Citations

BackgroundControversy exists regarding the optimal mode of delivery for fetuses with open neural tube defects.ObjectiveTo compare neurological outcomes among infants with open neural tube defects who underwent vaginal compared with caesarean delivery.Search strategyElectronic databasesMEDLINE,EMBASE, Scopus, and Clinicaltrials.gov were searched from inception to November 2017.Selection criteriaEligible studies included observational or randomised studies comparing vaginal and caesarean delivery in pregnancies with fetal open neural tube defects who did not undergo prenatal repair.Data collection and analysisTwo reviewers independently reviewed abstracts and full‐text articles. Outcomes were compared between vaginal and caesarean delivery and prelabour caesarean versus exposure to labour. The primary outcome was motor–anatomic level difference. Secondary outcomes included shunt requirement, sac disruption, meningitis, and ambulation at 2 years. Meta‐analysis was performed and mean difference or odds ratios with 95% CI were calculated.Main resultsOf 201 abstracts identified in the primary search, nine studies (672 women) met the eligibility criteria. Comparing vaginal and caesarean delivery, there was no significant difference in motor–anatomic level difference (mean difference –0.10, 95%CI−0.58 to 0.38;I2 = 57%). The vaginal delivery group was less likely to require a shunt or have sac disruption [odds ratio (OR) 0.37, 95%CI0.14–0.95 andOR0.46, 95%CI0.23–0.90, respectively]. Comparisons by prelabour caesarean versus exposure to labour showed no significant difference in motor–anatomic level difference (OR1.29, 95%CI0.63–3.21) or ambulation at 2 years (OR2.13, 95%CI0.35–13.12).ConclusionCaesarean delivery was not associated with improved neurological outcomes among fetuses with open neural tube defects.Tweetable abstractAvailable evidence does not support routine caesarean delivery for fetuses with open neural tube defects.

Abstract The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (P < 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P < 0.0001). Implications: TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy. Mol Cancer Res; 16(5); 805–12. ©2018 AACR.

Background: Mutations in the leucine rich repeat kinase 2 ( LRRK2) gene are among the most common genetic causes of Lewy body Parkinson’s disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. Objective: To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. Methods: From the brain donation program at the Parkinson’s Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD ( n = 20), MSA ( n = 4), or PSP ( n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. Results: We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. Conclusions: Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant ( LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant ( LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD. Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Abstract Objectives The purpose of this systematic review is to provide a comprehensive overview on the clinical course, perinatal outcome, and effectiveness of prenatal management options for pericardial teratoma. Methods A comprehensive search including Ovid MEDLINE, Ovid EMBASE, and Scopus was conducted from inception to September 2016. All studies that reported the prenatal course of pericardial teratoma in singleton or twin gestations were considered eligible. Standardized forms were used for data abstraction by two independent reviewers. Results Out of 217 screened abstracts, 59 studies reporting 67 fetuses with pericardial teratoma were included. Twenty‐three singleton fetuses and 3 fetuses in twin gestations underwent prenatal treatment, and 20 (76.9%) of them were hydropic at the time of intervention. Of those, 15/20 (75%) had a favorable outcome. In the non‐intervention group ( n = 41), 26 (63.4%) developed hydrops, and out of those, 8 (30.8%) had a favorable outcome. Conclusion Prenatal fluid drainage and other prenatal techniques have been utilized in the treatment of intrapericardial teratoma. While most fetuses tolerated pericardiocentesis, the neonatal benefit of this procedure is still uncertain, and outcomes of other interventions had variable success. Prenatal intervention for pericardial teratoma may be an option in specialized units but, given the maternal and fetal risks, needs careful consideration. © 2017 John Wiley & Sons, Ltd.

Esophageal varices are a significant complication of portal hypertension. Endoscopic variceal ligation (EVL) is one of the clinical standards for treating these varices and preventing their hemorrhage. Limitations of EVL include the risk of stricture formation and postband ulcer bleeding due to the damage caused to the esophageal mucosa, as well as the need for multiple endoscopic treatment sessions to eradicate the varices. The goal of this study is to develop a device and evaluate the technical feasibility of microwave ablation to seal esophageal varices, while preventing thermal damage to the surface mucosal tissue. A microwave applicator with a directional radiation pattern was developed for endoscopic ablation of esophageal varices. Electromagnetic and bioheat transfer computational models were employed to optimize the design of the microwave applicator and evaluate energy delivery strategies for this application. Experiments in ex vivo and in vivo tissue were employed to verify simulation results. Simulations predicted enhanced heating performance of the antenna using an angled monopole radiating element. Further, simulations indicate that while the endoscopic cap attenuated electric fields in tissue, it also enhanced surface cooling of tissue, increasing the likelihood of preserving mucosal tissue. Experiments in ex vivo tissue indicated the feasibility of sealing veins with 77 W microwave power delivered for 30 s. In vivo experiments demonstrated the ability to seal veins, while preserving surface tissue. This study demonstrated the technical feasibility of microwave thermal ablation for treating esophageal varices using a 2.45 GHz water-cooled directional microwave applicator.

Abstract Rationale Studies have shown the importance of simulation-based training on the outcomes of central venous catheter (CVC) insertion by trainees. Objectives To compare the performance of internal medicine trainees who underwent standardized simulation training of CVC insertion with that of internal medicine trainees who had traditional CVC training and were already deemed competent to perform the procedure during a proficiency evaluation using a training mannequin. Methods Trainees who perform CVC insertion were enrolled in the institutional Central Line Workshop, which includes both an online and an experiential simulation component. The training is followed by a certification station proficiency assessment. Residents and fellows previously certified competent to perform CVC placement without supervision completed the online module, but they could opt out of the experiential component and proceed directly to the evaluation. Results Forty-eight trainees participated in the study. Twenty-one (44%), 15 (31%), 6 (13%), 1 (2%), 2 (4%), and 3 (6%) were in postgraduate year 1 (PGY1), PGY2, PGY3, PGY4, PGY5, and PGY6, respectively. Twenty-nine completed the hands-on instruction, 28 (97%) of whom successfully passed the simulation-based assessment on their first attempt. Nineteen trainees previously credentialed to perform CVC placement without supervision opted out of the simulation-based experiential training. Of these, five (26%) failed in their first attempt (P = 0.02 vs. trainees who completed the simulation training). Conclusions Standardized simulation-based training can improve CVC insertion proficiency, even among trainees with previous experience sufficient to have been deemed competent in the procedure. Improved performance at simulation-based testing may translate to improved outcomes of CVC placement by trainees.

AbstractObjectiveTo evaluate the association between ultrasonographic renal parameters and urine biochemistry in fetuses with lower urinary tract obstruction (LUTO).MethodsData were collected prospectively from 31 consecutive fetuses with LUTO that underwent vesicocentesis for fetal urinary biochemistry between April 2013 and September 2015. The following renal ultrasound markers were assessed immediately before the vesicocentesis: renal echogenicity, presence of cortical cysts, presence of findings suggestive of ‘renal dysplasia’ (hyperechogenic cystic kidneys with no cortical‐medullary differentiation) and severe oligohydramnios (amniotic fluid < 5th percentile). The association of these parameters to the fetal urinary concentration of sodium, chloride, calcium, osmolality and beta2‐microglobulin was investigated by logistic regression analysis.ResultsThere was no relationship between any of the ultrasonographic fetal renal characteristics and fetal urinary biochemistry.ConclusionsIn LUTO, the ultrasound appearance of the fetal kidneys and urinary biochemistry are not correlated. It may be better to take both ultrasound and biochemistry into account when evaluating fetuses with fetal LUTO. © 2016 John Wiley & Sons, Ltd.