Unambiguous molecular detections with multiple genetic approach for the complicated chromosome 22q11 deletion syndrome

<p>Abstract</p> <p>Background</p> <p>Chromosome 22q11 deletion syndrome (22q11DS) causes a developmental disorder during the embryonic stage, usually because of hemizygous deletions. The clinical pictures of patients with 22q11DS vary because of polymorphisms: on average, approximately 93% of affected individuals have a de novo deletion of 22q11, and the rest have inherited the same deletion from a parent. Methods using multiple genetic markers are thus important for the accurate detection of these microdeletions.</p> <p>Methods</p> <p>We studied 12 babies suspected to carry 22q11DS and 18 age-matched healthy controls from unrelated Taiwanese families. We determined genomic variance using microarray-based comparative genomic hybridization (array-CGH), quantitative real-time polymerase chain reaction (qPCR) and multiplex ligation-dependent probe amplification (MLPA).</p> <p>Results</p> <p>Changes in genomic copy number were significantly associated with clinical manifestations for the classical criteria of 22q11DS using MPLA and qPCR (<it>p </it>< 0.01). An identical deletion was shown in three affected infants by MLPA. These reduced DNA dosages were also obtained partially using array-CGH and confirmed by qPCR but with some differences in deletion size.</p> <p>Conclusion</p> <p>Both MLPA and qPCR could produce a clearly defined range of deleted genomic DNA, whereas there must be a deleted genome that is not distinguishable using MLPA. These data demonstrate that such multiple genetic approaches are necessary for the unambiguous molecular detection of these types of complicated genomic syndromes.</p

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Applying Convolutional Neural Network in Automatic Assessment of Bone Age Using Multi-Stage and Cross-Category Strategy

Bone age is a common indicator of children’s growth. However, traditional bone age assessment methods usually take a long time and are jeopardized by human error. To address the aforementioned problem, we propose an automatic bone age assessment system based on the convolutional neural network (CNN) framework. Generally, bone age assessment is utilized amongst 0–18-year-old children. In order to reduce its variation in terms of regression model building, our system consists of two steps. First, we build a maturity stage classifier to identify the maturity stage, and then build regression models for each maturity stage. In this way, assessing bone age through the use of several independent regression models will reduce the variation and make the assessment of bone age more accurate. Some bone sections are particularly useful for distinguishing certain maturity stages, but may not be effective for other stages, and thus we first perform a rough classification to generally distinguish the maturity stage, and then undertake fine classification. Because the skeleton is constantly growing during bone development, it is not easy to obtain a clear decision boundary between the various stages of maturation. Therefore, we propose a cross-stage class strategy for this problem. In addition, because fewer children undergo X-rays in the early and late stages, this causes an imbalance in the data. Under the cross-stage class strategy, this problem can also be alleviated. In our proposed framework, we utilize an MSCS-CNN (Multi-Step and Cross-Stage CNN). We experiment on our dataset, and the accuracy of the MSCS-CNN in identifying both female and male maturity stages is above 0.96. After determining maturity stage during bone age assessment, we obtain a 0.532 and 0.56 MAE (mean absolute error) for females and males, respectively

Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type I disease

Abstract Background Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB). Methods We divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain. Results Transcranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme. Conclusions Transcranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy

Reevaluating Reference Ranges of Oxygen Saturation for Healthy Full-term Neonates Using Pulse Oximetry

We compared our clinical experience with currently available reference oxygen saturation level (SpO2) values from the American Academy of Pediatrics/American Heart Association (AAP/AHA) neonatal resuscitation program guidelines. Methods: We enrolled 145 healthy full-term neonates; infants showing respiratory distress and those with serious congenital anomalies were excluded. SpO2 values at every 1 minute until 10 minutes after birth were measured and recorded. Infants were classified into the cesarean section (CS) and normal spontaneous delivery (NSD) groups for evaluating differences. The 10th percentiles of SpO2 at each minute were used as the lower limits of normal oxygen saturation, and these were compared with the lowest target values recommended in the AAP/AHA guidelines. Results: Overall, 130 vigorous full-term neonates (median gestational age: 38 5/7 weeks; body weight at birth: 2405–3960 g) were analyzed. The median SpO2 were 67% and 89% at the 1st and 4th minute, respectively. On average, SpO2 values reached >90% at the 5th minute. No statistical differences were noted in the SpO2 values between the CS and NSD groups after 5 minutes; however, a trend of higher SpO2 was observed in the NSD group. We noted a gradually increasing trend for SpO2 values over time, similar to that noted in the AAP/AHA guidelines. However, SpO2 values at the 10th percentiles of each minute within the first 5 minutes in our study were equal to or significantly lower than those in the AAP/AHA guidelines; moreover, at the 10th minute, SpO2 values at the 10th percentiles were significantly higher than those in the guidelines. Conclusion: The delivery modes did not affect the SpO2 values of full-term healthy neonates. Discrepancies in SpO2 changes in full-term neonates not requiring resuscitation between this study and the AAP/AHA guidelines were significant. SpO2 ranges for each time point within the first 10 minutes after birth should therefore be reevaluated locally

Brief Report: Single‐nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians

ObjectiveThe increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects.MethodsPatients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort.ResultsTwo genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032.ConclusionGenetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis