Mortality and AIDS-defining events among young people following transition from paediatric to adult HIV care in the UK.

OBJECTIVES: To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV. METHODS: Records of people aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow-up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan-Meier and Cox regression. RESULTS: At the final paediatric visit, the 474 participants [51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5-13) years] had a median age of 18 (17-19) years and CD4 count of 471 (280-663) cell/µL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow-up in adult care of 3 (2-6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person-years). In multivariable analyses, lower CD4 count at the last paediatric visit [adjusted hazard ratio = 0.8 (95% confidence interval: 0.7-1.0)/100 cells/µL increment] and AIDS diagnosis in paediatric care [2.7 (1.4-5.5)] were associated with a new AIDS event/mortality in adult care. CONCLUSIONS: Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.

Air pollution and the incidence of ischaemic and haemorrhagic stroke in the South London Stroke Register: a case-cross-over analysis.

BACKGROUND: Few European studies investigating associations between short-term exposure to air pollution and incident stroke have considered stroke subtypes. Using information from the South London Stroke Register for 2005-2012, we investigated associations between daily concentrations of gaseous and particulate air pollutants and incident stroke subtypes in an ethnically diverse area of London, UK. METHODS: Modelled daily pollutant concentrations based on a combination of measurements and dispersion modelling were linked at postcode level to incident stroke events stratified by haemorrhagic and ischaemic subtypes. The data were analysed using a time-stratified case-cross-over approach. Conditional logistic regression models included natural cubic splines for daily mean temperature and daily mean relative humidity, a binary term for public holidays and a sine-cosine annual cycle. Of primary interest were same day mean concentrations of particulate matter <2.5 and <10 µm in diameter (PM2.5, PM10), ozone (O3), nitrogen dioxide (NO2) and NO2+nitrogen oxide (NOX). RESULTS: Our analysis was based on 1758 incident strokes (1311 were ischaemic and 256 were haemorrhagic). We found no evidence of an association between all stroke or ischaemic stroke and same day exposure to PM2.5, PM10, O3, NO2 or NOX. For haemorrhagic stroke, we found a negative association with PM10 suggestive of a 14.6% (95% CI 0.7% to 26.5%) fall in risk per 10 µg/m3 increase in pollutant. CONCLUSIONS: Using data from the South London Stroke Register, we found no evidence of a positive association between outdoor air pollution and incident stroke or its subtypes. These results, though in contrast to recent meta-analyses, are not inconsistent with the mixed findings of other UK studies.

Semi automated transformation to OWL formatted files as an approach to data integration. A feasibility study using environmental, disease register and primary care clinical data.

INTRODUCTION: This article is part of the Focus Theme of METHODS of Information in Medicine on "Managing Interoperability and Complexity in Health Systems". BACKGROUND: Data heterogeneity is one of the critical problems in analysing, reusing, sharing or linking datasets. Metadata, whilst adding semantic description to data, adds an additional layer of complexity in the heterogeneity of metadata descriptors themselves. This can be managed by using a pre-defined model to extract the metadata, but this can reduce the richness of the data extracted. OBJECTIVES: to link the South London Stroke Register (SLSR), the London Air Pollution toolkit (LAP) and the Clinical Practice Research Datalink (CPRD) while transforming data into the Web Ontology Language (OWL) format. METHODS: We used a four-step transformation approach to prepare meta-descriptions, convert data, generate and update meta-classes and generate OWL files. We validated the correctness of the transformed OWL files by issuing queries and assessing results against the original source data. RESULTS: We have transformed SLSR LAP and CPRD into OWL format. The linked SLSR and CPRD OWL file contains 3644 male and 3551 female patients. The linked SLSR and LAP OWL file shows that there are 17 out of 35 outward postcode areas, where no overlapping data can support further analysis between SLSR and LAP. CONCLUSIONS:  Our approach generated a resultant set of transformed OWL formatted files, which are in a query-able format to run individual queries, or can be easily converted into other more suitable formats for further analysis, and the transformation was faithful with no loss or anomalies. Our results have shown that the proposed method provides a promising general approach to address data heterogeneity.

The long-term outcomes of depression up to 10 years after stroke; the South London Stroke Register.

BACKGROUND: Post-stroke depression is a frequent chronic and recurrent problem that starts shortly after stroke and affects patients in the long term. The health outcomes of depression after stroke are unclear. AIMS: (1) To investigate the associations between depression at 3 months and mortality, stroke recurrence, disability, cognitive impairment, anxiety and quality of life (QoL), up to 5 years post-stroke. (2) To investigate these associations in patients recovering from depression by year 1. (3) To investigate associations between depression at 5 years and these outcomes up to 10 years. METHODS: Data from the South London Stroke Register (1997-2010) were used. Patients (n at registration=3240) were assessed at stroke onset, 3 months after stroke and annually thereafter. Baseline data included sociodemographics and stroke severity measures. Follow-up assessments included anxiety and depression (Hospital Anxiety and Depression scale), disability, QoL and stroke recurrence. Multivariable regression models adjusted for age, gender, ethnicity, stroke severity and disability were used to investigate the association between depression and outcomes at follow-up. RESULTS: Depression at 3 months was associated with: increased mortality (HR: 1.27 (1.04 to 1.55)), disability (RRs up to 4.71 (2.96 to 7.48)), anxiety (ORs up to 3.49 (1.71 to 7.12)) and lower QoL (coefficients up to -8.16 (-10.23-6.15)) up to year 5. Recovery from depression by 1 year did not alter these risks to 5 years. Depression in year 5 was associated with anxiety (ORs up to 4.06 (1.92 to 8.58)) and QoL (coefficients up to -11.36 (-14.86 to -7.85)) up to year 10. CONCLUSIONS: Depression is independently associated with poor health outcomes.

Lower incidence of inappropriate shock therapy in patients with combined cardiac resynchronisation therapy defibrillators (CRT-D) compared with patients with non-CRT defibrillators (ICDs).

INTRODUCTION: A significant number of patients experience inappropriate shock therapy (IST) from implantable cardioverter-defibrillators (ICD). An increasing number of patients with advanced heart failure receive combined ICD and cardiac resynchronisation therapy devices (CRT-D). The incidence of IST in this group is less well described. We aimed to assess the incidence and predictors of IST in CRT-D patients. METHODS: A retrospective cohort study of prospectively collected data on patients who received an ICD and CRT-D between October 2007 and January 2009 at our institution were studied. The primary outcome measures were the IST event rate and all-cause mortality. RESULTS: A total of 185 patients with ICD/CRT-D (100/85) were included in the analysis. Eighteen patients experienced 35 episodes of IST during the follow-up (21 ± 13 months). There was a significantly lower IST cumulative event rate in the CRT-D vs. ICD group, 5% (CI: 1-13%) vs. 19% (95% CI: 11-30%) by 24 months, (p = 0.017). The majority of the IST was caused by atrial arrhythmias with atrial fibrillation accounting for 28 episodes of IST in nine patients. Multivariate analysis using Cox hazard model including baseline characteristics and coexisting appropriate shock therapy showed that a history of atrial fibrillation/flutter was the strongest independent predictor of IST with a hazard ratio of 3.53 (p = 0.019). CONCLUSION: Patients with CRT-D had a significantly lower incidence of IST compared with patients receiving an ICD. Given that atrial arrhythmia remained the commonest trigger for IST, our finding lends support to the hypothesis that CRT may reduce atrial fibrillation burden in patients receiving CRT-D.

A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome.

BACKGROUND: There is no prognostic index for primary cutaneous T-cell lymphomas such as mycosis fungoides (MF) and Sezary syndrome (SS). METHOD: Two prognostic indices were developed for early (IA-IIA) and late stage (IIB-IVB) disease based on multivariate data from 1502 patients. End-points included overall survival (OS) and progression free survival (PFS). External validation included 1221 patients. FINDINGS: Significant adverse prognostic factors at diagnosis consisted of male gender, age >60, plaques, folliculotropic disease and stage N1/Nx for early stage, and male gender, age >60, stages B1/B2, N2/3 and visceral involvement for late stage disease. Using these variables we constructed two separate models each defined using 3 distinct groups for early and late stage patients: 0-1 (low risk), 2 (intermediate risk), and 3-5 factors (high risk). 10 year OS in the early stage model was 90.3% (low), 76.2% (intermediate) and 48.9% (high) and for the late stage model 53.2% (low), 19.8% (intermediate) and 15.0% (high). For the validation set significant differences in OS and PFS in early stage patients (both p<0.001) were also noted. In late stage patients, only OS differed between the groups (p=0.002). INTERPRETATION: This proposed cutaneous lymphoma prognostic index provides a model for prediction of OS in early and late stage MF/SS enabling rational therapeutic choices and patient stratification in clinical trials.

Frequency and predictors for the risk of stroke recurrence up to 10 years after stroke: the South London Stroke Register.

BACKGROUND: Data estimating the risk of, and predictors for, long-term stroke recurrence are lacking. METHODS: Data were collected from the population-based South London Stroke Register. Patients were followed up for a maximum of 10 years. Kaplan-Meier estimates and Cox proportional hazards models were used to assess the cumulative risk of and predictors for first stroke recurrence. Variables analysed included sociodemographic factors, stroke subtype (defined as cerebral infarction, intracerebral haemorrhage and subarachnoid haemorrhage), stroke severity markers and prior-to-stroke risk factors. RESULTS: Between 1995 and 2004, 2874 patients with first-ever stroke were included. The mean follow-up period was 2.9 years. During 8311 person-years of follow-up, 303 recurrent events occurred. The cumulative risk of stroke recurrence at 1 year, 5 years and 10 years was 7.1%, 16.2% and 24.5% respectively. No differences in stroke recurrence were noted between the stroke subtypes. Factors increasing the risk of recurrence at 1 year were previous myocardial infarction (HR 1.73; 95% CI 1.08 to 2.78) and atrial fibrillation (HR 1.61; 95% CI 1.04 to 4.27); at 5 years, hypertension (HR 1.47; 95% CI 1.08 to 1.99) and atrial fibrillation (HR 1.79; 95% CI 1.29 to 2.49); and at 10 years, older age (p = 0.04), and hypertension (HR 1.38, 95% CI 1.04 to 1.82), myocardial infarction (HR 1.50, 95% CI 1.06 to 2.11) and atrial fibrillation (HR 1.51, 95% CI 1.09 to 2.09). CONCLUSIONS: Very-long-term risk of stroke recurrence is substantial. Different predictors for stroke recurrence were identified throughout the follow-up period. Risk factors prior to initial stroke have a significant role in predicting stroke recurrence up to 10 years.

Public education and depth of primary malignant melanoma, Hutt Hospital, 1985-92.

AIMS: To document the depth of primary malignant melanoma treated at the Wellington regional plastic and maxillo-facial surgical unit, Hutt Hospital, from 1985-92. To determine the effects of public education campaigns commenced in 1987, on the presentation of melanoma at Hutt Hospital, and to ascertain whether the Department of Health, Health Goals for 1995 were attained in relation to Hutt Hospital. METHODS: A surgical audit was established in 1985 to record all cases of melanoma treated at the plastic surgical unit, Hutt Hospital. Data relating to the depth (Breslow index) of each primary melanoma was extracted from this audit, and reviewed. Metastatic or recurrent disease was excluded. RESULTS: The number of cases of primary melanoma treated at this unit increased greatly following the Cancer Society initiated Spotcheck programme in 1987. There was a significant increase (p < 0.001) in the number and proportion of thin (less than 0.76mm) invasive melanomas treated, from 30% of the total in 1985, through to 70% in 1992. There was no increase in the actual number of thick (> 0.75mm) invasive melanoma, with the total number of cases being treated remaining relatively constant from 1989 onwards. CONCLUSIONS: Significantly more patients are presenting with thin melanoma. This may be due to the nature of the disease itself, alterations in referral patterns, or due to earlier identification of malignant lesions due to greater public education. The education campaigns appear to be responsible for the observed increase in cases of melanoma presenting to our unit. The Department of Health goals for 1995 have already been achieved with > 60% of primary malignant melanoma being < 0.76 mm in depth at time of presentation.

The incidence of hyperemesis gravidarum is increased among Pacific Islanders living in Wellington.

AIMS: To compare the incidence of hyperemesis gravidarum among Pacific Islanders living in Wellington with nonPacific Islanders and to investigate some properties of the disorder. METHODS: Data were collected on all first time admissions to Wellington Women's Hospital for hyperemesis gravidarum over a 5-year period. Women were classified as having severe hyperemesis gravidarum if abnormalities of serum electrolytes and liver function tests results were present and as less severe if these abnormalities were absent. Almost all women had ketonuria. Mantel-Haenszel odds ratios, chi 2 analysis and Fisher's 2-tailed exact test were used for statistical analysis. RESULTS: The proportion of hyperemesis gravidarum patients who were Pacific Islanders was significantly increased when compared to their proportion in a control group (p < 0.01). The difference remained significant when the hyperemesis patients were divided into less and more severe. Abnormal thyroid function test results were more common among Pacific Island patients than among nonPacific Island patients. This difference was significant (p < 0.01) only in the less severe group. CONCLUSION: The incidence of hyperemesis gravidarum is significantly increased among Pacific Island women (especially Samoans) living in Wellington and is often associated with abnormalities of thyroid function test results.

Appraisal of gut lavage in the study of intestinal humoral immunity.

Direct investigation of intestinal humoral immunity requires collection of intestinal secretions or mucosal biopsy specimens, or both. A non-invasive technique of gut lavage, with a polyethyleneglycol electrolyte lavage solution as a means of collecting intestinal secretions for immunoglobulin and antibody studies, was evaluated. Fifty patients were studied--25 immunologically normal patients or volunteers, 15 patients with untreated coeliac disease, and 10 patients with active Crohn's disease. Protease inhibitors were added promptly to samples to prevent proteolysis of immunoglobulin content. Treated lavage samples were assayed by enzyme linked immunosorbent assay for immunoglobulin and antibody content. Studies of serial lavage specimens showed that early, faecally contaminated specimens contained negligible quantities of immunoglobulin, but once the specimens became clear a steady state was reached, with little variation in immunoglobulin content between serial specimens and with a uniform dilution (around 20%) of the ingested polyethyleneglycol. Gut lavage fluid IgA was predominantly secretory, comprising 92%, 81.6%, and 76.7% respectively of the total IgA gut lavage fluid content in the control, coeliac, and Crohn's groups. High values of total IgM and IgA and IgM antigliadin antibodies were detected in the coeliac group, and high values of IgG in the Crohn's disease group. This method of gut lavage is not only an effective bowel cleanser, but also a noninvasive means of obtaining intestinal secretions for the study of humoral immunity in gastrointestinal disease.

Electrophysiological properties of reactive glial cells in the kainate-lesioned hippocampal slice.

Kainate-lesioned hippocampal slices provide an excellent system for examining the electrophysiological properties of non-cultured glial cells without interfering signals from surrounding neurons. Intracellular recordings in the intensely gliotic CA3 region indicated that the resting membrane potential and input resistance of these reactive glial cells were similar to those reported for non-reactive astrocytes. Dye-coupling typical of astrocytes was also demonstrated amongst these cells, and was considerably reduced by cytoplasmic acidification. Occasionally these cells demonstrated spontaneous, rhythmic oscillations of membrane potential associated with large changes in whole cell input resistance. The action potentials reported in cultured astrocytes were not observed in reactive glial cells, even under conditions that maximize the observation of Ca2(+)-dependent responses. This suggests that reactive glial cells in this preparation have either no voltage-activated Ca2+ channels or a very low density of such channels. These cells also lack a bicarbonate conductance, but they do appear to have an apamin-sensitive conductance, possibly a Ca2(+)-activated gK.

GABA-activated Cl- channels in astrocytes of hippocampal slices.

We used kainic acid-lesioned hippocampal slices to examine glial responses to the inhibitory neurotransmitter GABA in a neuron-free environment. Slices were prepared from rats which received intracerebroventricular injections of kainic acid 1 month prior to experiments. Astrocytes (membrane potential averaged 81.4 +/- 5.5 mV; n = 46; mean +/- SD) were impaled in the CA3 region of the slice, which was completely depleted of neurons. GABA (1 mM) application by bath perfusion depolarized membrane potential from 1 to 5 mV. The GABA-induced depolarization was not affected by a tetrodotoxin (1 microM)/high-Mg2+/low-Ca2+ solution. Changing the Cl- equilibrium potential by reducing extracellular Cl- greatly increased the GABA-induced depolarization. Muscimol mimicked the GABA response, while picrotoxin (0.1 mM), an antagonist of the GABA-activated Cl- channel, resulted in a 60% blockade. The barbiturate, pentobarbital (0.1 mM), and the benzodiazepine agonist, flunitrazepam (1 mM), enhanced the depolarization by 60 and 40%, respectively. A blocker of glial GABA uptake, beta-alanine (1 mM), did not affect the GABA-induced membrane depolarization, indicating that the depolarization is not caused by electrogenic uptake of the amino acid. The pharmacological properties of the GABA response of astrocytes from the hippocampal slice is similar to that previously described for cultured astrocytes from rat cerebral hemispheres. Our data suggest that GABA receptors, which are coupled to Cl- channels, are also expressed by astrocytes in an intact tissue.

Kainic acid evokes a potassium efflux from astrocytes.

Cultured astrocytes are depolarized by excitatory amino acids such as kainic acid. In these experiments we tested the hypothesis that the kainic acid-induced depolarization also causes an efflux of K+ from astrocytes in the rat. Using K+-sensitive microelectrodes we measured a K+ efflux from cultured astrocytes during the perfusion of kainic acid. The effects of kainic acid were then tested on glial cells in the neuron-free CA3 region of kainic acid-lesioned hippocampus. Glial cells were depolarized by kainic acid and an efflux of K+ was recorded. These effects are most likely due to direct effects on the glial cells because histological examination of the hippocampus showed this area to be free of neurons. Therefore it is hypothesized that kainic acid and any transmitter that depolarizes glial cells, will increase neuronal excitability indirectly by a K+ efflux from glial cells. This will have widespread implications for iontophoretic studies of transmitter actions.

Propranolol in chronic liver disease: a controlled trial of its effect and safety over twelve months.

The effect and safety of propranolol (Inderal-LA) in 95 patients with mild to moderate chronic liver disease was studied in a double-blind placebo controlled trial. Over a 12-month period, three patients in the propranolol group died compared with eight in the control population. Upper gastrointestinal bleeding occurred in the placebo group only. Twenty-five patients were withdrawn, 12 in the propranolol and 13 in the placebo group. No deterioration in clinical condition or liver function tests was observed in the propranolol-treated patients, although serum testosterone levels fell significantly compared with the control patients. This study shows that long-term treatment with propranolol is safe in patients with chronic liver disease but further studies are required to define whether or not patients will benefit. Our observations on the response to placebo suggest that a significant proportion of patients are not likely to tolerate drug treatment for portal hypertension well.

Membrane conductance oscillations in astrocytes induced by phorbol ester.

Glial cells in the central nervous systems (CNS) have complex functions which are difficult to decipher because of the intimate intertwining of glial cells with neurons. We have therefore developed an essentially neuron-free preparation of CNS astrocytes in the kainic acid lesioned hippocampal slice. With this preparation we have examined the effect of activating protein kinase C in astrocytes with a phorbol ester, TPA (12-O-tetradecanoyl-phorbol-13-acetate). In most cells, TPA induced rhythmic oscillations (0.1-3.0 Hz) of membrane potential which were typically 5-10 mV in amplitude and were associated with increases of up to eightfold in input resistance during the depolarizing phase. These large changes in membrane conductance are the first reported observations of endogenously generated conductance changes in astrocytes of the mammalian CNS and they could influence excitability of surrounding neurons, possibly by altering extracellular ion concentrations.