Primary infection of Toxoplasma gondii during pregnancy can be transmitted to the unborn child and may have serious consequences, including retinochoroiditis, hydrocephaly, cerebral calcifications, ...encephalitis, splenomegaly, hearing loss, blindness, and death. Austria, a country with moderate seroprevalence, instituted mandatory prenatal screening for toxoplasma infection to minimize the effects of congenital transmission. This work compares the societal costs of congenital toxoplasmosis under the Austrian national prenatal screening program with the societal costs that would have occurred in a No-Screening scenario.
We retrospectively investigated data from the Austrian Toxoplasmosis Register for birth cohorts from 1992 to 2008, including pediatric long-term follow-up until May 2013. We constructed a decision-analytic model to compare lifetime societal costs of prenatal screening with lifetime societal costs estimated in a No-Screening scenario. We included costs of treatment, lifetime care, accommodation of injuries, loss of life, and lost earnings that would have occurred in a No-Screening scenario and compared them with the actual costs of screening, treatment, lifetime care, accommodation, loss of life, and lost earnings. We replicated that analysis excluding loss of life and lost earnings to estimate the budgetary impact alone. Our model calculated total lifetime costs of €103 per birth under prenatal screening as carried out in Austria, saving €323 per birth compared with No-Screening. Without screening and treatment, lifetime societal costs for all affected children would have been €35 million per year; the implementation costs of the Austrian program are less than €2 million per year. Calculating only the budgetary impact, the national program was still cost-saving by more than €15 million per year and saved €258 million in 17 years.
Cost savings under a national program of prenatal screening for toxoplasma infection and treatment are outstanding. Our results are of relevance for health care providers by supplying economic data based on a unique national dataset including long-term follow-up of affected infants.
Summary Background The interest in neonatal screening for lysosomal storage disorders has increased substantially because of newly developed enzyme replacement therapies, the need for early ...diagnosis, and technical advances. We tested for Gaucher's disease, Pompe's disease, Fabry's disease, and Niemann-Pick disease types A and B in an anonymous prospective nationwide screening study that included genetic mutation analysis to assess the practicality and appropriateness of including these disorders in neonatal screening panels. Methods Specimens from dried blood spots of 34 736 newborn babies were collected consecutively from January, 2010 to July, 2010, as part of the national routine Austrian newborn screening programme. Anonymised samples were analysed for enzyme activities of acid β-glucocerebrosidase, α-galactosidase, α-glucosidase, and acid sphingomyelinase by electrospray ionisation tandem mass spectrometry. Genetic mutation analyses were done in samples with suspected enzyme deficiency. Findings All 34 736 samples were analysed successfully by the multiplex screening assay. Low enzyme activities were detected in 38 babies. Mutation analysis confirmed lysosomal storage disorders in 15 of them. The most frequent mutations were found for Fabry's disease (1 per 3859 births), followed by Pompe's disease (1 per 8684), and Gaucher's disease (1 per 17 368). The positive predictive values were 32% (95% CI 16–52), 80% (28–99), and 50% (7–93), respectively. Mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. Interpretation The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected. Neonatal screening for lysosomal storage disorders is likely to raise challenges for primary health-care providers. Furthermore, the high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood. Funding Austrian Ministry of Health, Family, and Women.
Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic ...activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring.
Among our GLA-mutation proven FD patients, we screened 18 heterozygotes whose leukocyte α-GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry.
We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte α-GalA activities were in the normal range.
LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring.
Fabry disease (FD), an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A) and the accumulation of its substrates, globotriaosylceramide (Gb3) and ...its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Here, we compared the levels of Lyso-Gb3 in dried blood spots (DBS) and sera in affected males and heterozygotes with the “Classic” and “Later-Onset” phenotypes.
The Lyso-Gb3 concentrations in DBS and sera from 56 FD patients were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry.
The serum Lyso-Gb3 levels in 18 and 5 affected males with the Classic and Later-Onset phenotypes, were 61±38 and 14±12ng/mL, respectively. Lyso-Gb3 levels in 30 females from Classic families and three females from Later-Onset families were 10±5.4 and 2.4±1.0ng/mL, respectively. The linear regression model with serum Lyso-Gb3 as the dependent variable and DBS Lyso-Gb3 an independent variable was described by the function y=−1.83+1.68∗x and showed a high coefficient of determination, R2=0.976. The overall correlation between the Lyso-Gb3 levels in DBS and sera was high (R=0.99; p<0.001).
DBS provides a convenient, sensitive, and reproducible source to measure Lyso-Gb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with Fabry disease.
•DBS samples provide a convenient and reliable means to estimate the Lyso-Gb3 correlations in serum or plasma.•DBS samples also permit the initial assignment of phenotype.•Moreover, serial measurements of DBS Lyso-Gb3 allow for monitoring the effectiveness of treatment in Fabry disease.
Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive ...glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3).
In 69 consecutive adult FD patients (males: n=28 (41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry.
Serum levels of LysoGb3 were significantly higher in Classic compared with Later-Onset phenotype and higher in the latter compared with controls, both in males (52 40–83 vs 9.5 4.5–20 vs 0.47 0.41–0.61 ng/ml, P<0.001) and in females (9.9 7.9–14 vs 4.9 1.6–4.9 vs 0.41 0.33–0.48 ng/ml, P<0.001), respectively. Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (β=0.09, 95%CI 0.04–0.13, P<0.001) and the presence of cardiomyopathy (β=25, 95%CI 9.8–41, P=0.002). LysoGb3 levels were higher in males with frame-shift and nonsense mutations than in males with missense mutations (84 72–109 vs 41 37–52 ng/ml, P=0.002).
LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males. LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment. LysoGb3 appears to be one marker of metabolic phenotyping of FD.
•LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males.•LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment.•LysoGb3 appears to be one marker of metabolic phenotyping of FD.
Ureaplasma species (spp) are the bacteria most often isolated from the amniotic cavity of women with preterm labor or preterm premature rupture of membranes; thus, the link between intrauterine ...Ureaplasma spp infection and adverse pregnancy outcome clearly is established. However, because vaginal Ureaplasma spp colonization is very common in pregnant women, the reason that these microorganisms cause ascending infections in some cases but remain asymptomatic in most pregnancies is not clear. Previous studies suggested an association between vaginal colonization with Ureaplasma parvum as opposed to U urealyticum and preterm delivery. However, because of the high frequency of vaginal Ureaplasma spp colonization during pregnancy, additional risk factors are needed to select a group of women who might benefit from treatment.
To further identify pregnant women who are at increased risk for preterm delivery, the aim of the present study was to investigate U parvum serovar–specific pathogenicity in a large clinical cohort.
We serotyped 1316 samples that were positive for U parvum using a high-resolution melt polymerase chain reaction assay, and results were correlated with pregnancy outcome.
Within U parvum positive samples, serovar 3 was the most common isolate (43.3%), followed by serovar 6 (31.4%) and serovar 1 (25.2%). There was a significantly increased risk for spontaneous preterm birth at very low (<32 weeks gestation; P<.005) and extremely low (<28 weeks gestation; P<.005) gestational age in the group with vaginal U parvum serovar 3 colonization compared with the control group of pregnant women who tested negative for vaginal Ureaplasma spp colonization. This association was found for neither serovar 1 nor serovar 6. The combination of vaginal U parvum serovar 3 colonization and diagnosis of bacterial vaginosis in early pregnancy or a history of preterm birth further increased the risk for adverse pregnancy outcome.
Colonization with U parvum serovar 3, but not serovar 1 or serovar 6, in early pregnancy is associated with preterm delivery at very and extremely low gestational age. The combination of U parvum serovar 3 colonization and a history of preterm birth or bacterial vaginosis further increases the risk for spontaneous preterm birth at low gestational age and may define a target group for therapeutic intervention studies.
We have started a long-term reverberation mapping (RM) project using the Wyoming Infrared Observatory 2.3 m telescope titled "Monitoring AGNs with Hβ Asymmetry" (MAHA). The motivations of the project ...are to explore the geometry and kinematics of the gas responsible for complex Hβ emission-line profiles, ideally leading to an understanding of the structures and origins of the broad-line region (BLR). Furthermore, such a project provides the opportunity to search for evidence of close binary supermassive black holes. We describe MAHA and report initial results from our first campaign, from 2016 December to 2017 May, highlighting velocity-resolved time lags for four active galactic nuclei (AGNs) with asymmetric Hβ lines. We find that 3C 120, Ark 120, and Mrk 6 display complex features different from the simple signatures expected for pure outflow, inflow, or a Keplerian disk. While three of the objects have been previously reverberation mapped, including velocity-resolved time lags in the cases of 3C 120 and Mrk 6, we report a time lag and corresponding black hole mass measurement for SBS 1518+593 for the first time. Furthermore, SBS 1518+593, the least asymmetric of the four, does show velocity-resolved time lags characteristic of a Keplerian disk or virialized motion more generally. Also, the velocity-resolved time lags of 3C 120 have significantly changed since previously observed, indicating an evolution of its BLR structure. Future analyses of the data for these objects and others in MAHA will explore the full diversity of Hβ lines and the physics of AGN BLRs.
Based on a unique dataset comprising all 325,000 Austrian patients that were under pharmaceutical treatment for diabetes during 2006 and 2007, we measured the excess risk of developing diabetes ...triggered by undernourishment in early life. We studied the percentage of all diabetes patients in the total population specifically for each year of birth, from 1917 to 2007. We found a massive excess risk of diabetes in people born during the times of the three major famines and immediately after, which occurred in Austria in the 20th century: 1918–1919, 1938, and 1946–1947. Depending on the region, there was an up to 40% higher chance of having diabetes when born in 1919–1921, compared with 1918 or 1922, where age-specific typical diabetes ratios are observed. The excess risk for diabetes was practically absent in those provinces of Austria that were less affected by the famines. We show that diabetes rates exhibit nontrivial, age-specific sex differences, and correlate with the economic wealth of the region. Our results might be of relevance for establishing higher awareness in the health system for those born in high-risk years, and underline the importance of ensuring sufficient nutrition in prenatal and early stages of life.
Abstract
We present a search for helium in the upper atmospheres of three sub-Neptune-sized planets to investigate the origins of these ubiquitous objects. The detection of helium for a low-density ...planet would be strong evidence for the presence of a primary atmosphere accreted from the protoplanetary nebula because large amounts of helium are not expected in the secondary atmospheres of rocky planets. We used Keck+NIRSPEC to obtain high-resolution transit spectroscopy of the planets GJ 1214b, GJ 9827d, and HD 97658b around the 10833 Å He triplet feature. We did not detect helium absorption for any of the planets despite achieving a high level of sensitivity. We used the nondetections to set limits on the planets’ thermosphere temperatures and atmospheric loss rates by comparing grids of 1D models to the data. We also performed coupled interior structure and atmospheric loss calculations, which suggest that the bulk atmospheres (winds) of the planets would be at most modestly enhanced (depleted) in helium relative to their primordial composition. Our lack of detections of the helium triplet for GJ 1214b and GJ 9827d is highly inconsistent with the predictions of models for the present-day mass loss on these planets. Higher signal-to-noise data would be needed to detect the helium feature predicted for HD 97658b. We identify uncertainties in the extreme-ultraviolet fluxes of the host stars and the lack of detailed mass-loss models specifically for cool and metal-enhanced atmospheres as the main limitations to the interpretation of our results. Ultimately, our results suggest that the upper atmospheres of sub-Neptune planets are fundamentally different from those of gas giant planets.
A personalized treatment decision for Gaucher disease (GD) patients should be based on relevant markers that are specific to GD, play a direct role in GD pathophysiology, exhibit low genetic ...variation, reflect the therapy, and can be used for all patients. Thirty-four GD patients treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were analyzed for platelet count, chitotriosidase, and tartrate-resistant acid phosphatase activity in plasma samples, and quantitative measurement of Lyso-Gb1 was performed in dried blood spots. In our ERT and SRT study cohorts, plasma lyso-GL1 correlated significantly with chito-triosidase (ERT: r = 0.55, p < 0.001; SRT: r = 0.83, p < 0.001) and TRAP (ERT: r = 0.34, p < 0.001; SRT: r = 0.88, p < 0.001), irrespective of treatment method. A platelet count increase was associated with a Lyso-Gb1 decrease in both treatment groups (ERT: p = 0.021; SRT: p = 0.028). The association of Lyso-Gb1 with evaluated markers was stronger in the SRT cohort. Our results indicate that ERT and SRT in combination or in a switch manner could offer the potential of individual drug effectiveness for particular GD symptoms. Combination of the key biomarker of GD, Lyso-Gb1, with other biomarkers can offer improved response assessment to long-term therapy.
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