De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

Health needs of regional Australian children in out-of-home care.

AIM: This study aims to identify the health needs of children placed in out-of-home care in regional Queensland and to compare them with the needs of similar children in metropolitan Queensland. METHODS: Retrospective chart review and subsequent analysis of data from the first assessments of the children placed in care from January 2005 to April 2011. Health needs based on assessment recommendations were then compared with needs and recommendations from a similar clinic in metropolitan Brisbane. RESULTS: Two hundred thirty-nine first assessments were reviewed. The average number of health referrals arising out of each assessment was 2. 72% children were between 2 and 12 years of age and accounted for 76% of the health referrals made. The 10-13% of the children needed referrals for medical and surgical specialties, audiology, speech pathology, dental, and ophthalmology/optometry, each. A percentage of 30 needed ongoing paediatric care. The 15% needed immunisation catch up, 35% counselling and behaviour management, and 15% formal mental health referrals. These were comparable to the health needs identified in out-of-home care children residing in metropolitan Queensland. CONCLUSION: Children in care who live in a regional setting have similar health-care needs compared with urban children. Given restricted health services in regional settings, there is difficulty in accessing services to meet these needs.

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

OBJECTIVE: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection. DESIGN: Randomized controlled trial. SETTING: Multicenter trial in the United States. PARTICIPANTS: Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection. INTERVENTIONS: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures. MAIN OUTCOME MEASURES: The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures. RESULTS: The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups. CONCLUSIONS: No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00097773.

A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia.

The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.

Validating tumor linkage using the NAACCR site pairs table.

The objective of this study is to illustrate use of the Site Pairs Table developed by the North American Association of Central Cancer Registries (NAACCR) Record Linkage Work Group to validate tumor linkage in a central registry database and to identify potential cases with inaccurate tumor linkage. Central registries often receive reports for patients with multiple tumors, and they receive multiple reports from different sources for the same tumor. Tumor site pairs (pairs of unique tumors for patients with multiple tumors) ought not refer to the same tumor as represented in the Site Pairs Table. Likewise, abstract pairs (pairs of abstracts relating to the same tumor) ought to be identified during the tumor linkage process as belonging to the same tumor. Three central cancer registries represented on the work group contributed data to the study. The data included cases diagnosed 1992-2003 and represented 143,288 patients with multiple tumors and 280,227 tumors with multiple abstracts. Totals of 181,118 tumor site pairs and 391,670 abstract site pairs were generated from the data and compared to the Site Pairs Table. Of the abstract site pairs 381,389 (97.4%) were found in the Site Pairs Table. One registry reviewed its portion of the 2.6% not found in the table and determined 12% of the cases were incorrectly linked and should change from one tumor to two tumors. Of the tumor site pairs, 144,793 (80%) were not found in the Site Pairs Table. Further evaluation of the remaining 20% by paired site and laterality, histology and timing showed 19.3% were considered unique tumors and 0.7% were identified as potential cases with inaccurate tumor linkage. Two registries reviewed their portion of these cases. One registry changed two tumors to one tumor on 44% of the cases they reviewed. The other registry changed two tumors to one tumor on 53% of the cases they reviewed. Analyzing site pairs within the registry database using the Site Pairs Table assists in identifying inaccurate tumor linkages as was shown in this study.

Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study'.

BACKGROUND: The primary cause of morbidity and mortality in patients with cystic fibrosis (CF) is progressive obstructive pulmonary disease due to chronic endobronchial infection, particularly with Pseudomonas aeruginosa (Pa). Risk factors for and clinical impact of early Pa infection in young CF patients are less well understood. PURPOSE: The present studies are designed to evaluate risk factors and outcomes associated with early Pa acquisition, and the benefits and harms of four anti-pseudomonal treatment regimens in young CF patients initiated after the first Pa positive respiratory culture. METHODS: The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1-12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15-20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study. The broad goals of the observational study are to describe the risk factors and outcomes associated with early acquisition of Pa. 306 patients were randomized in the clinical trial and 1787 were enrolled in the cohort study. CONCLUSIONS: These companion studies will provide valuable epidemiological and microbiological information on early CF lung disease and Pa acquisition, and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the airways of young children with CF.

Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis.

RATIONALE: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality. Early intervention strategies include tobramycin solution for inhalation (TSI), which can eradicate lower airway Pa from cultures obtained at the end of 28 days of treatment in young children. METHODS: We conducted an open label, sequential cohort study of TSI in young children with CF to investigate duration of antimicrobial treatment effect. The primary outcome was lower airway Pa eradication per bronchoalveolar lavage (BAL) fluid culture. Sequential treatment cohorts varied by duration of treatment (28 or 56 days) and timing of follow-up BAL (at Days 56, 84, or 112). Subjects (N = 36) were treated with TSI, 300 mg twice daily, for 28 days or 56 days per cohort assignment. RESULTS: Among 31 evaluable subjects, culture based, lower airway Pa eradication was observed in the majority of subjects for up to 1-3 months following TSI treatment: 75% in Cohort 28/56 (days of treatment/day of follow-up BAL), 63% in Cohort 28/84, 82% in Cohort 56/112, and 75% in Cohort 28/112. Non-mucoid Pa at baseline and/or exotoxin A seronegativity were associated with higher rates of eradication. There was a less pronounced effect of TSI treatment on Pa eradication from oropharyngeal cultures in all cohorts. TSI treatment was associated with reduced neutrophilic airway inflammation and was not related to any serious adverse events. CONCLUSION: TSI monotherapy is safe and can eradicate lower airway Pa for up to 3 months after treatment in young children with CF.

Laboratory parameter profiles among patients with cystic fibrosis.

BACKGROUND: Clinical trials in cystic fibrosis (CF) currently use laboratory-specific reference ranges to evaluate chemistry and hematology measurements. Laboratory-specific normal reference ranges may not accurately reflect what is abnormal but clinically insignificant among CF patients. METHODS: To address this concern, data from the Phase III trial of inhaled tobramycin in CF patients was used to describe the distribution and variability of laboratory parameters. The laboratory specimens were analyzed at a central laboratory after being obtained at baseline and throughout the 24-week trial. RESULTS: At the time of entry into the clinical trial, 91% (463 of 508) of patients had at least a single value outside the normal range. Liver function tests (AST, ALT) were above the normal range in 16% and 12% of the patients respectively, with 2.4% of patients having an AST>2.0 times the upper limit of normal. Of the 243 patients on placebo, 242 (99.6%) had at least one laboratory parameter that changed from normal to abnormal during the 24-week follow-up period. Of those same placebo patients, 11.5% (N=28) had a laboratory parameter change from a Common Toxicity Criteria (CTC) grade 0 to grade 2 or higher during follow-up. CONCLUSIONS: Patients with CF frequently have laboratory values outside the normal range and have significant longitudinal variability of laboratory values. Interpretation of adverse events in the clinical trial setting may be complicated by the underlying high rates of some laboratory abnormalities in the CF population. This data was presented in poster format at the American Thoracic Society International Conference, Atlanta, USA, 2002, appearing subsequently in the Conference proceedings [Goss CH, Mayer-Hamblett N, Yunker A, Waltz DA, Kronmal RA, Ramsey BW. Laboratory parameter profiles among patients with cystic fibrosis. Am J Rep Crit Care Med 2002;165(8):A283].

Mortality from disease among fishermen employed in the UK fishing industry from 1948 to 2005.

BACKGROUND: Although commercial fishing has become established as the most hazardous occupation in Western countries, relatively little has been reported on mortality from disease among fishermen. OBJECTIVE: To investigate the causes of work-related mortality from disease in the UK fishing industry from 1948 to 2005, trends in mortality over time and how it varies according to the sector of the fishing industry, to investigate non-work related mortality among fishermen ashore, and to compare it with that in other populations. METHODS: Examination of paper death inquiry files, death registers and death returns, as well as GIS mapping for a defined population of 1.45 million fishermen-years at risk. RESULTS: From 1948 to 2005, there were a total of 449 work-related deaths from disease identified in the UK fishing industry, with a corresponding mortality rate of 30.9 per 100,000. The mortality rate increased from about 35 per 100,000 in the late 1940s to 60 in the early/mid 1970s but fell sharply to about 10 by the late 1970s. Most of the deaths were caused by ischaemic heart disease followed by other circulatory diseases, respiratory and gastrointestinal diseases. The highest mortality rates were identified for fishermen employed on board distant water trawlers, particularly those operating in Arctic waters. CONCLUSIONS: The study shows that fishermen in distant water trawlers, particularly in Arctic conditions, have the highest risks of mortality from disease. The high risks presumably reflect lifestyle risk factors as well as extremely hazardous and stressful working and sleeping conditions.

Realtime telemedicine for paediatric otolaryngology pre-admission screening.

We conducted a feasibility study to examine whether a paediatric patient at a regional hospital could be assessed by an ear, nose and throat (ENT) specialist via videoconference, therefore saving at least one journey to the tertiary hospital for a pre-admission appointment. A video-otoscope was used with standard videoconference equipment, and realtime images were transmitted at a bandwidth of 384 kbit/s. In all, 13 telepaediatric ENT clinics were conducted between November 2003 and April 2005, and 98 consultations were facilitated for 64 patients. The main reasons for referral were recurrent tonsillitis (25%) and obstructive sleep apnoea (23%). Of the 64 patients examined by telemedicine, 42 (66%) were recommended for surgery and placed on the surgical waiting list. About 12 patients (19%) required travel to the tertiary centre for further investigations and tests not available locally, while four patients (6%) were reviewed via videoconference during a scheduled clinic. Six patients (9%) required no further follow-up after their initial telepaediatric consultation. Videoconferencing is an effective method of assessing ENT conditions of paediatric patients and for pre-screening potential surgical admissions to a tertiary hospital. Careful consideration of a number of economic and logistical factors needs to be made before large investments are made to expand the service.

Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.

Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.

Survival against drugs: education for school-age children.

PROBLEM: Alcohol and drug use of young school-age children continue to escalate. Comprehensive, effective interventions are needed to treat and prevent future alcohol and drug use. METHODS: The alcohol and drug use of 69 school-age children participating in afterschool programs was explored; parents completed a family climate scale. An investigator-developed educational program was evaluated for its effect on self-efficacy of the children to prevent drug and alcohol use. FINDINGS: Although family climate scales indicated functioning families, 25% of the children indicated they have used drugs or alcohol and 49% indicated a possible problem with alcohol or drugs being used at home by parents. A significant correlation with a child's self-efficacy and drug use was found. CONCLUSIONS: The educational program taught children survival skills to resist the use of alcohol and drugs. Children with a plan to resist the use of drugs were more likely not to use drugs.