bluuebunny/crossref_metadata_2025 huggingface dataset:
Danish Sonographers’ Experiences of the Introduction of “Moderate Risk” in Prenatal Screening for Down Syndrome
Authors: Møller Anne , Vogel Ida , Petersen Olav Bjørn , Lou Stina
Published: October 2018

Objective. The aim of the study was to determine sonographers’ experiences with the introduction of an offer of noninvasive prenatal testing (NIPT) to a new moderate-risk (MR) group at the combined first-trimester prenatal screening (cFTS). Study Design. A qualitative approach consisting of seven semistructured interviews with five sonographers (midwives and nurses). Data was analyzed using thematic analysis. Main Outcome Measures. Sonographers’ perception of offering NIPT to women in MR. Results. The sonographers understood NIPT as a positive development in prenatal screening due to a safe procedure and high detection rates for trisomies 13, 18, and 21. Prior to the introduction of MR, the sonographers were concerned about inducing worry in pregnant women in this new risk group. However, the pregnant women responded very positively, which the sonographers attributed to several factors such as the women’s overall reason for participating in prenatal screening, the simplicity of the NIPT procedure, and the communicative strategies used by the sonographers. The strategies included all sonographers using the same words and explanations, emphasizing that statistics were in the women’s favor, initiating the presentation of MR with a positive message, and downplaying the MR category. Conclusion. Sonographers’ communicative strategies succeeded in limiting worry in pregnant women in MR. As such, the findings are valuable for health professionals, who are responsible for communicating about prenatal screening results and diagnostic options.
Cloudy Dialysate as the Initial Presentation for Lymphoma
Authors: Sriperumbuduri Sriram , Zimmerman Deborah
Published: October 2018

Turbid dialysate in a patient on peritoneal dialysis is usually due to peritonitis and almost all these patients are started on empirical antibiotics pending cultures. However, in few of them with culture negative fluid, this could represent other etiologies like chyle, which requires more intensive investigations, and analysis of fluid itself reveals some rare diagnosis. We present one such report of chylous ascites with prompt investigation leading to a diagnosis of malignancy in a peritoneal dialysis patient.
3D Printed Anatomy-Specific Fixture for Consistent Glenoid Cavity Position in Shoulder Simulator
Authors: Venne Gabriel , Esau Greg , Bicknell Ryan T. , Bryant J. Tim
Published: October 2018

Purpose. Fixation methods for consistent anatomical structure positioning in biomechanical testing can be challenging. Image-based 3D printing is an attractive method for fabrication of biomechanical supports of anatomical structure due to its ability to precisely locate anatomical features with respect to the loading system. Method. A case study is presented to provide a design guide for fixation block fabrication. The anatomy of interest was CT scanned and reconstructed in 3D. The model was imported into commercially available CAD software and modified into a solid object and to create the fixture block. The CAD fixture block is standardized such that anatomical features are always in the same position for the testing system by subtracting the anatomy from a base fixture block. Results. This method allowed a strong immobilization of anatomical specimens and a controlled and consistent positioning feature with respect to the testing system. Furthermore, the fixture block can be easily modified and adapted to anatomical structures of interest using CAD software. Conclusion. This approach allows preservation of the bony anatomy integrity and provides a repeatable and consistent anatomical positioning with respect to the testing system. It can be adapted for other anatomical structures in various other biomechanical settings.
AcuteStreptococcus mitisSacroiliitis in a Teenager with Unclear Source of Bacteremia: A Case Report and Literature Review
Authors: Al-Farsi Fatma , Al-Busaidi Ibrahim , Al-Zeedi Khalfan
Published: October 2018

Septic arthritis is an orthopedic emergency that is commonly caused byStaphylococcus aureus. Old age, diabetes mellitus, rheumatoid arthritis, prosthetic joint, and recent surgery are the main predisposing risk factors. Most cases of septic arthritis are caused by hematogenous spread of infection. Infectious sacroiliitis is a rare form of septic arthritis which is often clinically challenging to diagnose due its various and nonspecific presentations.Streptococcus mitisbelongs to viridans group streptococci (VGS) bacteria, which is a component of body flora that is commonly involved in bacterial endocarditis. VGS in general andS. mitisspecifically is an uncommon cause of osteoarticular infections. Here, we report a case of spontaneousStreptococcus mitisbacteremia complicated by septic sacroiliitis in a healthy teenager in the absence of infective endocarditis or a clear source of bacteremia.
Permanence and Almost Periodic Solutions for N‐Species Nonautonomous Lotka‐Volterra Competitive Systems with Delays and Impulsive Perturbations on Time Scales
Authors: Yu Xuxu , Wang Qiru , Bai Yuzhen
Published: October 2018

We investigate a class of nonautonomous N‐species Lotka‐Volterra‐type competitive systems with time delays and impulsive perturbations on time scales. By using comparison theorems of impulsive dynamic equations on time scales, we obtain sufficient conditions to guarantee the permanence of the system. Then based on the Massera‐type theorem for impulsive dynamic equations on time scales, we establish existence and uniformly asymptotic stability of the unique positive almost periodic solution of the system. Finally, an example is employed to illustrate our main results.
Combination of Maximum Shear Wave Elasticity Modulus and TIRADS Improves the Diagnostic Specificity in Characterizing Thyroid Nodules: A Retrospective Study
Authors: Hang Jing , Li Fan , Qiao Xiao-hui , Ye Xin-hua , Li Ao , Du Lian-fang
Published: October 2018

Objectives. The present study is aimed at evaluating the diagnostic value of combining shear wave elastography (SWE) parameters and the thyroid imaging reporting and data system (TIRADS) for differentiating between benign and malignant thyroid nodules. Methods. Patients who underwent conventional ultrasonography (US) and SWE before surgery were enrolled in the current study. Each nodule was given a TIRADS risk score. The effectiveness of the SWE parameters was assessed by odds ratios (ORs). The SWE scoring risk stratification was proposed beyond 95% probability, and the desired values were obtained according to the log-normal distribution. The area under the receiver-operating characteristic (AUC) was used to compare the diagnostic performance between TIRADS-alone and TIRADS + SWE. Results. A total of 262 patients with 298 thyroid nodules were enrolled in our study. The pathological analyses were conducted on 121 benign and 177 malignant nodules. The AUC values for TIRADS-alone and TIRADS + SWE were 0.896 (accuracy 83.2%) and 0.917 (accuracy 84.2%), respectively. However, the TIRADS + SWE scores showed a higher specificity (88.4%) and positive predictive value (91.2%) as compared with the TIRADS-alone of 73.6% and 83.2%, respectively. Conclusions. Combining SWE and TIRADS improves the specificity of TIRADS-alone in differentiating between benign and malignant thyroid nodules.
New Sustainable Biosorbent Based on Recycled Deoiled Carob Seeds: Optimization of Heavy Metals Remediation
Authors: Farnane M. , Machrouhi A. , Elhalil A. , Abdennouri M. , Qourzal S. , Tounsadi H. , Barka N.
Published: October 2018

In this study, an efficient biosorbent was developed from deoiled carob seeds, a agroindustrial waste. The biosorption efficiency was evaluated for cadmium and cobalt ions removal from aqueous solution under various parameters such as treating agent, solution pH, biosorbent dosage, contact time, initial metal ions concentration, and temperature. The effect of some major inorganic ions including Na+, K+, Ca2+, Mg2+, and Al3+on the biosorption was also established. Based on this preliminary study, four independent variables including solution pH, biosorbents dosage, initial metal concentration, and treating agent were chosen for the optimization of the process using full-factorial experimental design. It was found that chemical pretreatment of the raw deoiled carob seeds with NaOH strongly enhances its biosorption potential. Thus, the optimal conditions for high biosorption of cadmium(II) and cobalt(II) were achieved at pH of 6, biosorbent dosage of 1 g/L, and initial metal concentration of 50 mg/L. The biosorbents were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), Boehm titration, and the point of zero charge (pHPZC).
The Association of Unreported Sleep Disturbances and Systemic Inflammation: Findings from the 2005-2008 NHANES
Authors: Dennis Jeff A. , Alazzeh Ahmad , Kumfer Ann Marie , McDonald-Thomas Rebecca , Peiris Alan N.
Published: October 2018

Background/Objective. Sleep apnea is associated with elevated inflammatory markers. A subgroup of patients never report sleep disturbances to their physician. The inflammatory status of this subgroup is not known. The present study aims to evaluate two inflammatory markers, C-reactive protein (CRP) and red cell distribution width (RDW), in those with unreported sleep disturbances and compares these findings to those with and without reported sleep disorders. We also investigate the utility of RDW as an inflammatory marker in sleep disorders.Methods. Sample includes 9,901 noninstitutionalized, civilian, nonpregnant adults from the 2005-2008 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional U.S. study. Sleep questionnaire and laboratory data were used to compare inflammatory markers (CRP and RDW) in five subgroups of individuals: reporting physician-diagnosed sleep apnea, reporting another physician-diagnosed sleep disorder, reported sleep disturbance to physician with no resulting diagnosis, unreported sleep disturbance (poor sleep quality not reported to physician), and no diagnosed sleep disorder or sleep disturbance.Results. Individuals with unreported sleep disturbance had significantly higher odds of elevated RDW (>13.6%) when compared to those without a sleep disturbance in adjusted models (OR=1.33). Those with unreported sleep disturbance had significantly higher odds of elevated CRP levels (>1 mg/L) than those without sleep disturbances (OR 1.34), although the association was not significant when adjusted for obesity and other controls.Conclusion. Self-identified unreported sleep disturbances are associated with significantly higher odds of elevated RDW than those without sleep disturbances. RDW may serve as a valuable indicator in identifying individuals at higher risk for sleep apnea and other sleep disorders.
Stability of the Subaxial Spine after Penetrating Trauma: Do Classification Systems Apply?
Authors: Staggers Jackson Rucker , Niemeier Thomas Elliot , Neway William E. , Theiss Steven Michael
Published: October 2018

Objective. Blunt spinal trauma classification systems are well established and provide reliable treatment algorithms. To date, stability of the spine after civilian gunshot wounds (CGSWS) is poorly understood. Herein, we investigate the validity of trauma classification systems including the Thoracolumbar Injury Classification and Severity Score (TLICS), Subaxial Cervical Spine Injury Classification and Severity Score (SLIC), and Denis’ three-column model when applied to spinal penetrating trauma from gunshots, while secondarily evaluating stability of these injuries. Methods. Gunshot injuries to the spine were identified from an institutional database from ICD-nine codes. Trauma scorings systems were applied using traditional criteria. Neurologic compromise and spinal stability were evaluated using follow-up clinic notes and radiographs. Results. Thirty-one patients with CSGSW were evaluated. There was an equal distribution of injuries amongst the spinal levels and spinal columns. Twenty patients had neurological deficits at presentation. Eight patient had a TLICS score >4. Three patients had a SLIC score >4. One patient had surgical treatment. Nonoperative treatment did not lead to spinal instability or adverse outcomes in any cases. The posterior column had a high correlation with neurologic compromise, though not statistically significant (p=.118). Conclusions. The TLICS, SLIC, and three-column classification systems cannot be applied to CSGSW to quantify injury severity, predict outcomes, or guide treatment decision-making. Despite significant neurologic injuries and disruption of multiple spinal columns, CSGSW do not appear to result in unstable injuries requiring operative intervention. Further research is needed to identify the rare spinal gunshot injury that would benefit from immediate surgical intervention.
Complexity in the Acceptance of Sustainable Search Engines on the Internet: An Analysis of Unobserved Heterogeneity with FIMIX‐PLS
Authors: Palos-Sanchez Pedro , Martin-Velicia Felix , Saura Jose Ramon
Published: October 2018

This paper analyses the complexity of user behaviour when facing the challenge of using sustainable applications, such as Internet search engines. This paper analyses an acceptance model using extended TAM (Technology Acceptance Model) with Trust as an added external variable. It was suggested that Trust indirectly influences the final Intention to Use with the perceptions of Utility and Ease of Use. To test the proposed model, a survey was carried out with users from different geographical areas of Spain (n = 445). The second aim of this study was to understand the complexity of marketing segmentation by separating the application users into different user groups. Users were grouped by their preference of favorite Internet search engine. Unobserved heterogeneity was studied using FIMIX‐PLS, and three different user behaviours with search engines were identified. These corresponded to the number of inhabitants who live in the user area. In this way, the impact that the environment has on user choice, acceptance, and use of this type of sustainable applications was shown. The results were checked using PLS‐SEM and showed that the model for the adoption of sustainable search engines is explanatory and predictive because confidence and acceptance for this TAM were validated. The conclusions are interesting for developers of environmentally sustainable and responsible applications which want to coincide with current trends to ensure that users prefer them.
Effect of Collagen Cross-Linking on Alkali Burn-Induced Corneal Neovascularization in Rabbits
Authors: Xu Xiaoying , Liu Taixiang , Li Haixiang
Published: October 2018

Objective. This study aims at investigating the effects and molecular mechanism of riboflavin-ultraviolet-A-induced cross-linking (corneal collagen cross-linking, CXL) on corneal neovascularization (CNV) in a rabbit alkali burn model. Methods. A total of 60 rabbits were injured with alkali burns to induce CNV in the right eye and were randomly divided into six groups: Group A—injury and no treatment; Groups B, C, and D—CXL treatment for 30 min, 15 min, and 45 min administered immediately after injury, respectively; and Groups E and F—CXL treatment for 30 min administered 1 day and 3 days after injury, respectively. CNV area, corneal edema, and corneal epithelial defects were observed on days 4, 7, 10, and 14 after injury. Western blot was used to detect expression of the vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-2 (MMP-9), and tissue inhibitor of metalloproteinases 1 (TIMP-1) at 7 and 14 days after injury. Results. CXL treatment decreased CNV and corneal edema in all groups compared to Group A. On day 7, MMP-9 expression was significantly increased in all CXL treatment groups, and TIMP-1 was upregulated in Groups D and F compared to Group A. In addition, VEGF, MMP-2, MMP-9, and TIMP-1 expression were increased in Group A on day 14 after injury. Conclusions. Our results indicate that riboflavin-ultraviolet-A-induced cross-linking (corneal collagen cross-linking, CXL) significantly inhibits alkali burn-induced CNV in rabbits, possibly through downregulating VEGF, MMP-2, MMP-9, and TIMP-1 expression.
Applications of Shape Memory Polymers in Kinetic Buildings
Authors: Li Jing , Duan Qiuhua , Zhang Enhe , Wang Julian
Published: October 2018

Shape memory polymers (SMPs) have attracted significant attention from both industrial and academic researchers, due to their useful and fascinating functionality. One of the most common and studied external stimuli for SMPs is temperature; other stimuli include electric fields, light, magnetic fields, water, and irradiation. Solutions for SMPs have also been extensively studied in the past decade. In this research, we review, consolidate, and report the major efforts and findings documented in the SMP literature, according to different external stimuli. The corresponding mechanisms, constitutive models, and properties (i.e., mechanical, electrical, optical, shape, etc.) of the SMPs in response to different stimulus methods are then reviewed. Next, this research presents and categorizes up‐to‐date studies on the application of SMPs in dynamic building structures and components. Following this, we discuss the need for studying SMPs in terms of kinetic building applications, especially about building energy saving purposes, and review recent two‐way SMPs and their potential for use in such applications. This review covers a number of current advances in SMPs, with a view towards applications in kinetic building engineering.
Crude Polysaccharides from Okra Pods (Abelmoschus esculentus) Grown in Indonesia Enhance the Immune Response due to Bacterial Infection
Authors: Wahyuningsih Sri Puji Astuti , Pramudya Manikya , Putri Intan Permata , Winarni Dwi , Savira Nadyatul Ilma Indah , Darmanto Win
Published: October 2018

Okra pods were widely consumed by Indonesians to maintain health. The aim of this study was at investigating the potential of crude polysaccharides from okra pods on immune response in mice infected withStaphylococcus aureus.Thirty male Balb/C mice were divided into six groups: normal control, negative control, and treatment groups (administration of crude polysaccharides at doses of 25, 50, 75, and 100 mg/kg). Crude polysaccharides were administrated for fourteen days. Furthermore, mice were exposed toS. aureusat the fifteenth day. Two weeks after the end of treatment, the parameters were measured. This study showed that crude polysaccharides at a dose of 75 and 100 mg/kg improved phagocytic activity, spleen index, and splenocytes proliferation. Rising of TNF-αlevels was shown in groups treated with crude polysaccharides at doses of 25, 50, and 100 mg/kg. All treatment groups showed a decreasing level of IL-17. Crude okra polysaccharides also showed a slight increase in NK cells activity and IFN-γlevel. Thus, crude okra polysaccharides could act as an effective material to enhance immune response including phagocytic activity, spleen index, splenocytes proliferation, and control immune responses through cytokine production.
Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma
Authors: Job Sylvie , Draskovic Irena , Burnichon Nelly , Buffet Alexandre , Cros Jérôme , Lépine Charles , Venisse Annabelle , Robidel Estelle , Verkarre Virginie , Meatchi Tchao , Sibony Mathilde , Amar Laurence , Bertherat Jérôme , de Reyniès Aurélien , Londoño-Vallejo Arturo , Favier Judith , Castro-Vega Luis Jaime , Gimenez-Roqueplo Anne-Paule
Published: October 2018

Purpose:

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with SDHB- and FH-mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression.

Experimental Design: Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of TERT comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and ATRX mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.

Results:

Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in SDHB-mutated paragangliomas (P = 2.42e−09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group (P = 0.169), yet ATRX mutations were found preferentially in SDHB/FH-mutated metastatic tumors (P = 0.0014). Telomerase activation and ATRX mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; P = 6.50E−07 and 1.90E−07, respectively); OS (hazard ratio, 97.4 and 44.1; P = 4.30E−03 and 2.00E−03, respectively) and were associated with worse MFS and OS (log-rank tests P < 0.0001).

Conclusions:

Assessment of telomerase activation and ATRX mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.
Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma
Authors: Gupta Sumati , Albertson Daniel J. , Parnell Timothy J. , Butterfield Andrew , Weston Alexis , Pappas Lisa M. , Dalley Brian , O’Shea John M. , Lowrance William T. , Cairns Bradley R. , Schiffman Joshua D. , Sharma Sunil
Published: October 2018

Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had ARID1A mutations. ARID1A mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant ARID1A-mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies ARID1A loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.
Bone Involvement in Hodgkin’s Lymphoma: Clinical Features and Outcome
Authors: Gaudio Francesco , Pedote Pasquale , Niccoli Asabella Artor , Ingravallo Giuseppe , Sindaco Paola , Alberotanza Vito , Perrone Tommasina , Laddaga Fiomena Emanuela , Rubini Giuseppe , Stabile Ianora Amato Antonio , Specchia Giorgina
Published: October 2018

Hodgkin’s lymphoma (HL) is now a highly curable disease, with an improving 5-year survival rate that has now reached 86%. At the time of presentation, HL is usually almost entirely confined to the lymph nodes. We performed a retrospective single-institution study of 384 cases with a median follow-up of 44 months, with the aim of identifying clinical and radiological characteristics and outcomes of patients with bone HL; 32 patients (8%) had primary bone involvement, always with concurrent nodal disease. These included 22 men (69%) and 10 women (31%) with the median age as 41 years. Advanced stages and nodular sclerosis histology prevailed among the subgroup. Radiographic features of bone HL are not specific but indicate a destructive malignant process with osteosclerosis and/or osteolysis. With current chemotherapeutic regimens, the long-term prognosis of patients with osseous HL appears good. The presence of bone lesions in HL should not be interpreted as implying a worse prognosis than without bone involvement.
Prognostic Accuracy of Heart Rate Variability Analysis in Neonatal Encephalopathy: A Systematic Review
Authors: Oliveira Vânia , Martins Rui , Liow Natasha , Teiserskas Justinas , von Rosenberg Wilhelm , Adjei Tricia , Shivamurthappa Vijayakumar , Lally Peter J. , Mandic Danilo , Thayyil Sudhin
Published: October 2018

Background: Heart rate variability analysis offers real-time quantification of autonomic disturbance after perinatal asphyxia, and may therefore aid in disease stratification and prognostication after neonatal encephalopathy (NE). Objective: To systematically review the existing literature on the accuracy of early heart rate variability (HRV) to predict brain injury and adverse neurodevelopmental outcomes after NE. Design/Methods: We systematically searched the literature published between May 1947 and May 2018. We included all prospective and retrospective studies reporting HRV metrics, within the first 7 days of life in babies with NE, and its association with adverse outcomes (defined as evidence of brain injury on magnetic resonance imaging and/or abnormal neurodevelopment at ≥1 year of age). We extracted raw data wherever possible to calculate the prognostic indices with confidence intervals. Results: We retrieved 379 citations, 5 of which met the criteria. One further study was excluded as it analysed an already-included cohort. The 4 studies provided data on 205 babies, 80 (39%) of whom had adverse outcomes. Prognostic accuracy was reported for 12 different HRV metrics and the area under the curve (AUC) varied between 0.79 and 0.94. The best performing metric reported in the included studies was the relative power of high-frequency band, with an AUC of 0.94. Conclusions: HRV metrics are a promising bedside tool for early prediction of brain injury and neurodevelopmental outcome in babies with NE. Due to the small number of studies available, their heterogeneity and methodological limitations, further research is needed to refine this tool so that it can be used in clinical practice.
A Modified Surgical Technique for Transposition of the Vertebral Artery to the Common Carotid Artery
Authors: Seung Won-Bae
Published: October 2018

A proximal occluded vertebral artery (VA) with reconstitution by muscular collateral vessels is a relatively common finding. However, due to inadequate intracranial anastomosis and hypoplasia or stenosis of the opposite VA, a number of patients develop symptoms of brain ischemia. In the current case, a 63-year-old man presented with repeat neurological symptoms such as dizziness, nausea, vomiting, dysarthria, left hemiparesis, and right hemianopsia. Magnetic resonance imaging revealed multiple posterior infarctions. Angiography revealed the VA to be occluded and reconstituted by collateral vessels. Considering the above results, we performed vertebral carotid artery transposition. However, several technical difficulties were encountered due to space limitations in the operative field and the limited length of the vessels to be anastomosed. To overcome such situations, we introduced a modified posterior wall end-to-side anastomosis technique.
ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke
Authors: Cuoco Joshua A. , Busch Christopher M. , Klein Brendan J. , Benko Michael J. , Stein Rachel , Nicholson Andrew D. , Marvin Eric A.
Published: October 2018

Background: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. Summary: We performed a literature search using PubMed with the key words “ACTA2 mutation,” “ACTA2 cerebral arteriopathy,” and “multisystemic smooth muscle dysfunction syndrome.” Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.
Dispor para Funcionar
Authors: Areias Amanda
Published: October 2018

A série “Dispor para Funcionar” aplica-se a fugir do lugar comum ao investigar as feiras livres da cidade de São Paulo, Brasil. Comumente vistas como um território ideal e vívido, como lugar de intercâmbio e convivência pacífica em meio a uma selva de pedra, estes mercados de rua são, antes de tudo, lugar de contradição e conflito com o seu entorno. A série investiga as regras adotadas pelos feirantes na tentativa de amenizar tais embates. O que vemos é um espaço temporário mas visualmente complexo, intenso e fantástico, um cenário estético com uma profusão de cores, formas e linhas que tentam organizar o caos.
Yield of the
RYR2
Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation
Authors: Kapplinger Jamie D. , Pundi Krishna N. , Larson Nicholas B. , Callis Thomas E. , Tester David J. , Bikker Hennie , Wilde Arthur A.M. , Ackerman Michael J.
Published: October 2018

Background:

Pathogenic
RYR2
variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign
RYR2
variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the
RYR2
genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability.

Methods:

Frequency and location comparisons were made for
RYR2
variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of
RYR2
variants was examined. Six in silico tools were assessed using patient- and control-derived variants.

Results:

A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare
RYR2
variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign
RYR2
variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel
RYR2
variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation.

Conclusions:

Current expert recommendations have resulted in increased use of
RYR2
genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds
RYR2
variant interpretation.
Polygenic Risk Score for Coronary Heart Disease Modifies the Elevated Risk by Cigarette Smoking for Disease Incidence
Authors: Hindy George , Wiberg Frans , Almgren Peter , Melander Olle , Orho-Melander Marju
Published: October 2018

Background:

Coronary heart disease (CHD) is a multifactorial disease with both genetic and environmental components. Smoking is the most important modifiable risk factor for CHD. Our aim was to test whether the increased CHD incidence by smoking is modified by genetic predisposition to CHD.

Methods and Results:

Our study included 24 443 individuals from the MDCS (Malmö Diet and Cancer Study). A weighted polygenic risk score (PRS) was created by summing the number of risk alleles for 50 single-nucleotide polymorphisms associated with CHD. Individuals were classified as current, former, or never smokers. Interactions were primarily tested between smoking status and PRS and secondarily with individual single-nucleotide polymorphisms. Then, the predictive use of PRS for CHD incidence was tested among different smoking categories. During a median follow-up time of 19.4 years, 3217 incident CHD cases were recorded. The association between smoking and CHD was modified by the PRS (
P
interaction
=0.005). The magnitude of increased incidence of CHD by smoking was highest among individuals in the lowest tertile of PRS (odds ratio, 1.42; 95% confidence interval, 1.29–1.56 per smoking risk category) compared with the highest tertile (odds ratio, 1.20; 95% confidence interval, 1.11–1.30 per smoking risk category). This interaction was stronger among men (
P
interaction
=0.001) compared with women (
P
interaction
=0.44). The PRS provided a significantly better net reclassification and discrimination on top of traditional risk factors among never smokers compared with current smokers (
P
<0.001).

Conclusions:

Genetic predisposition to CHD modifies the associated increased CHD risk by smoking. The PRS has a better predictive use among never smokers compared with smokers.
Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults
Authors: Zhu Na , Gonzaga-Jauregui Claudia , Welch Carrie L. , Ma Lijiang , Qi Hongjian , King Alejandra K. , Krishnan Usha , Rosenzweig Erika B. , Ivy D. Dunbar , Austin Eric D. , Hamid Rizwan , Nichols William C. , Pauciulo Michael W. , Lutz Katie A. , Sawle Ashley , Reid Jeffrey G. , Overton John D. , Baras Aris , Dewey Frederick , Shen Yufeng , Chung Wendy K.
Published: October 2018

Background:

Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although
BMPR2
mutations underlie ≈70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood.

Methods:

We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing.

RESULTS:

We observed similar frequencies of rare, deleterious
BMPR2
mutations in pediatric- and adult-onset patients: ≈55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of
TBX4
mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset), and
TBX4
carriers had younger mean age-of-onset compared with
BMPR2
carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene-damaging and predicted deleterious missense variants.

Conclusions:

Mutations in known PAH risk genes accounted for ≈70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in
TBX4
are enriched in pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases.
Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection
Authors: Kaadan M. Ihsan , MacDonald Carolyn , Ponzini Francesca , Duran Jessica , Newell Kelsey , Pitler Linda , Lin Angela , Weinberg Ido , Wood Malissa J. , Lindsay Mark E.
Published: October 2018

Background:

Previous studies describing genetics evaluation in spontaneous coronary artery dissection (SCAD) have been retrospective in nature or presented as single case reports. As part of a dedicated clinical program, we evaluated patients in cardiovascular genetics clinic to determine the role of genetically triggered vascular disease and genetic testing in SCAD.

Methods and Results:

Patient data were entered prospectively into the Massachusetts General Hospital SCAD registry database from July 2013 to September 2017. Clinically indicated genetic testing was conducted based on patient imaging, family history, physical examination, and patient preference. Of the 107 patients enrolled in the registry, 73 underwent cardiovascular genetics evaluation at our center (average age, 45.3±9.4 years; 85.3% female), and genetic testing was performed for 44 patients. A family history of aneurysm or dissection was not a prevalent feature in the study population, and only 1 patient had a family history of SCAD. Six patients (8.2%) had identifiable genetically triggered vascular disease: 3 with vascular Ehlers–Danlos syndrome (
COL3A1
), 1 with Nail–patella syndrome (
LMX1B
), 1 with autosomal dominant polycystic kidney disease (
PKD1
), and 1 with Loeys–Dietz syndrome (
SMAD3
). None of these 6 had radiographic evidence of fibromuscular dysplasia.

Conclusions:

In this series, 8.2% of the SCAD patients evaluated had a molecularly identifiable disorder associated with vascular disease. The most common diagnosis was vascular Ehlers–Danlos syndrome. Patients with positive gene testing were significantly younger at the time of their first SCAD event. A low threshold for genetic testing should be considered in patients with SCAD.
Impact of a Metoprolol Extended Release Shortage on Post-Myocardial Infarction β-Blocker Utilization, Adherence, and Rehospitalization
Authors: Bykov Katsiaryna , Gagne Joshua J. , Wang Bo , Choudhry Niteesh K.
Published: October 2018

Background:

Shortages of chronic medications are an increasingly common problem, yet little is known about their impact on drug utilization and clinical outcomes. We evaluated the population-level impact of metoprolol extended release shortage that occurred in the United States in 2009 to 2010.

Methods and Results:

We conducted a population-based, time series analysis of 38 914 patients (mean age, 60 years; 69% men) discharged after hospitalization for myocardial infarction (MI) between January 2006 and November 2012 in a large commercial insurance database. The shortage period was defined as February 2009 to June 2010. Data before September 2008 was defined as preshortage period and data after June 2010 as postshortage period. Outcomes were proportion of patients who filled any long- or short-acting β-blocker within 30 days of discharge, adherence to β-blockers within the first year of therapy among patients who initiated β-blockers, and rates of 1-year rehospitalization for MI or unstable angina. Post-MI statin utilization and adherence were evaluated as control outcomes. During the preshortage period, 70% of patient filled a β-blocker, mean monthly adherence was 76%, and the average monthly rate of rehospitalization was 6.5 events per 100 person-years, as compared with β-blocker use of 62%, average adherence of 70%, and rehospitalization rate of 5.6 events per 100 person-years during the shortage. After accounting for the baseline (preshortage) trends, the shortage was associated with significant monthly reductions in postdischarge β-blocker use (−0.57% of patients [95% CI, −0.90 to −0.24] per month) and an immediate decrease in adherence (−4.58% days covered [95% CI, −6.12 to −3.04]). No negative impact on rates of rehospitalization, post-MI statin utilization, or statin adherence was observed. β-Blocker utilization began to increase after the resolution of the shortage.

Conclusions:

The nationwide metoprolol extended release shortage in the United States was associated with fewer patients receiving any long- or short-acting β-blocker post-MI and lower adherence to β-blocker therapy for those who did receive it, but did not appear to appreciably affect clinical outcomes at the population level.
Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling and Precision Medicine: A Scientific Statement From the American Heart Association
Authors: Musunuru Kiran , Sheikh Farah , Gupta Rajat M. , Houser Steven R. , Maher Kevin O. , Milan David J. , Terzic Andre , Wu Joseph C.
Published: October 2018

Induced pluripotent stem cells (iPSCs) offer an unprece-dented opportunity to study human physiology and disease at the cellular level. They also have the potential to be leveraged in the practice of precision medicine, for example, personalized drug testing. This statement comprehensively describes the provenance of iPSC lines, their use for cardiovascular disease modeling, their use for precision medicine, and strategies through which to promote their wider use for biomedical applications. Human iPSCs exhibit properties that render them uniquely qualified as model systems for studying human diseases: they are of human origin, which means they carry human genomes; they are pluripotent, which means that in principle, they can be differentiated into any of the human body’s somatic cell types; and they are stem cells, which means they can be expanded from a single cell into millions or even billions of cell progeny. iPSCs offer the opportunity to study cells that are genetically matched to individual patients, and genome-editing tools allow introduction or correction of genetic variants. Initial progress has been made in using iPSCs to better understand cardiomyopathies, rhythm disorders, valvular and vascular disorders, and metabolic risk factors for ischemic heart disease. This promising work is still in its infancy. Similarly, iPSCs are only just starting to be used to identify the optimal medications to be used in patients from whom the cells were derived. This statement is intended to (1) summarize the state of the science with respect to the use of iPSCs for modeling of cardiovascular traits and disorders and for therapeutic screening; (2) identify opportunities and challenges in the use of iPSCs for disease modeling and precision medicine; and (3) outline strategies that will facilitate the use of iPSCs for biomedical applications. This statement is not intended to address the use of stem cells as regenerative therapy, such as transplantation into the body to treat ischemic heart disease or heart failure.
Race/Ethnicity and the Prognostic Implications of Coronary Artery Calcium for All‐Cause and Cardiovascular Disease Mortality: The Coronary Artery Calcium Consortium
Authors: Orimoloye Olusola A. , Budoff Matthew J. , Dardari Zeina A. , Mirbolouk Mohammadhassan , Uddin S.M. Iftekhar , Berman Daniel S. , Rozanski Alan , Shaw Leslee J. , Rumberger John A. , Nasir Khurram , Miedema Michael D. , Blumenthal Roger S. , Blaha Michael J.
Published: October 2018

Background

Coronary artery calcium (CAC) predicts cardiovascular disease (CVD) events; however, less is known about how its prognostic implications vary by race/ethnicity
.

Methods and Results

A total of 38 277 whites, 1621 Asians, 977 blacks, and 1349 Hispanics from the CAC Consortium (mean age 55 years, 35% women) were followed over a median of 11.7 years. Modeling CAC in continuous and categorical (CAC=0; CAC 1–99; CAC 100–399; CAC ≥400) forms, we assessed its predictive value for all‐cause and CVD mortality by race/ethnicity using Cox proportional hazards and Fine and Gray competing‐risk regression, respectively. We also assessed the impact of race/ethnicity on risk within individual CAC strata, using whites as the reference. Models were adjusted for traditional cardiovascular risk factors. Increased CAC was associated with higher total and CVD mortality risk in all race/ethnicity groups, including Asians. However, the risk gradient with increasing CAC was more pronounced in blacks and Hispanics. In Fine and Gray subdistribution hazards models adjusted for traditional cardiovascular risk factors and CAC (continuous), blacks (subdistribution hazard ratio 3.4, 95% confidence interval, 2.5–4.8) and Hispanics (subdistribution hazard ratio 2.3, 95% confidence interval, 1.6–3.2) showed greater risk of CVD mortality when compared with whites, while Asians had risk similar to whites. These race/ethnic differences persisted when CAC=0.

Conclusions

CAC predicts all‐cause and CVD mortality in all studied race/ethnicity groups, including Asians and Hispanics, who may be poorly represented by the Pooled Cohort Equations. Blacks and Hispanics may have greater mortality risk compared with whites and Asians after adjusting for atherosclerosis burden, with potential implications for US race/ethnic healthcare disparities research.
Jews, Ships, and Death: A Consideration of Nautical Images in Jewish Mortuary Contexts
Authors: Stern Karen B.
Published: October 2018

Recurrences of ancient ship carvings and drawings in Jewish burial caves are curious phenomena, which rarely capture the attention of scholars. Few narrative Jewish texts, which might otherwise illuminate this pattern, explicitly describe any link between ships and death. The ubiquity of nautical images in graffiti and monumental art throughout the ancient Mediterranean, moreover, obscures their particular significance in any mortuary context, whether associated with Jews or their neighbors. This article suggests that consistent appearances of ship imagery in Jewish burial contexts throughout time and across distant regions, attest to the varied iconographic and ideational significances of ships to Jews within mortuary settings. Cross-cultural similarities between acts of drawing, carving, and commissioning ship images inside and around commemorative spaces, this article argues further, document corresponding continuities between the mortuary activities and beliefs of Jews and their Egyptian, Greco-Roman, and Christian neighbors throughout the ancient Mediterranean.