A statistically guided grid generation method and its application to intermolecular potential energy surfaces.

We present a method for the generation of points in space needed to create training data for fitting of nonlinear parametric models. This method uses statistical information extracted from an initial fit on a sparse grid to select optimal grid points in an iterative manner and is, therefore, called the iterative variance minimizing grid approach. We demonstrate the method in the case of six-dimensional intermolecular potential energy surfaces (PESs) fitted to ab initio computed interaction energies. The number of required grid points is reduced by roughly a factor of two in comparison to alternative systematic sampling methods. The method is not limited to fitting PESs and can be applied to any cases of fitting parametric models where data points may be chosen freely but are expensive to obtain.

Automatic Generation of Flexible-Monomer Intermolecular Potential Energy Surfaces.

A method is developed for automatic generation of nonreactive intermolecular two-body potential energy surfaces (PESs) including intramonomer degrees of freedom. This method, called flex-autoPES, is an extension of the autoPES method developed earlier, which assumes rigid monomers. In both cases, the whole PES development proceeds without any human intervention. The functional form used is a sum of products of site-site functions (both atomic and off-atomic sites can be used). The leading terms with sites involving different monomers are of physically motivated form. The long-range part of a PES is computed from monomer properties without using any dimer information. The close-range part is fitted to dimer interaction energies computed using electronic structure methods. Virtually any method can be used in such calculations, but the use of symmetry-adapted perturbation theory provides a seamless connection to the long-range part of the PES. The performance of the flex-autoPES code was tested by developing a full-dimensional PES for the water dimer and PESs including only some soft intramonomer degrees of freedom for the ethylene glycol dimer and for the ethylene glycol-water dimer. In the case of the water dimer, the root-mean-square error (RMSE) of the PES from the data points with negative total energies is 0.03 kcal/mol, and we expect this PES to be more accurate than any previously published PES of this type. For the ethylene glycol dimer and the ethylene glycol-water dimers, the analogous RMSEs are 0.25 and 0.1 kcal/mol, respectively.

Molecular dimers of methane clathrates: ab initio potential energy surfaces and variational vibrational states.

Motivated by the energetic and environmental relevance of methane clathrates, highly accurate ab initio potential energy surfaces (PESs) have been developed for the three possible dimers of the methane and water molecules: (H2O)2, CH4·H2O, and (CH4)2. While only a single monomer geometry was used for each monomer in the ab initio calculations, the PES parameterization makes it possible to produce distinct surfaces for all isotopologues within the rigid-monomer approximation. The PESs were fitted to computations at the frozen-core coupled-cluster level with single, double, and non-iterative triple excitations, employing basis sets of augmented triple- and quadruple-zeta quality plus bond functions, followed by extrapolations to the complete basis set limit. The long-range parts of the PESs are computed using the asymptotic version of symmetry-adapted perturbation theory based on a density-functional description of the monomers. All PESs are polarizable, i.e., in cluster or condensed-phase applications they approximate many-body effects by the induced dipole polarization model. The PESs were developed in a fully automated procedure applying the autoPES method, which is used for the first time to generate near-spectroscopic quality surfaces. The stationary points (SPs) on the PESs have been determined and compared with literature data. For CH4·H2O, previously unknown SPs have been identified and the first detailed study of the (CH4)2 potential energy landscape has been carried out. The PESs were used in variational quantum nuclear motion computations. For the water dimer, the resulting vibrational transitions are in excellent agreement with available high-resolution spectroscopic data. For (CH4)2, the intermonomer vibrational states are reported for the first time.

Outcome-Based Critical Result Thresholds in the Adult Patient Population.

OBJECTIVES: To derive outcome-based critical result thresholds in the adult patient population. METHODS: We extracted deidentified laboratory results and outcomes (death or discharged) of patients 18 years and older from the Medical Information Mart for Intensive Care database. The lower and upper critical result thresholds were obtained from the nearest minimum and maximum laboratory values, which corresponded to predicted probability of death at 90%. RESULTS: The critical value thresholds were sodium (<123, >153 mmol/L), potassium (<2.2, >6.6 mmol/L), bicarbonate (<15, >49 mmol/L), chloride (<82, >121 mmol/L), urea (>20 mmol/L), creatinine (>1,052 µmol/L), glucose (<1.5, >23.8 mmol/L), total calcium (<1.62, >2.95 mmol/L), magnesium (<0.37, >1.48 mmol/L), phosphate (<0.19, >2.52 mmol/L), pH (<7.22, >7.57), lactate (>5.0 mmol/L), hemoglobin (<4.6 g/dL), WBCs (>32 × 103/µL), prothrombin time (>90 seconds), and international normalized ratio (>10). CONCLUSIONS: The indirect approach described in this study is a pragmatic way to obtain threshold values that are clinically and operationally meaningful.

Laboratory performance of sweat conductivity for the screening of cystic fibrosis.

BACKGROUND: There are several complementary English-language guidelines for the performance of the sweat chloride test. These guidelines also incorporate information for the collection of conductivity samples. However, recommendations for the measurement and reporting of sweat conductivity are less clear than for sweat chloride. The aim of the study was to develop an understanding of the testing and reporting practices of sweat conductivity in Australasian laboratories. METHODS: A survey specifically directed at conductivity testing was sent to the 12 laboratories registered with the Royal College of Pathologists of Australasia Quality Assurance Programs. RESULTS: Nine (75%) laboratories participated in the survey, seven of whom used Wescor Macroduct® for collecting sweat and the Wescor SWEAT·CHEK™ for conductivity testing, and the remaining two used the Wescor Nanoduct®. There was considerable variation in frequency and staffing for this test. Likewise, criteria about which patients it was inappropriate to test, definitions of adequate collection sweat rate, cutoffs and actions recommended on the basis of the result showed variations between laboratories. CONCLUSIONS: Variations in sweat conductivity testing and reporting reflect many of the same issues that were revealed in sweat chloride test audits and have the potential to lead to uncertainty about the result and the proper action in response to the result. We recommend that sweat testing guidelines should include clearer statements about the use of sweat conductivity.

A retrospective cohort review of intrahepatic cholestasis of pregnancy in a South Australian population.

OBJECTIVE: To review the management and outcomes of Intrahepatic Cholestasis of Pregnancy (ICP) in South Australia (SA) over the past decade. DESIGN: Retrospective cohort review. SETTING: Public clinics at two teaching hospitals in SA. POPULATION: All pregnancies associated with ICP (defined as pruritus with serum bile acids≥10µmol/L) managed 2001-2010. METHODS: Identification of subjects (laboratory database), detailed chart-review to ascertain demographics, maternal/perinatal outcomes and associated pregnancy comorbidities, analysis of mild/severe disease cohorts, comparison with normal population data, using Student's t-test or Mann-Whitney U test as appropriate for continuous variables, and Pearson's chi-square test or Fisher's exact test for categorical variables. Unadjusted odds ratios (OR) with 95% confidence intervals (95% CI) were calculated in comparison with the general pregnant population for clinically significant outcomes. RESULTS: 320 women (359 pregnancies) were diagnosed with ICP over the 10-years: incidence 0.6%/year. Within the cohort, the incidences of gestational diabetes (12.5%; OR 3.06, 95% CI 2.23-4.18), pre-eclampsia (10.3%; OR 75.84, 95% CI 52.91-178.70), and spontaneous preterm labour (23.1%; OR 2.05, 95% CI 1.41-2.98) were much higher than in the general SA pregnant population. Pregnancies with severe ICP (serum bile acids≥40µmol/L) had ICP diagnosed earlier (231 vs 248 days, P<0.001), and ended earlier (256 vs 260 days, P<0.001) with lower birthweights (2827g vs 3093g, P <0.001) than those with mild ICP. Neonates of severe ICP mothers were more likely to require special-care-nursery admission, but perinatal complication rates did not differ. There were no stillbirths. CONCLUSION: This large Australian retrospective cohort study confirms generally favourable outcomes associated with ICP, mild or severe, with no stillbirths, likely secondary to proactive medical management. A high proportion of pregnancies were also affected by gestational diabetes, pre-eclampsia, and/or spontaneous pre-term labour compared with the general population.

Automatic Generation of Intermolecular Potential Energy Surfaces.

A method is developed for automatic generation of intermolecular two-body, rigid-monomer potential energy surfaces based on symmetry-adapted perturbation theory (SAPT). It is also possible to substitute SAPT interaction energies by values computed using sufficiently high-level supermolecular methods. The long-range component of the potential is obtained from a rigorous asymptotic expansion with ab initio computed coefficients which seamlessly connects to SAPT interaction energies at large separations. An accompanying software package has been developed and tested successfully on eight systems ranging in size from the Cl--H2O dimer to the cyclotrimethylene trinitramine dimer containing 42 atoms total. The potentials have a typical fit error of about 0.2 kcal/mol in the negative energy region. The accuracy may be further improved by including off-atomic sites or increasing their number. All aspects of potential development were designed to work reliably on a broad range of systems with no human intervention.

Screening for Down syndrome in the second trimester of pregnancy.

Antenatal screening for fetal anomalies has provided women and their partners with information to make reproductive choices based on the risk of serious chromosomal or structural defects since the 1990s. Alternative tests include first-trimester screening (combined ultrasound and maternal serum markers), second-trimester maternal serum markers and noninvasive cell-free DNA testing. The recent recommendations by the Royal Australian and New Zealand College of Obstetrics and Gynaecology and the Human Genetics Society of Australasia against second-trimester triple testing are based on unsound performance criteria, raise several contestable issues around access and equity and challenge the principles of governments providing affordable options.

Development of paediatric biochemistry centile charts as a complement to laboratory reference intervals.

Age-specific paediatric reference intervals are used in interpretation of laboratory results. However, interpretation may be problematic when a child just crosses an age bracket and the difference between the original and the subsequent age-specific reference interval is large. Moreover, details about the physiological changes with age may be masked. For the 12 months ending 30 September 2013, results of 16 common clinical biochemistry tests of ambulatory paediatric patients aged 0-19, requested by primary care physicians, were retrospectively collected in a large pathology service, and used to construct smoothed centile charts using a penalised maximum likelihood method. From the developed centile charts, the concentrations of sodium, bicarbonate, creatinine, urate, total protein, and albumin all increased with increasing age of the children. In contrast, the concentrations of potassium, chloride, anion gap, calcium, phosphate and lactate dehydrogenase decreased with increasing age of the children. Changes in the concentrations of urea, alkaline phosphatase, glucose, and total cholesterol varied by age. Generally, the boys and girls shared similar trend patterns until 10-15 years of age, when variations in the age of onset of puberty and development caused the trends of some biochemical measures to differ. The paediatric biochemistry centile charts are intuitive tools to use. They complement age-specific reference intervals in the tracking, interpretation and discussion of laboratory results. They also enhance the understanding of underlying physiological changes in biochemistry in children.

Diagnostic performance of serum cobalamin tests: a systematic review and meta-analysis.

AIMS: Serum cobalamin (cbl, vitamin B(12)) tests are routinely ordered for investigating conditions potentially amenable to cbl supplementation. This study aimed to systematically assess the evidence of diagnostic accuracy for serum cbl tests across patient subgroups. METHODS: Seven medical databases were searched (1990 to November 2009). Studies were included that compared serum cbl to a reference standard (all reference standards employed). Study quality was assessed using QUADAS. Summary estimates of test performance were determined using the bivariate model and hierarchical summary receiver operating characteristic curves (HSROC). RESULTS: Of 2878 identified studies, 54 were included. Studies rated poorly against QUADAS criteria. Positive (PLR) and negative likelihood ratios (NLR) were 2.72 [95% confidence interval (CI) 1.95, 3.81] and 0.59 (0.49, 0.72), respectively (studies employing methylmalonic acid as the referent). In studies employing a clinical reference standard, PLR was 3.33 (0.92, 12.10) and NLR 0.34 (0.13, 0.89). Test performance did not vary by clinical indication, test method or age. CONCLUSION: This review was limited by the quality of the evidence base and lack of a gold standard. From the available evidence, diagnosis of conditions amenable to cbl supplementation on the basis of serum cbl level alone cannot be considered a reliable approach to investigating suspected vitamin deficiency.

Determining urinary calcium/creatinine cut-offs for the paediatric population using published data.

BACKGROUND: The purpose of this study was to determine a cut-off above which a result is considered abnormal for 'spot' calcium-to-creatinine ratio (Ca/Cr) in urine in the paediatric age group. While the cut-offs are not well established, there are many published reports of urine Ca/Cr excretion ratio in the literature. Rather than undertaking a difficult, time-consuming, expensive, and ultimately redundant study, an analysis of these published works was undertaken to determine urine Ca/Cr cut-offs for the laboratory. METHODS: Fourteen studies reporting urine Ca/Cr ratio available in the literature were reviewed. Each study was abstracted for several characteristics. The data were plotted and the line of best fit describing the data was determined. Using the function describing the line, cut-offs by pertinent age were recalculated. These cut-offs were then compared to the original data and to in-house data. RESULTS: The function describing the line of best fit was y=-0.3175 ln(x) +1.46 (y=Ca/Cr in mmol/mmol and x=age in years), r2=0.85. After consultation with the paediatric nephrologists and comparison with our in-house data, cut-offs for age groups of <1, 1-<2, 2-<5, 5-<10, and 10-18 years in mmol/mmol of 1.50, 1.25, 1.00, 0.70, and 0.60, respectively, were derived. CONCLUSIONS: Using data from 14 published studies, suitable spot urine Ca/Cr cut-offs from birth to 18 years of age were determined.

Newborn screening in South Australia: is it universal?

OBJECTIVE: To determine the biochemical screening rate of newborns in South Australia and the factors associated with babies not being screened. DESIGN: Matching of data in the SA Newborn Screening Centre database (acquired from Guthrie cards) with the SA perinatal data collection (compiled from supplementary birth records) to determine how many newborns missed screening. Risk factors for missed screening were identified from sociodemographic and clinical variables recorded in the perinatal data collection and analysed by multivariable unconditional logistic regression analysis. PATIENTS AND SETTING: All live births (n = 18,426) in South Australia in 1999, in the 63 hospitals assisting deliveries or in the home. MAIN OUTCOME MEASURES: Rates of biochemical screening and missed screening in all newborns and among various subgroups; adjusted odds ratios (after multivariable logistic regression analysis) for risk factors for missed screening. RESULTS: The newborn screening rate in South Australia in 1999 was 97.8%. Babies born at home, born to an Aboriginal mother, or born to a mother who normally resided in another state were at higher risk of missed screening. Other factors associated with missed screening were having fewer than seven antenatal visits, prematurity (gestational age at birth < 32 weeks), congenital abnormality in the baby, use of paediatric intensive care, early discharge from hospital before 3 days (but especially after less than 1 day), and death of the baby during the neonatal period. CONCLUSION: In South Australia, while 2.2% of all newborns missed screening in 1999, in certain high-risk groups the proportions of unscreened babies were significantly higher. With a 2% missed screening rate, one might expect one newborn with a screening-detectable disorder to elude detection every other year in South Australia.