Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

Physician-Estimated Depth as a Screening Tool for Computed Tomography Evaluation of Pectus Excavatum.

BACKGROUND: Pectus excavatum (PE) is the most common congenital chest wall anomaly with a reported incidence of 1/300 to 1/400 live births and a male predominance. Preoperative evaluation of defect severity typically requires a calculation of the Haller index (HI) and/or correction index (CI) using computed tomography (CT) or x-rays. The purpose of this study was to determine whether physician-estimated depth (PED), a bedside screening tool, could be used to identify a subset of pediatric patients in whom CT was unnecessary. METHODS: After institutional review board approval (IRB #032018-091), we retrospectively reviewed all patients with a diagnosis of PE between 2009 and 2018 at our academic pediatric center. Demographic information including age, sex, and body mass index were abstracted. Imaging was reviewed to obtain HI and CI and to retrospectively calculate PED. The PED is calculated at the bedside by measuring the depth of the pectus at the site of greatest depression relative to a horizontal surface laid across the deformity. For this retrospective study, we calculated the CT-derived PED by measuring the depth from the horizontal on the respective CT images. Patients without imaging studies and patients with pectus carinatum, arcuatum, or mixed deformities were excluded from this study. RESULTS: A total of 94 patients met inclusion criteria. Of these, 82% were male, with a median age of 15 y. Patients were further subdivided by BMI, with 46% of patients having a BMI of <18.5 kg/m2 (i.e., underweight), whereas 54% of patients had a BMI of ≥18.5 kg/m2. Using a threshold PED of 2 cm, patients with a BMI of <18.5 kg/m2 had correct classification rates of 93% and 95% using PED relative to HI and CI, respectively. Patients with a BMI of ≥18.5 kg/m2 had correct classification rates of 80% and 88% using PED relative to HI and CI, respectively, at the same 2 cm threshold. CONCLUSIONS: PED is a viable screening tool for the preoperative evaluation of PE with a 2 cm threshold providing the combination of high sensitivity, specificity, and correct classification rates especially in underweight patients.

"Fatal Gastrointestinal and Peritoneal Ischemic Disease" of Unknown Cause at Arba Minch Hospital, Southern Ethiopia.

Gastrointestinal and peritoneal ischemic disease due to unknown etiology present with intestinal obstruction and/or peritonitis otherwise in healthy patient emerged as fatal disease at Arba Minch General Hospital. This disorder was diagnosed based on intraoperative finding. Clinical presentation and natural history of disease progression were similar. It is estimated that about 6-10 lives are being claimed each year at Arba Minch Hospital with this disease of unidentified cause accounting for the largest figure of surgical department. Here we report case analysis and literature review illustrating clinical presentation, workup, preoperative diagnosis, intraoperative diagnosis, and final outcome of fatal gastrointestinal and peritoneal ischemic disease.

Chemical cross-linking of a variety of green fluorescent proteins as Förster resonance energy transfer donors for Yukon orange fluorescent protein: A project-based undergraduate laboratory experience.

Förster resonance energy transfer (FRET) is the basis for many techniques used in biomedical research. Due to its wide use in molecular sensing, FRET is commonly introduced in many biology, chemistry, and physics courses. While FRET is of great importance in the biophysical sciences, the complexity and difficulty of constructing FRET experiments has resulted in limited usage in undergraduate laboratory settings. Here, we present a practical undergraduate laboratory experiment for teaching FRET using a diverse set of green-emitting fluorescent proteins (FPs) as donors for a cross-linked Yukon orange FP. This laboratory experiment enables students to make the connection of basic lab procedures to real world applications and can be applied to molecular biology, biochemistry, physical chemistry, and biophysical laboratory courses. Published 2018. This article is a U.S. Government work and is in the public domain in the USA., 46(5):516-522, 2018.

Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes.

Short tandem repeats (STRs) are hyper-mutable sequences in the human genome. They are often used in forensics and population genetics and are also the underlying cause of many genetic diseases. There are challenges associated with accurately determining the length polymorphism of STR loci in the genome by next-generation sequencing (NGS). In particular, accurate detection of pathological STR expansion is limited by the sequence read length during whole-genome analysis. We developed TREDPARSE, a software package that incorporates various cues from read alignment and paired-end distance distribution, as well as a sequence stutter model, in a probabilistic framework to infer repeat sizes for genetic loci, and we used this software to infer repeat sizes for 30 known disease loci. Using simulated data, we show that TREDPARSE outperforms other available software. We sampled the full genome sequences of 12,632 individuals to an average read depth of approximately 30× to 40× with Illumina HiSeq X. We identified 138 individuals with risk alleles at 15 STR disease loci. We validated a representative subset of the samples (n = 19) by Sanger and by Oxford Nanopore sequencing. Additionally, we validated the STR calls against known allele sizes in a set of GeT-RM reference cell-line materials (n = 6). Several STR loci that are entirely guanine or cytosines (G or C) have insufficient read evidence for inference and therefore could not be assayed precisely by TREDPARSE. TREDPARSE extends the limit of STR size detection beyond the physical sequence read length. This extension is critical because many of the disease risk cutoffs are close to or beyond the short sequence read length of 100 to 150 bases.

Identification of individuals by trait prediction using whole-genome sequencing data.

Prediction of human physical traits and demographic information from genomic data challenges privacy and data deidentification in personalized medicine. To explore the current capabilities of phenotype-based genomic identification, we applied whole-genome sequencing, detailed phenotyping, and statistical modeling to predict biometric traits in a cohort of 1,061 participants of diverse ancestry. Individually, for a large fraction of the traits, their predictive accuracy beyond ancestry and demographic information is limited. However, we have developed a maximum entropy algorithm that integrates multiple predictions to determine which genomic samples and phenotype measurements originate from the same person. Using this algorithm, we have reidentified an average of >8 of 10 held-out individuals in an ethnically mixed cohort and an average of 5 of either 10 African Americans or 10 Europeans. This work challenges current conceptions of personal privacy and may have far-reaching ethical and legal implications.

Exposure to prenatal consultation during pediatric surgery residency: Implications for training.

PURPOSE: Prenatal consultation is an important skill that should be learned during pediatric surgery training, but there are no formal guidelines for fellowship programs at this time. We sought to characterize the fellowship experience of recent pediatric surgery graduates and assess preparedness for providing prenatal consultation. METHODS: An anonymous online survey of pediatric surgery fellows graduating in 2012 and 2013 was performed. We asked respondents to describe participation in prenatal consultation and preparedness to perform consultation. We measured demographics and fellowship characteristics and tested associations between these variables and preparedness to perform prenatal consultation. RESULTS: A total of 49 out of 80 fellows responded to the survey (61% response rate). Most respondents (55%) saw five or fewer prenatal consults during fellowship, and 20% had not seen any prenatal consults. 47% said that fellowship could have better prepared them to perform prenatal consults. Fellows who saw more than 5 prenatal consults during fellowship (33% vs 77%, p=0.002) or described their fellowship as being structured to facilitate participation in prenatal consults (83% vs 27%, p<0.0001) were more likely to feel prepared. Stepwise logistic regression revealed that after adjusting for covariates, fellows graduating from programs that were 1) structured to facilitate participation in prenatal consults (OR 18, 95% CI 3.7-86.7), or 2) did NOT have an established fetal program (OR 5.5, 95% CI 1.1-27.8) were more likely to feel prepared. CONCLUSION: Exposure to prenatal consultation varies greatly across pediatric surgery fellowships, and many recent graduates do not feel prepared to perform prenatal consultation. The presence of an established fetal program did not necessarily translate into improved fellow training. Efforts should be made to standardize the approach to fellow education in this area and ensure that adequate guidance and resources are available to recently graduated pediatric surgeons.

Fluorescent proteins as biosensors by quenching resonance energy transfer from endogenous tryptophan: detection of nitroaromatic explosives.

Ensuring domestic safety from terrorist attack is a daunting challenge because of the wide array of chemical agents that must be screened. A panel of purified fluorescent protein isoforms (FPs) was screened for the ability to detect various explosives, explosive simulants, and toxic agents. In addition to their commonly used visible excitation wavelengths, essentially all FPs can be excited by UV light at 280 nm. Ultraviolet illumination excites electrons in endogenous tryptophan (W) residues, which then relax by Förster Resonance Energy Transfer (FRET) to the chromophore of the FP, and thus the FPs emit with their typical visible spectra. Taking advantage of the fact that tryptophan excitation can be quenched by numerous agents, including nitroaromatics like TNT and nitramines like RDX, it is demonstrated that quenching of visible fluorescence from UV illumination of FPs can be used as the basis for detecting these explosives and explosive degradation products. This work provides the foundation for production of an array of genetically-modified FPs for in vitro biosensors capable of rapid, simultaneous, sensitive and selective detection of a wide range of explosive or toxic agents.

Pediatric ovarian malignancies: how efficacious are current staging practices?

PURPOSE: Conventional staging is not routinely practiced because of a lack of preoperative indicators for pediatric ovarian malignancy. Children's Oncology Group (COG) developed guidelines for germ cell tumors to revise staging to correlate with primary pediatric ovarian pathology. Are COG guidelines being used, and are they applicable to all pediatric ovarian malignancies? METHODS: A 15(1/2)-year retrospective review of operative ovarian masses from a single academic center was performed. RESULTS: There were 424 patients identified, with 46 malignancies (11%). Most were stage I (73%). Complete COG staging was performed in 24%. Each staging component performed was as follows: oophorectomy (91%), examination with or without biopsy of omentum (72%), peritoneum (67%), retroperitoneum (63%), contralateral ovary (56%), and washings (46%). Advanced stages had visible findings at exploration to guide biopsies. Of site-directed biopsies, 40.5% were positive, whereas all random biopsies (n = 38) were negative. Two recurrences and all mortalities (n = 4) had complete initial COG operative staging. Mean duration of follow-up was 3.62 +/- 0.365 years. CONCLUSION: The COG staging is not consistently followed. All cases of advanced disease were visibly obvious and confirmed with site-directed biopsies. Random samplings were all negative and did not impact stage. Negative outcomes reflected inherent tumor biology not deviation from COG staging. The COG guidelines appear to be sufficient for all pediatric ovarian malignancies.

Can we preoperatively risk stratify ovarian masses for malignancy?

PURPOSE: Given a 10% malignancy rate in pediatric ovarian masses, what preoperative factors are helpful in distinguishing those at higher risk to risk stratify accordingly? METHODS: After institutional review board approval (IRB#022008-095), a 15(1/2)-year retrospective review of operative ovarian cases was performed. RESULTS: A total of 424 patients were identified, with a mean age 12.5 years (range, 1 day to 19 years), without an age disparity between benign (12.54 years, 89%) and malignant (11.8 years, 11%) cases. The 1- to 8-year age group had the highest percentage of malignancies (22%; odds ratio [OR], 3.02; 95% confidence interval [CI], 1.33-6.86). A chief complaint of mass or precocious puberty versus one of pain had an OR for malignancy of 4.84 and 5.67, respectively (95% CI, 2.48-9.45 and 1.60-20.30). Imaging of benign neoplasms had a mean size of 8 cm (range, 0.9-36 cm) compared with malignancies at 17.3 cm (6.2-50 cm, P < .001). An ovarian mass size of 8 cm or longer on preoperative imaging had an OR of 19.0 for malignancy (95% CI, 4.42-81.69). Ultrasound or computed tomographic findings of a solid mass, although infrequent, were most commonly associated with malignancy (33%-60%), compared with reads of heterogeneous (15%-21%) or cystic (4%-5%) lesions. The malignancies (n = 46) included germ cell (50%, n = 23), stromal (28%, n = 13), epithelial (17%, n = 8), and other (4%, n = 2). Tumor markers obtained in 71% of malignancies were elevated in only 54%, whereas 6.5% of those sent in benign cases were similarly elevated. Elevated beta-human chorionic gonadotropin (beta-HCG), alpha fetoprotein (alphaFP), and cancer antigen 125 (CA-125) were significantly associated with malignancy (P < .02) and an elevated carcinoembryonic antigen (CEA) was not (P = .1880). CONCLUSION: This reported series of pediatric ovarian masses demonstrates that preoperative indicators that best predict an ovarian malignancy are a complaint of a mass or precocious puberty, a mass exceeding 8 cm or a mass with solid imaging characteristics. Those patients aged 1 to 8 years have the greatest incidence of malignancy. Tumor markers, positive or negative, were not conclusive in all cases but useful for postoperative surveillance.

Pediatric ovarian malignancy presenting as ovarian torsion: incidence and relevance.

PURPOSE: With ovarian torsion, concern for underlying malignancy in the enlarged ovary has previously driven surgeons to resection. Detorsion alone has been recommended to allow for resolution of edema of the ovary with follow-up ultrasound surveillance to evaluate for a persistent mass, yet is not routine practice. However, the incidence of malignancies presenting as ovarian torsion is not documented. Does the risk of an underlying malignancy justify salpingoophorectomy and decreased fertility? METHOD: After institutional review board exemption (IRB#-022008-095), a 15(1/2)-year retrospective review was conducted to identify cases of operative ovarian torsion in our medical center. Tumors with neoplastic pathology (malignant and benign) were analyzed and compared with all reported cases in the literature. RESULTS: A total of 114 patients (mean +/- SEM age, 10 years, 2 days to 19 years +/- 0.53) with operatively proven ovarian torsion were identified. Four malignancies (3.5%) and 26 benign neoplasms (23%) were present in this age group. Malignancies consisted of serous borderline tumors (2), juvenile granulosa cell tumor (1), and dysgerminoma (1). All were stage I: the former were stage IA and cured with resection alone, and 1 was a stage IB dysgerminoma, which required chemotherapy. The literature yielded a total of 593 cases of operative ovarian torsion with 9 (1.5%) malignancies and 193 (33%) benign neoplasms. The malignancies were juvenile granulosa cell tumor (n = 4), dysgerminoma (n = 2), serous borderline tumors (n = 2), and 1 undifferentiated adenocarcinoma. CONCLUSION: By combining our series with 13 in the literature, a 1.8% malignancy rate occurred in 707 patients with ovarian torsion, markedly less than the reported malignancy rate of 10% in children with ovarian masses. Thus, neither a pathologic nor malignant lead point should be assumed in cases of torsion. In our series, which represents the largest series of torsion in the pediatric literature, all malignancies presented as stage I. These data further support the implementation of operative detorsion and close postoperative ovarian surveillance, with reoperation for persistent masses. Further study is needed to determine if delaying resection by weeks in those cases of persistent masses would result in tumor progression and thus change prognosis.

Cannot exclude torsion--a 15-year review.

BACKGROUND: Ovarian torsion remains a challenging diagnosis, often leading to delayed operative intervention and resultant ovarian loss. METHODS: Charts of patients with ovarian operative cases were retrospectively reviewed at a free-standing children's hospital over 15 years. Torsion was based on intraoperative findings. RESULTS: Of 328 operative ovarian cases, 97 (29.6%) demonstrated torsion. Mean patient age was 9.2 years (2 days to 17 years, +/-0.54 SEM), with 52% occurring between 9 and 14 years. Of the patients, 97% presented in pain. Presence of a pelvic mass 5 cm or larger on imaging had 83% sensitivity for torsion: an ultrasound reading was only 51% sensitive. Elevated white blood cell count was the only preoperative characteristic associated with prompt operative intervention. Utilization of laparoscopy increased during the latter half of the study (18%-42%, P < .0434). There was a positive trend, although insignificant, in the use of laparoscopy and ovarian salvage. Pathology was overwhelmingly benign (infarction [46%], cysts [33%], and benign neoplasms [19%]). CONCLUSION: Torsion was responsible for one third of all operative ovarian cases. Sonography is not reliable in diagnosis or exclusion of ovarian torsion. Thus, a strategy of earlier and liberal use of Diagnostic Laparoscopy (DL), particularly with a pelvic mass of approximately 5 cm, may improve ovarian salvage. Because pathology is predominantly benign, the edematous detorsed ovary is safe to salvage.

Permacol: a potential biologic patch alternative in congenital diaphragmatic hernia repair.

PURPOSE: Recurrence is a well-known complication after patch repair of congenital diaphragmatic hernia (CDH). We propose that a newer, "bioprosthetic" material may lower recurrence rates. The purpose of this study is to compare outcomes of CDH repair with synthetic Gore-Tex (W. L. Gore and Associates, Neward, Del) to the bioprosthetic Permacol (Tissue Science Laboratories Inc, Andover, Mass). METHODS: We performed a retrospective review of 100 consecutive patients with CDH with survival more than 30 days at Children's Medical Center of Dallas (Dallas, Tex) from 1999 to 2007. The incidence and timing of recurrence, as well as comorbidities were assessed. RESULTS: Primary repair was performed in 63 patients and patch repair in 37, divided between Gore-Tex (29) and Permacol (8). Overall recurrences were as follows: 1 (2%), 8 (28%), and 0 in the primary, Gore-Tex, and Permacol groups, respectively. Median follow-up was 57 months for Gore-Tex and 20 months for Permacol. Median time to recurrence in the Gore-Tex group was 12 months, with no Permacol recurrences. Both the Gore-Tex and Permacol groups had similar comorbidities, including prematurity, congenital heart disease (76% and 63%, respectively), and the need for extracorporeal membrane oxygenation support (38% and 25%). CONCLUSION: Our results suggest that Permacol may have lower recurrence rates compared to Gore-Tex and is a promising alternative biologic graft for CDH repair.

Effects of family presence during resuscitation and invasive procedures in a pediatric emergency department.

INTRODUCTION: No research exists evaluating family presence (FP) during resuscitation interventions (RIs) and invasive procedures (IPs) using ENA guidelines in a pediatric emergency department. The purpose of this study was to determine the effectiveness of an FP protocol in facilitating uninterrupted care and describe parents' and providers' experiences. METHODS: FP was offered by a family facilitator to parents of children undergoing RIs or IPs. Data were collected during 64 FP events (28 RIs and 36 IPs). Following the event, 92 providers and 22 parents completed a survey about their experiences. RESULTS: In 100% of FP cases, patient care was uninterrupted. Parents were positive about FP, believed it helped their child, and reported that it eased their fears. All parents described an active role during the event, and most believed they had a right to be present. Three months later, no parents reported traumatic memories. Providers also were positive about FP and reported that the presence of parents did not negatively affect care. Although most (70%) supported FP during RIs, more nurses (92%) and physicians (78%) supported it than did residents (35%, P < .05). DISCUSSION: The findings suggest the effectiveness of a pediatric emergency department FP protocol in facilitating uninterrupted patient care. The benefits identified for parents support implementation of FP programs.

Significance of 'blush' on computed tomography scan in children with liver injury.

BACKGROUND/PURPOSE: The aim of this study was to determine if the presence of "blush" (an indication of active bleeding) on abdominal CT in children with blunt liver injury adversely affected their clinical outcome as has been reported in adults. METHODS: The authors reviewed the records of 105 children ages 1 to 16 years with blunt liver injury seen on admission IV contrast CT seen over a 6-year period. Demographic characteristics measured were age, mechanism of injury, and injury severity score (ISS). Clinical outcomes included ICU stay, hospital length of stay (LOS), transfusion requirement (milliliters per kilogram), operations performed, and mortality rate. CT scans were evaluated retrospectively by a radiologist blinded to prior reports, for a "blush" and grade of liver injury. No patient underwent arterial embolization. The authors eliminated children with grade I-II injuries (30 patients), because only one had a blush, and analyzed the 75 patients with severe liver injuries (grades III-V). Those patients without a blush (n = 53) seen on CT were the control group, whereas patients with a blush (n = 22) were the study group. Data were analyzed using the Fisher's Exact and Mann-Whitney U test. The level of significance was set at.05. RESULTS: Patients with a blush had a significantly larger transfusion requirement (17.3 +/- 30.5 mL/kg v 5.0 +/- 10.9 mL/kg; P =.02) and mortality rate (23% v 4%; P =.02), but the ISS also was significantly greater (25.8 +/- 14.5 v 17.5 +/- 12.2; P =.019). All other data were similar between the 2 groups. CONCLUSIONS: Children with a blush seen on abdominal CT after blunt liver injury have higher transfusion requirements and greater risk of mortality than those without blush. Mortality is primarily related to the severity of their other injuries.