconomic status, smoking and under- or overweight; odds ratios ranged from 1.13-1.82. Antiviral use was not associated with PHN risk overall. The zoster case-control and PHN cohort study showed that patients with severely immunosuppressive conditions were at greatest risk of both zoster and PHN. Conclusions: A number of patient characteristics and comorbidities were associated with increased zoster and PHN risks. Patients at highest risk of zoster and PHN are those of older age and those with immunosuppression; currently, patients with immunosuppression are not eligible for vaccination, highlighting a need for alternative risk reduction strategies in this group. Low antiviral use at zoster diagnosis suggests treatment guidelines be revised to encourage greater use, especially among the immunosuppressed and older individuals who are recommended, but not routinely given, antivirals. Research on the cost-effectiveness of vaccinating patients with specific risk factors is needed

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Association Between Common Infections and Incident Post-Stroke Dementia:A Cohort Study Using the Clinical Practice Research Datalink

PURPOSE: To investigate the association between common infections and post-stroke dementia in a UK population-based cohort. MATERIALS AND METHODS: A total of 60,392 stroke survivors (51.2% male, median age 74.3 years, IQR 63.9-82.4 years) were identified using primary care records from the Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) with no history of dementia. Primary exposure was any GP-recorded infection (lower respiratory tract infection (LRTI), urinary tract infection (UTI) requiring antibiotics, skin and soft tissue infection requiring antibiotics) occurring after stroke. The primary outcome was incident all-cause dementia recorded in primary care records. In sensitivity analyses, we restricted to individuals with linked hospital records and expanded definitions to include ICD-10 coded hospital admissions. We used multivariable Cox regression to investigate the association between common infections and dementia occurring from 3 months to 5 years after stroke. RESULTS: Of 60,392 stroke survivors, 20,969 (34.7%) experienced at least one infection and overall 4512 (7.5%) developed dementia during follow-up. Early dementia (3 months to 1-year post-stroke) risk was increased in those with at least one GP-recorded infection (HR 1.44, 95% CI 1.21-1.71), with stronger associations when hospitalised infections were included (HR 1.84, 95% CI 1.58-2.14). Late dementia (1-5 years) was only associated with hospitalised, but not with GP-recorded, infections. CONCLUSION: There was evidence of an association between common infections and post-stroke dementia, strongest in the 3-12 months following stroke. Better understanding of this relationship could help inform knowledge of pathways to dementia post-stroke and targeting of preventive interventions

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Association of Relative Age in the School Year With Diagnosis of Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Depression

IMPORTANCE: Young relative age within the school year has previously been associated with attention-deficit/hyperactivity disorder (ADHD) diagnosis and, based on limited evidence, diagnosis of intellectual disability. No study to date has examined the association between relative age and diagnosis of depression. OBJECTIVE: To estimate the associations with intellectual disability and ADHD and investigate a potential novel association between relative age and childhood depression. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study of 1 042 106 children aged 4 to 15 years used electronic record data collected before January 3, 2017, from more than 700 general practices contributing to the UK Clinical Practice Research Datalink. Multivariable Cox proportional hazards regression modeling was used to explore the association between relative age and the incidence of intellectual disability, ADHD, and depression before age 16 years. Data were analyzed between July 2017 and January 2019. EXPOSURES: Relative age within school year determined by month of birth and categorized into four 3-month groups. MAIN OUTCOMES AND MEASURES: Intellectual disability, ADHD, and depression. RESULTS: In the total cohort of 1 042 106 children, 532 876 were male (51.1%) and the median age at study entry was 4.0 years (interquartile range, 4.0-5.0). There was evidence that being born in the last quarter of the school year (ie, being the youngest group in a school year) was associated with diagnosis of intellectual disability (adjusted hazard ratio [aHR], 1.30; 95% CI, 1.18-1.42), ADHD (aHR, 1.36; 95% CI, 1.28-1.45), and depression (aHR, 1.31; 95% CI, 1.08-1.59) compared with being born in the first quarter. A graded association was seen with intermediate age groups at a smaller increased risk of each diagnosis compared with the oldest group, with aHRs for intellectual disability for those born in the second quarter of 1.06 (95% CI, 0.96-1.17) and for those born in the third quarter of 1.20 (95% CI, 1.09-1.32); aHRs for ADHD for those born in the second quarter of 1.15 (95% CI, 1.08-1.23) and for those born in the third quarter of 1.31 (95% CI, 1.23-1.40); and aHRs for depression for those born in the second quarter of 1.05 (95% CI, 0.85-1.29) and for those born in the third quarter of 1.13 (95% CI, 0.92-1.38). CONCLUSIONS AND RELEVANCE: In this study, relative youth status in the school year is associated with an increased risk of diagnosis of ADHD, intellectual disability, and depression in childhood. Further research into clinical and policy interventions to minimize these associations appears to be needed

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

<p>Abstract</p> <p>Background</p> <p>Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.</p> <p>Methods</p> <p>The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.</p> <p>Results</p> <p>For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.</p> <p>Conclusion</p> <p>In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.</p

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Partner Bereavement and Detection of Dementia: A UK-Based Cohort Study Using Routine Health Data

BACKGROUND: In the UK, an estimated one third of people with dementia have not received a diagnosis. Good evidence suggests that dementia risk is increased among widowed individuals; however, it is not clear if they are being diagnosed in routine primary care. // OBJECTIVE: This study aimed to investigate if bereavement influenced the probability of having received a dementia diagnosis. // METHODS: A population-based cohort study using UK electronic health records, between 1997 and 2017, among 247,586 opposite-sex partners. Those experiencing partner bereavement were matched (age, sex, and date of bereavement) to a non-bereaved person living in a partnership. Multivariate cox regression was performed. // RESULTS: Partner bereavement was associated with an increased risk of receiving a diagnosis of dementia in the first three months (hazard ratio (HR) 1.43, 95% CI 1.20-1.71) and first six months (HR 1.24, 95% CI 1.09-1.41), while there was a small reduced risk of getting a dementia diagnosis over all follow-up (HR 0.94, 95% CI 0.89-0.98). // CONCLUSIONS: Partner bereavement appears to lead to a short-term increased risk of the surviving partner receiving a diagnosis of dementia, suggesting that bereavement unmasks existing undiagnosed dementia. Over the longer term, however, bereaved individuals are less likely to have a diagnosis of dementia in their health records than non-bereaved individuals