26 research outputs found

    Estimation of the infection attack rate of mumps in an outbreak among college students using paired serology

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    Mumps virus is a highly transmissible pathogen that is effectively controlled in countries with high vaccination coverage. Nevertheless, outbreaks have occurred worldwide over the past decades in vaccinated populations. Here we analyse an outbreak of mumps virus genotype G among college students in the Netherlands over the period 2009–2012 using paired serological data. To identify infections in the presence of preexisting antibodies we compared mumps specific serum IgG concentrations in two consecutive samples (n=746), whereby the first sample was taken when students started their study prior to the outbreaks, and the second sample was taken 2–5 years later. We fit a binary mixture model to the data. The two mixing distributions represent uninfected and infected classes. Throughout we assume that the infection probability increases with the ratio of antibody concentrations of the second to first sample. The estimated infection attack rate in this study is higher than reported earlier (0.095 versus 0.042). The analyses yield probabilistic classifications of participants, which are mostly quite precise owing to the high intraclass correlation of samples in uninfected participants (0.85, 95%CrI: 0.82−0.87). The estimated probability of infection increases with decreasing antibody concentration in the pre-outbreak sample, such that the probability of infection is 0.12 (95%CrI: 0.10−0.13) for the lowest quartile of the pre-outbreak samples and 0.056 (95%CrI: 0.044−0.068) for the highest quartile. We discuss the implications of these insights for the design of booster vaccination strategies

    Introduction of Heated Cow's Milk Protein in Challenge-Proven Cow's Milk Allergic Children:The iAGE Study

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    The introduction of baked milk products in cow's milk (CM) allergic children has previously been shown to accelerate induction tolerance in a selected group of children. However, there is no standardized baked milk product on the market. Recently, a new standardized, heated and glycated cow's milk protein (HP) product was developed. The aim of this study was to measure safety and tolerability of a new, well characterized heated CM protein (HP) product in cow's milk allergic (CMA) children between the age of 3 and 36 months. The children were recruited from seven clinics throughout The Netherlands. The HP product was introduced in six incremental doses under clinical supervision. Symptoms were registered after introduction of the HP product. Several questionnaires were filled out by parents of the children. Skin prick tests were performed with CM and HP product, sIgE to CM and α-lactalbumin (Bos d4), β-lactoglobulin (Bos d5), serum albumin (Bos d 6), lactoferrin (Bos d7) and casein (Bos d8). Whereas 72% percent (18 out of 25) of the children tolerated the HP product, seven children experienced adverse events. Risk factors for intolerance to the HP product were higher skin prick test (SPT) histamine equivalent index (HEP) results with CM and the HP product, higher specific IgE levels against Bos d4 and Bos d8 levels and Bos d5 levels. In conclusion, the HP product was tolerated by 72% of the CM allergic children. Outcomes of SPT with CM and the HP product, as well as values of sIgE against caseins, α-lactalbumin, and β-lactoglobulin may predict the tolerability of the HP product. Larger studies are needed to confirm these conclusions.</p

    Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants

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    Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10−5; U.S. cohort, P = 2.2×10−13). Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy

    Estimation of the infection attack rate of mumps in an outbreak among college students using paired serology

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    Mumps virus is a highly transmissible pathogen that is effectively controlled in countries with high vaccination coverage. Nevertheless, outbreaks have occurred worldwide over the past decades in vaccinated populations. Here we analyse an outbreak of mumps virus genotype G among college students in the Netherlands over the period 2009–2012 using paired serological data. To identify infections in the presence of preexisting antibodies we compared mumps specific serum IgG concentrations in two consecutive samples (n=746), whereby the first sample was taken when students started their study prior to the outbreaks, and the second sample was taken 2–5 years later. We fit a binary mixture model to the data. The two mixing distributions represent uninfected and infected classes. Throughout we assume that the infection probability increases with the ratio of antibody concentrations of the second to first sample. The estimated infection attack rate in this study is higher than reported earlier (0.095 versus 0.042). The analyses yield probabilistic classifications of participants, which are mostly quite precise owing to the high intraclass correlation of samples in uninfected participants (0.85, 95%CrI: 0.82−0.87). The estimated probability of infection increases with decreasing antibody concentration in the pre-outbreak sample, such that the probability of infection is 0.12 (95%CrI: 0.10−0.13) for the lowest quartile of the pre-outbreak samples and 0.056 (95%CrI: 0.044−0.068) for the highest quartile. We discuss the implications of these insights for the design of booster vaccination strategies

    Phenotypic expansion of EGP5-related Vici syndrome: 15 Dutch patients carrying a founder variant

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    Vici syndrome (OMIM 242840) is a very rare autosomal recessive multisystem disorder first described in 1988. In 2013, bi-allelic loss-of-function mutations in EPG5 were reported to cause Vici syndrome. Five principal diagnostic features of Vici syndrome have been proposed: agenesis of the corpus callosum, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. We identified 15 patients carrying a homozygous founder missense variant in EPG5 who all exhibit a less severe clinical phenotype than classic Vici syndrome. All 15 show typical brain abnormalities on MRI. The homozygous founder variant in EPG5 they carry results in a shorter in-frame transcript and truncated, but likely still residual, EPG5 protein. We speculate that the residual EPG5 protein explains their attenuated phenotype, which is consistent with two previous observations that low expression of EPG5 can lead to an attenuated Vici syndrome phenotype. We propose renaming this condition EPG5-related neurodevelopmental disorder to emphasize the clinical variability of patients with bi-allelic mutations in EPG5
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