Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

Beta-lactamase production by Kingella kingae in Israel is clonal and common in carriage organisms but rare among invasive strains.

The purpose of this study was to investigate the prevalence of ß-lactamase and the genomic clonality of a large collection of Kingella kingae isolates from Israeli patients with a variety of invasive infections and asymptomatic pharyngeal carriers. ß-lactamase production was studied by the nitrocefin method and the minimum inhibitory concentrations (MICs) of penicillin and amoxicillin-clavulanate were determined by the epsilon (Etest) method. The genotypic clonality of isolates was investigated by pulsed-field electrophoresis (PFGE). ß-lactamase was found in 2 of 190 (1.1 %) invasive isolates and in 66 of 429 (15.4 %) randomly chosen carriage organisms (p < 0.001). Overall, 73 distinct PFGE clones were identified (33 among invasive organisms and 56 among carriage isolates). ß-lactamase production was found to be limited to four distinct PFGE clones, which were common among carriage strains but rare among invasive strains, and all organisms in the collection belonging to these four clones expressed ß-lactamase. The penicillin MIC of ß-lactamase-producing isolates ranged between 0.094 and 2 mcg/mL (MIC50: 0.25 mcg/mL; MIC90: 1.5 mcg/mL) and that of amoxicillin-clavulanate between 0.064 and 0.47 mcg/mL (MIC50: 0.125 mcg/mL; MIC90: 0.125 mcg/mL). The penicillin MIC of ß-lactamase non-producing isolates ranged between <0.002 and 0.064 mcg/mL (MIC50: 0.023 mcg/mL; MIC90: 0.047 mcg/mL). Although ß-lactamase production is prevalent among K. kingae organisms carried by healthy carriers, the low invasive potential of most colonizing clones results in infrequent detection of the enzyme in isolates from patients with clinical infections. The exceptional presence of ß-lactamase among invasive organisms correlates with the favorable response of K. kingae infections to the administration of ß-lactamase-susceptible antibiotics.

Assessing patient safety risk before the injury occurs: an introduction to sociotechnical probabilistic risk modelling in health care.

Since 1 July 2001 the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has required each accredited hospital to conduct at least one proactive risk assessment annually. Failure modes and effects analysis (FMEA) was recommended as one tool for conducting this task. This paper examines the limitations of FMEA and introduces a second tool used by the aviation and nuclear industries to examine low frequency, high impact events in complex systems. The adapted tool, known as sociotechnical probabilistic risk assessment (ST-PRA), provides an alternative for proactively identifying, prioritizing, and mitigating patient safety risk. The uniqueness of ST-PRA is its ability to model combinations of equipment failures, human error, at risk behavioral norms, and recovery opportunities through the use of fault trees. While ST-PRA is a complex, high end risk modelling tool, it provides an opportunity to visualize system risk in a manner that is not possible through FMEA.

Long-stay patients in the pediatric intensive care unit.

OBJECTIVE: Length of stay in the pediatric intensive care unit (PICU) is a reflection of patient severity of illness and health status, as well as PICU quality and performance. We determined the clinical profiles and relative resource use of long-stay patients (LSPs) and developed a prediction model to identify LSPs for early quality and cost saving interventions. DESIGN: Nonconcurrent cohort study. SETTING: A total of 16 randomly selected PICUs and 16 volunteer PICUs. PATIENTS: A total of 11,165 consecutive admissions to the 32 PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: LSPs were defined as patients having a length of stay greater than the 95th percentile (>12 days). Logistic regression analysis was used to determine which clinical characteristics, available within the first 24 hrs after admission, were associated with LSPs and to create a predictive algorithm. Overall, LSPs were 4.7% of the population but represented 36.1% of the days of care. Multivariate analysis indicated that the following factors are predictive of long stays: age <12 months, previous ICU admission, emergency admission, no CPR before admission, admission from another ICU or intermediate care unit, chronic care requirements (total parenteral nutrition and tracheostomy), specific diagnoses including acquired cardiac disease, pneumonia, and other respiratory disorders, having never been discharged from the hospital, need for ventilatory support or an intracranial catheter, and a Pediatric Risk of Mortality III score between 10 and 33. The performance of the prediction algorithm in both the training and validation samples for identifying LSPs was good for both discrimination (area under the receiver operating characteristics curve of 0.83 and 0.85, respectively), and calibration (goodness of fit, p = .33 and p = .16, respectively). LSPs comprised from 2.1% to 8.1% of individual ICU patients and occupied from 15.2% to 57.8% of individual ICU bed days. CONCLUSIONS: LSPs have less favorable outcomes and use more resources than non-LSPs. The clinical profile of LSPs includes those who are younger and those that require chronic care devices. A predictive algorithm could help identify patients at high risk of prolonged stays appropriate for specific interventions.

Familial cerebellar ataxia with muscle coenzyme Q10 deficiency.

OBJECTIVE: To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency. BACKGROUND: Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retardation), and 3) ragged-red fibers and lipid storage in the muscle biopsy. METHODS: Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes. RESULTS: The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent. CONCLUSIONS: Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture.

Correction of glycogen storage disease type II by enzyme replacement with a recombinant human acid maltase produced by over-expression in a CHO-DHFR(neg) cell line.

Inherited genetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in the autosomal recessive glycogen storage disease type II (GSD II). To investigate whether we could generate a functional recombinant human GAA (rhGAA) for enzyme replacement therapy, we subcloned the cDNAs for human GAA and mouse dihydrofolate reductase (DHFR) into DHFR(neg) Chinese hamster ovary cells and established a stable cotransformant that expressed rhGAA. We cultured the recombinant cells in media with progressively increasing concentrations of methotrexate and found that human GAA enzyme activity increased to over 2,000 IU per gram protein. Importantly, the human GAA enzyme activity correlated to equivalent amounts of human GAA protein by rocketimmunoelectrophoresis. We confirmed that the human GAA enzyme activity corresponded to an amplification in human GAA mRNA by Northern analysis and human GAA cDNA copy number by Southern analysis. Exposing the rhGAA to human GSDII fibroblast cells or patient's lymphocytes or monocytes resulted in uptake of the rhGAA and reversal of the enzymatic defect. Mannose-6-phosphate in the media blocked uptake. GAA -/- mice were treated with the rhGAA at 1 mg/kg, which resulted in heterozygous levels of GAA in tissues, most notably skeletal muscle, heart and diaphragm after two infusions. More importantly, after multiple infusions, hind, and fore-limb muscle weakness was reversed. This rhGAA would be ideal for enzyme replacement therapy in GSD II.

Identification of two subtypes of infantile acid maltase deficiency.

Infantile patients with acid maltase deficiency have severe hypertrophic cardiomyopathy, left ventricular outflow obstruction, and generalized muscle weakness and die before 1 year of age. We identified 12 infants with acid maltase deficiency who had a similar clinical presentation but less severe cardiomyopathy and absence of left ventricular outflow obstruction, and 9 of 12 had longer survival with assisted ventilation and supplemental intubation.

A preliminary study of growth hormone therapy for Crohn's disease.

BACKGROUND: Crohn's disease is a chronic inflammatory disorder of the bowel. In a preliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease. METHODS: We randomly assigned 37 adults with moderate-to-severe active Crohn's disease to four months of self-administered injections of growth hormone (loading dose, 5 mg per day subcutaneously for one week, followed by a maintenance dose of 1.5 mg per day) or placebo. We instructed all patients to increase their protein intake to at least 2 g per kilogram of body weight per day. Patients continued to be treated by their usual physicians and to receive other medications for Crohn's disease. The primary end point was the change in scores on the Crohn's Disease Activity Index from base line to month 4. Scores can range from 0 to 600, with higher scores indicating more disease activity. RESULTS: At base line, the mean (+/-SD) score on the Crohn's Disease Activity Index was somewhat higher among the 19 patients in the growth hormone group than among the 18 patients in the placebo group (287+/-134 vs. 213+/-120, P=0.09). Three patients in the placebo group withdrew before their first follow-up visit and were not included in the data analysis. At four months, the Crohn's Disease Activity Index score had decreased by a mean of 143+/-144 points in the growth hormone group, as compared with a decrease of 19+/-63 points in the placebo group (P=0.004). Side effects in the growth hormone group included edema (in 10 patients) and headache (in 5) and usually resolved within the first month of treatment. CONCLUSIONS: Our preliminary study suggests that growth hormone may be a beneficial treatment for patients with Crohn's disease.

The impact of prematurity: a perspective of pediatric intensive care units.

OBJECTIVE: To evaluate the relative resource use of pediatric intensive care unit (PICU) patients who had been born prematurely. DESIGN: Nonconcurrent cohort study. SETTING: Consecutive admissions to 16 voluntary PICUs. PATIENTS: A total of 431 formerly premature patients (FPP) and 5,319 nonpremature patients. INTERVENTIONS: None METHODS: Patients with a history of prematurity and a prematurity-related complication or an anatomical deformity were compared for demographic and resource requirements to a group of non-premature patients by a bivariable logistic regression analysis that controlled for age as a co-morbid factor. RESULTS: Compared with other patients, FPP were younger (34.9 +/- 2.2 months vs. 72.4 +/- 1.0 months; p < .001), readmitted to the PICU more often during the same hospitalization (11.1% vs. 5.5%; p < .001), used more chronic technologies (ventilators, gastrostomy tubes, tracheostomy tubes, and parenteral nutrition; 30.3% vs. 5.6%; p < .001), and had longer lengths of stay (5.98 +/-0.59 days vs. 3.56 +/- 0.12 days; p = .004). FPP had significantly higher use of ventilators (45.5% vs. 35.0%; p < .007) and lower use of arterial catheters (27.8% vs. 35.9%, p = .006) and central venous catheters (16.9% vs. 20.9%, p = .026) than nonprematures. The need for other PICU resources, including vasopressors, were similar. CONCLUSIONS: FPP used more chronic and acute care resources than patients who were not prematurely born. Continued improvements in neonatal care will influence change in many aspects of the health care system. This will also affect the delivery of care to the current patient base of the PICU.

Amnestic agents in pediatric bronchoscopy.

STUDY OBJECTIVE: To assess the risk for complications with the use of sedation and analgesia techniques in pediatric fiberoptic bronchoscopy. DESIGN: A retrospective case series. SETTING: The ICU of a 325-bed tertiary care research hospital. PATIENTS: Patients from 1 to 18 years of age who underwent fiberoptic bronchoscopy with BAL or transbronchial biopsy between June 1991 and December 1995 and received IV sedation and analgesia. INTERVENTIONS: None. METHODS: A retrospective chart review was performed. Extracted data included anesthetics and sedatives used and their per kilogram dosages, procedure durations, and complications including oxygen desaturations < 90%, vital sign alterations that required intervention, and emergence reactions to ketamine. RESULTS: A total of 103 bronchoscopies were performed on 64 patients. Ketamine was used as the primary anesthetic in 60 procedures (58%). A combination of fentanyl and midazolam was used in 38 of the 43 remaining procedures. A variety of combinations were used in the five remaining procedures. Complications occurred in 13 procedures and included oxygen desaturations, stridor, cough, apnea, and nasal bleeding. Twelve of the 13 complications occurred in patients with a diagnosis of HIV infection. Eight of the13 complications involved children < or = 3 years of age. CONCLUSIONS: Pediatric bronchoscopy is a safe and valuable procedure. However, in this study, anesthetic selection was shown to adversely affect the complication rate in the subsets of children < or = 3 years of age and with an underlying diagnosis of HIV infection.

Necessity of complete intake of phenylalanine-free amino acid mixture for metabolic control of phenylketonuria.

The importance of complete or almost complete intake of the recommended amount of phenylalanine-free amino acid mixture (AAM) for control of blood phenylalanine level in patients being treated for phenylketonuria (PKU) has not been universally appreciated. We observed the effect of complete intake of AAM on plasma phenylalanine levels during hospitalization in 6 patients with PKU (5 pregnant women with PKU and 1 child) who had poor metabolic control because of less than full compliance with prescribed AAM intake. Before hospitalization, all but 1 of the patients had blood phenylalanine levels above 1,000 mumol/L; in 1 patient the blood phenylalanine level was 703 mumol/L. During 9 periods of observation in the 6 patients, the levels of plasma phenylalanine decreased to the recommended range of below 360 mumol/L within 2 to 6 days of hospitalization. These experiences indicate a close relationship between compliance with prescribed AAM intake and control of blood phenylalanine level. We propose that hospitalization be considered when patients with PKU who are consuming a phenylalanine-restricted diet fail to maintain blood phenylalanine levels in the targeted range despite reported compliance with the prescribed intake of dietary phenylalanine and AAM.