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High-throughput technologies applied to the analysis of vaccine responses are likely to reveal the mechanisms responsible for vaccine-induced protection, aid understanding of vaccine safety and help accelerate vaccine development and clinical trials.

Background: Community treatment orders (CTOs) have not been shown in randomised trials to reduce readmission to hospital in patients with psychosis, but these trials have been short (11-12 months). We previously investigated the effect of CTOs on readmission rates over 12 months in a randomised trial (OCTET). Here, we present follow-up data for a cohort of individuals recruited to our original trial to examine the long-term effect of CTOs on readmissions and the risk of patients disengaging from mental health services temporarily or enduringly., Methods: For OCTET, an open-label, parallel, randomised controlled trial, we recruited patients aged 18-65 years involuntarily admitted to mental health hospitals in 32 trusts in England, with a diagnosis of psychosis and deemed suitable for CTOs by their clinicians. Between Nov 10, 2008, and Feb 22, 2011, we recruited and randomly assigned 336 eligible patients (1:1) to be discharged on either a CTO (n=167) or to voluntary status via Section 17 leave (control group; n=169). For the analysis presented in this report, we assessed data at 36 months for 330 of these patients. We tested rates of readmission to hospital, time to first readmission, number of readmissions, and duration of readmission in patients assigned to CTO versus those assigned to control, and in all patients with CTO experience at any time in the 36 months versus those without. We also tested whether duration of CTO affected readmission outcomes in patients with CTO experience. We examined discontinuation (≥60 days between clinical contacts) and disengagement from services (no clinical contact for ≥90 days with no return to contact) in the whole cohort. OCTET is registered with isrctn.com, number ISRCTN73110773., Findings: We obtained data for 330 patients in the relevant period between Nov 10, 2008 and Feb 22, 2014 (36 months after the last patient was randomly assigned to OCTET). We identified no difference between the randomised groups in the numbers of patients readmitted (100 [61%] of 165 CTOs vs 113 [68%] of 165 controls; relative risk 0·88 [95% CI 0·75-1·03]), number of readmissions (mean 2·4 readmissions [SD 1·91] vs 2·2 [1·43]; incident density ratio [IDR] 0·97 [95% CI 0·76-1·24]), duration of readmissions (median 117·5 days [IQR 63-303] vs 139·5 days [63·0-309·5]; IDR 0·84 [95% CI 0·51-1·38]), or time to first readmission (median 601·0 days [95% CI 387·0-777·0] vs 420·0 days [352·0-548·0]; hazard ratio [HR] 0·81 [95% CI 0·62-1·06]). The CTO experience group had significantly more readmissions than the group without (IDR 1·39 [95% CI 1·07-1·79]) and we noted no significant difference between groups in readmission rates, duration of readmission, or time to first readmission. We did not identify a linear relationship between readmission outcomes and duration of CTO. 19 (6%) patients disengaged from services (12 [7%] of 165 CTOs vs 7 [4%] of 165 controls). Longer duration of compulsion was associated with later disengagement (HR 0·946 [95% CI 0·90-0·99, p=0·023). 187 (57%) experienced no discontinuities, and we noted no significant difference between the CTO and control groups for time to disengagement or number of discontinuities. Levels of discontinuity were associated with compulsion (IDR 0·973 [95% CI 0·96-0·99, p<0·0001]. We identified no effect of baseline characteristics on the associations between compulsion and disengagement., Interpretation: We identified no evidence that increased compulsion leads to improved readmission outcomes or to disengagement from services in patients with psychosis over 36 months. The level of persisting clinical follow-up was much higher than expected, irrespective of CTO status, and could partly account for the absence of CTO effect. The findings from our 36-month follow-up support our original findings that CTOs do not provide patient benefits, and the continued high level of their use should be reviewed., Funding: National Institute for Health Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A re-audit of prescribing of post-exposure prophylaxis for HIV following sexual exposure in the Thames Valley demonstrated that an updated proforma has led to significant improvements in clinician-led outcomes, but had no impact on completion or follow-up rates., (© The Author(s) 2014.)

Glucokinase-maturity-onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. GCK gene mutations are present in ∼1 in 1,000 of the population, but most are not diagnosed. They are common causes of MODY (10-60%): persistent incidental childhood hyperglycemia (10-60%) and gestational diabetes mellitus (1-2%). GCK-MODY has a unique pathophysiology and clinical characteristics, so it is best considered as a discrete genetic subgroup. People with GCK-MODY have a defect in glucose sensing; hence, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycemia (5.4-8.3 mmol/L, HbA1c range 5.8-7.6% [40-60 mmol/mol]), which is present from birth and shows slight deterioration with age. Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population. Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications. In pregnancy, fetal growth is primarily determined by whether the fetus inherits the GCK gene mutation from their mother. Insulin treatment of the mother is only appropriate when increased fetal abdominal growth on scanning suggests the fetus is unaffected. The impact on outcome of maternal insulin treatment is limited owing to the difficulty in altering maternal glycemia in these patients. Making the diagnosis of GCK-MODY through genetic testing is essential to avoid unnecessary treatment and investigations, especially when patients are misdiagnosed with type 1 or type 2 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The 2015 British Thoracic Society (BTS) Home Oxygen Guidelines provides detailed evidence-based guidance for the use of oxygen by patients in their own homes or other non-acute hospital settings., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence., Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL., Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples., Setting: The study was conducted at university hospitals., Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study., Outcome: Outcomes included genetic screening and clinical characteristics., Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context., Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Background: Acute postoperative pain occurs as a result of tissue damage following surgery. Administering the appropriate analgesia to children is a complex process and it is unclear whether children's postoperative pain is more successfully treated by using 'as required' (when pain occurs) (termed 'pro re nata' or PRN) or (irrespective of pain at the time of administration)., Objectives: To assess the efficacy of as required versus fixed schedule analgesic administration for the management of postoperative pain in children under the age of 16 years., Search Methods: On 2 July 2014, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL databases. We reviewed the bibliographies of all included studies and of reviews, and searched two clinical trial databases, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform, to identify additional published or unpublished data., Selection Criteria: We included randomised controlled trials (RCTs) comparing PRN versus ATC analgesic administration for postoperative pain in children under the age of 16 years who had undergone any surgical procedure requiring postoperative pain relief, in any setting., Data Collection and Analysis: Two review authors (AH, PW) independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias as recommended in the Cochrane Handbook for Systematic Reviews of Interventions., Main Results: We included three RCTs (four reports) of 246 children aged under 16 years undergoing tonsillectomy. Children were given weight-appropriate doses of the study medication, either PRN or ATC, by a parent or carer at home for up to four days following surgery. We did not identify any studies assessing the management of postoperative pain in children in any other setting (i.e. as an inpatient). All studies included in this review were based on the use of paracetamol, and an opioid was added to paracetamol in two studies. Analgesics were administered either orally (tablet or elixir) or rectally (suppository). Reporting quality was poor and there were fewer than 50 children in each arm. Mean pain intensity scores decreased over time, as did medication use. However, children were still reporting pain at the final assessment, suggesting that no administration schedule provided adequate analgesia. There were no significant differences in pain intensity scores at any time point. The studies reported adverse events that may have been related to the study medication, such as nausea and vomiting, and constipation, but no statistically significant differences were noted between the groups. There were too few data from only three small studies and meta-analysis was not possible. One study reported that a higher amount of analgesics was consumed in the ATC group compared with the PRN group: it would have been helpful to show that the higher volume in the ATC group led to better analgesia but we were not able to demonstrate this., Authors' Conclusions: There was limited evidence available to draw any conclusions about the efficacy of PRN versus ATC analgesic administration for the management of postoperative pain in children.

There are an increasing number of healthcare smartphone applications ('apps') available. Urolithiasis presents a major healthcare burden. Patients are increasingly keen to educate themselves regarding the diagnosis and management of their condition. There is no formal regulation of healthcare apps, including a large number of apps relating to urolithiasis. This review aims to examine the range of apps available, and the prevalence of healthcare professional input. Four international smartphone app stores were searched: Apple's App Store, Google Play (Android), BlackBerry App World and the Windows Phone App store. A total of 42 unique apps were downloaded and analysed. Recorded data included the cost (£/$), publisher information, number of ratings, average rating and any documentation of medical professional involvement. Twenty-one (50%) apps required payment for download. The mean cost was £3.58 ($6.04) with range £0.61-£34.90 ($1.03-$58.87). Thirty-three (79%) of the 42 apps were designed to be used by patients. Fifteen (36%) of the 42 apps had clear input from health professionals. Twenty-two apps offered patient information, including dietary advice on lowering calcium intake, which is contrary to current evidence-based practice. We conclude that urolithiasis apps have future potential to inform both patients and healthcare professionals on stone management. However, inaccuracies in the recommendations made by some apps can be misleading or even harmful due to a lack of specialist involvement. We recommend improving the usefulness of these apps by seeking a 'quality stamp' from recognised urological organisations and greater clinician involvement in future app development.

Purpose: To evaluate the performance of active surveillance as a management strategy in broad populations and to inform the development of surveillance schedules by individual patient data regarding timing and type of relapse., Methods: Retrospective study including data from 2,483 clinical stage I (CSI) patients, 1,139 CSI nonseminoma and 1,344 CSI seminoma managed with active surveillance, with the majority treated between 1998 and 2010. Clinical outcomes including relapse and death, time distribution, extent of relapse and method of relapse detection observed on active surveillance were recorded., Results: Relapse occurred in 221 (19%) CSI-nonseminoma and 173 (13%) CSI-seminoma patients. Median time to relapse was 4 months (range, 2-61 months), 8 months (range, 2-77 months) and 14 months (range, 2-84 months) for lymphovascular invasion-positive CSI nonseminoma, lymphovascular invasion-negative CSI nonseminoma and CSI seminoma. Most relapses were observed within the first 2 years/3 years after orchiectomy for CSI nonseminoma (90%)/CSI seminoma (92%). Relapses were detected by computed tomography scan/tumor-markers in 87%/3% of seminoma recurrences, in 48%/38% of lymphovascular invasion-negative and 41%/61% of lymphovascular invasion-positive patients, respectively. 90% of CSI-nonseminoma and 99% of CSI-seminoma relapses exhibited International Germ Cell Collaborative Group good-risk features. Three patients with CSI nonseminoma died of disease (0.3%). One patient with CSI seminoma and two patients with CSI nonseminoma died because of treatment-related events. Overall, advanced disease was seen in both early- and late-relapse patients. All late recurrences were cured with standard therapy. Five-year disease-specific survival was 99.7% (95% CI, 99.24% to 99.93%)., Conclusion: Active surveillance for CSI testis cancer leads to excellent outcomes. The vast majority of relapses occur within 2 years of orchiectomy for CSI nonseminoma and within 3 years for CSI seminoma. Late and advanced stage relapse are rarely seen. These data may inform further refinement of rationally designed surveillance schedules., (© 2014 by American Society of Clinical Oncology.)

Cancer complicates approximately 0.1% of all pregnancies, and the incidence is expected to increase, as more women elect to defer child-bearing to a later age. For these women and the clinicians treating them, there is little rigorous evidence with which to guide their management, but thought must be given to the effects of chemotherapeutic agents on the developing fetus and the effects of physiological changes within the pregnant women. We examine the evidence available for the effects of cytotoxic chemotherapy on the development of the fetus and for the health of the child in the longer term, and the effects of transplacental transfer and physiological changes of pregnancy on the pharmacokinetics of these drugs. These factors may have significant influence on the appropriate dosing of chemotherapeutic agents in pregnant women, compared to their nonpregnant counterparts, and further research is required into the implications of these findings for the successful treatment of cancer in pregnancy.

Cardiomyocytes from human embryonic stem cells (hESC-CMs) and induced pluripotent stem cells (hiPSC-CMs) represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR) agonist phenylephrine (PE) compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.

Inhibition of type 1 insulin-like growth factor receptor (IGF-1R) enhances tumor cell sensitivity to ionizing radiation. It is not clear how this effect is mediated, nor whether this approach can be applied effectively in the clinic. We previously showed that IGF-1R depletion delays repair of radiation-induced DNA double-strand breaks (DSBs), unlikely to be explained entirely by reduction in homologous recombination (HR) repair. The current study tested the hypothesis that IGF-1R inhibition induces a repair defect that involves non-homologous end joining (NHEJ). IGF-1R inhibitor AZ12253801 blocked cell survival and radiosensitized IGF-1R-overexpressing murine fibroblasts but not isogenic IGF-1R-null cells, supporting specificity for IGF-1R. IGF-1R inhibition enhanced radiosensitivity in DU145, PC3 and 22Rv1 prostate cancer cells, comparable to effects of Ataxia Telangiectasia Mutated inhibition. AZ12253801-treated DU145 cells showed delayed resolution of γH2AX foci, apparent within 1 h of irradiation and persisting for 24 h. In contrast, IGF-1R inhibition did not influence radiosensitivity or γH2AX focus resolution in LNCaP-LN3 cells, suggesting that radiosensitization tracks with the ability of IGF-1R to influence DSB repair. To differentiate effects on repair from growth and cell-survival responses, we tested AZ12253801 in DU145 cells at sub-SF50 concentrations that had no early (⩽48 h) effects on cell cycle distribution or apoptosis induction. Irradiated cultures contained abnormal mitoses, and after 5 days IGF-1R-inhibited cells showed enhanced radiation-induced polyploidy and nuclear fragmentation, consistent with the consequences of entry into mitosis with incompletely repaired DNA. AZ12253801 radiosensitized DNA-dependent protein kinase (DNA-PK)-proficient but not DNA-PK-deficient glioblastoma cells, and did not radiosensitize DNA-PK-inhibited DU145 cells, suggesting that in the context of DSB repair, IGF-1R functions in the same pathway as DNA-PK. Finally, IGF-1R inhibition attenuated repair by both NHEJ and HR in HEK293 reporter assays. These data indicate that IGF-1R influences DSB repair by both major DSB repair pathways, findings that may inform clinical application of this approach.

Background: Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A METHODS: In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769., Findings: Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine., Interpretation: Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens., Funding: The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre., (Copyright © 2014 Satti et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS., Methods: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing., Results: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases., Conclusions: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Parathyroid hormone-like hormone (PTHLH, MIM 168470) is a humoral factor, structurally and functionally related to parathyroid hormone, which mediates multiple effects on chondrocyte, osteoblast and osteoclast function. Mutations and copy number imbalances of the PTHLH locus and in the gene encoding its receptor, PTHR1, result in a variety of skeletal dysplasias including brachydactyly type E, Eiken syndrome, Jansen metaphyseal chondrodysplasia and Blomstrand type chondrodysplasia. Here we describe three individuals with duplications of the PTHLH locus, including two who are mosaic for these imbalances, leading to a hitherto unrecognized syndrome characterized by acro-osteolysis, cortical irregularity of long bones and metadiaphyseal enchondromata.

There is now a requirement for every doctor in the UK to obtain patient feedback for revalidation. This can be an onerous and time-consuming task. The objective of this study was to evaluate a novel electronic patient feedback method in an outpatient lithotripsy service setting. Between September 2013 and January 2014, 100 patients attending an outpatient lithotripsy service in Oxford were asked to complete a selection of pre-approved NHS questions about the service they had received. Questions were presented on a tablet device (iPad™) and answered using the touch screen. Departmental staff were unaware of the questions in the survey. Patients were asked to complete the survey by an independent research nurse. Questions were created online in a free-to-use web-based survey application and presented on the tablet device in a user-friendly format via an application. Data were uploaded via wifi™ to the online system. Data were viewed, automatically analysed and displayed graphically. The age range of the patients surveyed was 20-80 years of age. All 100 patients completed the survey without difficulty. All patients answered every question. Data could be automatically viewed, analysed and presented graphically. This method of collecting patient feedback proved to be rapid and efficient. The feedback highlighted a high patient satisfaction with the lithotripsy service. A touch screen tablet device is an efficient and effective method of collecting truly objective patient feedback. This method of patient feedback could be employed in other clinical environments to collect data for revalidation purposes.

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years., Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics., Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29)., Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

There are few prospective studies evaluating the role of extracorporeal photopheresis (ECP) in chronic GVHD (cGVHD) and only occasional reports of the effect of ECP on patients' quality of life (QoL). We report a single-centre prospective study of patients undergoing fortnightly ECP for moderate or severe cGVHD. Response was assessed after 6 months of treatment using NIH scoring criteria and reduction in immunosuppression. QoL assessments were undertaken at baseline and at 6 months using the chronic GVHD symptom scale (cGVHD SS) and dermatology life quality index (DLQI). An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial response. Twenty-seven out of 38 patients completed 6 months of ECP treatment and 70% (19/27) had a complete or partial response. Eighty per cent of patients who completed 6 months of ECP treatment had a reduction in immunosuppression dose. A subset of patients completed QoL questionnaires. Seventeen out of 18 patients (94%) showed an improvement in scores. The mean cGVHD SS and mean DLQI score were both significantly lower after 6 months of ECP (22 compared with 36, P=0.012 and 3.4 compared with 6.9, P=0.009, respectively). This study confirms that ECP can lead to objective clinical responses and, in addition, may lead to an improvement in QoL in cGVHD.

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: The TNF receptor-associated protein 1 (TRAP1) is a mitochondrial HSP that has been related to drug resistance and protection from apoptosis in colorectal and prostate cancer. Here, the effect of TRAP1 ablation on cell proliferation, survival, apoptosis, and mitochondrial function was determined in non-small cell lung cancer (NSCLC). In addition, the prognostic value of TRAP1 was evaluated in patients with NSCLC. These results demonstrate that TRAP1 knockdown reduces cell growth and clonogenic cell survival. Moreover, TRAP1 downregulation impairs mitochondrial functions such as ATP production and mitochondrial membrane potential as measured by TMRM (tetramethylrhodamine methylester) uptake, but it does not affect mitochondrial density or mitochondrial morphology. The effect of TRAP1 silencing on apoptosis, analyzed by flow cytometry and immunoblot expression (cleaved PARP, caspase-9, and caspase-3) was cell line and context dependent. Finally, the prognostic potential of TRAP1 expression in NSCLC was ascertained via immunohistochemical analysis which revealed that high TRAP1 expression was associated with increased risk of disease recurrence (univariate analysis, P = 0.008; multivariate analysis, HR: 2.554; 95% confidence interval, 1.085-6.012; P = 0.03). In conclusion, these results demonstrate that TRAP1 impacts the viability of NSCLC cells, and that its expression is prognostic in NSCLC., Implications: TRAP1 controls NSCLC proliferation, apoptosis, and mitochondrial function, and its status has prognostic potential in NSCLC., Competing Interests: of potential conflicts of interest: No potential conflicts of interest are disclosed, (©2014 AACR.)

Stroke is a leading cause of disability across the developed world, affecting an increasing number of younger people. In this article, we seek to understand the experience of stroke as a disabling life situation among young people and the strategies that they use to recover and cope. Directed content analysis was conducted from interviews with 17 community-dwelling stroke survivors aged 55 years and younger across the United Kingdom. The sample was drawn from a larger maximum variation sample of stroke survivors. Using the sociological concepts of biographical disruption and biographical repair as a guide, excerpts from the interviews pertaining to aspects of the patients' life that were interrupted, in addition to how they coped with the changes, were selected and analysed. All individuals described an "altered sense of self," a theme that included loss of identity, family disruption, and/or loss of valued activities. Individuals sought to adapt their sense of self by seeking external support, by restoring normality, and/or through positive reflection. Despite the adapted self that emerged, most individuals continued to experience impairments. While young stroke survivors adapt to their illness over time, they continue to experience impairments and disruptions in their personal and work lives. A holistic model of rehabilitation that helps individuals regain the capacity for everyday activities related to work, family life, and leisure can begin to address the emotional ramifications of diseases such as stroke, restore wellness, and work towards minimizing the burden felt by family caregivers and children.

Background: Chest physiotherapy is widely used in people with cystic fibrosis in order to clear mucus from the airways., Objectives: To determine the effectiveness and acceptability of chest physiotherapy compared to no treatment or spontaneous cough alone to improve mucus clearance in cystic fibrosis., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 04 February 2013., Selection Criteria: Randomised or quasi-randomised clinical studies in which a form of chest physiotherapy (airway clearance technique) were taken for consideration in people with cystic fibrosis compared with either no physiotherapy treatment or spontaneous cough alone., Data Collection and Analysis: Both authors independently assessed study eligibility, extracted data and assessed study quality. There was heterogeneity in the published outcomes, with variable reporting which meant pooling of the data for meta-analysis was not possible., Main Results: The searches identified 144 studies, of which eight cross-over studies (data from 96 participants) met the inclusion criteria. There were differences between studies in the way that interventions were delivered, with several of the intervention groups combining more than one treatment modality. One included study looked at autogenic drainage, six considered conventional chest physiotherapy, three considered oscillating positive expiratory pressure, seven considered positive expiratory pressure and one considered high pressure positive expiratory pressure. Of the eight studies, six were single-treatment studies and in two, the treatment intervention was performed over two consecutive days (once daily in one, twice daily in the other). This enormous heterogeneity in the treatment interventions prevented any meta-analyses from being performed.Four studies, involving 28 participants, reported a higher amount of expectorated secretions during chest physiotherapy as compared to a control. One study, involving 18 participants, reported no significant differences in sputum weight. In five studies radioactive tracer clearance was used as an outcome variable. In three of these (28 participants) it was reported that chest physiotherapy, including coughing, increased radioactive tracer clearance as compared to the control period. One study (12 participants) reported increased radioactive tracer clearance associated with all interventions compared to control, although this was only reported to have reached significance for postural drainage with percussion and vibrations; and the remaining study (eight participants) reported no significant difference in radioactive tracer clearance between chest physiotherapy, without coughing, compared to the control period. Three studies, involving 42 participants reported no significant effect on pulmonary function variables following intervention; but one further study did report significant improvement in pulmonary function following the intervention in some of the treatment groups., Authors' Conclusions: The results of this review show that airway clearance techniques have short-term effects in the terms of increasing mucus transport. No evidence was found on which to draw conclusions concerning the long-term effects.

Objective: To determine renal function and cardiovascular outcomes after living donor nephrectomy (LDN). Living donor kidney transplantation has become established as the treatment of choice for end-stage renal failure. Benefits to the recipient have to be balanced against perioperative and long-term health risks to the donor., Subjects/patients and Methods: The UK Transplant Registry (UKTR) was used to identify 4586 living donors who had donated a kidney for transplantation in the UK between 2001 and 2008. This study was conducted with the consent and support of the NHS Blood and Transplant (NHSBT) Kidney and Pancreas Research Group., Results: The mean glomerular filtration rate (GFR) fell from 103 mL/min/1.73 m(2) before LDN to 58 mL/min/1.73 m(2) 1 year after LDN. At 1 year after LDN 60% of donors had a GFR of <60 mL/min/1.73 m(2). A GFR of <60 mL/min/1.73 m(2) after LDN was associated with older age, females, lower GFR before LDN, White ethnicity, earlier LDN period, unrelated donor type and body mass index of >25 kg/m(2). Over a 2-year period after LDN there was an overall mortality rate of 0.39%, cardiovascular death in one patient (mortality rate of 0.02%) and a major cardiovascular event rate of 0.44%., Conclusion: In this study we show that mild renal dysfunction is common after LDN; however, due to the short duration of follow-up we are unable to comment on whether this subsequently leads to an increased risk of developing of cardiovascular disease., (© 2013 BJU International.)

Use of extracorporeal lithotripsy is declining in North America and many European countries despite international guidelines advocating it as a first-line therapy. Traditionally, lithotripsy is thought to have poor efficacy at treating lower pole renal stones. We evaluated the success rates of lithotripsy for lower pole renal stones in our unit. 50 patients with lower pole kidney stones ≤15 mm treated between 3/5/11 and 19/4/12 were included in the study. Patients received lithotripsy on a fixed-site Storz Modulith SLX F2 lithotripter according to a standard protocol. Clinical success was defined as stone-free status or asymptomatic clinically insignificant residual fragments (CIRFs) ≤3 mm at radiological follow-up. The mean stone size was 7.8 mm. The majority of stones (66 %) were between 5 and 10 mm. 28 % of stones were between 10 and 15 mm. For solitary lower pole stones complete stone clearance was achieved in 63 %. Total stone clearance including those with CIRFs was achieved in 81 % of patients. As expected, for those with multiple lower pole stones the success rates were lower: complete clearance was observed in 39 % and combined clearance including those with CIRFs was 56 %. Overall, complete stone clearance was observed in 54 % of patients and clearance with CIRFs was achieved in 72 % of patients. Success rate could not be attributed to age, stone size or gender. Our outcome data for the treatment of lower pole renal stones (≤15 mm) compare favourably with the literature. With this level of stone clearance, a non-invasive, outpatient-based treatment like lithotripsy should remain the first-line treatment option for lower pole stones. Ureteroscopy must prove that it is significantly better either in terms of clinical outcome or patient satisfaction to justify replacing lithotripsy.

Background: Meta-analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose-intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway., Methods: Eighty consecutive patients with MIBC were treated with AMVAC as NAC by 2 UK multidisciplinary uro-oncology teams. Three or 4 cycles of AMVAC (methotrexate 30 mg/m(2) , vinblastine 3 mg/m(2) , doxorubicin 30 mg/m(2) , and cisplatin 70 mg/m(2) ) were given at 2-week intervals, with granulocyte colony-stimulating factor support, prior to either radical surgery or radical radiotherapy., Results: All planned cycles of chemotherapy were completed, without dose reduction or delay in 84% of patients. All 80 patients subsequently received their planned definitive therapy. Grade 3/4 toxicities were seen in 26% of the 42% of patients for whom toxicity data are available, including 12% grade 3/4 neutropenia. Pathological complete response to AMVAC was seen in 43% of 60 surgical patients. Objective radiological local response was seen in 83% of 57 evaluable patients. Two-year disease-free and overall survival were 65% and 77%, respectively., Conclusions: AMVAC is safe and appears to be a well-tolerated and effective NAC regimen for MIBC. It minimizes delays to definitive treatment and produces excellent pathological and radiological response rates. It is an appropriate comparator for future randomized trials., (Copyright © 2011 American Cancer Society.)

Respiratory distress develops in up to 25% of adults and 40% of children with severe falciparum malaria. Its diverse causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary edema, concomitant pneumonia, and severe anemia. Patients with severe falciparum, vivax, and knowlesi malaria may develop acute lung injury (ALI) and ARDS, often several days after antimalarial drug treatment. ARDS rates, best characterized for severe Plasmodium falciparum, are 5% to 25% in adults and up to 29% in pregnant women; ARDS is rare in young children. ARDS pathophysiology centers on inflammatory-mediated increased capillary permeability or endothelial damage leading to diffuse alveolar damage that can continue after parasite clearance. The role of parasite sequestration in the pulmonary microvasculature is unclear, because sequestration occurs intensely in P falciparum, less so in P knowlesi, and has not been shown convincingly in P vivax. Because early markers of ALI/ARDS are lacking, fluid resuscitation in severe malaria should follow the old adage to "keep them dry." Bacteremia and hospital-acquired pneumonia can complicate severe malaria and may contribute to ALI/ARDS. Mechanical ventilation can save life in ALI/ARDS. Basic critical care facilities are increasingly available in tropical countries. The use of lung-protective ventilation has helped to reduce mortality from malaria-induced ALI/ARDS, but permissive hypercapnia in unconscious patients is not recommended because increased intracranial pressure and cerebral swelling may occur in cerebral malaria. The best antimalarial treatment of severe malaria is IV artesunate.

Unlabelled: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Haematuria clinics with same day imaging and flexible cystoscopy are an efficient way for investigating patients with haematuria. The principal role of haematuria clinics with reference to bladder cancer is to determine which patients are 'normal' and may be discharged, and which patients are abnormal and should undergo rigid cystoscopy. It is well recognised that CT urography offers a thorough evaluation of the upper urinary tract for stones, renal masses and urothelial neoplasms but the role of CT urography for diagnosing bladder cancer is less certain. The aim of the present study was to evaluate the diagnostic accuracy of CT urography in patients with visible haematuria aged >40 years and to determine if CT urography has a role for diagnosing bladder cancer. This study shows that the optimum diagnostic strategy for investigating patients with visible haematuria aged >40 years with infection excluded is a combined strategy using CT urography and flexible cystoscopy. Patients positive for bladder cancer on CT urography should be referred directly for rigid cystoscopy and so avoid flexible cystoscopy. The number of flexible cystoscopies required therefore may be reduced by 17%. The present study also shows that the diagnostic accuracy of voided urine cytology is too low to justify its continuing use in a haematuria clinic using CT urography and flexible cystoscopy., Objectives: To evaluate and compare the diagnostic accuracy of computed tomography (CT) urography with flexible cystoscopy and voided urine cytology for diagnosing bladder cancer. To evaluate diagnostic strategies using CT urography as: (i) an additional test or (ii) a replacement test or (iii) a triage test for diagnosing bladder cancer in patients referred to a hospital haematuria rapid diagnosis clinic., Patients and Methods: The clinical cohort consisted of a consecutive series of 778 patients referred to a hospital haematuria rapid diagnosis clinic from 1 March 2004 to 17 December 2007. Criteria for referral were at least one episode of macroscopic haematuria, age >40 years and urinary tract infection excluded. Of the 778 patients, there were 747 with technically adequate CT urography and flexible cystoscopy examinations for analysis. On the same day, patients underwent examination by a clinical nurse specialist followed by voided urine cytology, CT urography and flexible cystoscopy. Voided urine cytology was scored using a 5-point system. CT urography was reported immediately by a uroradiologist and flexible cystoscopy performed by a urologist. Both examinations were scored using a 3-point system: 1, normal; 2, equivocal; and 3, positive for bladder cancer. The reference standard consisted of review of the hospital imaging and histopathology databases in December 2009 for all patients and reports from the medical notes for those referred for rigid cystoscopy. Follow-up was for 21-66 months., Results: The prevalence of bladder cancer in the clinical cohort was 20% (156/778). For the diagnostic strategy using CT urography as an additional test for diagnosing bladder cancer, when scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 1.0 (95% confidence interval [CI] 0.98-1.00), specificity was 0.94 (95% CI 0.91-0.95), the positive predictive value (PPV) was 0.80 (95% CI 0.73-0.85) and the negative predictive value (NPV) was 1.0 (95% CI 0.99-1.00). For the diagnostic strategy using CT urography as a replacement test for flexible cystoscopy for diagnosing bladder cancer, when scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 0.95 (95% CI 0.90-0.97), specificity was 0.83 (95% CI 0.80-0.86), the PPV was 0.58 (95% CI 0.52-0.64), and the NPV was 0.98 (95% CI 0.97-0.99). Similarly using flexible cystoscopy for diagnosing bladder cancer, if scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 0.98 (95% CI 0.94- 0.99), specificity was 0.94 (95% CI 0.92-0.96), the PPV was 0.80 (95% CI 0.73-0.85) and the NPV was 0.99 (95% CI 0.99-1.0). For the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow-up (option 1), patients with a positive CT urography score are referred directly for rigid cystoscopy, and patients with an equivocal or normal score were referred for flexible cystoscopy. Sensitivity was 1.0 (95% CI 0.98-1.0), specificity was 0.94 (95% CI 0.91-0.95), the PPV was 0.80 (95% CI 0.73-0.85), and the NPV was 1.0 (95% CI 0.99-1.0). For the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow-up (option 2), patients with a positive CT urography score are referred directly for rigid cystoscopy, patients with an equivocal score are referred for flexible cystoscopy and patients with a normal score undergo clinical follow-up. Sensitivity was 0.95 (95% CI 0.90-0.97), specificity was 0.98 (95% CI 0.97-0.99), the PPV was 0.93 (95% CI 0.87-0.96), and the NPV was 0.99 (95% CI 0.97-0.99). For voided urine cytology, if scores of 0-3 were classified as negative and 4-5 as positive for bladder cancer, sensitivity was 0.38 (95% CI 0.31-0.45), specificity was 0.98 (95% CI 0.97-0.99), the PPV was 0.82 (95% CI 0.72-0.88) and the NPV was 0.84 (95% CI 0.81-0.87)., Conclusions: There is a clear advantage for the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow-up (option 1), in which patients with a positive CT urography score for bladder cancer are directly referred for rigid cystoscopy, but all other patients undergo flexible cystoscopy. Diagnostic accuracy is the same as for the additional test strategy with the advantage of a 17% reduction of the number of flexible cystoscopies performed. The sensitivity of voided urine cytology is too low to justify its continuing use in a hospital haematuria rapid diagnosis clinic using CT urography and flexible cystoscopy., (© 2011 BJU INTERNATIONAL.)

Background and Purpose: Lithotripsy is an established method to fragment kidney stones that can be performed without general anesthesia in the outpatient setting. Discomfort and/or noise, however, may deter some patients. It has been demonstrated that audiovisual distraction (AV) can reduce sedoanalgesic requirements and improve patient satisfaction in nonurologic settings, but to our knowledge, this has not been investigated with lithotripsy. This randomized controlled trial was designed to test the hypothesis that AV distraction can reduce perceived pain during lithotripsy., Patients and Methods: All patients in the study received identical analgesia before a complete session of lithotripsy on a fixed-site Storz Modulith SLX F2 lithotripter. Patients were randomized to two groups: One group (n=61) received AV distraction via a wall-mounted 32″ (82 cm) television with wireless headphones; the other group (n=57) received no AV distraction. The mean intensity of treatment was comparable in both groups. Patients used a visual analogue scale (0-10) to record independent pain and distress scores and a nonverbal pain score was documented by the radiographer during the procedure (0-4)., Results: In the group that received AV distraction, all measures of pain perception were statistically lower. The patient-reported pain score was reduced from a mean of 6.1 to 2.4 (P<0.0001), and the distress score was reduced from a mean of 4.4 to 1.0 (P=0.0001). The mean nonverbal score recorded by the radiographer was reduced from 1.5 to 0.5 (<0.0001)., Conclusions: AV distraction significantly lowered patients' reported pain and distress scores. This correlated with the nonverbal scores reported by the radiographer. We conclude that AV distraction is a simple method of improving acceptance of lithotripsy and optimizing treatment.

Objective: To summarize the changes in prevalence and treatment of upper urinary tract stone disease in the UK over the last 10 years., Methods: Data from the Hospital Episode Statistics (HES) website (http://www.hesonline.nhs.uk) were extracted, summarized and presented., Results: The number of upper urinary tract stone hospital episodes increased by 63% to 83,050 in the 10-year period. The use of shock wave lithotripsy (SWL) for treating all upper tract stones increased from 14,491 cases in 2000-2001 to 22,402 cases in 2010 (a 55% increase) with a 69% increase in lithotripsy for renal stones. There was a 127% increase in the number of ureteroscopic stone treatments from 6,283 to 14,242 cases over the 10-year period with a 49% increase from 2007/2008 to 2009/2010. There was a decline in open surgery for upper tract stones from 278 cases in 2000/2001 to 47 cases in 2009/2010 (an 83% reduction). Treatment for stone disease has increased substantially in comparison with other urological activity. In 2009/2010, SWL was performed almost as frequently as transurethral resection of the prostate or transurethral resection of bladder tumour, ureteroscopy for stones was performed more frequently than nephrectomy, radical prostatectomy and cystectomy combined, and percutaneous nephrolithotomy was performed more frequently than cystectomy., Conclusions: The present study highlights the increase in prevalence and treatment of stone disease in the UK over the last 10 years. If this trend continues it has important implications for workforce planning, training, service delivery and research in the field of urolithiasis., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

The primary objective of organ preservation is to deliver a viable graft with minimal risk of impaired postoperative graft function. In current clinical practice, preservation of transplanted organs is based on hypothermia. Organs are flushed and stored using specific preservation solutions to reduce cellular metabolism and prevent cell swelling. However, the ongoing organ donor shortage and consequent expansion of donor criteria to include the use of grafts that would once have been discarded as unsuitable have underlined the need for a technique that prevents any further damage during the preservation period. The principle of normothermic machine perfusion preservation is the maintenance of cellular metabolism in a physiological environment throughout the preservation period. Normothermic preservation, at least in theory, thereby overcomes the 3 major weaknesses inherent in traditional static cold storage by (1) avoiding ischemia/reperfusion injury, (2) avoiding cold injury, and (3) allowing viability assessment. Furthermore, normothermic machine perfusion might transpire to be the ideal vehicle to deliver other therapeutic interventions during preservation to modulate and optimize the graft before transplantation. By restoring function in marginal donor organs and enabling the clinician to appraise its viability, the donor pool might be greatly expanded., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Isolation of pure platelet samples from whole blood is crucial for the study of platelet gene expression. The main obstacles to overcome in order to successfully isolate platelets from whole blood include (1) platelet activation; (2) leukocyte and red blood cell contamination, and (3) time-dependent platelet mRNA degradation. This chapter describes a rapid and highly efficient method for isolating human circulating platelets from small volumes of whole blood based on efficient inhibition of platelet activation and leukocyte removal by filtration followed by magnetic bead-depletion of residual contaminating leukocytes and red blood cells. Also described are methods for RNA extraction, cDNA synthesis, and platelet gene expression studies using both quantitative real-time PCR and microarray.

This article provides a summary of the efficacy, and relative efficacy, of 38 different drugs or drug combinations tested in standard postoperative pain trials. It will help clinicians and patients make informed choices about analgesia based on pain relief, duration of action, and adverse events, which can then be put into context for the individual patient, depending on local availability. This article highlights the fact that no single drug is effective in all patients--even the best drugs fail to provide good levels of pain relief in at least 30%. These patients should try a different analgesic.

Purpose: Our objective was to design an intranet-based database to streamline stone patient management and data collection., Materials and Methods: The system developers used a rapid development approach that removed the need for laborious and unnecessary documentation, instead focusing on producing a rapid prototype that could then be altered iteratively. By using open source development software and website best practice, the development cost was kept very low in comparison with traditional clinical applications. Information about each patient episode can be entered via a user-friendly interface., Results: The bespoke electronic stone database removes the need for handwritten notes, dictation, and typing. From the database, files may be automatically generated for clinic letters, operation notes. and letters to family doctors. These may be printed or e-mailed from the database. Data may be easily exported for audits, coding, and research., Conclusions: Data collection remains central to medical practice, to improve patient safety, to analyze medical and surgical outcomes, and to evaluate emerging treatments. Establishing prospective data collection is crucial to this process. In the current era, we have the opportunity to embrace available technology to facilitate this process. The database template could be modified for use in other clinics. The database that we have designed helps to provide a modern and efficient clinical stone service.

Objective: • To compare immunostaining protocols using different antibodies for the type 1 insulin-like growth factor receptor (IGF-1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF-1R expression varies with time in serial prostate cancer specimens from individual patients., Methods: • We studied IGF-1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart. • Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate-specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation. • After an optimization process using three commercially-available IGF-1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips., Results: • Santa Cruz antibody sc713 gave positive staining in IGF-1R null R- cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R- cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively. • There was significant correlation of IGF-1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF-1R staining scores generated by the CS antibody were used to analyze the clinical data. • Most patients (six of seven) with falling IGF-1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response) between operations. Conversely, in seven of eight patients who had progression to androgen-independence between procedures, IGF-1R levels increased or remained high. Finally, seven of 11 patients who developed radiologically confirmed metastases between procedures showed stable or increasing IGF-1R staining scores., Conclusion: • The present study is the first to assess changes in IGF-1R expression in serial prostate cancer samples. The results obtained indicate that IGF-1R expression usually remains high throughout the course of histologically-proven disease progression in serial specimens, suggesting that the IGF-1R remains a valid treatment target for advanced prostate cancer., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

The average glomerular filtration rate (GFR) is lower in the elderly than in the young and is usually a consequence of biological ageing, the rate of which varies between individuals. In some subjects, the decline is aggravated by concomitant vascular disease. The prevalence of significant kidney disease in the elderly has been overestimated - largely by rendering a diagnosis of chronic kidney disease by reference to estimates of GFR which are found in the young. A stable low GFR in the elderly, provided it is physiologically sufficient to meet homeostatic demands, is not a disease per se and seldom progresses to true kidney failure. However, it can be a risk factor for acute kidney injury drug misdosing, and possibly cardiovascular disease, so it should be noted., (Copyright © 2011 S. Karger AG, Basel.)

Many radiologists find it challenging to distinguish between the different interstitial idiopathic pneumonias (IIPs). The British Thoracic Society guidelines on interstitial lung disease (2008) recommend the formation of multidisciplinary meetings, with diagnoses made by combined radiological, pathological, and clinical findings. This review focuses on understanding typical and atypical radiological features on high-resolution computed tomography between the different IIPs, to help the radiologist determine when a confident diagnosis can be made and how to deal with uncertainty., (Copyright (c) 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

We report on differences in patient demographics in those men choosing to undergo radical prostatectomy in a UK center where there is no influence of robotic surgery and in those choosing radical prostatectomy in a US center where there is a strong robotic influence. Demographic and pathologic data were prospectively recorded in parallel for 78 consecutive men undergoing robot-assisted radical prostatectomy in a tertiary care academic US center and 69 consecutive men concurrently undergoing open radical prostatectomy in a similar UK center. Although average patient age was significantly younger in the US cohort (58.8 years, range 43.1-77.6 vs. 62.2 years, range 51.7-70.5; P = 0.002), the US cohort encompassed a wider age range and older patients than the UK cohort. Average preoperative prostate-specific antigen (PSA) was significantly lower in the US group (6.0, range 2.0-6.0 vs. 8.60, range 4.6-12.6; P < 0.01). Biopsy Gleason score, clinical stage, final pathology Gleason score, pathologic staging and positive margin rate were not significantly different between the two groups. Blood loss and transfusion rate were significantly lower in the US group. 16.7% of men in the US cohort had overall positive surgical margins compared to 29% in the UK group (P = 0.07). This data confirms our belief that patient age ranges are different in a setting influenced by robotic surgery. Although pathologic parameters were similar, the age distribution of robotic surgery patients was much wider, suggesting robotics attracts men previously reluctant to undergo surgery in the open setting or to pursue active surveillance protocols. Larger studies are needed to verify this finding.

Introduction: Metastatic renal cell carcinoma is associated with a poor prognosis. Given the current lack of effective systemic therapies and data suggesting a survival benefit from cytoreductive nephrectomy (CRN) before systemic therapy, we have retrospectively analyzed the experience of laparoscopic cytoreductive nephrectomy (LCRN) in three U.K. centers. The focus of this study was to assess the peri- and postoperative safety and hence feasibility of LCRN in the United Kingdom., Patients and Methods: Twenty-five patients with metastatic renal cell carcinoma deemed suitable for systemic therapy underwent LCRN in three U.K. centers over a 4-year period., Results: The tumors ranged from 3.4 cm in diameter to 12 cm. Operating times ranged from 89 (minimum) to 310 minutes (maximum), median 175 minutes. The median amount of blood loss was 150 mL, and hence the transfusion rate was low with only one patient requiring on-table transfusion and two patients requiring additional blood before discharge. Hospital stay ranged between 2.5 and 11 days; median postoperative stay was 3 days., Conclusions: In our initial experience, LCRN seems safe and feasible with low morbidity and a good perioperative outcome.

Purpose of Review: To review recent developments in imaging for bladder cancer (BCa) diagnosis and staging., Recent Findings: Recent technical advances in multidetector computed tomography (CT) and, especially, CT urography make CT the preferred imaging modality for diagnosis and staging of BCa. CT urography combined with cystoscopy is emerging as the diagnostic imaging pathway of choice for investigating haematuria. CT provides information about local, lymph node and distant spread in a single examination., Summary: Imaging for BCa should only be performed when it makes a difference to patient management. CT is the preferred imaging modality for diagnosing and staging urothelial cancer. Magnetic resonance (MR) imaging is superior for evaluation of the depth of tumour invasion into the bladder wall, but this knowledge may not ultimately affect treatment as feasibility for radical cystectomy depends on staging by a combination of clinical, histopathological and imaging findings. Radical cystectomy may include resection of adjacent organs and regional lymph nodes. The current purpose of CT or MR imaging is to detect T3b disease or higher and, especially, locoregional lymph node metastases. In the future, MR imaging with ultrasmall superparamagnetic iron oxide contrast agents may detect lymph nodes containing metastatic tumour, which may change treatment from surgery to chemotherapy with or without radiotherapy.

Background: Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors were developed to avoid COX-1-related gastrointestinal (GI) problems while maintaining the analgesic and anti-inflammatory activity of traditional non-steriodal anti-inflammatory drugs (NSAIDs)., Objectives: To review the analgesic efficacy, duration of analgesia, and adverse effects of a single oral dose of lumiracoxib for moderate to severe postoperative pain in adults., Search Strategy: We searched Cochrane CENTRAL, MEDLINE, and EMBASE to February 2010., Selection Criteria: Single oral dose, randomised, double-blind, placebo-controlled trials of lumiracoxib for relief of established moderate to severe postoperative pain in adults., Data Collection and Analysis: Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Numbers of participants using rescue medication, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected., Main Results: In this updated review four studies met the inclusion criteria. In total 366 participants were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 212 with placebo. Active comparators were naproxen 500 mg, rofecoxib 50 mg, celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 400 mg. With lumiracoxib 400 mg 50% of participants had at least 50% pain relief over six hours, compared with 8% given placebo; RB 6.9 (95% CI 4.1 to 12), NNT 2.4 (2.1 to 2.8).Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than placebo (>12 hours). Fewer participants needed rescue medication with lumiracoxib (64%) than with placebo (91%) over 12 to 24 hours; NNT to prevent remedication 3.7 (2.9 to 5.0). The weighted median time to use of rescue medication was 9.4 hours for lumiracoxib 400 mg and 1.7 hours for placebo.Adverse events were generally mild to moderate in severity, with one serious event reported in a placebo patient., Authors' Conclusions: Lumiracoxib 400 mg given as a single oral dose is an effective analgesic for acute postoperative pain, and has a relatively long duration of action. Adverse events with lumiracoxib did not differ from placebo.

Metopic synostosis (MS) accounts for approximately 10-15% of all craniosynostosis and is etiologically heterogeneous. This study aimed to examine the causes of MS, as observed in a tertiary craniofacial unit. We reviewed the case notes of 110 children with a diagnosis of MS, attending the craniofacial unit in Oxford between 1991 and 2008. Our results showed 38 children (38/110 or 34.6%) who had at least one additional structural abnormality or had a known syndromic diagnosis were classed as having syndromic MS. Chromosomal abnormalities were noted in 8/38 (21.4%) children: mosaic marker chromosome 2, 9p deletion (2/8), 11q deletion, 12pter deletion and duplication of 15q25 with other additional chromosomal abnormalities (3/8). Other syndromic diagnoses included Silver-Russell syndrome and Greig cephalopolysyndactyly. Prenatal exposure to sodium valproate (VPA) was noted in 8/110 children (7.8%), with the dose of the VPA being >or=1,000 mg/day in all cases. Other prenatal exposures reported in this study were: maternal diabetes (6/110), enoxaparin for hypercoagulable state (1/110), and thyroxine (1/110). The majority of patients (72/110 or 65.4%) had nonsyndromic MS. Speech delay was present in 11 children with nonsyndromic MS (11/72 or 15.3%) and 10 children with syndromic MS (10/38 or 26.3%). We conclude that approximately two-thirds of all MS is nonsyndromic. Prenatal exposure to VPA is a common cause of MS. Maternal diabetes, not previously linked to MS, was noted in 5.5% of cases. Chromosomal abnormalities account for about 6% of MS. An increased risk of speech delay is seen with both the syndromic and nonsyndromic forms., ((c) 2010 Wiley-Liss, Inc.)

We present a patient with features of Ulnar Mammary syndrome (UMS) consisting of bilateral ulnar defects, inverted nipples, short stature with associated growth hormone deficiency, and cryptorchidism. Our patient also had a hypoplastic anterior pituitary and an ectopic posterior pituitary gland, ventricular septal defect (VSD), and cardiac conduction defects consistent with Wolff-Parkinson-White (WPW) syndrome. Although TBX3 is known to be expressed in both the developing heart and the pituitary gland, conduction defects and anatomical pituitary abnormalities have not been previously described in UMS. This may, in part, be due to the fact that these features are not actively sought in individuals with UMS. Because these new findings have important clinical implications, we suggest that clinicians caring for individuals with UMS offer brain imaging, growth hormone testing, and cardiac arrhythmia screening. The diagnosis of UMS was confirmed on mutation analysis of TBX3. The mother of the propositus was also found to carry the same mutation, although she did not show the classical features of UMS. Therefore, our report also supports the variable expressivity of UMS within the same family.

Obesity in nontransplant patients has been associated with hypertension, hyperlipi-demia, diabetes, and proteinuria. To determine whether renal transplant recipients with an elevated BMI have worse long term graft survival, we prospectively studied 92 patients transplanted between April 1999 and July 2000. Weight (Wt) and height of the patients were recorded prior to transplantation and two weeks, one, two and three years post transplantation. Blood urea nitrogen (BUN), creatinine (Cr) and blood pressure were checked monthly, while triglyceride, cholesterol, high den-sity lipoprotein (HDL), and low density lipoprotein (LDL) were obtained 3 monthly for 3 years post transplantation. Graft dysfunction was defined as serum Cr > 1.8 mg/dL. While BMI and Wt of the patients before transplantation did not show any significant correlation with chronic renal allograft dysfunction (CRAD), patients with higher Wt and BMI two weeks after transplantation showed an increased risk of developing CRAD during the three year post transplant independent of other risk factors (P< 0.05). Patients with greater Wt loss in the first two weeks post transplantation showed a decreased risk of developing CRAD in the following 3 years (P< 0.001). Our study suggests that high Wt and BMI are significantly associated with worse graft survival 3 years post renal trans-plantation.

Aim: To evaluate and compare the diagnostic accuracy of multidetector computed tomography urography (CTU) and ultrasonography (US) for diagnosing bladder cancer., Materials and Methods: A consecutive series of 143 patients over 40-years of age, presenting with macroscopic haematuria and without urinary tract infection underwent same-day CTU, US, and flexible cystoscopy. CTU and US were independently rated on a five-point scale for the presence of bladder cancer without knowledge of the reference standard of flexible or rigid cystoscopy and/or biopsy results. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analysis and likelihood ratios., Results: For CTU, a rating of 5 (definitely tumour) was highly specific for bladder cancer (96.5%, 95%CI: 91.3-99%), effectively confirming diagnosis (positive likelihood ratio 25.6, 95%CI: 9.7-67.4). For US, specificity was also high (94.7%, 95%CI: 88.9-98%) with a positive likelihood ratio of 13.1 (95%CI: 5.8-29.6). Sensitivity at this rating was substantially higher for CTU (89.7%, 95%CI: 72.7-97.8%) than US (69%, 95%CI: 49.2-84.7%). Standardized partial area (Az) under the ROC curve between 95-100% specificity, representing the average sensitivity in this range, was significantly greater (0.88 versus 0.61, p<0.05) for CTU than US., Conclusion: The specificities of CTU and US for the diagnosis of bladder cancer were similar, but CTU was more sensitive. Although the sensitivity of CTU was not high enough to replace flexible cystoscopy in the diagnostic pathway, the high specificity enables direct referral to rigid cystoscopy, bypassing flexible cystoscopy and expediting diagnosis and treatment in those patients testing positive.

Background: Gene expression has a strong stochastic element resulting in highly variable mRNA levels between individual cells, even in a seemingly homogeneous cell population. Access to fundamental information about cellular mechanisms, such as correlated gene expression, motivates measurements of multiple genes in individual cells. Quantitative reverse transcription PCR (RT-qPCR) is the most accessible method which provides sufficiently accurate measurements of mRNA in single cells., Results: Low concentration of guanidine thiocyanate was used to fully lyse single pancreatic beta-cells followed by RT-qPCR without the need for purification. The accuracy of the measurements was determined by a quantitative noise-model of the reverse transcription and PCR. The noise is insignificant for initial copy numbers >100 while at lower copy numbers the noise intrinsic of the PCR increases sharply, eventually obscuring quantitative measurements. Importantly, the model allows us to determine the RT efficiency without using artificial RNA as a standard. The experimental setup was applied on single endocrine cells, where the technical and biological noise levels were determined., Conclusion: Noise in single-cell RT-qPCR is insignificant compared to biological cell-to-cell variation in mRNA levels for medium and high abundance transcripts. To minimize the technical noise in single-cell RT-qPCR, the mRNA should be analyzed with a single RT reaction, and a single qPCR reaction per gene.

Glycoconjugate vaccines have dramatically reduced the incidence of encapsulated bacterial diseases in toddlers under 2 years of age, but vaccine-induced antibody levels in this age group wane rapidly. We immunized adults and 12-month-old toddlers with heptavalent pneumococcal conjugate vaccine to determine differences in B-cell and antibody responses. The adults and 12-month-old toddlers received a pneumococcal conjugate vaccine. The toddlers received a second dose at 14 months of age. The frequencies of diphtheria toxoid and serotype 4, 14, and 23F polysaccharide-specific plasma cells and memory B cells were determined by enzyme-linked immunospot assay. The toddlers had no preexisting polysaccharide-specific memory B cells or serum immunoglobulin G (IgG) antibody but had good diphtheria toxoid-specific memory responses. The frequencies of plasma cells and memory B cells increased by day 7 (P < 0.0001) in the adults and the toddlers following a single dose of conjugate, but the polysaccharide responses were significantly lower in the toddlers than in the adults (P = 0.009 to <0.001). IgM dominated the toddler antibody responses, and class switching to the IgG was serotype dependent. A second dose of vaccine enhanced the antibody and memory B-cell responses in the toddlers but not the ex vivo plasma cell responses. Two doses of pneumococcal conjugate vaccine are required in toddlers to generate memory B-cell frequencies and antibody class switching for each pneumococcal polysaccharide equivalent to that seen in adults.