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Optimal management of patent ductus arteriosus (PDA) is unclear. One treatment, surgical ligation, is associated with adverse outcomes. We reviewed data from the Kids' Inpatient Database (2000-2012) to determine if PDA ligation rates: (1) changed over time, (2) varied geographically, or (3) influenced surgical complication rates. In 2012, 47,900 infants <1500g birth weight were born in the United States, including 2,800 undergoing PDA ligation (5.9%). Ligation was more likely in infants <1000g (85.9% vs. 46.2%), and associated with necrotizing enterocolitis (59.2% vs. 37.5%), BPD (54.6% vs. 15.2%), severe intraventricular hemorrhage (16.4% vs. 5.3%), and hospital transfer (37.6% vs. 16.4%). Ligation rates peaked in 2006 at 87.4 per 1000 hospital births, dropping to 58.8 in 2012, and were consistently higher in Western states. Infants undergoing ligation were more likely to experience comorbidities. Rates of ligation-associated vocal cord paralysis increased over time (1.2-3.9%); however, mortality decreased (12.4-6.5%). Thus, PDA ligation has become less frequent, although infants being ligated are smaller and more medically complex. Despite increase in some complications, mortality rates improved perhaps reflecting advances in care.
Copyright © 2018 Elsevier Inc. All rights reserved.

The new paradigm of mutations in chromatin-modifying genes as driver events in the development of cancers has proved challenging to resolve the complex influences over disease phenotypes. In particular, impaired activities of members of the SWI/SNF chromatin remodeling complex have appeared in an increasing variety of tumors. Mutations in SNF5, a member of this ubiquitously expressed complex, arise in almost all cases of malignant rhabdoid tumor in the absence of additional genetic alterations. Therefore, we studied how activation of additional oncogenic pathways might shift the phenotype of disease driven by SNF5 loss. With the use of a genetically engineered mouse model, we examined the effects of a hypomorphic Vhl allele on disease phenotype, with a modest up-regulation of the hypoxia response pathway. Snf5;Vhl mice did not demonstrate a substantial difference in overall survival or a change in malignant rhabdoid tumor development. However, a high percentage of female mice showed complex hemorrhagic ovarian cysts, a phenotype rarely found in either parental mouse strain. These lesions also showed mosaic expression of SNF5 by immunohistochemistry. Therefore, our studies implicate that modest changes in angiogenic regulation interact with perturbations of SWI/SNF complex activity to modulate disease phenotypes.
Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation ().
Copyright© 2017 Ferrata Storti Foundation.

The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.

PURPOSE - Meckel diverticula containing gastric heterotopia predispose to local hyperacidity, mucosal ulceration, and gastrointestinal bleeding in children. Eradication of acid-producing oxyntic cells is performed by either of two surgical methods: segmental enterectomy including the diverticulum or diverticulectomy only.
METHODS - Retrospective review of all children having surgical resection of a Meckel diverticulum at a tertiary-referral children's hospital from 2002 to 2016 was performed. Demographic data, surgical method, pathological specimens, and outcomes were evaluated.
RESULTS - 102 children underwent surgical resection of a Meckel diverticulum during the study period. 27 (26.5%) children presented with bleeding, of which 16 (59%) had diverticulectomy only, and 11 (41%) had segmental ileal resection. All Meckel diverticula in children presenting with bleeding contained gastric heterotopia, and resection margins were free of gastric mucosa. Histologically, 19 specimens showed microscopic features of ulceration, on average 2.95mm (SD 4.49) from the nearest gastric mucosa (range: 0-16mm). Mean length of hospitalization after ileal resection was 4.0days (SD 1.2) compared to 1.6days (SD 0.9) for diverticulectomy only (p<0.001), with no re-bleeding occurrences.
CONCLUSION - In the operative management of children having a bleeding Meckel diverticulum, diverticulectomy-only completely eradicates gastric heterotopia without increased risk of continued bleeding or complications and significantly shortens hospitalization.
LEVEL OF EVIDENCE - Treatment Study: Level III.
Copyright © 2017 Elsevier Inc. All rights reserved.

With advances in brain imaging and completion of randomized clinical trials (RCTs) for primary and secondary stroke prevention, the natural history of central nervous system (CNS) complications in sickle cell disease (SCD) is evolving. In order of current prevalence, the primary CNS complications include silent cerebral infarcts (39% by 18 years), headache (both acute and chronic: 36% in children with sickle cell anemia [SCA]), ischemic stroke (as low as 1% in children with SCA with effective screening and prophylaxis, but ∼11% in children with SCA without screening), and hemorrhagic stroke in children and adults with SCA (3% and 10%, respectively). In high-income countries, RCTs (Stroke Prevention in Sickle Cell Anemia [STOP], STOP II) have demonstrated that regular blood transfusion therapy (typically monthly) achieves primary stroke prevention in children with SCA and high transcranial Doppler (TCD) velocities; after at least a year, hydroxycarbamide may be substituted (TCD With Transfusions Changing to Hydroxyurea [TWiTCH]). Also in high-income countries, RCTs have demonstrated that regular blood transfusion is the optimal current therapy for secondary prevention of infarcts for children with SCA and strokes (Stroke With Transfusions Changing to Hydroxyurea [SWiTCH]) or silent cerebral infarcts (Silent Infarct Transfusion [SIT] Trial). For adults with SCD, CNS complications continue to be a major cause of morbidity and mortality, with no evidence-based strategy for prevention.
© 2016 by The American Society of Hematology.

BACKGROUND - Few studies comment on the association between fibroids and symptoms among pregnant women. These studies generally are retrospective and do not to assess the influence of number of tumours or their volume on risk of symptoms.
METHODS - Right from the Start is a prospective cohort that enrolled pregnant women from the southeastern USA between 2000 and 2012. In the first trimester, all participants had standardised ultrasounds to determine the presence or absence of fibroids. Symptoms were queried in a telephone survey. We used polytomous logistic regression to model odds of bleeding, pain, or both symptoms in relation to increasing total fibroid number and volume among white and black women.
RESULTS - Among 4509 participants, the prevalence of fibroids was 11%. Among those reporting symptoms (70%), 11% reported only bleeding, 59% reported only pain, and 30% reported both symptoms. After adjusting for age, race, parity, hypertension, smoking, alcohol use, and study site, increasing number of fibroids was associated with pain [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.00, 1.33] and both symptoms [OR 1.25, 95% CI 1.08, 1.45] but not with bleeding among all women. Fibroid volume was not associated with symptoms among black women, but white women with the smallest fibroid volumes were more likely to report both symptoms than those without fibroids [OR 1.79, 95% CI 1.17, 2.72].
CONCLUSIONS - Very large tumours are not requisite for experiencing symptoms, as small fibroids and increasing number of tumours are associated with pain and both symptoms.
© 2015 John Wiley & Sons Ltd.

CONTEXT - Transbronchial cryobiopsy technique yields larger biopsies with enhanced quality. The benefits and safety of cryobiopsies have not been thoroughly studied in lung allografts.
OBJECTIVE - To compare size, quality, reproducibility of interpretation of rejection and complications of cryobiopsies with those of conventional biopsies from lung allografts.
DESIGN - All cryobiopsies (March 2014-January 2015) of lung allografts performed at Mayo Clinic, Rochester, and medical records were reviewed. For comparison, conventional biopsies from the same patient or, if unavailable, from a random patient, were selected. Two pathologists blinded to outcome reviewed all biopsies. Specimen volume, number of alveoli, small airways, and pulmonary vessels were counted and statistically compared.
RESULTS - Fifty-four biopsies (27 cryobiopsies) from 18 patients (11 men) were reviewed. A median of 3 (range, 2-5) and 10 (range, 6-12) specimens were obtained with cryobiopsies and conventional biopsies, respectively. Cryobiopsies were larger and contained more alveoli (P < .001, both) and small airways (P = .04). Conventional biopsies showed more fresh alveolar hemorrhage (procedural) and crush artifact/atelectasis (P < .001, both). Cryobiopsies contained more pulmonary veins and venules (P < .001). There was no significant difference between the types of biopsies with respect to the reviewers' agreement on grades of rejection. Complications were more frequent in the cryobiopsy group, though the difference was not statistically significant.
CONCLUSIONS - Cryobiopsies of lung allografts are larger and have less artifact. However, complications occur and should be considered. Three cryobiopsy specimens appear sufficient for histopathologic evaluation of lung allografts.

Abnormal platelet reactivity is associated with recurrent ischemia and bleeding following percutaneous coronary intervention (PCI). Protease-activated receptor-1 (PAR1), encoded by F2R, is a high affinity thrombin receptor on platelets and the target of the antiplatelet drug vorapaxar. The intronic single nucleotide polymorphism F2R IVS-14 A/T affects PAR1 receptor density and function. We hypothesized that carriers of the T allele, who have been shown to have decreased platelet reactivity, would be at lower risk for thrombotic events, but higher risk for bleeding following PCI. Using BioVU, the Vanderbilt DNA repository linked to the electronic medical record, we studied 660 patients who underwent PCI for unstable or stable coronary artery disease. Primary outcome measures were major adverse cardiovascular events (MACE, composite of revascularization, MI, stroke, death) and bleeding (assessed by Bleeding Academic Research Consortium scale) over 24 months. The minor allele (T) frequency was 14.8 %. There were no genotypic differences in the frequency of MACE (33.7, 28.8, and 31.6 % for A/A, A/T, and T/T respectively, P = 0.50) or bleeding (15.7, 14.7, and 18.8 % for A/A, A/T, and T/T respectively, P = 0.90). In a Cox regression model, fully adjusted for age, race, sex, BMI, and smoking status, carrying a T allele was not associated with MACE (HR 1.19, 95 % CI 0.89-1.59, P = 0.23) or bleeding (HR 0.73, 95 % CI 0.37-1.4, P = 0.34). In conclusion, in our population, F2R IVS-14 PAR1 variability does not affect risk of MACE or bleeding following PCI.

We examined the reliability and ease of use of a novel automated transcranial Doppler (TCD) system in comparison to a conventional TCD system. TCD ultrasound allows non-invasive monitoring of cerebral blood flow, and can predict arterial vasospasm after a subarachnoid hemorrhage (SAH). The Presto 1000 TCD system (PhysioSonics, Bellevue, WA, USA) is designed for monitoring flow through the M1 segment of the middle cerebral artery (MCA) via temporal windows. The Presto 1000 system was tested across multiple preclinical and clinical settings in parallel with a control predicate TCD system. In a phantom flow generating device, both the Presto 1000 and Spencer system (Spencer Technologies, Redmond, WA, USA) were able to detect velocities with high accuracy. In nine volunteer patients, the Presto system was able to locate the MCA in 14 out of 18 temporal windows, in an average of 12.5s. In the SAH cohort of five patients with a total of 25 paired measurements, the mean absolute difference in flow velocities of the M1 segment, as measured by the two systems, was 17.5 cm/s. These data suggest that the Presto system offers an automated TCD that can reliably localize and detect flow of the MCA, with relative ease of use. The system carries the additional benefit of requiring minimal training for the operator, and can be used by many providers across multiple bedside settings. The mean velocities that were generated warrant further validation across an extended group of patients, and the predictive value for vasospasm should be checked against the current standard of angiography.
Copyright © 2015 Elsevier Ltd. All rights reserved.