Current patient and healthcare worker attitudes to eHealth and the personally controlled electronic health record in major hospitals.

BACKGROUND: The current health system in Australia is comprised of both electronic- and paper-based medical records. The Federal Government has approved funding for the development of an individual health identifier and a universally adopted online health repository. AIMS: To determine attitudes and beliefs of patients and healthcare workers regarding the use of stored medical information and the personally controlled electronic health record (PCEHR) in selected major hospitals in Victoria. METHODS: Qualitative survey of patients and healthcare workers (n = 600 each group) conducted during 2014 across five major hospitals in Melbourne to measure the awareness, attitudes and barriers to electronic health and the PCEHR. RESULTS: Of the patients, 93.3% support the concept of a shared electronic healthcare record, 33.7% were aware of the PCEHR and only 11% had registered. The majority of healthcare workers believed that the presence of a shared health record would result in an increased appropriateness of care and patient safety by reducing adverse drug events and improving the timeliness of care provided. However, only 46% of healthcare workers were aware of the PCEHR. CONCLUSIONS: This study provides a baseline evaluation of perceptions surrounding eHealth and PCHER in acute health services in five metropolitan centres. While there appears to be a readiness for adoption of these strategies for healthcare documentation, patients require motivation to register for the PCEHR, and healthcare workers require more information on the potential benefits to them to achieve more timely and efficient care.

Demonstration of elevated levels of active cathepsin S in dextran sulfate sodium colitis using a new activatable probe.

BACKGROUND: Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use in a mouse model of colitis. METHODS: We designed and synthesized a new fluorescent activatable probe, NB200, for the detection of active cathepsin S. Colitis was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). Homogenized mouse colons, with or without the addition of the specific cathepsin S inhibitor MV026031, were incubated with NB200 in a fluorescent plate reader. KEY RESULTS: NB200 selectively detected purified cathepsin S and not other common inflammatory proteases. Homogenates of colon from mice with DSS colitis induced a significant fluorescent increase when compared to control animals (control vs DSS: p < 0.05 at 200 min and p < 0.01 at 220-240 min), indicating cathepsin S activation. The cathepsin S inhibitor abolished this increase in fluorescence (DSS vs DSS + MV026031: p < 0.05 at 140 min, p < 0.01 at 180 min, p < 0.001 at 200-240 min), which confirms cathepsin S activation. Cathepsin S activity correlated with the disease activity index (Spearman r = 0.77, p = 0.017). CONCLUSIONS & INFERENCES: Our investigation has demonstrated the utility of activatable probes for detecting protease activity in intestinal inflammation. Panels of such probes may allow 'signature' protease profiles to be established for a range of inflammatory diseases and disorders.

The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status.

BACKGROUND/OBJECTIVES: Methionine synthase catalyzes the conversion of 5-methyltetrahydrofolate to tetrahydrofolate and homocysteine (Hcy) to methionine using vitamin B(12) as a cofactor. Transcobalamin is the main transporter of vitamin B(12) from blood into cells. This study was undertaken to assess the relationship between the transcobalamin P259R (TCN2 776C>G) polymorphism and both serum vitamin B(12) and total Hcy (tHcy) levels. SUBJECTS/METHODS: The population comprised 613 men from Northern Ireland, aged 30-49 years, for whom tHcy, serum vitamin B(12) and serum folate concentrations were available. TCN2 776C>G genotypes were determined using a TaqMan 5' nuclease Real-Time PCR assay. Standard statistical tests of association were applied to assess the relationships between the polymorphism and phenotypic variables. RESULTS: The TCN2 776CC homozygous genotype was associated with lower serum vitamin B(12) concentrations compared with the 776CG (P(unadjusted)=0.01; P(adjusted)=0.03) and 776GG genotypes (P(unadjusted)=0.015; P(adjusted)=0.045). Among individuals with vitamin B(12) concentrations in the lower half of the distribution, tHcy concentrations were higher in TCN2 776GG homozygotes than in individuals with the other genotypes (P(unadjusted)=0.015; P(adjusted)=0.06). CONCLUSIONS: These data suggest that, relative to transcobalamin with arginine at position 259 (776G), transcobalamin with proline at this position (776C) is either more efficient at vitamin B(12) transport from blood to tissues or has higher affinity for vitamin B(12). Furthermore, vitamin B(12) status influences the relationship between TCN2 776C>G genotype and tHcy concentrations. Thus, the TCN2 776C>G polymorphism may contribute to the risk of pathologies associated with a low B(12), and high tHcy phenotype.

Descriptive epidemiology of nonsyndromic omphalocele in Texas, 1999-2004.

Omphalocele is a congenital malformation that involves protrusion of abdominal contents into the umbilicus. Though omphalocele may present as a manifestation of several chromosomal and Mendelian syndromes, the etiology for nonsyndromic omphalocele is unknown. The present study sought to estimate the birth prevalence of nonsyndromic omphalocele in offspring of women residing in Texas from 1999 to 2004, and to describe prevalence as a function of parental and infant demographic characteristics. Data on 325 cases with nonsyndromic omphalocele and 2,208,758 live births delivered during 1999-2004 were obtained from the Texas Birth Defects Registry. These data were used to estimate omphalocele birth prevalence and obtain both crude and adjusted prevalence ratios for the association of nonsyndromic omphalocele with parental and infant demographic characteristics. Nonsyndromic omphaloceles were significantly more common among the offspring of women without previous live births (adjusted prevalence ratio: 1.80, 95% CI: 1.41-2.30), compared to the offspring of women with previous live births. The prevalence of nonsyndromic omphalocele was also increased among women aged 25-29 (adjusted prevalence ratio: 1.68, 95% CI: 1.12-2.50) and women aged 40 and older (adjusted prevalence ratio: 4.83, 95% CI: 2.63-8.86) compared to the offspring of women age <20, and in infants of multiple gestation pregnancies compared to singleton infants (adjusted prevalence ratio: 2.03, 95% CI: 1.22-3.37). In addition, among Hispanic women, the prevalence of nonsyndromic omphalocele was higher in the offspring of those born in the U.S. as compared to those born elsewhere (adjusted prevalence ratio: 1.50, 95% CI: 1.12-2.00). These findings augment the existing omphalocele literature.

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10.

Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50-70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.

Prevalence of hypotensive disorders in older patients with a pacemaker in situ who attend the Accident and Emergency Department because of falls or syncope.

AIMS: To ascertain the proportion of adults with a pacemaker in situ attending the Accident and Emergency Department because of syncope or unexplained falls and the cause of index symptoms in these patients, including the prevalence of hypotensive syndromes. METHODS AND RESULTS: Patients presenting to the Accident and Emergency Department with unexplained syncope or non-accidental falls, who had a pacemaker in situ, were studied. Eligible patients had cardiovascular assessment (morning orthostatic blood pressure measurement, heart rate and BP measurements during carotid sinus stimulation (supine and upright), head-up tilt at 70 degrees for 40 min), assessment of haemodynamics during fixed mode pacing and gait and balance assessment. Of 5863 patients screened, 13.5% had unexplained syncope or a non-accidental fall; of these only 3% (26 patients) had pacemakers in situ. Of 18 study patients (82 +/- 8 years), 10 were female. Sixteen had a hypotensive diagnosis. Seven had more than one attributable hypotensive diagnosis. Five of 13 with vasodepressor carotid sinus syndrome had no previous diagnosis of carotid sinus hypersensitivity. No patients had vasovagal syncope induced during passive head-up tilt testing. CONCLUSION: It is rare for patients who attend the Accident and Emergency Department because of syncope or unexplained falls to have a pacemaker in situ. In those who do, hypotensive disorders are a common finding.

Evaluation of two putative susceptibility loci for oral clefts in the Danish population.

Previous studies suggest that the risk of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate (CP) is influenced by genetic variation at several loci and that the relation between specific genetic variants and disease risk may be modified by environmental factors. The present study evaluated potential associations between CL+/-P and CP and two putative clefting susceptibility loci, MSX1 and TGFB3, using data from a nationwide case-control study conducted in Denmark from 1991 to 1994. The potential effects of interactions between these genes and two common environmental exposures, first trimester exposure to maternal cigarette smoke and alcohol intake, were also examined. Analyses of these data provide evidence of an association between the risk of CP and variation at the TGFB3 locus. However, there is no evidence that the risk of CL+/-P or CP is influenced by gene-environment interactions involving MSX1 or TGFB3 and either first trimester exposure to maternal cigarette smoke or alcohol consumption.

Relationship between case-control studies and the transmission/disequilibrium test.

Case-control studies provide a powerful approach for detecting disease susceptibility loci that have only a weak to moderate impact on the risk of disease, or markers that are in linkage disequilibrium with such loci. However, since any association detected in a case-control study may result from uncontrolled confounding, evidence for disease-marker associations obtained from such studies must be confirmed by alternative methods. Since studies that use the transmission/disequilibrium test or TDT are frequently employed to confirm disease-marker associations detected in case-control studies, data are increasingly available from both case-control studies and "TDT studies" of the same disease-marker association. It would, therefore, be useful to have a single measure of the magnitude of the disease-marker association that would allow for comparison of results from these two study designs. Such a measure could also be used to estimate minimum sample size requirements for TDT studies of previously reported disease-marker associations. An obvious measure of the disease-marker association in TDT studies is the frequency (T) with which heterozygous parents transmit the putative, high-risk marker allele to affected offspring. In this paper, it is shown that T can also be estimated from case-control data with a minimum of assumptions, and that T is the critical parameter for determining power and estimating sample sizes for the TDT.

Genetic influences on premature parturition in an Australian twin sample.

We investigated possible genetic influences on women's liability to preterm birth, using data from a large sample of Australian female twin pairs. In a 1988-90 questionnaire survey, both members of 905 parous twin pairs (579 monozygotic and 326 dizygotic) reported on whether deliveries had been more than two weeks preterm. Tetrachoric twin pair correlations for first birth were rMZ = 0.20+/-0.11 and rDZ = -0.03+/-0.14, and for any birth were rMZ = 0.30+/-0.08 and rDZ = 0.03+/-0.11. Best-fitting models to data contained only additive genetic influences and individual environmental effects. Heritability was 17% for preterm delivery in first pregnancy, and 27% for preterm delivery in any pregnancy. In the former case, however, we could not reject a model without genetic influences. Although our data did not allow for differentiation of the varying aetiologies of premature parturition, results from this exploratory analysis suggest that further investigation of genetic influences on specific reasons for preterm birth is warranted.

Frequency of 22q11 deletions in patients with conotruncal defects.

OBJECTIVES: This study was designed to determine the frequency of 22q11 deletions in a large, prospectively ascertained sample of patients with conotruncal defects and to evaluate the deletion frequency when additional cardiac findings are also considered. BACKGROUND: Chromosome 22q11 deletions are present in the majority of patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes in which conotruncal defects are a cardinal feature. Previous studies suggest that a substantial number of patients with congenital heart disease have a 22q11 deletion. METHODS: Two hundred fifty-one patients with conotruncal defects were prospectively enrolled into the study and screened for the presence of a 22q11 deletion. RESULTS: Deletions were found in 50.0% with interrupted aortic arch (IAA), 34.5% of patients with truncus arteriosus (TA), and 15.9% with tetralogy of Fallot (TOF). Two of 6 patients with a posterior malalignment type ventricular septal defect (PMVSD) and only 1 of 20 patients with double outlet right ventricle were found to have a 22q11 deletion. None of the 45 patients with transposition of the great arteries had a deletion. The frequency of 22q11 deletions was higher in patients with anomalies of the pulmonary arteries, aortic arch or its major branches as compared to patients with a normal left aortic arch regardless of intracardiac anatomy. CONCLUSIONS: A substantial proportion of patients with IAA, TA, TOF and PMVSD have a deletion of chromosome 22q11. Deletions are more common in patients with aortic arch or vessel anomalies. These results begin to define guidelines for deletion screening of patients with conotruncal defects.

Genetic effects on variation in red-blood-cell folate in adults: implications for the familial aggregation of neural tube defects.

Recent studies have implicated folic acid as an important determinant of normal human growth, development, and function. Insufficient folate levels appear to be a risk factor for neural tube defects (NTD), as well as for several chronic diseases of adulthood. However, relatively little is known about the factors that influence folate status in the general population. To estimate the relative contribution of genetic and nongenetic factors to variation in folate, we have evaluated red blood cell (RBC) folate levels in 440 pairs of MZ twins and in 331 pairs of DZ twins. The data were best described by a model in which 46% of the variance in RBC folate was attributable to additive genetic effects, 16% of the variance was due to measured phenotypic covariates, and 38% of the variance was due to random environmental effects. Moreover, the correlations for RBC folate in MZ co-twins (r = .46) and in repeat measures from the same individual (r = .51) were very similar, indicating that virtually all repeatable variation in RBC folate is attributable to genetic factors. On the basis of these results, it would seem reasonable to initiate a search for the specific genes that influence RBC folate levels in the general population. Such genes ultimately may be used to identify individuals at increased risk for NTD and other folate-related diseases.

Transforming growth factor alpha locus and nonsyndromic cleft lip with or without cleft palate: a reappraisal.

An association between nonsyndromic cleft lip with or without cleft palate (CL +/- P) and genetic variation at the transforming growth factor alpha (TGFA) locus was originally reported in 1989. Subsequent population-based studies of this association have provided conflicting results. The present analyses were undertaken to determine if the cumulative weight of the available data convincingly supports or refutes this association. The published data were analyzed for differences in allele frequencies between Caucasian CL +/- P patients (i.e., cases) and controls, and for heterogeneity between Caucasian samples. When all data except the original report were considered, there was a statistically significant association between TGFA and CL +/- P (M.H.O.R. = 1.43; 95% C.I. 1.12-1.80). However, there was evidence of significant heterogeneity in the TGFA allele frequencies between cases, but not controls, from different studies. The data suggest that the observed heterogeneity is unlikely to be attributable to differences in the ethnic composition of the cases among the various studies but may reflect differences in the proportion of cases with bilateral lip defects and/or with positive family histories of CL +/- P. Definitive conclusions regarding the source(s) of the observed heterogeneity could not, however, be drawn on the basis of the available data. Hence, at present, the evidence regarding an association between genetic variation at the TGFA locus and CL +/- P remains inconclusive.

Genetic epidemiology of birth defects: nonsyndromic cleft lip and neural tube defects.

This review has focused on only two common structural malformations. However, the difficulties and successes encountered while attempting to elucidate the genetic contribution to these two conditions are likely to be echoed in studies of other complex congenital anomalies. As our understanding of the mechanisms which give rise to a particular malformation gradually unfolds, the importance of a multidisciplinary approach to understanding the genetic contribution to these conditions becomes increasingly apparent. Experience indicates that both traditional and genetic epidemiologic approaches will be integral components of any such efforts, since the identification of environmental risk factors (e.g., folic acid) may provide clues regarding the nature of disease susceptibility loci, and the identification of susceptibility loci will provide new opportunities to explore potential environmental covariates of disease risk (e.g., maternal cigarette smoke). Although we are not yet in a position to completely describe the genetic contribution to any single structural malformation, advances over the past decade have led to a rapid increase in our ability to elucidate the relevant genetic factors. Given the complex nature of the nonsyndromic structural malformations, there is undoubtedly much work to be done before we fully understand the genetic contribution to even a single malformation. However, for the first time, such an understanding and the accompanying potential for prevention seem within our reach.

PCR assay for screening patients at risk for 22q11.2 deletion.

Deletions of 22q11.2 have been detected in the majority of patients with DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes by either cytogenetic analysis, fluorescence in situ hybridization (FISH), or Southern blot hybridization. However, these techniques may not be the most efficient or cost-effective means of screening large numbers of "at-risk" patients. Therefore, we developed a PCR assay to assess a patient's likelihood of having a 22q11.2 deletion based on homozygosity at consecutive markers in the DiGeorge chromosomal region. The sensitivity and specificity of PCR screening were evaluated in a cohort of cardiac patients. We conclude that a PCR-based assay is a reliable and efficient means of identifying which patients are at greatest risk for a 22q11.2 deletion and should have FISH studies to confirm their deletion status.

Observations on a recent increase in plagiocephaly without synostosis.

OBJECTIVE: To verify and determine the cause of an increase in the referral of infants with plagiocephaly without synostosis (PWS) to a single tertiary craniofacial center. DESIGN: A chart review was performed for 269 infants with a diagnosis of PWS who presented to a single tertiary craniofacial center between 1979 and 1994. The pattern of referral for PWS was analyzed using both simple linear regression and time series regression analyses. In addition, the referral pattern for PWS was compared with that for infants seen at the same center who received a diagnosis of synostotic plagiocephaly. Changes in the distribution of several demographic, perinatal, and clinical variables during the study period were also assessed. Finally, in an effort to identify correlates of the risk of PWS developing, characteristics of patients who were Missouri residents and presented between 1992 and 1994 were evaluated and compared with those of the 1993 Missouri live birth cohort. SETTING: The Cleft Palate and Craniofacial Deformities Institute, St Louis Children's Hospital, Washington University Medical Center. RESULTS: The average annual number of referrals to our center for PWS in the period 1992 to 1994 was more than sixfold greater than that for the preceding 13 years. There was a statistically significant increase in the annual number of referrals to our center during the 16-year study period. Moreover, there was evidence that the average annual increase in referrals was significantly greater during the last 3 years (1992 through 1994) of the study than in the first 13 years. This shift in the referral patterns is roughly contemporaneous with the American Academy of Pediatrics recommendations regarding infant sleep position. There was no evidence that either the mean number of referrals or the average annual increase in referrals for patients with synostosis changed during the study period. Among patients with PWS, the average age at presentation did not change during the study period. There were also no significant changes in the distribution of other demographic, perinatal, and clinical variables. When compared with the Missouri birth cohort, infants with PWS were significantly more likely to be boys and to have been delivered by forceps. There was also some evidence that patients with PWS were more likely to be born prematurely and to be products of multiple-gestation pregnancies. These associations were, however, of only borderline statistical significance. CONCLUSION: Referrals to our center for PWS increased markedly in 1992 relative to previous years. The temporal coincidence of this increase with the American Academy of Pediatrics recommendation to avoid the prone sleeping position, to reduce the risk of sudden infant death syndrome, suggests a possible causal relationship. If this association is causal, education regarding the need for head position rotation coupled with that for sudden infant death syndrome should obviate positional PWS.