Cystic fibrosis-related diabetes onset can be predicted using biomarkers measured at birth.

PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Quantized Pulse Propagation in Josephson Junction Arrays.

We present time-domain electrical measurements and simulations of the quantized voltage pulses that are generated from series-connected Josephson junction (JJ) arrays. The transmission delay of the JJ array can lead to a broadening of the net output pulse, depending on the direction of the output pulse propagation relative to the input bias pulse. To demonstrate this, we compare time-domain measurements of output pulses from radio-frequency Josephson Arbitrary Waveform Synthesizer (RF-JAWS) circuits fabricated with two different output measurement configurations, so that the backward-propagating and forward-propagating pulses can be measured. Measurements were made on arrays with 1200 and 3600 JJs and show that the net backward-propagating output pulse is broadened by timing delays in the JJ array while the net forward-propagating output pulse is insensitive to delay effects and can theoretically be further scaled to longer JJ array lengths without significant output pulse broadening. These measurements match well with simulations and confirm the expectation that the net output pulses arise from the time-delayed superposition of individual JJ output pulses from the series array of JJs. The measurements and analysis shown here have important implications for the realization of RF-JAWS circuits to be used as quantum-based reference sources for communications metrology.

Jitter Sensitivity Analysis of the Superconducting Josephson Arbitrary Waveform Synthesizer.

We present the first jitter sensitivity analysis of a superconducting voltage reference waveform synthesizer with fundamentally accurate output pulses. Successful deployment of a reference waveform source at microwave frequencies will represent a new paradigm for radio frequency metrology. The programmable waveform synthesizer considered in this paper contains a 1.5 bit delta-sigma digital-to-analog converter (DAC) with a sampling frequency of 28 GHz. We quantify the impact of random and deterministic output pulse position jitter (PPJ) on: 1) the amplitude accuracy of the output fundamental tone and 2) the in-band signal-to-noise and distortion ratio (SNDR). The superconducting DAC features a complete lack of output pulsewidth jitter, and random PPJ up to 200 fs rms has a negligible impact on accuracy and SNDR for synthesized tones up to 1 GHz. However, application of nonzero dc bias current is shown to produce deterministic PPJ of up to 5 ps, which, in turn, is shown to degrade the in-band SNDR by 30 dB at 1 GHz unless eliminated with techniques discussed in this paper. We verify the predicted effects of random and deterministic PPJ with simulations in the range of 100 kHz-1 GHz and with experiments in the range of 100 kHz-3 MHz.

Matter wave lensing to picokelvin temperatures.

Using a matter wave lens and a long time of flight, we cool an ensemble of ^{87}Rb atoms in two dimensions to an effective temperature of less than 50_{-30}^{+50} pK. A short pulse of red-detuned light generates an optical dipole force that collimates the ensemble. We also report a three-dimensional magnetic lens that substantially reduces the chemical potential of evaporatively cooled ensembles with a high atom number. By observing such low temperatures, we set limits on proposed modifications to quantum mechanics in the macroscopic regime. These cooling techniques yield bright, collimated sources for precision atom interferometry.

Ultra-large nonlinear parameter in graphene-silicon waveguide structures.

Mono-layer graphene integrated with optical waveguides is studied for the purpose of maximizing E-field interaction with the graphene layer, for the generation of ultra-large nonlinear parameters. It is shown that the common approach used to minimize the waveguide effective modal area does not accurately predict the configuration with the maximum nonlinear parameter. Both photonic and plasmonic waveguide configurations and graphene integration techniques realizable with today's fabrication tools are studied. Importantly, nonlinear parameters exceeding 10(4) W(-1)/m, two orders of magnitude larger than that in silicon on insulator waveguides without graphene, are obtained for the quasi-TE mode in silicon waveguides incorporating mono-layer graphene in the evanescent part of the optical field. Dielectric loaded surface plasmon polariton waveguides incorporating mono-layer graphene are observed to generate nonlinear parameters as large as 10(5) W(-1)/m, three orders of magnitude larger than that in silicon on insulator waveguides without graphene. The ultra-large nonlinear parameters make such waveguides promising platforms for nonlinear integrated optics at ultra-low powers, and for previously unobserved nonlinear optical effects to be studied in a waveguide platform.

Unsupervised home spirometry is not equivalent to supervised clinic spirometry in children and young people with cystic fibrosis: Results from the CLIMB-CF study.

BACKGROUND: Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested. METHODS: Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes. RESULTS: Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread. CONCLUSION: In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.

Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children. METHODS: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes. RESULTS: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls. CONCLUSIONS: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Ultralow power artificial synapses using nanotextured magnetic Josephson junctions.

Neuromorphic computing promises to markedly improve the efficiency of certain computational tasks, such as perception and decision-making. Although software and specialized hardware implementations of neural networks have made tremendous accomplishments, both implementations are still many orders of magnitude less energy efficient than the human brain. We demonstrate a new form of artificial synapse based on dynamically reconfigurable superconducting Josephson junctions with magnetic nanoclusters in the barrier. The spiking energy per pulse varies with the magnetic configuration, but in our demonstration devices, the spiking energy is always less than 1 aJ. This compares very favorably with the roughly 10 fJ per synaptic event in the human brain. Each artificial synapse is composed of a Si barrier containing Mn nanoclusters with superconducting Nb electrodes. The critical current of each synapse junction, which is analogous to the synaptic weight, can be tuned using input voltage spikes that change the spin alignment of Mn nanoclusters. We demonstrate synaptic weight training with electrical pulses as small as 3 aJ. Further, the Josephson plasma frequencies of the devices, which determine the dynamical time scales, all exceed 100 GHz. These new artificial synapses provide a significant step toward a neuromorphic platform that is faster, more energy-efficient, and thus can attain far greater complexity than has been demonstrated with other technologies.

Devising and evaluating a model for teaching therapeutic handling and moving skills to complementary therapists.

This two phase, mixed methods study, developed and evaluated the effectiveness of a model for teaching the neuromuscular approach (NMA) to human movement. From an original volunteer sample of 74 students, 33 completed the 15-week (Phase 1) moving and handling training which demonstrated that the model resulted in significant change (p<0.05) in movement patterns and detection of potentially hazardous postures. Phase 2, using 24 students, showed that the model worked successfully (95% positive evaluation) in the context of a Complementary Therapies degree programme.

Seasonal patterns of leaf gas exchange and water relations in dry rain forest trees of contrasting leaf phenology.

Diurnal and seasonal patterns of leaf gas exchange and water relations were examined in tree species of contrasting leaf phenology growing in a seasonally dry tropical rain forest in north-eastern Australia. Two drought-deciduous species, Brachychiton australis (Schott and Endl.) A. Terracc. and Cochlospermum gillivraei Benth., and two evergreen species, Alphitonia excelsa (Fenzal) Benth. and Austromyrtus bidwillii (Benth.) Burret. were studied. The deciduous species had higher specific leaf areas and maximum photosynthetic rates per leaf dry mass in the wet season than the evergreens. During the transition from wet season to dry season, total canopy area was reduced by 70-90% in the deciduous species and stomatal conductance (g(s)) and assimilation rate (A) were markedly lower in the remaining leaves. Deciduous species maintained daytime leaf water potentials (Psi(L)) at close to or above wet season values by a combination of stomatal regulation and reduction in leaf area. Thus, the timing of leaf drop in deciduous species was not associated with large negative values of daytime Psi(L) (greater than -1.6 MPa) or predawn Psi(L) (greater than -1.0 MPa). The deciduous species appeared sensitive to small perturbations in soil and leaf water status that signalled the onset of drought. The evergreen species were less sensitive to the onset of drought and g(s) values were not significantly lower during the transitional period. In the dry season, the evergreen species maintained their canopies despite increasing water-stress; however, unlike Eucalyptus species from northern Australian savannas, A and g(s) were significantly lower than wet season values.

Delineation of prevalence and risk factors for early coronary artery disease by electron beam computed tomography in young adults with type 1 diabetes.

OBJECTIVE: Type 1 diabetes increases the risk for coronary artery disease (CAD), but limited information is available regarding the early natural history of this process. Electron beam tomography (EBT) can measure coronary artery calcification (CAC), an early marker for CAD. This study was designed to assess the prevalence and risk factors for CAC in young adults with established type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 101 subjects aged 17-28 years with type 1 diabetes of over 5 years' duration and no history of heart disease underwent cardiac EBT with calcium scoring. Medical histories were obtained and physical examinations were conducted to document the presence of cardiac risk factors as well as evidence of microvasculopathy and diabetic arthropathy. Laboratory evaluation included measurement of fasting lipoproteins, homocysteine concentration, lipoprotein(a) [Lp(a)], urinary microalbumin, and HbA(1c). Contingency table analysis was used to assess bivariate relationships. Logistic regression was employed to construct a parsimonious model of independent risk factors. RESULTS: Eleven subjects (10.9%) had CAC. Smokers were nearly five times more likely than nonsmokers to have CAC (P = 0.03). In addition, each 0.36-mm/l increment of Lp(a) was associated with a 10% increased risk for CAC (P = 0.05) after controlling for potentially confounding factors. There was no association of other CAD or diabetes risk factors studied with CAC. CONCLUSIONS: The prevalence of early CAD as evidenced by CAC in young adults with type 1 diabetes is significant. Smoking and Lp(a) levels independently predict the presence of CAC. Additional study is necessary to delineate the natural history of CAC and the role of risk factor modification to prevent progression of CAD in this high-risk population.

Management of aortopulmonary collaterals in children following cardiac transplantation for complex congenital heart disease.

BACKGROUND: Heart transplantation (HTx) is increasingly utilized as therapy for end-stage cyanotic congenital heart disease. This study investigates the presence and impact of aortopulmonary collaterals (APCs) associated with cyanotic heart disease on the early post-operative course of patients undergoing transplantation. High output cardiac failure due to residual aortopulmonary collaterals can affect outcome following heart transplantation. METHODS: Seven patients with hemodynamically significant APCs post-transplant were identified among 40 patients with cyanotic congenital heart disease undergoing HTx. The peri- and intra-operative courses of these patients were reviewed. All 7 patients required prolonged inotropic support despite normal ventricular function and no allograft rejection; 5 were ventilator-dependent due to significant pulmonary vascular congestion. Selective angiography demonstrated the presence of significant aortopulmonary collaterals at 7 to 19 days post-transplant. Coil embolization of aortopulmonary collaterals was performed in all patients; a mean of 6 (2 to 16) vessels/patient were embolized. RESULTS: After embolization, pulmonary edema resolved and heart size normalized in all patients; inotropic support was weaned within 2 to 10 days in 5 patients. One patient developed transient renal failure secondary to excessive contrast load and another had enterococcal sepsis within 24 hours after the procedure. All patients were asymptomatic from 4 to 10 years of follow-up post-HTx. CONCLUSIONS: Aortopulmonary collaterals should be considered a cause of early donor heart failure in children following HTx for cyanotic congenital heart disease. Early detection and treatment of aortopulmonary collaterals by coil embolization is necessary to improve the post-transplant course in these complex patients.

Fitting and interpreting occupancy models.

We show that occupancy models are more difficult to fit than is generally appreciated because the estimating equations often have multiple solutions, including boundary estimates which produce fitted probabilities of zero or one. The estimates are unstable when the data are sparse, making them difficult to interpret, and, even in ideal situations, highly variable. As a consequence, making accurate inference is difficult. When abundance varies over sites (which is the general rule in ecology because we expect spatial variance in abundance) and detection depends on abundance, the standard analysis suffers bias (attenuation in detection, biased estimates of occupancy and potentially finding misleading relationships between occupancy and other covariates), asymmetric sampling distributions, and slow convergence of the sampling distributions to normality. The key result of this paper is that the biases are of similar magnitude to those obtained when we ignore non-detection entirely. The fact that abundance is subject to detection error and hence is not directly observable, means that we cannot tell when bias is present (or, equivalently, how large it is) and we cannot adjust for it. This implies that we cannot tell which fit is better: the fit from the occupancy model or the fit ignoring the possibility of detection error. Therefore trying to adjust occupancy models for non-detection can be as misleading as ignoring non-detection completely. Ignoring non-detection can actually be better than trying to adjust for it.

Effect of opioid compounds on feeding and activity of the cockroach, Periplaneta americana.

Opioid peptides have been implicated in regulation of feeding in invertebrates. Studies have suggested that receptors for opioids are present in cockroaches and that these receptors play roles in affecting both behaviour and feeding. We examined the effect of micro, delta, and kappa opioid receptor agonists and antagonists on feeding, mass changes and activity in the cockroach, Periplaneta americana. The kappa antagonist, nor-binaltorphimine, significantly increased food intake, while naltrexone (general antagonist) and naloxonazine (micro antagonist) both reduced feeding. A large mass loss was observed in cockroaches treated with nor-binaltorphimine, despite the increased food intake. Males did not lose as much mass during the 3h as females, although drug treatment did have some effect on the loss. Time of activity (%) was not influenced by any drug. Water loss experiments suggested that nor-binaltorphimine increased water loss, accounting for the mass loss despite the increased feeding. We suggest that two populations of opioid receptors are present as previously reported, with one affecting feeding and the other involved with evaporative water loss.

Effectiveness of computational methods in haplotype prediction.

Haplotype analysis has been used for narrowing down the location of disease-susceptibility genes and for investigating many population processes. Computational algorithms have been developed to estimate haplotype frequencies and to predict haplotype phases from genotype data for unrelated individuals. However, the accuracy of such computational methods needs to be evaluated before their applications can be advocated. We have experimentally determined the haplotypes at two loci, the N-acetyltransferase 2 gene ( NAT2, 850 bp, n=81) and a 140-kb region on chromosome X ( n=77), each consisting of five single nucleotide polymorphisms (SNPs). We empirically evaluated and compared the accuracy of the subtraction method, the expectation-maximization (EM) method, and the PHASE method in haplotype frequency estimation and in haplotype phase prediction. Where there was near complete linkage disequilibrium (LD) between SNPs (the NAT2 gene), all three methods provided effective and accurate estimates for haplotype frequencies and individual haplotype phases. For a genomic region in which marked LD was not maintained (the chromosome X locus), the computational methods were adequate in estimating overall haplotype frequencies. However, none of the methods was accurate in predicting individual haplotype phases. The EM and the PHASE methods provided better estimates for overall haplotype frequencies than the subtraction method for both genomic regions.