Dysregulation of the chromatin environment leads to differential alternative splicing as a mechanism of disease in a human model of autism spectrum disorder.

Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.

Perforated Peptic Ulcer of the Duodenum After the Laparoscopic Roux-en-Y Gastric Bypass.

Perforated ulcers of the gastric remnant and duodenum seem to be a rare complication after a Roux-en-Y gastric bypass. Diagnosis of this complication can be difficult given a vague presentation, however, early intervention is critical to prevent further morbidity. We present the case of a 38-year-old male with a perforated duodenal ulcer nearly a year after Roux-en-Y gastric bypass. Upon presentation, he complained of 8 hours of epigastric pain. His medical history was significant for chronic peptic ulcer disease and a negative history of H. pylori. Recently, he had been prescribed naproxen by his primary care physician for knee pain. His vital signs were normal with the exception of his systolic blood pressure which was 190 mmHg. He was diaphoretic and peritonitic on exam. He was taken emergently for a diagnostic laparoscopy and found to have a perforation of ∼5 mm of the anterior portion of his duodenum. This was repaired laparoscopically with an omental patch and the patient recovered without any further intervention required. While this is a rare complication reported in the literature, this or similar complications of the remnant stomach may be underrepresented in publications. The surgical intervention of this disease will either be resection of the remnant or an omental patch. However, controversy remains as to the proper post-operative medical treatment. For our patient, the inciting agent was likely the naproxen he was given and this was stopped immediately. Patient education and ownership should remain a cornerstone for patients that have undergone a Roux-en-y gastric bypass.

Comparing Emotional Valence Scores of Twitter Messages from Human Coding and Machine Learning Algorithms Among Hispanic and African American Family Caregivers of Persons with Dementia.

We compared emotional valence scores as determined via machine learning approaches to human-coded scores of direct messages on Twitter from our 2,301 followers during a Twitter-based clinical trial screening for Hispanic and African American family caregivers of persons with dementia. We manually assigned emotional valence scores to 249 randomly selected direct Twitter messages from our followers (N=2,301), then we applied three machine learning sentiment analysis algorithms to extract emotional valence scores for each message and compared their mean scores to the human coding results. The aggregated mean emotional scores from the natural language processing were slightly positive, while the mean score from human coding as a gold standard was negative. Clusters of strongly negative sentiments were observed in followers' responses to being found non-eligible for the study, indicating a significant need for alternative strategies to provide similar research opportunities to non-eligible family caregivers.

Status of Robotic-Assisted Surgery (RAS) in the Department of Defense (DoD).

INTRODUCTION: Since inception of robotic-assisted surgery (RAS) in 1999, there has been an exponential rise in RAS in both number and complexity of surgical cases performed. The majority of these cases are gynecologic surgery in nature, with only a quarter of them labeled as general surgery. The purpose of this study is to determine if RAS in the Department of Defense (DoD) mirrors these trends. METHODS: A total of 6,204 RAS cases from across the DoD were reviewed between 01 January 2015 and 30 September 2017 from every Military Treatment Facility (MTF) that employs a robotic surgical device (various models of the da Vinci robotic surgical system by Intuitive Surgical). Specialty, number, and surgeon were recorded for each case. These end points were also examined for trends overtime and compared to similar civilian data. RESULTS: The number of MTFs performing robotic surgery and the number of cases performed increased significantly. An average of 373 cases per quarter-year were performed in 2015, 647 in 2016, and 708 in 2017. The number of RAS cases increased by about 10% every quarter-year during this time period. RAS was most commonly performed by general surgery in 10 of the 14 MTFs examined. CONCLUSIONS: MTFs implemented RAS much later than the civilian world. However, since its implementation, the frequency of RAS use has increased at a faster rate in the DoD than in the civilian world. Possible reasons for this are a younger pool of surgeons in the military and less demands on cost-effective productivity, allowing these younger surgeons to focus on emerging technology rather than maximizing surgical cost efficiency. General surgery constitutes the majority of RAS cases in the DoD. It is unclear why this difference from the civilian world exists.

Management of Bullet Emboli to the Heart and Great Vessels.

INTRODUCTION: Firearm-related injuries account for 20% of all injury-related deaths and are responsible for 105,000 injuries annually. The occurrence of bullet emboli to the heart is exceedingly rare. Given the rarity of emboli, controversy exists over management. The primary endpoint of this study is to establish a management algorithm for venous bullet emboli to the heart. MATERIALS AND METHODS: A literature search was performed using PubMed and Google Scholar with the following search terms: cardiac bullet embolus, cardiac missile embolus, and bullet embolus. Any discoverable case report(s) or series after 1960 were included in the review. The following data points were collected: age, sex, presentation, imaging, foreign body entry site, foreign body destination site, management, and outcomes. RESULTS: Fifty-four articles met our search criteria. A total of 62 patients with thoracic venous bullet emboli were identified with the following distributions: right atrium (9.7%), right ventricle (54.8%), pulmonary arterial tree (32.3%), and intra-thoracic inferior vena cava (3.2%). Only 11.3% of patients had symptoms directly related to the cardiac venous emboli; however, all patients with acute symptoms underwent immediate intervention. Of those patients with bullet emboli to the pulmonary arterial tree, 45% were observed; whereas, only 20% with emboli to the right heart were observed. Those without signs or symptoms usually underwent an intervention (72.7%). Endovascular retrieval was successful in 53% of attempts. Of the endovascular attempts that failed, 28.6% were observed and 71.4% underwent open retrieval. Those who were asymptomatic and observed had no reported adverse sequelae during the follow-up. No mortalities were discovered in this review. CONCLUSION: Bullet emboli can prove to be a clinical challenge. Adjuncts such as X-ray, computed tomography, transthoracic, and/or transesophageal echocardiography help establish the emboli location. While observation in the asymptomatic patient is reasonable in some circumstances, most patients undergo removal. Removal of bullet cardiac emboli is safe with the availability of modern techniques.

Determination of Proper Timing for the Placement of Intra-Abdominal Mesh after Incidental Enterotomy in a Rodent Model (Rattus norvegicus).

Controversy exists regarding the appropriate timing for placement of permanent intra-abdominal mesh after inadvertent enterotomy during elective hernia repair. The aim of this study was to examine mesh placement at variable postoperative periods and the subsequent risk of infection. Fifty rodents were divided into five groups. Groups one to four underwent laparotomy, enterotomy, and repair. Physiomesh® was placed at the index operation one, three, or seven days postoperatively in Groups 1, 2, 3, and 4. Group 5 underwent mesh placement only. Necropsy with mesh harvest was performed seven days after placement. Cultures of mesh were obtained and Fisher's exact test was used to compare groups. Bacterial growth postsonication was identified in 30, 30, 50, and 90 per cent versus 20 per cent in controls. Compared with controls, there was significantly increased risk of mesh infection when it was placed seven days after enterotomy (P = 0.006). There was no significant difference in bacterial growth when mesh was placed at the time of enterotomy, one or three days later. The risk of bacterial contamination of permanent mesh placed immediately after inadvertent enterotomy during elective hernia repair is as safe as placing mesh at one or three days. Placing mesh at seven days significantly increased the risk of mesh contamination.

Risk factors for hypotension in urgently intubated burn patients.

BACKGROUND: When urgently intubating patient in the burn intensive care unit (BICU), various induction agents, including propofol, are utilized that may induce hemodynamic instability. METHODS: A retrospective review was performed of consecutive critically ill burn patients who underwent urgent endotracheal intubation in BICU. Basic burn-related demographic data, indication for intubation, and induction agents utilized were recorded. The primary outcomes of interest were clinically significant hypotension requiring immediate fluid resuscitation, initiation or escalation of vasopressors immediately after intubation. Secondary outcomes included ventilator days, stay length, and in-hospital mortality. RESULTS: Between January 2003 and August 2010, we identified 279 urgent intubations in 204 patients. Of these, the criteria for presumed sepsis were met in 60% (n=168) of the intubations. After intubation, 117 patients (42%) experienced clinically significant hypotension. Propofol (51%) was the most commonly utilized induction agent followed by etomidate (23%), ketamine (15%), and midazolam (11%). On multiple logistic regression, %TBSA (OR 1.016, 95% CI 1.004-1.027, p<0.001) and presumed sepsis (OR 1.852, 95% CI 1.100-3.117, p=0.02) were the only significant predictors of hypotension. None of the induction agents, including propofol, were significantly associated with hypotension in patients with or without presumed sepsis. CONCLUSIONS: In critically ill burn patients undergoing urgent endotracheal intubation, specific induction agents, including propofol, were not associated with clinically significant hypotension. Presumed sepsis and %TBSA were the most important risk factors.