Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

An overview of pediatric peritoneal dialysis and renal replacement therapy in infants: A review for the general pediatric surgeon.

Currently, there are about 10,000 pediatric patients in the United States who rely on dialysis for renal replacement therapy. Dialysis allows children with chronic kidney disease a means of support until renal transplant is feasible. All forms of renal replacement therapy require a surgical intervention, whether the modality is hemodialysis or peritoneal dialysis. Despite peritoneal dialysis being the most common modality of dialysis in children, there is not prospectively collected much evidence in the literature which can guide the pediatric surgeon about best practices on access placement, management of complications, and timing of removal. Most available studies are small, single-center retrospective reviews. This limits the power of the data collected to help guide decision-making in the management of peritoneal dialysis catheters. The purpose of this review is to provide a consolidated source of best available evidence and identify important areas for future study. Furthermore, this is an area of pediatric surgical care that lacks up to date outcomes research with robust surgeon participation. Lack of coordinated, evidence-based best practices likely results in heterogenous surgical practices and uneven strategies for managing complications. Furthermore, with improvements in neonatal critical care and fetal interventions available for obstructive uropathies and other congenital kidney disorders, there is increased likelihood of the need for dialysis access in more infants, who represent a particularly vulnerable patient population. Importantly, peritoneal dialysis access should be instituted into the national PEDScore curriculum for pediatric surgical fellows, as this procedure is common enough that any pediatric surgeon could be consulted for catheter placement and management. Surgeon awareness of, and participation in the formulation, of guidelines and prospective studies is of paramount importance to ensure optimal care of this vulnerable population of children.

Clinical regression of inguinal hernias in premature infants without surgical repair.

BACKGROUND: The incidence of inguinal hernias in premature infants is approximately 30%. Due to concerns about a high risk of incarceration, early repair is commonly performed. We present a series of patients whose families opted to delay repair until after 55 weeks corrected gestational age (GA) and experienced safe clinical regression of their hernias. METHODS: Between June 2015 and July 2020, premature infants (< 37 weeks GA) diagnosed with inguinal hernias on physical examination were identified. Families of eligible infants were offered either immediate or delayed repair after 55 weeks corrected GA. Infants whose families elected to delay were followed until their hernia(s) clinically regressed, or until older than 55 weeks. RESULTS: Families of 68 infants consented to delay repair. 23 infants (33.8%) had hernias that clinically regressed at median follow up from diagnosis of 14.1 weeks. Univariate analysis demonstrated female sex as a significant predictor of hernia clinical regression (OR: 3.08; p = 0.046). Of the 45 infants who underwent repair, 84.4% safely progressed to 55 weeks corrected GA prior to. CONCLUSION: Delaying inguinal hernia repair in this series of premature infants until after 55 weeks corrected GA revealed that one third of hernias, especially in females, safely regressed upon follow-up examination.

Upregulation of human endogenous retrovirus-K (HML-2) mRNAs in hepatoblastoma: Identification of potential new immunotherapeutic targets and biomarkers.

PURPOSE: Hepatoblastoma is the most common liver malignancy in children. In order to advance therapy against hepatoblastoma, novel immunologic targets and biomarkers are needed. Our purpose in this investigation is to examine hepatoblastoma transcriptomes for the expression of a class of genomic elements known as Human Endogenous Retrovirus (HERVs). HERVs are abundant in the human genome and are biologically active elements that have been associated with multiple malignancies and proposed as immunologic targets in a subset of tumors. A sub-family of HERVs, HERV-K(HML-2) (HERV-K), have been shown to be tightly regulated in fetal development, making investigation of these elements in pediatric tumors paramount. METHODS: We first created a HERVK-FASTA file utilizing 91 previously described HML-2 proviruses. We then concatenated the file onto the GRCh38.95 cDNA library from Ensembl. We used this reference database to evaluate existing RNA-seq data from 10 hepatoblastoma tumors and 3 normal liver controls (GEO accession ID: GSE8977575). Quantification and differential proviral expression analysis between hepatoblastoma and normal liver controls was performed using the pseudo-alignment program Salmon and DESeq2, respectively. RESULTS: HERV-K mRNA was expressed in hepatoblastoma from multiple proviral loci. All expressed HERV-K proviral loci were upregulated in hepatoblastoma compared to normal liver controls. Five HERV-K proviruses (1q21.3, 3q27.2, 7q22.2, 12q24.33 and 17p13.1) were significantly differentially expressed (p-adjusted value <0.05, |log2 fold change| > 1.5) across conditions. The provirus at 17p13.1 had an approximately 300-fold increased expression in hepatoblastoma as compared to normal liver. This was in part due to the near absence of HERV-K mRNA at the 17p13.1 locus in fully differentiated liver samples. CONCLUSIONS: Our investigation demonstrates that HERV-K is expressed from multiple loci in hepatoblastoma and that the expression is increased for several proviruses compared to normal liver controls. Our results suggest that HERV-K mRNA expression may be useful as a biomarker in hepatoblastoma, given the large differential expression profiles in hepatoblastoma, with very low mRNA levels in liver control samples.

A Quality Improvement Intervention to Reduce Postoperative Opiate Use in Neonates.

BACKGROUND AND OBJECTIVES: Opiate use in neonates can affect clinical outcomes after surgery and may alter future neurodevelopment. We implemented a multimodal opioid reduction strategy in our NICU for infants undergoing nonemergent gastrointestinal surgery. METHODS: After multiple stakeholder's meetings, our opioid reduction intervention included giving neonates postoperative standing intravenous acetaminophen every 6 hours for 48 hours, a standardized postsurgical sign-out with the NICU team in which pain control was directly addressed, and a series of postsurgical pain education seminars with NICU providers. To assess the impact of our quality improvement project, we used process control charts to investigate trends in postoperative opioid use in our preintervention (January 2012 to April 2016) and postintervention (May 2016 to September 2019) cohorts. RESULTS: A total of 77 infants were included in the study (40 in the preintervention cohort and 37 in the postintervention cohort). Patient characteristics were equivalent. The intervention significantly reduced the trend in postoperative morphine equivalents (median: 7.96 mg/kg in preintervention cohort versus 0.095 mg/kg in postintervention cohort; P < .0001). The Neonatal Pain, Agitation, and Sedation Scale pain scores and safety profiles were equivalent in both groups. The intervention was also associated with a 24-hour reduction in postoperative ventilation time (P < .048) and a 7-day reduction in the use of total parenteral nutrition (P < .017). CONCLUSIONS: Standing intravenous acetaminophen coupled with provider education can successfully reduce opioid use in postsurgical neonates. Given the concern for opioid exposure in neonatal neurodevelopment as well as clinical benefits of reduced opioids, similar strategies for opioid reduction may prove useful at other institutions.

Human endogenous retrovirus-K mRNA expression and genomic alignment data in hepatoblastoma.

Human Endogenous Retroviruses are a class of genomic elements that are the result of ancient retroviral infection of the human germline. Many are biologically active elements that have been implicated in multiple diseases including cancer. The most recent class to invade the human genome is the HERV-K(HML-2) (HERV-K) family. Approximately 90 HERV-K proviruses and many smaller elements have been identified to date in the human genome. Additional proviruses are continually being discovered with the rapid advancement of deep-sequencing and long-read sequencing technologies. HERV-K proviruses are poorly annotated in human transcriptome databases making their analysis in RNA-seq data difficult. To enable analysis, we compiled the sequences of 91 HERV-K proviruses identified in NCBI GenBank (ID JN675007-JN675097) and created a proviral alignment tool for visualizing RNA-seq reads aligned across individual proviruses. This allowed us to analyse publicly available RNA-seq data from 10 hepatoblastoma samples and 3 normal liver controls (GEO Accession ID: GSE89775). This data report includes the raw FASTA sequence files of the HERV-K proviruses from NCBI, a differential gene expression list between hepatoblastoma samples, and genomic alignment figures from 5 HERV-K proviruses identified as differentially expressed in the companion research article "Upregulation of Human Endogenous Retrovirus-K (HML-2) mRNAs in hepatoblastoma: Identification of potential new immunotherapeutic targets and biomarkers [1]. The data provided here are available for other research groups interested in evaluating individual HERV-K proviral expression using RNA-seq data. Furthermore, the data analysis is highly flexible and will accommodate the addition of other HERV-K proviruses.

Strictures, stones and cysts: an unusual cause of pancreatitis in a 20-month-old female child.

Choledochal cysts are dilations of the biliary tree that cause a variety of clinical symptoms and can lead to several types of complications. Choledochal cysts are most commonly diagnosed in childhood and frequently present with abdominal pain, jaundice and, in infants, an abdominal mass. Although the most concerning complication is malignant transformation of the cyst epithelium, other complications such as stone formation, acute pancreatitis and stricture can also occur and lead to patient morbidity. Treatment is aimed at not only relieving patient symptoms, but also decreasing a long-term cancer risk. We present a case of a child presenting with abdominal pain and vomiting secondary to a type IVa choledochal cyst complicated by acute pancreatitis, a common bile duct stricture and cystolithiasis.

Close to the Bedside: A Systematic Review of Endogenous Retroviruses and Their Impact in Oncology.

BACKGROUND: Human endogenous retroviruses (HERVs) are genetic elements in the human genome, which resulted from ancient retroviral germline infections. HERVs have strong transcriptional promoters and enhancers that affect a cell's transcriptome. They also encode proteins that can exert effects in human cells. This review examines how our increased understanding of HERVs have led to their potential use as biomarkers and immunologic targets. MATERIAL AND METHODS: PubMed/Medline, Embase, Web of Science, and Cochrane databases were used in a systematic search to identify all articles studying the potential impact of HERVs on surgical diseases. The search included studies that involved clinical patient samples in diseases including cancer, inflammatory conditions, and autoimmune disease. Articles focused on conditions not routinely managed by surgeons were excluded. RESULTS: Eighty six articles met inclusion and quality criteria for this review and were included. Breast cancer and melanoma have robust evidence regarding the use of HERVs as potential tumor markers and immunologic targets. Reported evidence of the activity of HERVs in colorectal cancer, pancreatic cancer, hepatocellular cancer, prostate and ovarian cancer, germ cell tumors as well as idiopathic pulmonary hypertension, and the inflammatory response in burns was also reviewed. CONCLUSIONS: Increasingly convincing evidence indicates that HERVs may play a role in solid organ malignancy and present important biomarkers or immunologic targets in multiple cancers. Innovative investigation of HERVs is a valuable focus of translational research and can deepen our understanding of cellular physiology and the effects of endogenous retroviruses on human biology. As strategies for treatment continue to focus on genome-based interventions, understanding the impact of endogenous retroviruses on human disease will be critical.

Sutureless closure: a versatile treatment for the diverse presentations of gastroschisis.

OBJECTIVE: Case series have demonstrated sutureless closures to be safe for the correction of gastroschisis. We hypothesize that sutureless closure is efficacious in patients requiring silo reduction without need for intubation. STUDY DESIGN: We conducted a retrospective case control study of infants who underwent gastroschisis repair at our institution (January 2011-August 2018). Patient characteristics and clinical outcomes were compared between sutureless closure and primary fascial repair groups. RESULTS: Seventeen patients in the sutureless group and 28 patients in the primary fascial repair group were included. Success of sutureless closure was 94%. Mechanical ventilation was reduced by 2.8 days in the sutureless group (P < 0.0001) and fewer patients required general anesthesia (29.4% vs. 100%, P < 0.0001). CONCLUSIONS: Sutureless closure is effective for the diverse presentations of gastroschisis. Given the concerns of effects of general anesthesia on the developing brain, sutureless closure should be strongly considered.

Cesarean Section Induces Microbiota-Regulated Immune Disturbances in C57BL/6 Mice.

Epidemiological studies have shown that children born by cesarean section (CS) are at higher risk of developing chronic inflammatory diseases, and it has been suggested that a skewed gut microbial colonization process early in life and altered priming of the immune system are causative. The aim of this study was to clarify whether impaired regulatory immunity in CS-delivered C57BL/6 mice is dependent on gut microbiota (GM) disturbances. The GM of conventionally bred mice born by CS differed clearly from mice born by vaginal delivery. The proportion of regulatory T cells was reduced in mice born by CS, whereas the invariant NKT (iNKT) cell subset was increased compared with vaginal delivery mice. In addition, regulatory markers (Foxp3, Il10, Ctla4) and macrophage markers (Cd11c, Egr2, Nos2) were downregulated, whereas iNKT markers (Il4, Il15) were upregulated in ileum of CS-delivered mice. The GM of CS-delivered mice was sufficient to transfer the shifts in immunity associated with delivery mode when inoculated into germ-free mice. Feeding a prebiotic diet reestablished gene expression of intestinal immune markers and iNKT cells in CS mice but was not sufficient to restore the level of regulatory T cells. The results support that CS delivery is associated with microbiota-mediated shifts in regulatory immunity and, therefore, provide a basis for future microbiota-directed therapeutics to infants born by CS.

Siglec-1 Macrophages and the Contribution of IFN to the Development of Autoimmune Congenital Heart Block.

Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjögren syndrome, are linked with an upregulation of IFN and type I IFN-stimulated genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of congenital heart block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro-associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal hearts dying with CHB and three healthy gestational age-matched hearts, and 3) autopsy tissue from three additional human CHB hearts and one healthy heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45+CD11c+ and CD45+CD11c- human leukocytes flow sorted from the CHB hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1-positive macrophages as integral to the process.

Long-Term Skills Retention Following a Randomized Prospective Trial on Adaptive Procedural Training.

OBJECTIVE: Cumulative sum (CuSum) is a real-time proficiency-monitoring tool adapted for simulation-based training. This study's objective was to investigate long-term outcomes of a double blinded, randomized control trial conducted with medical students assessing CuSum-guided curriculum against volume-based standards. The trial found a nearly 20% reduction in practice time to reach proficiency using the CuSum curriculum but long-term effects of decreased practice volume on proficiency is unknown. DESIGN: Prior participants completed a survey assessing confidence, exposure, and feedback at 12 to 18 months following trial completion. They underwent retention testing of suturing, intubation, and central venous catheter placement (CVC), which was video-recorded and assessed by an expert evaluator. Baseline characteristics among repeat subjects were compared using chi-squared tests. Retention and initial trial outcome were compared using paired parametric statistical methods. SETTING: The study was conducted at a major tertiary care center and training hospital. PARTICIPANTS: Medical students, which completed the initial randomized control trial were eligible for enrollment. A total of 30/46(65%) responded to the survey, whereas 33/46(72%) completed retention testing. RESULTS: Average scores and decay in procedural tasks over time for suturing, intubation and CVC were 91.6% (-4.7%), 86.1% (-4.1%), and 76.2% (-14.8%), respectively. Compared to the control group, the CuSum group mean difference in retention evaluation scores was -5.6% (p = 0.12). Confidence was not associated with initial or retention testing performance in any procedural task. Higher confidence was associated with additional exposure to the procedural task in suturing and intubation (p = 0.03 and p = 0.02, respectively). For intubation, higher confidence was reported by participants who received positive feedback (p = 0.01), and those assigned to the volume-based training arm (p = 0.03). CONCLUSION: CuSum-guided training was equivalent to conventional training for suturing, intubation, and CVC. These findings importantly suggest medical students can retain competency in invasive surgical tasks with modest decay in proficiency over time regardless of initial training method.

Vessel Ligation Fundamentals: A Comparison of Technical Evaluations by Crowdsourced Nonclinical Personnel and Surgical Faculty.

BACKGROUND: Evaluation of fundamental surgical skills is invaluable to the training of medical students and junior residents. This study assessed the effectiveness of crowdsourcing nonmedical personnel to evaluate technical proficiency at simulated vessel ligation. STUDY DESIGN: Fifteen videos were captured of participants performing vessel ligation using a low-fidelity model (5 attending surgeons and 5 medical students before and after training). These videos were evaluated by nonmedical personnel recruited through Amazon Mechanical Turk, as well as by 3 experienced surgical faculty. Evaluation criteria were based on Objective Structured Assessment of Technical Skills (scale: 5-25). Results were compared using Wilcoxon signed rank-sum and Cronbach's alpha (α). RESULTS: Thirty-two crowd workers evaluated all 15 videos. Crowd workers scored attending surgeon videos significantly higher than pretraining medical student videos (20.5 vs 14.9, p < 0.001), demonstrating construct validity. Across all videos, crowd evaluations were more lenient than expert evaluations (19.1 vs 14.5, p < 0.001). However, average volunteer evaluations correlated more strongly with average expert evaluations (α = 0.95) than the strength of correlation between any 2 individual expert evaluators (α = 0.72-0.88). Combined reimbursement for all workers was $80.00. CONCLUSION: After adjustments for score inflation, crowdsourced can evaluate surgical fundamentals with excellent validity. This resource is considerably less costly and potentially more reliable than individual expert evaluations.

Laparoscopic Appendicostomy Low-Profile Balloon Button for Antegrade Enemas in Children.

INTRODUCTION: The Malone appendicostomy is a continent channel used for antegrade enemas. It requires daily cannulation and is susceptible to stenosis. We use an indwelling low-profile balloon button tube inserted through the appendix into the cecum for antegrade enemas. We hypothesized that this method is effective at managing constipation or fecal incontinence and is associated with a low rate of stenosis. METHODS: Children who underwent laparoscopic appendicostomy balloon button placement at our institution from January 2011 to April 2017 were identified. The primary outcome was success in managing constipation or fecal continence as measured by the Malone continence scale. Postoperative complications were analyzed. RESULTS: Thirty-six children underwent the procedure, 35 of which met the inclusion criteria. Thirty-one patients (88.5%) underwent the operation for idiopathic constipation, 3 patients (8.6%) for anorectal malformation, and 1 patient (2.9%) for hypermobility. Rate of open conversion was 3%. A full response was obtained in 24 patients (68.6%), partial response in 9 patients (25.7%), and 2 patients failed (5.7%). One patient developed an internal hernia requiring laparotomy and later developed mucosal prolapse. One patient developed a stricture noted at button change. Seven patients (20%) underwent reversal of their appendicostomy tube: 5 due to return of normal bowel function and 2 due to discomfort with flushes. CONCLUSION: A laparoscopic appendicostomy with a balloon button tube is an effective means of addressing chronic constipation or fecal incontinence. The stenosis rate associated with tube appendicostomy may be lower than those reported for Malone antegrade continence enema procedures.

Cardiac fibroblast transcriptome analyses support a role for interferogenic, profibrotic, and inflammatory genes in anti-SSA/Ro-associated congenital heart block.

The signature lesion of SSA/Ro autoantibody-associated congenital heart block (CHB) is fibrosis and a macrophage infiltrate, supporting an experimental focus on cues influencing the fibroblast component. The transcriptomes of human fetal cardiac fibroblasts were analyzed using two complementary approaches. Cardiac injury conditions were simulated in vitro by incubating human fetal cardiac fibroblasts with supernatants from macrophages transfected with the SSA/Ro-associated noncoding Y ssRNA. The top 10 upregulated transcripts in the stimulated fibroblasts reflected a type I interferon (IFN) response [e.g., IFN-induced protein 44-like (IFI44L), of MX dynamin-like GTPase (MX)1, MX2, and radical S-adenosyl methionine domain containing 2 (Rsad2)]. Within the fibrotic pathway, transcript levels of endothelin-1 (EDN1), phosphodiesterase (PDE)4D, chemokine (C-X-C motif) ligand (CXCL)2, and CXCL3 were upregulated, while others, including adenomedullin, RAP guanine nucleotide exchange factor 3 (RAPGEF3), tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, and dual specificity phosphatase 1, were downregulated. Agnostic Database for Annotation, Visualization and Integrated Discovery analysis revealed a significant increase in inflammatory genes, including complement C3A receptor 1 (C3AR1), F2R-like thrombin/trypsin receptor 3, and neutrophil cytosolic factor 2. In addition, stimulated fibroblasts expressed high levels of phospho-MADS box transcription enhancer factor 2 [a substrate of MAPK5 (ERK5)], which was inhibited by BIX-02189, a specific inhibitor of ERK5. Translation to human disease leveraged an unprecedented opportunity to interrogate the transcriptome of fibroblasts freshly isolated and cell sorted without stimulation from a fetal heart with CHB and a matched healthy heart. Consistent with the in vitro data, five IFN response genes were among the top 10 most highly expressed transcripts in CHB fibroblasts. In addition, the expression of matrix-related genes reflected fibrosis. These data support the novel finding that cardiac injury in CHB may occur secondary to abnormal remodeling due in part to upregulation of type 1 IFN response genes.NEW & NOTEWORTHY Congenital heart block is a rare disease of the fetal heart associated with maternal anti-Ro autoantibodies which can result in death and for survivors, lifelong pacing. This study provides in vivo and in vitro transcriptome-support that injury may be mediated by an effect of Type I Interferon on fetal fibroblasts.

Associations between Unconventional Natural Gas Development and Nasal and Sinus, Migraine Headache, and Fatigue Symptoms in Pennsylvania.

BACKGROUND: Unconventional natural gas development (UNGD) produces environmental contaminants and psychosocial stressors. Despite these concerns, few studies have evaluated the health effects of UNGD. OBJECTIVES: We investigated associations between UNGD activity and symptoms in a cross-sectional study in Pennsylvania. METHODS: We mailed a self-administered questionnaire to 23,700 adult patients of the Geisinger Clinic. Using standardized and validated questionnaire items, we identified respondents with chronic rhinosinusitis (CRS), migraine headache, and fatigue symptoms. We created a summary UNGD activity metric that incorporated well phase, location, total depth, daily gas production and inverse distance-squared to patient residences. We used logistic regression, weighted for sampling and response rates, to assess associations between quartiles of UNGD activity and outcomes, both alone and in combination. RESULTS: The response rate was 33%. Of 7,785 study participants, 1,850 (24%) had current CRS symptoms, 1,765 (23%) had migraine headache, and 1,930 (25%) had higher levels of fatigue. Among individuals who met criteria for two or more outcomes, adjusted odds ratios for the highest quartile of UNGD activity compared with the lowest were [OR (95% CI)] 1.49 (0.78, 2.85) for CRS plus migraine, 1.88 (1.08, 3.25) for CRS plus fatigue, 1.95 (1.18, 3.21) for migraine plus fatigue, and 1.84 (1.08, 3.14) for all three outcomes together. Significant associations were also present in some models of single outcomes. CONCLUSIONS: This study provides evidence that UNGD is associated with nasal and sinus, migraine headache, and fatigue symptoms in a general population representative sample. Citation: Tustin AW, Hirsch AG, Rasmussen SG, Casey JA, Bandeen-Roche K, Schwartz BS. 2017. Associations between unconventional natural gas development and nasal and sinus, migraine headache, and fatigue symptoms in Pennsylvania. Environ Health Perspect 125:189-197; http://dx.doi.org/10.1289/EHP281.

Predicting surgical skill acquisition in preclinical medical students.

BACKGROUND: The purpose of this study was to identify factors that predict medical student success in acquiring invasive procedural skills. We hypothesized that students with interest in surgery and with prior procedural experience would have higher rates of success. METHODS: Preclinical students were enrolled in a simulation course comprised of suturing, intubation, and central venous catheterization. Students completed surveys to describe demographics, specialty interest area, prior experience, and confidence. Using linear regression, variables predictive of proficiency were identified. RESULTS: Forty-five participants completed the course. Under univariate analysis, composite pretest score was inversely associated with confidence (P = .039). Under multivariable analysis, female gender was associated with higher pretest suturing score (P = .016). Male gender (P = .029) and high confidence (P = .021) were associated with greater improvement in suturing. CONCLUSIONS: Among novices, higher confidence can predict lower baseline technical proficiency. Although females had higher pretest suturing scores, high confidence and male gender were associated with the greatest degree of improvement.

Association Between Unconventional Natural Gas Development in the Marcellus Shale and Asthma Exacerbations.

IMPORTANCE: Asthma is common and can be exacerbated by air pollution and stress. Unconventional natural gas development (UNGD) has community and environmental impacts. In Pennsylvania, UNGD began in 2005, and by 2012, 6253 wells had been drilled. There are no prior studies of UNGD and objective respiratory outcomes. OBJECTIVE: To evaluate associations between UNGD and asthma exacerbations. DESIGN: A nested case-control study comparing patients with asthma with and without exacerbations from 2005 through 2012 treated at the Geisinger Clinic, which provides primary care services to over 400 000 patients in Pennsylvania. Patients with asthma aged 5 to 90 years (n = 35 508) were identified in electronic health records; those with exacerbations were frequency matched on age, sex, and year of event to those without. EXPOSURES: On the day before each patient's index date (cases, date of event or medication order; controls, contact date), we estimated activity metrics for 4 UNGD phases (pad preparation, drilling, stimulation [hydraulic fracturing, or "fracking"], and production) using distance from the patient's home to the well, well characteristics, and the dates and durations of phases. MAIN OUTCOMES AND MEASURES: We identified and defined asthma exacerbations as mild (new oral corticosteroid medication order), moderate (emergency department encounter), or severe (hospitalization). RESULTS: We identified 20 749 mild, 1870 moderate, and 4782 severe asthma exacerbations, and frequency matched these to 18 693, 9350, and 14 104 control index dates, respectively. In 3-level adjusted models, there was an association between the highest group of the activity metric for each UNGD phase compared with the lowest group for 11 of 12 UNGD-outcome pairs: odds ratios (ORs) ranged from 1.5 (95% CI, 1.2-1.7) for the association of the pad metric with severe exacerbations to 4.4 (95% CI, 3.8-5.2) for the association of the production metric with mild exacerbations. Six of the 12 UNGD-outcome associations had increasing ORs across quartiles. Our findings were robust to increasing levels of covariate control and in sensitivity analyses that included evaluation of some possible sources of unmeasured confounding. CONCLUSIONS AND RELEVANCE: Residential UNGD activity metrics were statistically associated with increased risk of mild, moderate, and severe asthma exacerbations. Whether these associations are causal awaits further investigation, including more detailed exposure assessment.

Cumulative sum: An individualized proficiency metric for laparoscopic fundamentals.

BACKGROUND: A reliable metric of technical proficiency is indispensable to the training of fellows and residents. The purpose of this study was to determine whether cumulative sum (Cusum) has predictive validity in laparoscopic training. We hypothesized that Cusum would be a better predictor of technical ability in fundamentals of laparoscopic surgery (FLS) than traditional practice volume metrics. METHODS: Twenty medical students were recruited to practice three FLS tasks: peg transfer, circle cut, and intracorporeal knot tie. Up to 7hours of self-directed practice was allotted to each participant. Practice attempts were scored by standard FLS criteria and monitored via Cusum. Each participant's terminal Cusum performance was analyzed retrospectively. Posttests were conducted by faculty blinded to practice performance. RESULTS: Eighteen participants completed the study (90%). Median adjusted posttest scores were 102.3, 84.1, and 78.6 for peg transfer, circle cut, and knot tie, respectively. For the knot tie task, participants who exceeded the Cusum decision interval during their final practice attempts performed significantly higher on posttesting (81.2 vs 71.5, p=0.015). Knot tie terminal Cusum score was positively associated with posttest performance after adjusting for practice volume (p=0.031). Total practice volume and practice time were not significantly associated with posttest performance for any FLS task. CONCLUSION: Cusum score is a more valid representation of FLS proficiency than practice volume or practice time. Incorporating Cusum in a clinical setting may promote more efficient allocation of time resources and operative volume.