Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.

Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.

Reliability and discriminant validity of the quantitative timed up and go in typically developing children and children with cerebral palsy GMFCS levels I-II.

PURPOSE: The purpose of this study was to examine the reliability and discriminant validity of the Quantitative Timed up and Go (QTUG) in typically developing (TD) children and children with cerebral palsy (CP). METHODS: Twenty-eight TD children and 8 with CP (GMFCS I-II) completed 3 TUG trials while wearing QTUG sensors. Test-retest reliability and discriminative ability were examined for the 57 constituent parameters of the TUG. Relationships between age and these parameters were also examined. RESULTS: Forty-four of the parameters demonstrated moderate to excellent test-retest reliability, with measures of angular velocity being the most reliable. Twenty-six parameters were different between TD children and those with CP, and twenty-eight gait parameters demonstrated correlations with age, further supporting its discriminative ability. CONCLUSION: The QTUG is a clinically feasible tool that is capable of both reliably measuring and discriminating many of the movement parameters with the TUG mobility task in TD children and those with CP GMFCS I-II. The results of the present study provide preliminary evidence that the QTUG can discriminate between children on several of the gait parameters within the TUG.

Delayed Presentation of Gluteal Compartment Syndrome due to Pseudoaneurysm Rupture: A Case Report.

CASE: We present a 26-year-old active duty man who sustained a coccygeal fracture and gluteus maximus hematoma after a fall from height during training. The patient returned 3 weeks postinjury with symptoms and physical examination findings concerning for gluteal compartment syndrome. An expanding gluteal hematoma was confirmed on imaging and the patient was taken to the operating room for emergent evacuation and endovascular hemostasis. CONCLUSIONS: This case of gluteal compartment syndrome is a unique contribution to the literature with respect to the specific vascular injury observed and the delayed presentation of gluteal compartment syndrome.

Research to knowledge: promoting the training of physician-scientists in the biology of pregnancy.

Common disorders of pregnancy, such as preeclampsia, preterm birth, and fetal growth abnormalities, continue to challenge perinatal biologists seeking insights into disease pathogenesis that will result in better diagnosis, therapy, and disease prevention. These challenges have recently been intensified with discoveries that associate gestational diseases with long-term maternal and neonatal outcomes. Whereas modern high-throughput investigative tools enable scientists and clinicians to noninvasively probe the maternal-fetal genome, epigenome, and other analytes, their implications for clinical medicine remain uncertain. Bridging these knowledge gaps depends on strengthening the existing pool of scientists with expertise in basic, translational, and clinical tools to address pertinent questions in the biology of pregnancy. Although PhD researchers are critical in this quest, physician-scientists would facilitate the inquiry by bringing together clinical challenges and investigative tools, promoting a culture of intellectual curiosity among clinical providers, and helping transform discoveries into relevant knowledge and clinical solutions. Uncertainties related to future administration of health care, federal support for research, attrition of physician-scientists, and an inadequate supply of new scholars may jeopardize our ability to address these challenges. New initiatives are necessary to attract current scholars and future generations of researchers seeking expertise in the scientific method and to support them, through mentorship and guidance, in pursuing a career that combines scientific investigation with clinical medicine. These efforts will promote breadth and depth of inquiry into the biology of pregnancy and enhance the pace of translation of scientific discoveries into better medicine and disease prevention.

Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo.

OBJECTIVE: To assess whether there are evident adverse effects of 17 alpha-hydroxyprogesterone caproate after in utero exposure. METHODS: This study evaluated surviving children of mothers who participated in a multicenter placebo-controlled trial of weekly intramuscular 17 alpha-hydroxyprogesterone caproate, with a 2:1 allocation to 17 alpha-hydroxyprogesterone caproate and placebo, respectively. The guardian was interviewed about the child's general health. Children underwent a physical examination and developmental screen with the Ages and Stages Questionnaire. Gender-specific roles were assessed with the Preschool Activities Inventory. RESULTS: Of 348 eligible surviving children, 278 (80%) were available for evaluation (194 in the 17 alpha-hydroxyprogesterone caproate group and 84 in the placebo group). The mean age at follow-up was 48 months. No significant differences were seen in health status or physical examination, including genital anomalies, between 17 alpha-hydroxyprogesterone caproate and placebo children. Scores for gender-specific roles (Preschool Activities Inventory) were within the normal range and similar between 17 alpha-hydroxyprogesterone caproate and placebo groups. CONCLUSION: 17 alpha-hydroxyprogesterone caproate seems to be safe for the fetus when administered in the second and third trimesters.