Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2013"

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Abstract: Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Acute Skeletal Muscle Wasting in Critical Illness

Abstract: Importance Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. Objective To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. Design, Setting, and Participants Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. Main Outcomes and Measures Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. Results There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% [95% CI, −20.9% to −4.8%]; P P P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) ( P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = −0.83, P = .005) and decreased synthesis (n = 9, r = −0.69, P = .04). Conclusions and Relevance Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.

The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study

Abstract: A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location.

Factors Affecting Auditory Performance of Postlinguistically Deaf Adults Using Cochlear Implants: An Update with 2251 Patients

Abstract: Objective: To update a 15-year-old study of 800 postlinguistically deaf adult patients showing how duration of severe to profound hearing loss, age at cochlear implantation (CI), age at onset of severe to profound hearing loss, etiology and CI experience affected CI outcome. Study Design: Retrospective multicenter study. Methods: Data from 2251 adult patients implanted since 2003 in 15 international centers were collected and speech scores in quiet were converted to percentile ranks to remove differences between centers. Results: The negative effect of long duration of severe to profound hearing loss was less important in the new data than in 1996; the effects of age at CI and age at onset of severe to profound hearing loss were delayed until older ages; etiology had a smaller effect, and the effect of CI experience was greater with a steeper learning curve. Patients with longer durations of severe to profound hearing loss were less likely to improve with CI experience than patients with shorter duration of severe to profound hearing loss. Conclusions: The factors that were relevant in 1996 were still relevant in 2011, although their relative importance had changed. Relaxed patient selection criteria, improved clinical management of hearing loss, modifications of surgical practice, and improved devices may explain the differences.

A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant Staphylococcus aureus pandemic

Abstract: The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens.

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

Abstract: Summary Background Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes ( TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 , and ADAR ). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r =−0·604; serum, r =−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union's Seventh Framework Programme; European Research Council.

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

Abstract: Few prospective, randomized controlled clinical trials address the diagnosis and management of patientswith Alportsyndrome or thinbasement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18recommendationsarebased onLevel D (Expert opinion withoutexplicitcritical appraisal,orbasedonphysiology, bench research, or first principles—NationalHealth Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees—U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstrationofitsmodeofinheritance;theneedtoidentifyandfollowallaffectedmembersofa family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and considerationofgenetictestingtoexcludeX-linkedAlportsyndromeinsomeindividualswith thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

Prognostic Relevance of Treatment Response Measured by Flow Cytometric Residual Disease Detection in Older Patients With Acute Myeloid Leukemia

Abstract: Purpose Older patients with acute myeloid leukemia (AML) have a high relapse rate after standard chemotherapy. We investigated whether measuring chemotherapy sensitivity by multiparameter flow cytometric minimal residual disease (MFC-MRD) detection has prognostic value in patients older than age 60 years or is simply a surrogate for known age-related risk factors. Patient and Methods Eight hundred ninety-two unselected patients treated intensively in the United Kingdom National Cancer Research Institute AML16 Trial were assessed prospectively for MFC-MRD during treatment. Eight hundred thirty-three patients had leukemia-associated immunophenotypes (LAIPs) identified by pretreatment screening. Four hundred twenty-seven patients entered complete remission (CR) after one or two courses (designated C1 and C2, respectively) and were MFC-MRD assessable by LAIP detection in CR bone marrow for at least one of these time points. MRD positivity was defined as residual disease detectable by LAIP. Results MFC-MRD neg...

Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial.

Abstract: BACKGROUND Fibrinogen is suggested to play an important role in managing major bleeding. However, clinical evidence regarding the effect of fibrinogen concentrate (derived from human plasma) on transfusion is limited. The authors assessed whether fibrinogen concentrate can reduce blood transfusion when given as intraoperative, targeted, first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery. METHODS In this single-center, prospective, placebo-controlled, double-blind study, patients aged 18 yr or older undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to fibrinogen concentrate or placebo, administered intraoperatively. Study medication was given if patients had clinically relevant coagulopathic bleeding immediately after removal from cardiopulmonary bypass and completion of surgical hemostasis. Dosing was individualized using the fibrin-based thromboelastometry test. If bleeding continued, a standardized transfusion protocol was followed. RESULTS Twenty-nine patients in the fibrinogen concentrate group and 32 patients in the placebo group were eligible for the efficacy analysis. During the first 24 h after the administration of study medication, patients in the fibrinogen concentrate group received fewer allogeneic blood components than did patients in the placebo group (median, 2 vs. 13 U; P < 0.001; primary endpoint). Total avoidance of transfusion was achieved in 13 (45%) of 29 patients in the fibrinogen concentrate group, whereas 32 (100%) of 32 patients in the placebo group received transfusion (P < 0.001). There was no observed safety concern with using fibrinogen concentrate during aortic surgery. CONCLUSIONS Hemostatic therapy with fibrinogen concentrate in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life-threatening coagulopathy.

Identifying infants at high risk of peanut allergy: The Learning Early About Peanut Allergy (LEAP) screening study

Abstract: Background Peanut allergy (PA) is rare in countries in which peanuts are introduced early into infants' diets. Learning Early About Peanut Allergy (LEAP) is an interventional study aiming to assess whether PA can be prevented by oral tolerance induction. Objective We sought to characterize a population screened for the risk of PA. Methods Subjects screened for the LEAP interventional trial comprise the LEAP screening study cohort. Infants were aged 4 to 10 months and passed a prescreening questionnaire. Results This analysis includes 834 infants (mean age, 7.8 months). They were split into the following: group I, patients with mild eczema and no egg allergy (n = 118); group II, patients with severe eczema, egg allergy, or both but 0-mm peanut skin prick test (SPT) wheal responses (n = 542); group III, patients with severe eczema, egg allergy, or both and 1- to 4-mm peanut wheal responses (n = 98); and group IV, patients with greater than 4-mm peanut wheal responses (n = 76). Unexpectedly, many (17%) in group II had peanut-specific IgE sensitization (≥0.35 kU/L); 56% of group III were similarly sensitized. In contrast, none of the patients in group I and 91% of those in group IV had peanut-specific IgE sensitization. Sensitization on skin testing to peanut (SPT response of 1-4 mm vs 0 mm) was associated with egg allergy and severe eczema (odds ratio [OR], 2.31 [95% CI, 1.39-3.86] and 2.47 [95% CI, 1.14-5.34], respectively). Similar associations were observed with specific IgE sensitization. Black race was associated with a significantly higher risk of peanut-specific IgE sensitization (OR, 5.30 [95% CI, 2.85-9.86]). Paradoxically, for a given specific IgE level, black race was protective against cutaneous sensitization (OR, 0.15 [95% CI, 0.04-0.61]). Conclusion Egg allergy, severe eczema, or both appear to be useful criteria for identifying high-risk infants with an intermediate level of peanut sensitization for entry into a PA prevention study. The relationship between specific IgE level and SPT sensitization needs to be considered within the context of race.

GAPSS: the Global Anti-Phospholipid Syndrome Score

Abstract: Objective. To develop and validate a risk score [global APS score (GAPSS)] derived from the combination of independent risk for thrombosis and pregnancy loss (PL), taking into account the aPL profile, conventional cardiovascular risk factors and the autoimmune antibody profile. Methods. This cross-sectional study included 211 consecutive SLE patients. Data on clinical manifestations, conventional cardiovascular risk factors, aPL profile, ANAs, ENA and anti-dsDNA were collected. Long-term low-dose aspirin, oral anticoagulant and HCQ treatment were also included in the analysis. Patients were randomly divided into two sets by a computer-generated randomized list. We developed GAPSS in the first set of patients (n = 106), assigning the risk factors identified by multivariate analysis weighted points proportional to the b-regression coefficient values. GAPSS was validated in the second set of patients (n = 105). The relationship between GAPPS and thrombosis and/or PL was analysed. Results. In the first set, higher values of GAPSS were seen in patients who experienced thrombosis and/ or PL compared with those without clinical events [GAPSS 9.3 (4.8) (range 119) and 5.3 (4) (range 016), P < 0.001]. Also taken separately, patients who experienced thrombosis or PL showed higher GAPSS compared with those without clinical events [GAPSS 9.6 (4.8) (range 119) vs 4.9 (5) (range 014), P = 0.027 for thrombosis; 7.3 (5) vs 3.9 (5.1) (range 016), P = 0.024 for PL, respectively]. In the second set, the results were similar, with statistically higher values of GAPSS in patients with a clinical history of thrombosis and/or PL compared with those without events [GAPSS 9.5 (5.6) (range 020) and 3.9 (4.1) (range 017), P < 0.001). Higher values were also seen when subclassifying the patients according to the clinical manifestation, thrombosis or PL [GAPSS 9.5 (5.6) (range 020) vs 4.8 (5.4) (range 017), P = 0.036 for thrombosis; 7.9 (3.3) vs 3.8 (5.4) (range 016), P = 0.037 for PL, respectively). Conclusion. These data propose a substantial improvement in risk prediction of thrombosis or PL in SLE based on assessment of the GAPSS, a quantitative scoring system.

Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens

Abstract: Objective To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens. Method Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007–2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase. Results Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect. Conclusions Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Abstract: Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10-5), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10-4) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10-9). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches

Abstract: UK Biobank is a prospective cohort study with 500,000 participants aged 40 to 69. Recently an enhanced imaging study received funding. Cardiovascular magnetic resonance (CMR) will be part of a multi-organ, multi-modality imaging visit in 3–4 dedicated UK Biobank imaging centres that will acquire and store imaging data from 100,000 participants (subject to successful piloting). In each of UK Biobank’s dedicated bespoke imaging centres, it is proposed that 15–20 participants will undergo a 2 to 3 hour visit per day, seven days a week over a period of 5–6 years. The imaging modalities will include brain MRI at 3 Tesla, CMR and abdominal MRI at 1.5 Tesla, carotid ultrasound and DEXA scans using carefully selected protocols. We reviewed the rationale, challenges and proposed approaches for concise phenotyping using CMR on such a large scale. Here, we discuss the benefits of this imaging study and review existing and planned population based cardiovascular imaging in prospective cohort studies. We will evaluate the CMR protocol, feasibility, process optimisation and costs. Procedures for incidental findings, quality control and data processing and analysis are also presented. As is the case for all other data in the UK Biobank resource, this database of images and related information will be made available through UK Biobank’s Access Procedures to researchers (irrespective of their country of origin and whether they are academic or commercial) for health-related research that is in the public interest.

TLRs to cytokines: Mechanistic insights from the imiquimod mouse model of psoriasis

Abstract: Psoriasis is an inflammatory disease of the skin affecting 2-3% of the population, characterized by a thickening of the epidermis and immune infiltrates throughout the dermis and epidermis, causing skin lesions that can seriously affect quality of life. The study of psoriasis has historically been hampered by the lack of good animal models. Various genetically induced models exist, which have provided some information about possible mechanisms of disease, but these models rely mostly on intrinsic imbalances of homeostasis. However, a mouse model of psoriasiform dermatitis caused by the repeated topical application of Aldara™ containing 5% imiquimod was described in 2009. The mechanisms of action of Aldara™ are complex. Imiquimod is an effective ligand for TLR7 (and TLR8 in humans) and also interferes with adenosine receptor signaling. In addition, isostearic acid present in the Aldara™ vehicle has been shown to be biologically active and of importance for activating the inflammasome. Interestingly, the repetitive application of Aldara™ reveals a complex aetiology involving multiple cell types, cytokines, and inflammatory pathways. In this review, we will dissect the findings of the imiquimod model to date and ask how this model can inform us about the immunological aspects of human disease.

Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

Abstract: Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan

Abstract: Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.

Primary Esophageal Cancer: Heterogeneity as Potential Prognostic Biomarker in Patients Treated with Definitive Chemotherapy and Radiation Therapy

Abstract: Tumor heterogeneity is associated with survival and adds additional prognostic information to morphologic tumor response.

Pregnancy in Renal Transplant Recipients: A UK National Cohort Study

Abstract: Summary Background and objectives Most reports of pregnancy outcome in women with kidney transplants are single-center, retrospective, and include small numbers and few are compared with controls. The aim of this study was to collect information about pregnancy outcomes among all kidney transplant recipients in the United Kingdom, managed with current antenatal and nephrologic care, and to compare these data with a contemporaneous control group. Design, setting, participants, & measurements Pregnant women with a kidney transplant were identified through the UK Obstetric Surveillance System (UKOSS) between January 1, 2007 and December 31, 2009. Data on a comparison cohort were obtained from the UKOSS database, containing information on comparison women identified in previous studies. Outcomes were also compared with national data. Results There were 105 pregnancies identified in 101 recipients. Median prepregnancy creatinine was 118 μmol/L. Preeclampsia developed in 24% compared with 4% of the comparison group. Median gestation at delivery was 36 weeks, with 52% of women delivering at 1 previous kidney transplant ( P =0.03), first trimester serum creatinine >125 μmol/L ( P =0.001), and diastolic BP >90 mmHg in the second ( P =0.002) and third trimesters ( P =0.05). Conclusions Most pregnancies in the United Kingdom in women with kidney transplants are successful but rates of maternal and neonatal complications remain high.

Cardiovascular disease in chronic kidney disease: untying the Gordian knot

Abstract: Summary Chronic kidney disease (CKD) affects around 10–13% of the general population, with only a small proportion in end stage renal disease (ESRD), either on dialysis or awaiting renal transplantation It is well documented that CKD patients have an extremely high risk of developing cardiovascular disease (CVD) compared with the general population, so much so that in the early stages of CKD patients are more likely to develop CVD than they are to progress to ESRD Various pathophysiological pathways and explanations have been advanced and suggested to account for this, including endothelial dysfunction, dyslipidaemia, inflammation, left ventricular hypertrophy and cardiac autonomic dysfunction In this review, we try to understand and further explore the link between CKD and CVD, as well as offering interventional advice where available, while exposing the current lack of RCT-based research and trial evidence in this area We also suggest pragmatic Interim measures we could take while we wait for definitive RCTs

The persistence and stability of psychiatric problems in adolescents with autism spectrum disorders

Abstract: Background: Psychiatric problems are common in autism spectrum disorders (ASDs), but the reasons are poorly understood. We use a longitudinal population-representative cohort to examine for the first time the persistence of psychiatric problems and to identify risk factors for their occurrence and stability. Methods: Eighty-one 16-year olds (75 male, six female), initially seen at 12 years, were re-assessed using the parent-report Strengths and Difficulties Questionnaire (SDQ). Child, family and contextual characteristics from age 12 were tested as risk factors for psychopathology. Results: Prevalence rates varied depending on whether general population or ASD-specific SDQ cut-offs were used. While the former suggested a decrease in psychiatric problems over time, the ASD-specific cut-offs showed no significant differences. With the exception of ADHD, the ASD-specific cut-offs identified a smaller proportion of individuals as ‘affected’ than did the general population cut-offs. There was longitudinal domain specificity, with parent correlations ranging from 0.50 to 0.58 and teacher SDQ reports at age 12 correlating 0.33–0.53 with parent reports at 16 years. In examining the role of risk factors, lower IQ and adaptive functioning predicted higher hyperactivity and total difficulties scores. Greater emotional problems at 16 were predicted by poorer maternal mental health, family-based deprivation and lower social class. Improvement from 12 to 16 years in conduct problems was predicted by greater neighbourhood deprivation and special school attendance. Conclusions: This is the first longitudinal study of other psychiatric symptoms in ASD. Additional psychiatric problems in ASD are persistent and domain-specific from childhood to adolescence. The finding that age-related reduction in SDQ symptoms does not apply when ASD-specific cut-offs are used requires further evaluation using diagnostic measures. Only a few of the expected risk factor-psychopathology predictions expected from general population studies were found, raising the possibility that the causes of psychopathology in ASD differ from those in the general population.

Coffin–Siris Syndrome and the BAF Complex: Genotype–Phenotype Study in 63 Patients

Abstract: De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.

Global incidence and outcome of testicular cancer.

Abstract: Background Testicular cancer is a rare tumor type accounting for 1% of malignancies in men. It is, however, the most common cancer in young men in Western populations. The incidence of testicular cancer is increasing globally, although a decline in mortality rates has been reported in Western countries. It is important to identify whether the variations in trends observed between populations are linked to genetic or environmental factors.

Neurofibromatosis type 1 (NF1): diagnosis and management

Abstract: Neurofibromatosis 1 (NF1) is an inherited neurocutaneous disease that has a major impact on the nervous system, eye, skin, and bone. Individuals with NF1 have a predisposition to benign and malignant tumor formation and the hallmark lesion is the neurofibroma, a benign peripheral nerve sheath tumor. The gene for NF1 was cloned on chromosome 17q11.2 and neurofibromin, the NF1 protein, controls cell growth and proliferation by regulating the proto-oncogene Ras and cyclic adenosine monophosphate (AMP). Advances in molecular biology and mouse models of disease have enhanced our understanding of the pathogenesis of NF1 complications and facilitated targeted therapy. Progress has been made in developing robust clinical and radiological outcome measures and clinical trials are underway for children with learning difficulties and for individuals with symptomatic plexiform neurofibromas.

Cardiovascular risk factors and cognitive decline in adults aged 50 and over: a population-based cohort study

Abstract: Objectives: the objective of the present study was to explore the association between cardiovascular risk and cognitive decline in adults aged 50 and over. Methods: participants were older adults who participated in the English Longitudinal Study of Ageing. Outcome measures included standardised z-scores for global cognition, memory and executive functioning. Associations between cardiovascular risk factors and 10-year Framingham risk scores with cognitive outcomes at 4-year and 8-year follow-ups were estimated. Results: the mean age of participants (n= 8,780) at 2004–05 survey was 66.93 and 55% were females. Participants in the highest quartile of Framingham stroke risk score (FSR) had lower global cognition (b= −0.73,CI: −1.37, −0.10), memory (b= −0.56, CI: −0.99, −0.12) and executive (b= −0.37, CI: −0.74, −0.01) scores at 4-year follow-up compared with those in the lower quartile. Systolic blood pressure ≥160 mmHg at 1998–2001 survey was associated with lower global cognitive (b= −1.26, CI: −2.52, −0.01) and specific memory (b= −1.16, CI: −1.94, −0.37) scores at 8-year follow-up. Smoking was consistently associated with lower performance on all three cognitive outcomes. Conclusion: elevated cardiovascular risk may be associated with accelerated decline in cognitive functioning in the elderly. Future intervention studies may be better focused on overall risk rather than individual risk factor levels.