Genetic drivers of kidney defects in the digeorge syndrome

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P = 4.5×1014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-Altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

The effect of an active on-ward participation of hospital pharmacists in Internal Medicine teams on preventable Adverse Drug Events in elderly inpatients: protocol of the WINGS study (Ward-oriented pharmacy in newly admitted geriatric seniors)

<p>Abstract</p> <p>Background</p> <p>The potential of clinical interventions, aiming at reduction of preventable Adverse Drug Events (preventable ADEs) during hospital stay, have been studied extensively. Clinical Pharmacy is a well-established and effective service, usually consisting of full-time on-ward participation of clinical pharmacists in medical teams. Within the current Hospital Pharmacy organisation in the Netherlands, such on-ward service is less feasible and therefore not yet established. However, given the substantial incidence of preventable ADEs in Dutch hospitals found in recent studies, appears warranted. Therefore, "Ward-Oriented Pharmacy", an on-ward service tailored to the Dutch hospital setting, will be developed. This service will consist of multifaceted interventions implemented in the Internal Medicine wards by hospital pharmacists. The effect of this service on preventable ADEs in elderly inpatients will be measured. Elderly patients are at high risk for ADEs due to multi-morbidity, concomitant disabilities and polypharmacy. Most studies on the incidence and preventability of ADEs in elderly patients have been conducted in the outpatient setting or on admission to a hospital, and fewer in the inpatient setting. Moreover, recognition of ADEs by the treating physicians is challenging in elderly patients because their disease presentation is often atypical and complex. Detailed information about the performance of the treating physicians in ADE recognition is scarce.</p> <p>Methods/Design</p> <p>The design is a multi-centre, interrupted time series study. Patients of 65 years or older, consecutively admitted to Internal Medicine wards will be included. After a pre-measurement, a Ward-Oriented Pharmacy service will be introduced and the effect of this service will be assessed during a post-measurement. The primary outcome measures are the ADE prevalence on admission and ADE incidence during hospital stay. These outcomes will be assessed using structured retrospective chart review by an independent expert panel. This assessment will include determination of causality, severity and preventability of ADEs. In addition, the extent to which ADEs are recognised and managed by the treating physicians will be considered.</p> <p>Discussion</p> <p>The primary goal of the WINGS study is to assess whether a significant reduction in preventable ADEs in elderly inpatients can be achieved by a Ward-Oriented Pharmacy service offered. A comprehensive ADE detection method will be used based on expert opinion and retrospective, trigger-tool enhanced, chart review.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN64974377">ISRCTN64974377</a></p

Adverse Drug Reactions in Children—A Systematic Review

Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided

Topical antibiotics as a major contextual hazard toward bacteremia within selective digestive decontamination studies: a meta-analysis

BACKGROUND: Among methods for preventing pneumonia and possibly also bacteremia in intensive care unit (ICU) patients, Selective Digestive Decontamination (SDD) appears most effective within randomized concurrent controlled trials (RCCT’s) although more recent trials have been cluster randomized. However, of the SDD components, whether protocolized parenteral antibiotic prophylaxis (PPAP) is required, and whether the topical antibiotic actually presents a contextual hazard, remain unresolved. The objective here is to compare the bacteremia rates and patterns of isolates in SDD-RCCT’s versus the broader evidence base. METHODS: Bacteremia incidence proportion data were extracted from component (control and intervention) groups decanted from studies investigating antibiotic (SDD) or non-antibiotic methods of VAP prevention and summarized using random effects meta-analysis of study and group level data. A reference category of groups derived from purely observational studies without any prevention method under study provided a benchmark incidence. RESULTS: Within SDD RCCTs, the mean bacteremia incidence among concurrent component groups not exposed to PPAP (27 control; 17.1%; 13.1-22.1% and 12 intervention groups; 16.2%; 9.1-27.3%) is double that of the benchmark bacteremia incidence derived from 39 benchmark groups (8.3; 6.8-10.2%) and also 20 control groups from studies of non-antibiotic methods (7.1%; 4.8 – 10.5). There is a selective increase in coagulase negative staphylococci (CNS) but not in Pseudomonas aeruginosa among bacteremia isolates within control groups of SDD-RCCT’s versus benchmark groups with data available. CONCLUSIONS: The topical antibiotic component of SDD presents a major contextual hazard toward bacteremia against which the PPAP component partially mitigates. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0714-x) contains supplementary material, which is available to authorized users

Characterization of statin-associated myopathy case reports in thailand using the health product vigilance center database

HMG-CoA reductase inhibitors [statins], a widely prescribed cholesterol-lowering therapy, are associated with muscle-related adverse events. While characteristics of such events are well documented in Western countries, little data exists for the Thai population.The aim of this study was to determine the characteristics of patients, type and dosing of statin, and to identify patterns of drug use that may be associated with such adverse events using the national pharmacovigilance database known as Thai Vigibase.Muscle-related adverse events involving statins in the Thai Vigibase from 1996 to December 2009 were identified. For each report, the following information was extracted: patient demographics, co-morbidities, detailed information of adverse event, detailed information of suspected drug, treatment and outcome, as well as causality assessment and quality of reports. Descriptive statistics were performed for all study variables.A total of 198 cases of statin-associated muscle-related adverse events were identified. Mean age was 61.4 ± 12.4 years of age and 59.6% were female. Simvastatin, atorvastatin, rosuvastatin and cerivastatin were implicated as the suspected drug in 163 (82.3%), 24 (12.1%), 10 (5.1%) and 1 (0.5%) cases, respectively. Rhabdomyolysis accounted for 55.6% of all muscle-related adverse events. Drug interactions known to enhance such toxicity of statins were identified in 40.9% of the total set of reports. Similar to studies from Western countries, fibrates, HIV protease inhibitors, non-dihydropyridine calcium channel blockers, azole antifungals and macrolides were commonly found in such cases. Interestingly, colchicine has been identified as the second most common drug interaction in our database. Case fatality rates were 0.9, 1.6 and 16.7%, when there were 0, 1 and ≥2 interacting drugs, respectively.Characteristics of muscle-related adverse events with statins in the Thai population showed some similarities and differences compared with Western countries. Such similarities included advanced age, female sex, certain co-morbidities and drug interactions. While the majority of interacting drugs are well known, a big proportion of cases of statin-colchicine interaction attributed to long-term use of colchicine in Thailand was noted and should be further investigated. Based on these results, an attempt to avoid dangerous and well-known drug interactions among statin users should be implemented nationwide