Showing papers by "Leicester Royal Infirmary published in 2013"

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Abstract: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 10 × 10(-4)) In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 50 × 10(-8)), 3 of which we found after conditioning on previously identified variants Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals

Prevalence of Metabolic Syndrome and Metabolic Abnormalities in Schizophrenia and Related Disorders—A Systematic Review and Meta-Analysis

Abstract: Individuals with schizophrenia have high levels of medical comorbidity and cardiovascular risk factors. The presence of 3 or more specific factors is indicative of metabolic syndrome, which is a significant influence upon future morbidity and mortality. We aimed to clarify the prevalence and predictors of metabolic syndrome (MetS) in adults with schizophrenia and related disorders, accounting for subgroup differences. A PRISMA systematic search, appraisal, and meta-analysis were conducted of 126 analyses in 77 publications (n 525 692). The overall rate of MetSwas 32.5% (95% CI 5 30.1%–35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females. Older age had a modest influence on the rate of MetS (adjusted R 2 5 .20;P 38 y) are shown in supplementary appendix 2 online. Regarding prescribed antipsychotic medication, highest rates were seen in those prescribed clozapine (51.9%) and lowest rates of MetS in those who were unmedicated (20.2%). Present findings strongly support the notion that patients with schizophrenia should be considered a high-risk group. Patients with schizophrenia should receive regular monitoring and adequate treatment of cardio-metabolic risk factors.

Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis

Abstract: Summary Background Cancer survival has improved in the past 20 years, affecting the long-term risk of mood disorders. We assessed whether depression and anxiety are more common in long-term survivors of cancer compared with their spouses and with healthy controls. Methods We systematically searched Medline, PsycINFO, Embase, Science Direct, Ingenta Select, Ovid, and Wiley Interscience for reports about the prevalence of mood disorders in patients diagnosed with cancer at least 2 years previously. We also searched the records of the International Psycho-oncology Society and for reports that cited relevant references. Three investigators independently extracted primary data. We did a random-effects meta-analysis of the prevalences of depression and anxiety in cancer patients compared with spouses and healthy controls. Findings Our search returned 144 results, 43 were included in the main analysis: for comparisons with healthy controls, 16 assessed depression and ten assessed anxiety; of the comparisons with spouses, 12 assessed depression and five assessed anxiety. The prevalence of depression was 11·6% (95% CI 7·7–16·2) in the pooled sample of 51 381 cancer survivors and 10·2% (8·0–12·6) in 217 630 healthy controls (pooled relative risk [RR] 1·11, 95% CI 0·96–1·27; p=0·17). The prevalence of anxiety was 17·9% (95% CI 12·8–23·6) in 48 964 cancer survivors and 13·9% (9·8–18·5) in 226 467 healthy controls (RR 1·27, 95% CI 1·08–1·50; p=0·0039). Neither the prevalence of depression (26·7% vs 26·3%; RR 1·01, 95% CI 0·86–1·20; p=0·88) nor the prevalence of anxiety (28·0% vs 40·1%; RR 0·71, 95% CI 0·44–1·14; p=0·16) differed significantly between cancer patients and their spouses. Interpretation Our findings suggest that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls. Efforts should be made to improve recognition and treatment of anxiety in long-term cancer survivors and their spouses. Funding None.

Optimization of Chemotherapy for Younger Patients With Acute Myeloid Leukemia: Results of the Medical Research Council AML15 Trial

Abstract: Purpose. Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. Patients and Methods. Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m2 or 1.5 g/m2 (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227). Results. Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m2), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. Conclusion. FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m2 is equivalent to a 3 g/m2 dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.

Cancer chemoprevention: a rapidly evolving field

Abstract: Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy. The potential value of this approach has been demonstrated with trials in breast, prostate and colon cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of chemoprevention and highlight potential new developments.

Barth syndrome

Abstract: First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.

Influence of Plasma Processing on Recovery and Analysis of Circulating Nucleic Acids

Abstract: Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer. However there is wide variation in blood processing and methods for isolation of circulating free DNA (cfDNA) and microRNAs (miRNAs). Here we compare the extraction efficiency and reproducibility of 4 commercially available kits for cfDNA and 3 for miRNA using spike-in of reference templates. We also compare the effects of increasing time between venepuncture and centrifugation and differential centrifugation force on recovery of CNAs. cfDNA was quantified by TaqMan qPCR and targeted deep sequencing. miRNA profiles were assessed with TaqMan low-density arrays and assays. The QIAamp® DNA Blood Mini and Circulating nucleic acid kits gave the highest recovery of cfDNA and efficient recovery (>90%) of a 564bp spike-in. Moreover, targeted sequencing revealed overlapping cfDNA profiles and variant depth, including detection of HER2 gene amplification, using the Ion AmpliSeq™Cancer Hotspot Panel v2. Highest yields of miRNA and the synthetic Arabidopsis thaliana miR-159a spike-in were obtained using the miRNeasy Serum/Plasma kit, with saturation above 200 µl of plasma. miRNA profiles showed significant variation with increasing time before centrifugation (p 12 years, highlighting the potential for analysis of stored sample biobanks. In the era of the liquid biopsy, standardisation of methods is required to minimise variation, particularly for miRNA.

Gray matter damage predicts the accumulation of disability 13 years later in MS.

Abstract: Objectives: To assess the value of conventional and magnetization transfer (MT) MRI measures of white matter (WM) and gray matter (GM) damage, and their 12-month change, in predicting long-term disability and cognitive impairment in multiple sclerosis (MS). Methods: Conventional and MT MRI brain scans were obtained at baseline and at 12 months in 73 patients, who were followed prospectively with clinical visits and rating of the Expanded Disability Status Scale score and the MS severity score (MSSS) for a median period of 13.3 years. At 13-year follow-up, a neuropsychological assessment was also performed when possible. T2-hyperintense and T1-hypointense lesion volumes, GM fraction (GMF), WM fraction, thalamic fraction, average lesion MT ratio (MTR), average GM MTR, average normal-appearing WM MTR, and thalamic MTR were measured. Random forest and multivariable analyses were performed to identify the predictors of neurologic deterioration and cognitive impairment at 13 years. Results: At 13-year follow-up, 66% of patients showed significant worsening of disability and 37% had worsened cognitively. The multivariable model, in which Expanded Disability Status Scale deterioration at final follow-up was the dependent variable, identified baseline GMF (odds ratio [OR] = 0.79, p = 0.01) as the only predictor of worsening of disability (C-index = 0.69). Baseline disease duration (OR = 1.50, p = 0.08) and average GM MTR (OR = 0.87, p = 0.03) were independent variables associated with cognitive deterioration (C-index = 0.97). Baseline MSSS (β = 0.50, p p = 0.0005) predicted MSSS at follow-up ( r 2 = 0.45). Conclusions: GM damage is one of the key factors associated with long-term accumulation of disability and cognitive impairment in MS.

Opioids and immune modulation: more questions than answers

Abstract: Summary Opioid addicts are more likely to present with infections suggesting opioids are immune modulators. The potential sites/mechanism(s) for this modulation are controversial and on close inspection not well supported by the current literature. It has long been assumed that opioid-induced immune modulation occurs via a combination of direct actions on the immune cell itself, via the hypothalamic-pituitary-adrenal (HPA) axis, or both. Opioid receptors are classified as MOP (μ, mu), DOP (δ, delta), and KOP (κ, kappa)'classical naloxone sensitive receptors'or NOP (the receptor for nociceptin/orphanin FQ), which is naloxone insensitive. Opioids currently used in clinical practice predominantly target the MOP receptor. There do not appear to be classical opioid receptors present on immune cells. The evidence for HPA activation is also poor and shows some species dependence. Most opioids used clinically or as drugs of abuse do not target the NOP receptor. Other possible target sites for immune modulation include the sympathetic nervous system and central sites. We are currently unable to accurately define the cellular target for immune modulation and suggest further investigation is required. Based on the differences observed when comparing studies in laboratory animals and those performed in humans we suggest that further studies in the clinical setting are needed.

The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison

Abstract: The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Abstract: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Early and ultra-early surgery in hip fracture patients improves survival.

Abstract: Background Hip fracture is a common injury with associated high mortality. Recent drives by the Department of Health have sought to prioritise these patients’ care. In April 2010, the Best Practice Tariff was introduced in England and Wales. This offers financial incentives to institutions that provide holistic care and surgery within 36 h for hip fracture patients. The England and Wales National Institute for Health and Clinical Excellence (NICE) published its first guidance on hip fracture management in June 2011, and emphasised the need for surgery on the day or day after admission. In spite of the emphasis placed on this injury, the predictors of in-hospital mortality remain ill-defined. In particular the effect of the timing of surgery remains contentious. Objective To address the issues raised by NICE around surgical timing and examine whether surgery before a 36 h watershed improves survival. In addition, to examine survival outcomes for each 12 h watershed following admission. Materials and methods Prospectively collected data on 2056 patients presenting to our unit with hip fractures between February 2008 and May 2011 were retrospectively reviewed. Multivariate regression analysis was used to correct for confounders, and so determine the effect of various parameters on in-patient mortality. Results Age ( p p p p p p p Conclusions Expeditious surgery is associated with improved patient survival. Other predictors of in-hospital mortality include age, gender, in-hospital fracture and ASA-grade. Ultra-early surgery (within 12 h) reduces risk of in-hospital mortality.

The predictive properties of frailty-rating scales in the acute medical unit

Abstract: Background: older people are at an increased risk of adverse outcomes following attendance at acute hospitals. Screening tools may help identify those most at risk. The objective of this study was to compare the predictive properties of five frailty-rating scales. Method: this was a secondary analysis of a cohort study involving participants aged 70 years and above attending two acute medical units in the East Midlands, UK. Participants were classified at baseline as frail or non-frail using five different frailty-rating scales. The ability of each scale to predict outcomes at 90 days (mortality, readmissions, institutionalisation, functional decline and a composite adverse outcome) was assessed using area under a receiver-operating characteristic curve (AUC). Results: six hundred and sixty-seven participants were studied. Frail participants according to all scales were associated with a significant increased risk of mortality [relative risk (RR) range 1.6–3.1], readmission (RR range 1.1–1.6), functional decline (RR range 1.2–2.1) and the composite adverse outcome (RR range 1.2–1.6). However, the predictive properties of the frailty-rating scales were poor, at best, for all outcomes assessed (AUC ranging from 0.44 to 0.69). Conclusion: frailty-rating scales alone are of limited use in risk stratifying older people being discharged from acute medical units.

Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration--a clinical pilot study including assessment of patient acceptability.

Abstract: Curcumin, the main constituent of turmeric, is suspected to possess cancer chemopreventive properties Pharmacokinetic and pharmacodynamic parameters have been reported, but few data exist describing whether methodologies are suitably robust for curcuminoid detection in colonic biopsy specimens Information on the acceptability of prolonged administration of daily curcumin is not available This is of vital importance to implement chemoprevention strategies This study aimed to quantify levels of curcuminoids in colorectal mucosa of patients undergoing colorectal endoscopy or surgical resection and to obtain information on the acceptability and compliance with daily curcumin Curcumin C3 complex (235 g) was administered to patients once daily for 14 days before endoscopic biopsy or colonic resection Safety and tolerance were monitored Analysis of curcuminoids in plasma, urine, and colonic mucosa was conducted by ultraperformance liquid chromatography (UPLC)-UV with characterization by liquid chromatography/tandem mass spectrometry (LC/MS-MS) Twenty-four of 26 patients commencing curcumin completed the course Six patients reported mild gastrointestinal adverse events Curcuminoids were detectable in nine of 24 plasma samples, 24 of 24 urine samples, and in the colonic mucosa of all 23 biopsied participants Mean tissue levels were 484 μg/g (1278 nmol/g) of parent curcuminoids The major conjugate, curcumin glucuronide, was detectable in 29 of 35 biopsies High levels of topical curcumin persisted in the mucosa for up to 40 hours postadministration Sixteen participants (67%) stated that they would take curcumin long-term should it be of proven benefit In summary, pharmacologically active levels of curcumin were recovered from colonic mucosa The regimen used here seems safe, and patients support its use in long-term trials

U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T‐cell lymphoma

Abstract: Summary Background Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced-stage (IIB–IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid-modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side-effects are dose dependent and may be controlled with corrective therapy or dose adjustments. Objectives To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect. Methods Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature. Results The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting. Conclusion Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose.

The Identification of Seniors at Risk (ISAR) score to predict clinical outcomes and health service costs in older people discharged from UK acute medical units

Abstract: Background: tools are required to identify high-risk older people in acute emergency settings so that appropriate services can be directed towards them. Objective: to evaluate whether the Identification of Seniors At Risk (ISAR) predicts the clinical outcomes and health and social services costs of older people discharged from acute medical units. Design: an observational cohort study using receiver–operator curve analysis to compare baseline ISAR to an adverse clinical outcome at 90 days (where an adverse outcome was any of death, institutionalisation, hospital readmission, increased dependency in activities of daily living (decrease of 2 or more points on the Barthel ADL Index), reduced mental well-being (increase of 2 or more points on the 12-point General Health Questionnaire) or reduced quality of life (reduction in the EuroQol-5D) and high health and social services costs over 90 days estimated from routine electronic service records. Setting: two acute medical units in the East Midlands, UK. Participants: a total of 667 patients aged ≥70 discharged from acute medical units. Results: an adverse outcome at 90 days was observed in 76% of participants. The ISAR was poor at predicting adverse outcomes (AUC: 0.60, 95% CI: 0.54–0.65) and fair for health and social care costs (AUC: 0.70, 95% CI: 0.59–0.81). Conclusions: adverse outcomes are common in older people discharged from acute medical units in the UK; the poor predictive ability of the ISAR in older people discharged from acute medical units makes it unsuitable as a sole tool in clinical decision-making.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial

Abstract: Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing ‘Medical Research Council (MRC) Chemotherapy’+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified ‘Spanish’) therapy. MRC treatment comprised four courses with ATRA in courses 1–2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1–3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P 10 × 109/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

The challenge of delivering endocrine care and successful transition to adult services in adolescents with congenital adrenal hyperplasia: experience in a single centre over 18 years

Abstract: BACKGROUND: Congenital adrenal hyperplasia (CAH) has implications throughout a patient's life. The challenges of organising transition from paediatric to adult care in endocrinology are recognised. OBJECTIVE: To evaluate whether young people with CAH have been successfully transitioned from paediatric care to specialist adult services and the influence of the introduction of a Young Person Clinic (YPC) where the young person is introduced to the adult endocrinologist. DESIGN, PATIENTS AND MEASUREMENTS: Patients aged 16+ years with CAH who had attended the adrenal clinic at Royal Manchester Children's Hospital between 1992 and 2009 were identified. Clinical information, attendance data in paediatric and adult services were obtained from patient records and the electronic appointment system. RESULTS: 61 patients (27 male) were identified. 36 patients were referred to specialist adult services from the paediatric service, 18 of these (50%) were lost to follow up (2 were never offered an appointment). Only 53% of the whole group attended their first new and subsequent second appointment (i.e. good early attenders). There was no difference in engagement with adult services in those who transitioned through the YPC. Good early attenders were less likely to get lost to follow up compared with poor early attenders (11-33% lost to follow up compared with 63-71%). CONCLUSIONS: Half of all young people with CAH referred to specialist adult services are no longer attending. Introducing the adult endocrinologist prior to transfer had no positive effect on engagement with adult services. Attendance at the first two appointments in the adult services should be seen as an indicator of "reasonable" engagement. � 2012 Blackwell Publishing Ltd.

Enhancement of CD154/IL4 proliferation by the T follicular helper (Tfh) cytokine, IL21 and increased numbers of circulating cells resembling Tfh cells in chronic lymphocytic leukaemia

Abstract: Chronic lymphocytic leukaemia (CLL) cells encounter T-cells and proliferate in response to T-cell signals in the lymph node microenvironment. In this report we determined interleukin 21 (IL21) function in CLL and showed that IL21 and interleukin 4 (IL4) act co-operatively to promote leukaemic cell proliferation without apoptosis or differentiation We further show that IL21 increased side population (SP) cells, which are associated with resistance to chemotherapy and increased self-renewal capacity in CLL. IL21 and IL4 are the major cytokines produced by the recently described CD4(+) T follicular helper (Tfh) cell subset. Determination of Tfh cells in peripheral blood showed that patients had significantly increased numbers as compared to normal subjects although no association was found between Tfh numbers and IGHV gene mutational status or clinical stage. Our data suggests that the Tfh cytokines, IL4 and IL21, contribute to driving leukaemic cell proliferation in the lymph node microenvironment, and may contribute to the specific production of cells resistant to conventional chemotherapy. We suggest that increased circulating Tfh cells is a component of T-cell dysregulation in CLL. Our findings have implications for the therapeutic use of IL21.

Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath

Abstract: Background: In-community non-invasive identification of asthma-specific volatile organic compounds (VOCs) in exhaled breath presents opportunities to characterize phenotypes, and monitor disease state and therapies. The feasibility of breath sampling with children and the preliminary identification of childhood asthma markers were studied. Method: End-tidal exhaled breath was sampled (2.5 dm3) from 11 children with asthma and 12 healthy children with an adaptive breath sampler. VOCs were collected onto a Tenax®/Carbotrap hydrophobic adsorbent trap, and analyzed by GC–MS. Classification was by retention-index and mass spectra in a ‘breath matrix‘ followed by multivariate analysis. Results: A panel of eight candidate markers (1-(methylsulfanyl)propane, ethylbenzene, 1,4-dichlorobenzene, 4-isopropenyl-1-methylcyclohexene, 2-octenal, octadecyne, 1-isopropyl-3-methylbenzene and 1,7-dimethylnaphtalene) were found to differentiate between the asthmatic and healthy children in the test cohort with complete separa...

Predicting aortic complications after endovascular aneurysm repair.

Abstract: Background Lifelong surveillance is standard after endovascular repair of abdominal aortic aneurysm (EVAR), but remains costly, heterogeneous and poorly calibrated. This study aimed to develop and validate a scoring system for aortic complications after EVAR, informing rationalized surveillance. Methods Patients undergoing EVAR at two centres were studied from 2004 to 2010. Preoperative morphology was quantified using three-dimensional computed tomography according to a validated protocol, by investigators blinded to outcomes. Proportional hazards modelling was used to identify factors predicting aortic complications at the first centre, and thereby derive a risk score. Sidak tests between risk quartiles dichotomized patients to low- or high-risk groups. Aortic complications were reported by Kaplan–Meier analysis and risk groups were compared by log rank test. External validation was by comparison of aortic complications between risk groups at the second centre. Results Some 761 patients, with a median age of 75 (interquartile range 70–80) years, underwent EVAR. Median follow-up was 36 (range 11–94) months. Physiological variables were not associated with aortic complications. A morphological risk score incorporating maximum aneurysm diameter (P < 0·001) and largest common iliac diameter (measured 10 mm from the internal iliac origin; P = 0·004) allocated 75 per cent of patients to a low-risk group, with excellent discrimination between 5-year rates of aortic complication in low- and high-risk groups at both centres (centre 1: 12 versus 31 per cent, P < 0·001; centre 2: 12 versus 45 per cent, P = 0·002). Conclusion The risk score uses commonly available morphological data to stratify the rate of complications after EVAR. The proposals for rationalized surveillance could provide clinical and economic benefits.

Interventions for treating wrist fractures in children

Abstract: Background Wrist fractures, involving the distal radius, are the most common fractures in children. Most are buckle fractures, which are stable fractures, unlike greenstick and other usually displaced fractures. There is considerable variation in practice, such as the extent of immobilisation for buckle fractures and use of surgery for seriously displaced fractures. Objectives To assess the effects (benefits and harms) of interventions for common distal radius fractures in children, including skeletally immature adolescents. Search methods We searched the Cochrane Bone, Joint and Muscle Trauma Group's Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, trial registries and reference lists to May 2018. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs comparing interventions for treating distal radius fractures in children. We sought data on physical function, treatment failure, adverse events, time to return to normal activities (recovery time), wrist pain, and child (and parent) satisfaction. Data collection and analysis At least two review authors independently performed study screening and selection, 'Risk of bias' assessment and data extraction. We pooled data where appropriate and used GRADE for assessing the quality of evidence for each outcome. Main results Of the 30 included studies, 21 were RCTs, seven were quasi-RCTs and two did not describe their randomisation method. Overall, 2930 children were recruited. Typically, trials included more male children and reported mean ages between 8 and 10 years. Eight studies recruited buckle fractures, five recruited buckle and other stable fractures, three recruited minimally displaced fractures and 14 recruited displaced fractures, typically requiring closed reduction, typically requiring closed reduction. All studies were at high risk of bias, mainly reflecting lack of blinding. The studies made 14 comparisons. Below we consider five prespecified comparisons:Removable splint versus below-elbow cast for predominantly buckle fractures (6 studies, 695 children)One study (66 children) reported similar Modified Activities Scale for Kids - Performance scores (0 to 100; no disability) at four weeks (median scores: splint 99.04; cast 99.11); low-quality evidence. Thirteen children needed a change or reapplication of device (splint 5/225; cast 8/219; 4 studies); very low-quality evidence. One study (87 children) reported no refractures at six months. One study (50 children) found no between-group difference in pain during treatment; very low-quality evidence. Evidence was absent (recovery time), insufficient (children with minor complications) or contradictory (child or parent satisfaction). Two studies estimated lower healthcare costs for removable splints.Soft or elasticated bandage versus below-elbow cast for buckle or similar fractures (4 studies, 273 children)One study (53 children) reported more children had no or only limited disability at four weeks in the bandage group; very low-quality evidence. Eight children changed device or extended immobilisation for delayed union (bandage 5/90; cast 3/91; 3 studies); very low-quality evidence. Two studies (139 children) reported no serious adverse events at four weeks. Evidence was absent, insufficient or contradictory for recovery time, wrist pain, children with minor complications, and child and parent satisfaction. More bandage-group participants found their treatment convenient (39 children).Removal of casts at home by parents versus at the hospital fracture clinic by clinicians (2 studies, 404 children, mainly buckle fractures)One study (233 children) found full restoration of physical function at four weeks; low-quality evidence. There were five treatment changes (home 4/197; hospital 1/200; 2 studies; very low-quality evidence). One study found no serious adverse effects at six months (288 children). Recovery time and number of children with minor complications were not reported. There was no evidence of a difference in pain at four weeks (233 children); low-quality evidence. One study (80 children) found greater parental satisfaction in the home group; low-quality evidence. One UK study found lower healthcare costs for home removal.Below-elbow versus above-elbow casts for displaced or unstable both-bone fractures (4 studies, 399 children)Short-term physical function data were unavailable but very low-quality evidence indicated less dependency when using below-elbow casts. One study (66 children with minimally displaced both-bone fractures) found little difference in ABILHAND-Kids scores (0 to 42; no problems) (mean scores: below-elbow 40.7; above-elbow 41.8); very low-quality evidence. Overall treatment failure data are unavailable, but nine of the 11 remanipulations or secondary reductions (366 children, 4 studies) were in the above-elbow group; very low-quality evidence. There was no refracture or compartment syndrome at six months (215 children; 2 studies). Recovery time and overall numbers of children with minor complications were not reported. There was little difference in requiring physiotherapy for stiffness (179 children, 2 studies); very low-quality evidence. One study (85 children) found less pain at one week for below-elbow casts; low-quality evidence. One study found treatment with an above-elbow cast cost three times more in Nepal.Surgical fixation with percutaneous wiring and cast immobilisation versus cast immobilisation alone after closed reduction of displaced fractures (5 studies, 323 children)Where reported, above-elbow casts were used. Short-term functional outcome data were unavailable. One study (123 children) reported similar ABILHAND-Kids scores indicating normal physical function at six months (mean scores: surgery 41.9; cast only 41.4); low-quality evidence. There were fewer treatment failures, defined as early or problematic removal of wires or remanipulation for early loss in position, after surgery (surgery 20/124; cast only 41/129; 4 studies; very low-quality evidence). Similarly, there were fewer serious advents after surgery (surgery 28/124; cast only 43/129; 4 studies; very low-quality evidence). Recovery time, wrist pain, and satisfaction were not reported. There was lower referral for physiotherapy for stiffness after surgery (1 study); very low-quality evidence. One USA study found similar treatment costs in both groups. Authors' conclusions Where available, the quality of the RCT-based evidence on interventions for treating wrist fractures in children is low or very low. However, there is reassuring evidence of a full return to previous function with no serious adverse events, including refracture, for correctly-diagnosed buckle fractures, whatever the treatment used. The review findings are consistent with the move away from cast immobilisation for these injuries. High-quality evidence is needed to address key treatment uncertainties; notably, some priority topics are already being tested in ongoing multicentre trials, such as FORCE.

HDAC inhibitor confers radiosensitivity to prostate stem-like cells.

Abstract: Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction. Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2β1integrinhi/CD133+), transit-amplifying (TA, α2β1integrinhi/CD133−) and committed basal (CB, α2β1integrinlo) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser. Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation. Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction.

Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009†

Abstract: Objective: To investigate whether center differences in glycemic control are present in prepubertal children Research Design and Methods: This cross-sectional study involved 18 pediatric centers worldwide. All children, Results: A total of 1133 children participated (mean age: 8.0 +/- 2.1 y; females: 47.5%, mean diabetes duration: 3.8 +/- 2.1 y). HbA1c (overall mean: 8.0 +/- 1.0%; range: 7.3-8.9%) and severe hypoglycemia frequency (mean 21.7 events per 100 patient-years), but not DKA, differed significantly between centers (p Conclusions: Center differences in metabolic outcomes are present in children