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Objective To assess stroke/systemic embolism, major bleeding and other outcomes, and treatment effect of apixaban versus warfarin, in patients with atrial fibrillation (AF) and different types of valvular heart disease (VHD), using data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Methods There were 14 793 patients with known VHD status, categorised as having moderate or severe mitral regurgitation (MR) (n=3382), aortic regurgitation (AR) (n=842) or aortic stenosis (AS) (n=324); patients with moderate or severe mitral stenosis were excluded from the trial. Baseline characteristics, efficacy and safety outcomes were compared between each type and no significant VHD. Treatment effect was assessed using an adjusted model. Results Patients with MR or AR had similar rates of stroke/systemic embolism and bleeding compared with patients without MR or AR, respectively. Patients with AS had significantly higher event rates (presented as rate per 100 patient-years of follow-up) of stroke/systemic embolism (3.47 vs 1.36; adjusted HR (adjHR) 2.21, 95% CI 1.35 to 3.63), death (8.30 vs 3.53; adjHR 1.92, 95% CI 1.41 to 2.61), major bleeding (5.31 vs 2.53; adjHR 1.80, 95% CI 1.19 to 2.75) and intracranial bleeding (1.29 vs 0.51; adjHR 2.54, 95% CI 1.08 to 5.96) than patients without AS. The superiority of apixaban over warfarin on stroke/systemic embolism was similar in patients with versus without MR (HR 0.69, 95% CI 0.46 to 1.04 vs HR 0.79, 95% CI 0.63 to 1.00; interaction P value 0.52), with versus without AR (HR 0.57, 95% CI 0.27 to 1.20 vs HR 0.78, 95% CI 0.63 to 0.96; interaction P value 0.52), and with versus without AS (HR 0.44, 95% CI 0.17 to 1.13 vs HR 0.79, 95% CI 0.64 to 0.97; interaction P value 0.19). For each of the primary and secondary efficacy and safety outcomes, there was no evidence of a different effect of apixaban over warfarin in patients with any VHD subcategory. Conclusions In anticoagulated patients with AF, AS is associated with a higher risk of stroke/systemic embolism, bleeding and death. The efficacy and safety benefits of apixaban compared with warfarin were consistent, regardless of presence of MR, AR or AS. Clinical trial registration ARISTOTLE clinical trial number NCT00412984.

Objective: To report the presentation, diagnosis, management, and convalescence of labyrinthine sequestrum (LS) and summarize all previously published cases. Patient(s): Eleven-year-old female with LS. Intervention(s): Multidisciplinary diagnostic evaluation and treatment. Main Outcome Measures: Imaging and laboratory findings, medical and surgical treatment. Results: We describe a case of LS secondary to medically recalcitrant suppurative otitis media in an 11-year-old female and review all eight previously reported cases. The index patient presented after 6 months of otitis media, profound unilateral hearing loss, with symptoms suggesting meningitis. Temporal bone CT demonstrated marked bony destruction of the left otic capsule. Gadolinium-enhanced MRI showed an enhancing process with evidence of meningitis and subdural empyema. The patient was treated with surgical debridement and culture directed antibiotic therapy. Posttreatment imaging showed resolution of intracranial infection with fibrous bony healing of the otic capsule resembling fibrous dysplasia. Conclusion: LS is a rare form of labyrinthitis characterized by centrifugal destruction of the otic capsule. The current index case highlights the importance of combined medical and surgical treatment and describes for the first time in the literature the fibrous ossification of the otic capsule following disease resolution.

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.

We sought to determine whether the proximal colon modifies its capacity to accommodate contents by altering the tone within its wall. In dogs equipped with manometric recorders in the terminal ileum and proximal colon, a highly compliant bag was introduced into the proximal colon. With the use of an electromechanical barostat, the capacity of the colonic segment was monitored at a constant low-distending pressure; the volume of air required to maintain a preset pressure in the bag was recorded by the barostat. During fasting, rhythmic cycles of volume were recorded, with a cycle frequency of approximately 1/min. Importantly, this phenomenon was not related to the simultaneous recording of manometric pressures in the adjacent bowel or to the interdigestive cycle (phase III) in the ileum. Peristaltic-like pressure complexes (recorded manometrically) in the ileocolonic region were associated with receptive relaxation of the proximal colon. Feeding, bethanechol, and morphine reduced volumes accommodated in the bag, presumably by increasing tone in the wall of the colon. Atropine had the opposite effect. These results support the concept that tonic changes in the wall of the proximal colon, which could influence accommodation and storage in the large bowel, are not always recorded by conventional techniques.

Our hypothesis was that the canine ileocolonic sphincter (ICS), per se, would have little regulatory effect on the transit of chyme from ileum to colon. We argued, from earlier observations, that the ileocolonic junction was influenced more by functional motor integration of the ileum, ICS, and proximal colon. In five dogs, the ileocolonic sphincter was ablated by extramucosal sphincterotomy; the operation significantly lowered tonic pressures at the ICS. Animals were then studied in the fasting state and postprandially. Ileal flow was estimated by marker dilution, and ileocolonic flow was estimated by total recovery of chyme from a colonic cannula. Transit times were measured after the bolus infusion of nonabsorbable markers. Ileocolonic sphincterotomy did not significantly alter flow rates or transit times of chyme across the ICS, although ileal motor patterns were changed after sphincterotomy. We concluded that the ICS probably has only a small effect on transit and flow at the ileocolonic junction. These findings argue for the importance of integrated motility of the ileum, ICS, and proximal colon in controlling the flow of chyme in this region.

We describe here further observations on a novel motor phenomenon that can be recorded regularly from the canine ileum in the late postprandial period, i.e., when residue of a meal reaches the distal small bowel. We reported before that this unique pattern of motility consisted of intraluminal pressure waves at a frequency (20-24/min) much greater than that of the ileal slow wave. In the current experiments, we document that these intraluminal pressure waves coincide with contraction of the circular muscle layer, as recorded from serosal strain gauges. However, the cellular origin and propagation of these contractile events are still unclear. By studying dogs with ileal loops and those with an intact bowel, we conclude that this is a local response of the ileum to the arrival of nutrients in its lumen and that it is under cholinergic control. This report supports the concept that the ileum may be particularly sensitive to its local intraluminal environment.

We report here a novel motor phenomenon that we recorded from the canine terminal ileum in the postprandial period. In chronic models that allowed us to monitor myoelectrical activity and intraluminal pressure from the jejunum and distal ileum, we regularly saw in the ileum, but not in the jejunum, a rhythmic sequence of intraluminal pressure waves at a frequency of 19-24 cycles/min. This unusual motor pattern was rarely seen in the first 2 h after food and was essentially absent during fasting; it appeared reproducibly 1-4 h after food, at the time when chyme reached the ileum. The phenomenon was accompanied by spike bursts that were usually at the same rapid, rhythmic frequency, but the rate of the ileal slow wave persisted at the preprandial level (13-15/min). These findings further exemplify differences in the regulation of the motility between jejunum and ileum; moreover, the phenomenon highlights the capacity of the distal small intestine to response specifically to the nature of its luminal contents. This reaction of the ileum to the arrival of dietary residues is deserving of further study in the evaluation of the small bowel's response to a meal.