Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

An experimental study of OH(A2Σ+) + H2: Electronic quenching, rotational energy transfer, and collisional depolarization.

Zeeman quantum beat spectroscopy has been used to determine the thermal (300 K) rate constants for electronic quenching, rotational energy transfer, and collisional depolarization of OH(A2Σ+) by H2. Cross sections for both the collisional disorientation and collisional disalignment of the angular momentum in the OH(A2Σ+) radical are reported. The experimental results for OH(A2Σ+) + H2 are compared to previous work on the OH(A2Σ+) + He and Ar systems. Further comparisons are also made to the OH(A2Σ+) + Kr system, which has been shown to display significant non-adiabatic dynamics. The OH(A2Σ+) + H2 experimental data reveal that collisions that survive the electronic quenching process are highly depolarizing, reflecting the deep potential energy wells that exist on the excited electronic state surface.

That's why I take my ONS. Means-end chain as a novel approach to elucidate the personally relevant factors driving ONS consumption in nutritionally frail elderly users.

Oral nutritional supplements (ONS) are a recommended form of nutritional intervention for older malnourished persons when a 'food first' approach and/or food fortification prove ineffective. The efficacy of ONS will depend on, amongst other factors, whether persons do, or do not, consume their prescribed amount. Factors influencing ONS consumption can be product, context, or person related. Whereas product and context have received some attention, little is known about the person factors driving ONS consumption. In addition, the relative importance of the product, context, and person factors to ONS consumption is not known. Using the means-end chain (MEC) method, the current study elucidated personally relevant factors (product, context, and person factors) related to ONS consumption in two groups of older nutritionally frail ONS users: community-dwelling persons and care home residents with mainly somatic disorders. To our knowledge, the current work is the first to apply the MEC method to study older nutritionally frail ONS users. Forty ONS users (n = 20 per group) were recruited via healthcare professionals. The level of frailty was assessed using the FRAIL scale. Both groups were interviewed for 30 to 45 minutes using the soft laddering technique. The laddering data were analysed using LadderUX software™. The MEC method appeared to work well in both groups. The majority of the participants took ONS on their doctor's or dietician's prescription as they trusted their advice. The community-dwelling group took ONS to prolong their independence, whereas the care home group reported values that related more to small improvements in quality of life. In addition, care home residents perceived themselves as dependent on their caregiver for their ONS arrangements, whereas this dependence was not reported by community-dwelling persons. Key insights from this work will enable doctors and dieticians to customize their nutritional interventions to ONS users' personal needs and thus positively impact health outcomes.

Density of states of helically symmetric boron carbon nitride nanotubes.

Motivated by the existence of helical wrapping patterns in composite nanotube systems, in this work we study the effects of the helical incorporation of carbon atoms in boron nitride nanotubes. We consider the substitutional carbon atoms distributed in stripes forming helical patterns along the nanotube axis. The density of states and energy band gap were calculated adopting Green function formalism by using the Rubio-Sancho technique in order to solve the matrix Dyson equation. We report the effects of the helical atomic distribution of carbon atoms on the behaviour of the density of states and the energy band gap. In particular, we show that the electronic energy band gap displays a non-monotonical dependence on the helical pattern, oscillating as a function of the helical angle θ.

Evaluation of an Australian chest pain assessment unit.

BACKGROUND: In order to mitigate the risk of missing atypical or low probability presentations of acute coronary syndromes (ACS), many hospitals have designated resources specifically for the assessment of chest pain. AIM: This study aims to evaluate the introduction of a chest pain assessment unit (CPAU) in a North Queensland hospital. METHODS: Information on admission status, diagnosis, procedures, length of stay and chest pain representation rates was obtained for patients presenting with chest pain to the emergency department (ED) at The Townsville Hospital in the 2.5 years prior to the introduction of a CPAU in March 2007 (n = 6665). This was compared with information on chest pain patients (n = 7885) presenting to the ED in the 2.5 years after it opened. RESULTS: The CPAU resulted in a reduction in the percentage of 'missed' cases of ACS. The rate of people who represented with chest pain at 3 months and who ultimately received an ACS diagnosis reduced from 1.9% to 1.4%. There was an increased rate of apparently appropriate angiograms from 6.7% to 9.4% of chest pain admissions. The admission rate of ED chest pain presentations was stable as was the median length of stay (1.14-1.16 days). A relative decrease in the proportion of admitted patients diagnosed with ACS compared with those with unspecified chest pain was observed. CONCLUSION: The implementation of a CPAU at The Townsville Hospital resulted in improved care of those presenting to the ED with chest pain. Further Australian CPAU evaluations are recommended.

Modification of syphilitic genital ulcer manifestations by coexistent HIV infection.

BACKGROUND: Conflicting data exist regarding whether HIV infection leads to changes in the clinical manifestations and severity of genital ulcer disease (GUD). GOAL: To determine the impact of HIV on the etiology and clinical severity of GUD. STUDY DESIGN: From July 1990 to July 1992, consecutive patients presenting to the two Baltimore City Health Department (BCHD) Sexually Transmitted Diseases clinics were approached as candidates for enrollment in a prospective study to determine factors associated with the transmission and acquisition of sexually transmitted diseases (STDs). RESULTS: Of the 1368 patients who presented to the BCHD, 214 (16%) had genital ulcerations: 160 (21%) of 757 men and 54 (9%) of 611 women. Among the patients with GUD who had undergone HIV testing, 28 (14%) of 204 were infected with HIV: 25 (17%) of 151 men and 3 (6%) of 53 women. Although both groups-those infected with HIV and those not infected with HIV--presented with GUD of similar duration (10 versus 11 days; P = 0.17), multiple lesions were found more frequently in men with HIV infection than in uninfected men: 87% versus 62% (P = 0.02). Although not statistically significant, GUD in men with HIV infection more often were deep (64% versus 44%, respectively) rather than superficial (36% versus 57%, respectively; P = 0.08), and larger (505 mm(2) versus 109 mm 2; P = 0.06). Primary syphilis caused more GUD among men with HIV infection than among uninfected men: 9 (36%) of 25 versus 24 (19%) of 126, respectively (P < 0.01). Secondary syphilis was diagnosed with concomitant GUD more frequently among men with HIV infection than among uninfected men: 3 (13%) of 25 versus 3 (2%) of 123, respectively (P < 0.01). CONCLUSIONS: In this study, patients who presented with GUD were more likely to be infected with HIV. A higher proportion of men with HIV infection had multiple lesions, and the lesions were more likely to be caused by syphilis.

HealthMarts, HIPCs (health insurance purchasing cooperatives), MEWAs (multiple employee welfare arrangements), and AHPs (association health plans): a guide for the perplexed.

This paper considers how pending proposals to authorize new forms of group purchasing arrangements for health insurance would fit and function within the existing, highly complex market and regulatory landscape and whether these proposals are likely to meet their stated objectives and avoid unintended consequences. Cost savings are more likely to result from increased risk segmentation than through true market efficiencies. Thus, these proposals could erode previous market reforms whose goal is increased risk pooling. On the other hand, these proposals contain important enhancements, clarifications, and simplification of state and federal regulatory oversight of group purchasing vehicles. Also, they address some of the problems that have hampered the performance of purchasing cooperatives. On balance, although these proposals should receive cautious and careful consideration, they are not likely to produce a significant overall reduction in premiums or increase in coverage.

Distribution of α-tocopherol in beef muscles following dietary α-tocopheryl acetate supplementation.

The objective of this study was to determine the effect of dietary vitamin E supplementation on the distribution and concentration of α-tocopherol in beef muscles. Crossbred cattle (n=8) were selected and divided into two groups and fed diets containing 20 (basal) and 3000 mg (supplemented) α-tocopheryl acetate/head/day for 135 days prior to slaughter. Carcasses were split centrally and chilled at 4°C for 10 days. Muscles (n=16) were identified and removed from the left side of each animal and stored at -20°C until required. Mean α-tocopherol levels in muscles were significantly (P<0.05) higher in all supplemented muscles with the exception of m. infraspinatis and m. deltoidous compared to controls. Mean α-tocopherol levels in muscles from the supplemented group decreased in the order m. supraspinatis > m. psoas major > m. trapezius > m. gluteus medius > m. triceps caput brachii lumborum > m. rhomboidous > m. seratus ventralis > m. gluteobiceps > m. semitendinosus > m. semimembranosus > m. infraspinatis > m. subscapularis > m. tricepscaputbrachiilaterale > m. deltoidous > m. longissimus thorasis > m. longissimus lumborum. Significant (P<0.05) differences in α-tocopherol distribution within muscles were observed for supplemented m. psoas major and control m. seratus ventralis (highest levels in posterior ends and lowest in anterior ends) only. However, trends showed definite distribution patterns for other muscles. Levels of α-tocopherol were found to be highest in oxidative muscles (m. psoas major and m. gluteus medius) and lowest in glycolytic muscles (m. longissimus thoracis and m. longissimus lumborum) while moderate levels of α-tocopherol occurred in intermediate muscles (m. semimembranosus).

Definitions of genital ulcer disease and variation in risk for prevalent human immunodeficiency virus infection.

OBJECTIVES: Although genital ulcer disease (GUD) has been associated with human immunodeficiency virus (HIV) infection in a number of studies, definitions of genital ulceration have varied. The authors hypothesized that the association of GUD with prevalent HIV infection may vary according to the definition of GUD that is used. METHODS: As part of a prospective cohort study, 863 patients were interviewed and examined who presented to a sexually transmitted disease (STD) clinic for new symptom evaluation and who agreed to HIV testing to determine demographic and behavioral risk associated with prevalent HIV infection. To determine the association between GUD and prevalent HIV, the following definitions of GUD were used: observed ulcers, history of syphilis, serologic evidence of syphilis, observed culture-proven genital herpes, and serologic evidence of herpes simplex virus type II (HSV-2) infection. RESULTS: Of 481 men and 382 women enrolled, prevalent HIV infection was detected in 12.5% and 5.2%, respectively. In multivariate analyses controlling for known HIV risk behaviors, prevalent HIV infection was associated with observed GUD (odds ratio [OR] = 2.0, 95% confidence intervals (CI) = 1.0-3.9), a history of syphilis (OR = 6.0, CI = 2.8-12.7), and serologic evidence of syphilis (OR = 3.7, CI = 1.9-7.0), but not with serologic evidence of HSV-2 (OR = 1.2, CI = 0.7-2.1), nor with observed HSV-2 culture-positive genital ulcerations (OR = 1.0, CI = 0.4-4.2). Factors contributing to different strengths of association between HIV infection and a history of syphilis or serologic evidence of syphilis included the presence of underdiagnosed syphilis infection in people with reactive serologic tests and the absence of serologic reactivity in people with a positive history. CONCLUSIONS: Although GUD is strongly associated with prevalent HIV, the strength of the association depends on the definition of GUD used. For accurate evaluation of people at risk for HIV, clinicians and researchers should use multiple definitions of GUD.

Voluntary testing for human immunodeficiency virus (HIV) in a prison population with a high prevalence of HIV.

This study evaluated voluntary testing for human immunodeficiency virus (HIV) in a prison population with a high HIV seroprevalence. Data on demographic variables and participation in voluntary testing were linked to a blinded HIV serosurvey of consecutive Maryland prison entrants (April-July 1991). Among 2,842 entrants, HIV seroprevalence was 8.5% (men, 7.9%; women, 15.3%). Voluntary testing was accepted by 47% of the entrants, and it identified 34% of the HIV-seropositive inmates detected by serosurvey. Refusers of testing were more likely to test HIV-seropositive than were accepters (adjusted odds ratio (OR) = 1.84, 95% confidence interval (CI) 1.58-2.16). Refusers and accepters of testing had similar risk factors for HIV infection, chiefly current syphilis infection (adjusted OR = 5.96, 95% CI 3.15-10.27) and prior injected drug use (adjusted OR = 4.26, 95% CI 3.15-5.76). Among 100 entrants asked why they refused testing, primary reasons given included low risk of HIV, fear of testing HIV-seropositive, and lack of interest. Voluntary testing appears only moderately successful in identifying HIV-seropositive inmates in a high-seroprevalence prison population. However, the alternative, mandatory HIV testing of prisoners, can be construed as discriminatory and unethical when similar screening is not imposed on the population at large. Data presented here suggest strategies to improve acceptance of voluntary testing, especially by high risk inmates.

A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia.

In a family expressing euthyroid hyperthyroxinemia, an increased association of plasma thyroxine (T4) with transthyretin (TTR) is transmitted by autosomal dominant inheritance and is secondary to a mutant TTR molecule with increased affinity for T4. Eight individuals spanning three generations exhibited the abnormality. Although five of eight individuals had elevated total T4 concentrations, all affected individuals were clinically euthyroid and all had normal free T4 levels. Purified TTR from the propositus had an affinity for 125I-T4 three times that of control TTR. Exons 2, 3, and 4 (representing greater than 97% of the coding sequence) of the TTR gene of DNA prepared from the propositus' peripheral blood leukocytes were amplified using the polymerase chain reaction (PCR) and were sequenced after subcloning. Exons 2 and 3 were indistinguishable from normal. In 50% of clones amplified from exon 4, a substitution of adenine (ACC) for guanine (GCC) in codon 109 resulted in the replacement of threonine-for-alanine, a mutation confirmed by amino acid sequencing of tryptic peptides derived from purified plasma TTR. The adenine-for-guanine substitution abolishes one of two Fnu 4H I restriction sites in exon 4. PCR amplification of exon 4 of TTR and restriction digestion with Fnu 4H I confirmed that five affected family members with increased binding of 125I-T4 to TTR are heterozygous for the threonine 109 substitution that increases the affinity of this abnormal TTR for T4.

Evaluation of free thyroxin measurements in patients with non-thyroidal illnesses.

Sera from 51 euthyroid patients with various non-thyroidal illnesses were used for the evaluation of free thyroxin measurements by use of two commercially available radioimmunoassay kits. A derived value for the percentage of free thyroxin was then calculated as the ratio of the free and total thyroxin concentrations. Values for the percentage of free thyroxin as measured directly via equilibrium dialysis were compared with those derived from both the Corning Medical (r = 0.56) and the Clinical Assays (r = 0.85) kit procedures. The Clinical Assays procedure, in which a solid-phase "immunoextraction" is used, demonstrated a large dynamic range of response for this patient population, in contrast to the narrow response seen with the Corning Medical procedure. Results for euthyroid patients with significant systemic illness by the Clinical Assays procedure compared favorably with those by equilibrium dialysis.

"Nephrogenic adenoma": an unusual metaplastic change of urothelium.

"Nephrogenic adenoma" is a papillary bladder lesion of uncertain pathogenesis. We have studied 2 patients with this lesion for several years with serial biopsies in both cases. We believe that the natural history of "nephrogenic adenoma" and its invariable association with bladder irritation, coupled with the histopathologic and ultrastructural findings, strongly suggest that this "tumor" represents a papillary and glandular transformation of urothelium, in response to prolonged exposure to various injurious agents. It is best regarded as a metaplastic process rather than a hamartoma or a benign neoplasm. There is no reasonable basis for supposing that the process originates from mesonephric-derived epithelium. While not itself neoplastic nephrogenic metaplasia (our preferred term) is rarely associated with the late development of invasive but not, to date, metastasizing neoplasia. Routine cystoscopy would seem the most appropriate means of following these patients.

Cord blood hypertriglyceridaemia as an index of fetal stress: use of a simple screening test and results of further biochemical analysis.

In this preliminary study, 120 cord blood samples were subjected to a simple on-the-ward triglyceride screening procedure and 15 were designated as being high and another 15 randomly selected as controls. All the samples were then subjected to detailed biochemical analysis for fatty acid profiles and/or concentrations of free fatty acids, triglycerides (TG), phospholipids, cholesterol esters and glycerol. Eleven of the samples designated 'high' were associated with one or more of the following clinical conditions: family history of ischaemic heart disease, maternal starvation, fetal distress, light-for-dates babies and excessive weight gain during pregnancy. There was an association between high TG levels and high glycerol levels. The fatty acid pattern of the TG was altered when at abnormally high concentration, in particular oleic acid was increased relative to the others, and this was associated with an increase in cholesterol ester oleic acid. The possible mechanisms resulting in cord hypertriglyceridaemia are discussed.

Source of fetal-stored lipids during maternal starvation in rabbits.

The effect of 48 h maternal starvation on the composition of fetal rabbit brown and white adipose tissue was examined. Compared with fed control rabbits, adipose tissue triglyceride fatty acids took on a composition more like that of maternal plasma free fatty acids (FFA), whose concentration more than doubled after 48 h starvation. It is concluded that maternal FFA contribution to the fetal lipids increases during starvation and certain fetal acids, in particular linoleic acid, may in the fed state be derived from maternal lipids other than the FFA.