bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Levels of MicroRNA-155 Are Upregulated with Long-Term Left Ventricular Assist Device Support
Authors: Wang Teresa , O’Brien Emily C. , Rogers Joseph G. , Jacoby Daniel L. , Chen Michael E. , Testani Jeffrey M. , Bowles Dawn E. , Milano Carmelo A. , Felker G. Michael , Patel Chetan B. , Bonde Pramod N. , Ahmad Tariq
Published: March 2017

Left ventricular assist device (LVAD) therapy unloads the failing heart but exposes the human body to unique pathophysiologic demands such as continuous blood flow and complete univentricular support, which are associated with increased risk of adverse clinical outcomes. MicroRNAs (miRNAs) are 22–23 nucleotide RNAs involved in regulation of multiple biologic processes including the pathogenesis of heart failure (HF). Thus, measurement of miRNAs may have potential in both diagnostics as circulating biomarkers and in therapeutics for targeted interventions. We examined 23 distinct miRNAs that have previously been shown to play a role in HF pathogenesis and measured them in 40 individuals both before continuous-flow LVAD implantation and at a median of 96.5 days after implantation. Quantitative real-time polymerase chain reaction was performed for miRNA amplification, and 19 miRs were included in statistical analysis. Wilcoxon signed-rank tests were used to compare within-patient median relative quantification values pre- and post-LVAD placement. The median age of patients was 67 years, and 57.5% were at Interagency Registry for Mechanically Assisted Circulatory Support level 1–2. After LVAD support, only miR-155 was found to be statistically significant (p < 0.002), with an upregulation in plasma expression levels with LVAD support, which persisted regardless of the direction of change in serial HF biomarker levels. MicroRNA-155, which has been shown to play a central role in inflammation and neovascularization, was upregulated with long-term LVAD support. If validated by future studies, miR-155 may help further inform on underlying LVAD physiology and has a role as a therapeutic target in this patient population.
Episode-of-Care Characteristics and Costs for Hip and Knee Replacement Surgery in Hospitals Belonging to the High Value Healthcare Collaborative Compared With Similar Hospitals in the Same Health Care Markets
Authors: Weeks William B. , Schoellkopf William J. , Ballard David J. , Kaplan Gary S. , James Brent , Weinstein James N.
Published: March 2017

Background:

To inform consumers and restrain health care cost growth, efforts to promote transparency and to reimburse for care episodes are accelerating in the United States.

Objective:

To compare characteristics and costs of 30-day episode of care for hip and knee replacement occurring in High Value Healthcare Collaborative (HVHC)-member hospitals to those occurring in like non–HVHC-member hospitals in the same 15 health care markets before interventions by HVHC members to improve health care value for those interventions.

Research Design:

This is a retrospective analysis of fee-for-service Medicare data from 2012 and 2013.

Subjects:

For hip arthroplasty, 4030 HVHC-member and 7572 non–HVHC-member, and for knee arthroplasty, 6542 HVHC-member and 13,900 non–HVHC-member fee-for-service Medicare patients aged 65 and older.

Measures:

Volumes, patient demographics, hospital stay characteristics, and acute and postacute care standardized costs for a 30-day episode of care.

Results:

HVHC-member hospitals differed from similar non–HVHC-member hospitals in the same health care markets when considering volumes of surgeries, patient demographics, Charlson scores, and patient distance to care during the index admission. There was little variation in acute care costs of hip or knee replacement surgery across health care markets; however, there was substantial variation in postacute care costs across those same markets. We saw less variation in postacute care costs within markets than across markets. Regression analyses showed that HVHC-member status was not associated with shorter lengths of stay, different complication rates, or lower total or postacute care costs for hip or knee replacement.

Conclusions:

Health care regions appear to be a more important predictor of episode costs of care than HVHC status.
Hospital Characteristics Associated With Risk-standardized Readmission Rates
Authors: Horwitz Leora I. , Bernheim Susannah M. , Ross Joseph S. , Herrin Jeph , Grady Jacqueline N. , Krumholz Harlan M. , Drye Elizabeth E. , Lin Zhenqiu
Published: March 2017

Background:

Safety-net and teaching hospitals are somewhat more likely to be penalized for excess readmissions, but the association of other hospital characteristics with readmission rates is uncertain and may have relevance for hospital-centered interventions.

Objective:

To examine the independent association of 8 hospital characteristics with hospital-wide 30-day risk-standardized readmission rate (RSRR).

Design:

This is a retrospective cross-sectional multivariable analysis.

Subjects:

US hospitals.

Measures:

Centers for Medicare and Medicaid Services specification of hospital-wide RSRR from July 1, 2013 through June 30, 2014 with race and Medicaid dual-eligibility added.

Results:

We included 6,789,839 admissions to 4474 hospitals of Medicare fee-for-service beneficiaries aged over 64 years. In multivariable analyses, there was regional variation: hospitals in the mid-Atlantic region had the highest RSRRs [0.98 percentage points higher than hospitals in the Mountain region; 95% confidence interval (CI), 0.84–1.12]. For-profit hospitals had an average RSRR 0.38 percentage points (95% CI, 0.24–0.53) higher than public hospitals. Both urban and rural hospitals had higher RSRRs than those in medium metropolitan areas. Hospitals without advanced cardiac surgery capability had an average RSRR 0.27 percentage points (95% CI, 0.18–0.36) higher than those with. The ratio of registered nurses per hospital bed was not associated with RSRR. Variability in RSRRs among hospitals of similar type was much larger than aggregate differences between types of hospitals.

Conclusions:

Overall, larger, urban, academic facilities had modestly higher RSRRs than smaller, suburban, community hospitals, although there was a wide range of performance. The strong regional effect suggests that local practice patterns are an important influence. Disproportionately high readmission rates at for-profit hospitals may highlight the role of financial incentives favoring utilization.
Factor Structure of the Cultural Competence Items in the National Home and Hospice Care Survey
Authors: AbuDagga Azza , Mara Constance A. , Carle Adam C. , Weech-Maldonado Robert
Published: March 2017

Background:

There is a need for validated measures of cultural competency practices in home health and hospice care (HHHC).

Objective:

To establish the factor structure of the cultural competency items included in the agency-component of the 2007 public-use National Home and Hospice Care Survey file.

Data Source:

We used weighted survey data from 1036 HHHC agencies.

Research Design and Participants:

We used exploratory factor analyses to identify a preliminary factor structure, and then performed confirmatory factor analysis to provide further support for identified factor structure.

Measures:

We examined 9 cultural competency items.

Results:

Exploratory factor analyses suggested an interpretable 2-factor solution: (1) the provision of mandatory cultural competency training; and (2) the provision of cultural competency communication practices. Each factor consisted of 3 items. The remaining 3 items did not load well on these factors. A similar, but more restrictive, confirmatory factor analysis model without cross-loadings supported the 2-factor model:

JOURNAL/mcar/04.03/00005650-201804000-00013/inline-formula1/v/2023-08-21T230356Z/r/image-tiff

=9.50, P=0.30, root mean square error of approximation (RMSEA)=0.01, comparative fit index (CFI)=0.99, Tucker-Lewis Index (TLI)=0.99.

Conclusions:

Two constructs with 3 items each appeared to be internally valid measures of cultural competency in this nationally representative survey of HHHC agencies: cultural competency training and cultural competency communication practices. These measures could be used by HHHC managers in quality improvement efforts and by policy makers in monitoring cultural competency practices.
Impact of rare variants in autosomal dominant hypercholesterolemia causing genes
Authors: Calandra Sebastiano , Tarugi Patrizia , Bertolini Stefano
Published: March 2017

Purpose of review

The systematic analysis of the major candidate genes in autosomal dominant hypercholesterolemia (ADH) and the use of next-generation sequencing (NGS) technology have made possible the discovery of several rare gene variants whose pathogenic effect in most cases remains poorly defined.

Recent findings

One major advance in the field has been the adoption of a set of international guidelines for the assignment of pathogenicity to low-density lipoprotein receptor (LDLR) gene variants based on the use of softwares, complemented with data available from literature and public databases. The clinical impact of several novel rare variants in LDLR, APOB, PCSK9, APOE genes have been reported in large studies describing patients with ADH found to be homozygotes/compound heterozygotes, double heterozygotes, or simple heterozygotes. In-vitro functional studies have been conducted to clarify the effect of some rare ApoB variants on LDL binding to LDLR and the impact of a rare ApoE variant on the uptake of VLDL and LDL by hepatocytes.

The update of the ADH gene variants database and the classification of variants in categories of pathogenicity is a major advance in the understanding the pathophysiology of ADH and in the management of this disorder. The studies of molecularly characterized patients with ADH have emphasized the impact of a specific variant and the variable clinical expression of different genotypes. The functional studies of some variants have increased our understanding of the molecular bases of some forms of ADH.
Immunotherapy for food allergy
Authors: Reisacher William R. , Davison Wesley
Published: March 2017

Purpose of review

The current review discusses strategies for administering specific immunotherapy (SIT) for the treatment of food allergy. It focuses on three delivery routes for food allergens, immunomodulatory adjuvants and allergen modifications.

Recent findings

Interest in SIT for food allergy has been increasing significantly. Sublingual immunotherapy is effective for desensitization with a very favorable adverse event profile. Epicutaneous immunotherapy is also effective, most notably in younger children, with a high rate of local reactions. Oral immunotherapy demonstrates high efficacy, but with a higher risk of gastrointestinal and systemic adverse events. The need for long-term application to sustain desensitization is currently unclear. Immunomodulatory adjuvants may be added to enhance or diminish the immunogenicity of proteins, whereas genetic modifications of food allergens are designed to limit the risk of adverse reactions and address the issues of standardization and supply.

SIT for food allergy is reaching the point where it may soon be used routinely in clinical practice. Current research focuses on new delivery routes and methods to enhance the effectiveness of the therapy while minimizing the risk of adverse reactions. Future efforts are underway to determine the optimal dose for each delivery method and the length of maintenance dosing required to retain the protective effect.
Pediatric solid tumors in Africa: different biology?
Authors: Nyagetuba John K.M. , Hansen Erik N.
Published: March 2017

Purpose of review

To review the recent literature regarding biologic characteristics of pediatric solid tumors in African children.

Recent findings

Data regarding pediatric solid tumors in Africa, while increasing, remain sparse when considering the ethnic and geographic diversity of the continent. Recent work, especially regarding nephroblastoma in Kenya, has identified some biologic variability among local tribes but also when compared with North American tumors. In general, reports from across the continent reveal markedly poorer survival for pediatric patients with solid tumors when compared with high-resourced regions.

Multiple resource-related and infrastructure-related challenges contribute to poorer outcomes, and these require systematic, multidisciplinary, and structured solutions. Socioeconomic factors and limited access to care currently seem to drive the survival outcomes in children with solid cancers in Africa.
Central venous access in children: indications, devices, and risks
Authors: Ares Guillermo , Hunter Catherine J.
Published: March 2017

Purpose of review

Central venous catheters (CVCs) have a prominent role in the diagnostic and therapy of neonates and children. Herein, we describe the multiple indications for CVC use and the different devices available for central venous access. Given the prevalent use of CVCs, healthcare systems are focused on reducing complications from their use, particularly central line-associated bloodstream infections (CLABSIs). The most up-to-date information available sheds light on best practices and future areas of investigation.

Recent findings

Large systematic reviews of randomized trials suggest that ultrasound guidance for placement of CVCs in children is safer than using blind technique, at least for internal jugular vein access. Appropriate catheter tip placement is associated with decreased complications. Furthermore, the prophylactic use of ethanol lock between cycles of parenteral nutrition administration has reduced the rates of CLABSI. A recent randomized trial in pediatric CVCs showed a benefit with antibiotic-coated CVCs.

Based on the available evidence, multiple techniques for CVC placement are still valid, including the landmark technique based on practitioner experience, but ultrasound guidance has been shown to decrease complications from line placement. Adherence to CVC care protocols is essential in reducing infectious complications.
Symptomatic Acute-on-Chronic Subdural Hematoma
Authors: Castellani Rudy J. , Mojica-Sanchez Gruschenka , Schwartzbauer Gary , Hersh David S.
Published: March 2017

The pathophysiology of acute-on-chronic subdural hematoma (ACSDH) is complex and incompletely understood. Evidence to date indicates that the overall process is initiated by rotational force with movement of the brain inside the skull, which exerts tensile strain and rupture of bridging veins, leading in turn to acute hemorrhage in the subdural potential space. This is followed by the proliferation of mesenchymal elements with angiogenesis and inflammation, which in turn becomes a substrate for repeated hemorrhage and expansion of the lesion. Given the prevalence of traumatic subdural processes in the forensic setting and the importance of proper assessment of timing, etiology, risk factors, and clinicopathological correlation, we studied 47 patients presenting to the University of Maryland Shock Trauma Center, all of whom underwent craniotomy with resection of the outer membrane due to symptomatic ACSDH. The surgically resected tissue was examined for histopathologic features in all cases. Our findings highlight that ACSDH is a condition precipitated by trauma that affects middle-aged and older adults, is relatively indolent, is unilateral or asymmetric, and has a low in-hospital mortality rate. Pathological analysis demonstrates a substantial outer membrane in all cases with varying degrees of inflammation and organization that cannot be precisely dated as a function of clinical presentation. The extrapolation of adult ACSDH to mixed acute and chronic subdural hemorrhage in the pediatric setting is problematic due to substantial differences in clinical presentation, severity of underlying brain injury, gross and microscopic findings, and outcome.
Videolaryngoscopy in Neonates, Infants, and Children*
Authors: Balaban Onur , Tobias Joseph D.
Published: March 2017

Airway management is vital during anesthetic care and during resuscitative efforts in the PICU, the emergency department, and the delivery room. Given specific anatomic and physiologic differences, neonates and infants may be more prone to complications during airway management. Videolaryngoscopy may offer an alternative to or advantages over direct laryngoscopy in specific clinical scenarios. The following article reviews some of the basic types of videolaryngoscopy and discusses their potential applications in the pediatric population.
HPV-independent Differentiated Vulvar Intraepithelial Neoplasia (dVIN) is Associated With an Aggressive Clinical Course
Authors: McAlpine Jessica N. , Kim So Youn , Akbari Ardalan , Eshragh Sima , Reuschenbach Miriam , von Knebel Doeberitz Magnus , Prigge Elena S. , Jordan Suzanne , Singh Naveena , Miller Dianne M. , Gilks C. Blake
Published: March 2017

Differentiated vulvar intrapeithelial neoplasia (dVIN) is an human papillomavirus (HPV)–independent precursor of squamous cell carcinoma (SCC), and the aim of this study was to better characterize its natural history. Cases of dVIN were identified from the pathology archives. Outcomes of patients with dVIN only, without associated invasive SCC, were compared with a cohort of patients with high-grade squamous intraepithelial lesion [HSIL(VIN3)]. Eighteen patients diagnosed with dVIN with adjacent invasive SCC (SCC/dVIN) and 7 patients with dVIN only, without invasive carcinoma, were identified. Mean age in both cohorts was 75 yr. All lesions but 1 were unifocal. In 35% of SCC/dVIN cases the surgical resection margins were positive for SCC, with 75% and 60% having margins positive for dVIN in the SCC/dVIN and dVIN-only cohorts, respectively. In total, 23/25 women with dVIN only or dVIN/SCC, for whom there was follow-up information, experienced either progression to or recurrence of invasive SCC, respectively, at a median of 1.1 yr, including all but 1 case of dVIN only, where the median time of progression to invasive SCC was 1.9 yr. A total of 22/25 women died of disease with a median overall survival of 3.4 yr. The outcome (i.e. progression to invasive carcinoma) of patients with dVIN only was significantly worse than that of a comparison group of 18 patients with HSIL(VIN3) (progression-free survival log-rank, P<0.001; disease-specific survival, P=0.04; overall survival, P=0.01). Six of 7 patients with dVIN only developed invasive carcinoma on follow-up, compared with 0 of 18 patients with HSIL(VIN3). The diagnosis of dVIN indicates the presence of a high-risk human papillomavirus–negative precursor of invasive SCC. These patients are likely to progress to invasive carcinoma over a relatively short period, at which point their prognosis is guarded.
Survivin Expression in Simple Endometrial Polyps and Tamoxifen-associated Endometrial Polyps
Authors: Gokmen Karasu Ayse F. , Sonmez Fatma C. , Aydin Serdar , Adanir Ilknur , Marasli Mustafa , Ilhan Gulsah K.
Published: March 2017

Endometrial polyps are benign pathologies originating as localized overgrowths of basal endometrium. Risk factors include endogenous and exogenous estrogen excess and tamoxifen (TAM) exposure. Our main objective was to investigate the role of an apoptosis-inhibiting protein, survivin, in endometrial polyps. We performed a cross-sectional, analytical study; our samples were obtained from the archives of the Department of Pathology. Sixty samples were included, comprising 20 TAM polyps, 20 simple endometrial polyps, and 20 cases of simple endometrial hyperplasia without atypia not associated with TAM use. Immunohistochemical staining with rabbit monoclonal anti-human survivin, clone EP 119, was performed. Survivin staining score was highest in the endometrial polyp group and lowest in the TAM polyp group (P<0.001). There was no correlation between survivin staining score and the age of patient (r=0.09), TAM exposure (r=−0.02), nor endometrial thickness (r=0.25). Endometrial polyps are frequently associated with TAM. The low expression of the antiapoptotic marker survivin in TAM polyps but high expression in other polypoid endometrium illustrates that different mechanisms are responsible in the pathogenesis of endometrial polyps. It is possible that there is a direct effect of TAM on apoptosis or indirect effect through a progesterone-related mechanism.
FOXL2 Mutation Status in Granulosa Theca Cell Tumors of the Ovary
Authors: Nolan Amber , Joseph Nancy M. , Sangoi Ankur R. , Rabban Joseph , Zaloudek Charles , Garg Karuna
Published: March 2017

Ovarian sex-cord stromal tumors that have between 10% and 50% granulosa cells in a prominent fibrothecomatous background have been referred to as granulosa theca cell tumors or mixed granulosa theca cell tumors. The classification and prognosis of these tumors is not clear. Most adult granulosa cell tumors of the ovary harbor a mutation in the FOXL2 gene, whereas fibromas and thecomas lack this mutation. The aim of our study was to assess the FOXL2 mutation status of ovarian granulosa theca cell tumors and to correlate the mutation status with morphologic and clinical characteristics. A FOXL2 mutation was detected in 6 of 12 (50%) granulosa theca cell tumors. Tumors with higher cellularity of granulosa cells were more likely to harbor a FOXL2 mutation as were tumors in which the granulosa cells formed large lobules. No conclusions could be drawn regarding the clinical and prognostic significance of the presence of a mutation given the small number of cases and limited clinical follow-up. Our study shows that half of granulosa theca cell tumors harbor the same FOXL2 mutation that characterizes adult granulosa cell tumors but there is no outcome evidence to guide whether mutation status should alter the classification of the tumor or the management of the patient.
Podoplanin and SOX2 Expression in CIN 3–like Squamous Cell Carcinoma of the Cervix
Authors: Stewart Colin J.R. , Crook Maxine L.
Published: March 2017

Squamous cell carcinoma (SCC) of the uterine cervix occasionally demonstrates a deceptive growth pattern that mimics endocervical crypt involvement by cervical intraepithelial neoplasia, grade 3 (CIN 3). Such CIN 3–like SCCs may be misinterpreted as noninvasive or minimally invasive leading to delays in diagnosis. Little is known of the factors that influence the growth patterns of cervical SCC but we suggested recently that CIN 3–like tumors might demonstrate “collective cellular invasion,” which is characterized by a retained epithelial phenotype. This contrasts with the more overtly infiltrative growth of conventional SCC, which exhibits features suggestive of epithelial-mesenchymal transition. In the current study we investigated podoplanin (PP) and SOX2 expression in normal squamous epithelium, in CIN 3 and in 16 CIN 3–like SCCs 11 of which also showed a conventional invasive component. Compared with normal epithelium, CIN 3 often showed a focal loss of basal PP staining and most cases showed increased, typically diffuse, SOX2 expression. Although the immunohistochemical findings were not uniform, they generally supported collective cellular invasion in CIN 3–like tumor areas as these were often PP positive and showed diffuse SOX2 expression. In contrast, most conventional SCCs showed only focal SOX2 staining and they were typically negative, or only focally positive, for PP. The staining patterns did not reliably distinguish CIN 3 from CIN 3–like SCC. Small infiltrative tumor nests around the margins of CIN 3 or deeply invasive CIN 3–like SCC often showed a localized reduction in SOX2 expression suggesting SOX2 downregulation during the transition to invasive growth.
Vulvar Carcinosarcoma Composed of Intestinal-type Mucinous Adenocarcinoma Associated With Anaplastic Pleomorphic and Spindle Cell Carcinoma and Heterologous Chondrosarcomatous and Osteosarcomatous Elements: A Case Report and Review of the Literature
Authors: Lordello Leonardo , Webb Patricia , Oliva Esther
Published: March 2017

Carcinosarcomas (CS) are exceedingly rare in the vulva, with only 3 cases reported in the English literature, associated with squamous cell carcinoma (2) or spiradenocarcinoma (1). We first report a vulvar CS with intestinal-type mucinous adenocarcinoma associated with anaplastic pleomorphic and spindle cell carcinoma and heterologous chondro- and osteosarcomatous elements in a 62-year-old woman, who presented with a painless, slow-growing vulvar cyst for almost 2 years, that rapidly enlarged and hardened in the last 4 months forming a mass. The tumor was widely excised, but recurred 2 months later, and she died 2 months after recurrence. A review on this entity is performed highlighting its morphologic and immunohistochemical features, and discussing issues in nomenclature and potential origins within the vulva.
Effects of Medical Interventions on Gender Dysphoria and Body Image: A Follow-Up Study
Authors: van de Grift Tim C. , Elaut Els , Cerwenka Susanne C. , Cohen-Kettenis Peggy T. , De Cuypere Griet , Richter-Appelt Hertha , Kreukels Baudewijntje P.C.
Published: March 2017

Objective

The aim of this study from the European Network for the Investigation of Gender Incongruence is to investigate the status of all individuals who had applied for gender confirming interventions from 2007 to 2009, irrespective of whether they received treatment. The current article describes the study protocol, the effect of medical treatment on gender dysphoria and body image, and the predictive value of (pre)treatment factors on posttreatment outcomes.

Methods

Data were collected on medical interventions, transition status, gender dysphoria (Utrecht Gender Dysphoria Scale), and body image (Body Image Scale for transsexuals). In total, 201 people participated in the study (37% of the original cohort).

Results

At follow-up, 29 participants (14%) did not receive medical interventions, 36 hormones only (18%), and 136 hormones and surgery (68%). Most transwomen had undergone genital surgery, and most transmen chest surgery. Overall, the levels of gender dysphoria and body dissatisfaction were significantly lower at follow-up compared with clinical entry. Satisfaction with therapy responsive and unresponsive body characteristics both improved. High dissatisfaction at admission and lower psychological functioning at follow-up were associated with persistent body dissatisfaction.

Conclusions

Hormone-based interventions and surgery were followed by improvements in body satisfaction. The level of psychological symptoms and the degree of body satisfaction at baseline were significantly associated with body satisfaction at follow-up.
Infective endocarditis in children: an update
Authors: Dixon Garth , Christov Georgi
Published: March 2017

Purpose of review

Infective endocarditis in children remains a clinical challenge. Here, we review the impact of the updated 2015 American Heart Association and European Society of Cardiology guidelines on management as well as the significance of the new predisposing factors, diagnostic and treatment options, and the impact of the 2007–2008 change in prophylaxis recommendations.

Recent findings

The new 2015 infective endocarditis guidelines introduced the endocarditis team, added the new imaging modalities of computer tomography and PET–computer tomography into the diagnostic criteria and endorsed the concept of safety of relatively early surgical treatment. The impact of the restriction of infective endocarditis prophylaxis since the 2007–2008 American Heart Association and National Institute for Health and Care Excellence recommendations is uncertain, with some studies showing no change and other more recent studies showing increased incidence. The difficulties in adjusting for varying confounding factors are discussed. The relative proportion of the device-related infective endocarditis is increasing. Special attention is paid to relatively high incidence of percutaneous pulmonary valve implantation-related infective endocarditis with low proportion of positive echo signs, disproportionate shift in causative agents, and unusual complication of acute obstruction. The significance of incomplete neoendothelialization on the risk of infective endocarditis on intracardiac devices is also discussed.

The impact of changes in the infective endocarditis prophylaxis recommendations in pediatric patients is still uncertain. The device-related infective endocarditis has increasing importance, with the incidence on transcatheter implanted bovine jugular vein pulmonary valves being relatively high. The use of novel imaging, laboratory diagnostic techniques, and relatively early surgery in particular circumstances is important for management of paediatric infective endocarditis.
Endothelial cells and lymphatics at the interface between the immune and central nervous systems: implications for multiple sclerosis
Authors: Meyer Céline , Martin-Blondel Guillaume , Liblau Roland S.
Published: March 2017

Purpose of review

The central nervous system (CNS) has a unique relationship with the immune system. This review highlights the distinct roles of lymphatic vessels and endothelial cells in the interface between CNS and immune cells and invites to revisit the concept of CNS immune privilege.

Recent findings

T cells can follow several routes to penetrate the CNS parenchyma but may also benefit, together with antigen-loaded presenting cells, from the newly described lymphatic network to exit the CNS. CNS endothelial cells (EC) critically positioned at the interface between circulating immune cells and the CNS regulate the multistep cascade for immune cell trafficking into the CNS. They can also be considered as semiprofessional antigen-presenting cells through their ability to present antigens to T cells and to regulate their activation through co-stimulatory and inhibitory molecules.

The lymphatic network linking the CNS to draining lymph nodes may contribute to the inflammatory reaction occurring in multiple sclerosis (MS). The abundance and strategic positioning of endothelial cells at the blood–brain barrier level most likely endow them with an important role in controlling local adaptive immune responses, rendering them potential therapeutic targets in neuro-inflammatory such as MS.
Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges in Coma—Incidence and Interrater Reliability of Continuous EEG After a Standard Stimulation Protocol: A Prospective Study
Authors: Alsherbini Khalid A. , Plancher Joao Mc-O'Neil , Ficker David M. , Foreman Brandon P. , Adeoye Opeolu M. , Ying Jun , Privitera Michael D.
Published: March 2017

Purpose:

Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) are often seen during continuous electroencephalographic (cEEG) monitoring in coma. Given their uncertain clinical significance, our prospective study evaluated incidence of SIRPIDs in comatose patients in the neuroscience intensive care unit (NSICU) who underwent a standard stimulation protocol and defined interreader reliability for cEEG.

Methods:

Of 146 patients prospectively screened who underwent cEEG during a 6-month period, 53 patients were included and 93 patients were excluded. Our protocol used a sequence of auditory, mild tactile, and painful stimuli tested in a quiet room. Continuous electroencephalogram were then reviewed offline by blinded experts, with interrater agreement assessed by kappa statistic. By Pearson χ2 and Wilcoxon rank-sum tests, we then compared binary and numerical clinical features between those with and without SIRPIDs.

Results:

Of 53 patients who underwent our protocol, one patient with a corrupt cEEG file was excluded. Traumatic brain injury was the most common diagnosis. Moderate interrater agreement was observed for 66 total stimulations: 20 patients (38.5%) had possible or definite SIRPIDs by minimum one reviewer. For 19 stimulations reviewed by a third reviewer, consensus was reached in 10 cases making the incidence of SIRPIDs 19.3% in our cohort. There was a moderate interrate agreement with kappa of 0.5 (95% confidence interval: 0.1, 0.7). Median intensive care unit stay was 15 days in patients with SIRPIDs versus 6.5 days in those without (P = 0.021).

Conclusions:

Our prospective study of SIRPIDs in the neuroscience intensive care unit found a 19% incidence by cEEG using a standard stimulation protocol, most often rhythmic delta activity, and showed a moderate interrater agreement.
Bridging Computational Neuroscience and Machine Learning on Non-Stationary Multi-Armed Bandits
Authors: Velentzas George , Tzafestas Costas , Khamassi Mehdi
Published: March 2017

Fast adaptation to changes in the environment requires both natural and artificial agents to be able to dynamically tune an exploration-exploitation trade-off during learning. This trade-off usually determines a fixed proportion of exploitative choices (i.e. choice of the action that subjectively appears as best at a given moment) relative to exploratory choices (i.e. testing other actions that now appear worst but may turn out promising later). The problem of finding an efficient exploration-exploitation trade-off has been well studied both in the Machine Learning and Computational Neuroscience fields. Rather than using a fixed proportion, non-stationary multi-armed bandit methods in the former have proven that principles such as exploring actions that have not been tested for a long time can lead to performance closer to optimal - bounded regret. In parallel, researches in the latter have investigated solutions such as progressively increasing exploitation in response to improvements of performance, transiently increasing exploration in response to drops in average performance, or attributing exploration bonuses specifically to actions associated with high uncertainty in order to gain information when performing these actions. In this work, we first try to bridge some of these different methods from the two research fields by rewriting their decision process with a common formalism. We then show numerical simulations of a hybrid algorithm combining bio-inspired meta-learning, kalman filter and exploration bonuses compared to several state-of-the-art alternatives on a set of non-stationary stochastic multi-armed bandit tasks. While we find that different methods are appropriate in different scenarios, the hybrid algorithm displays a good combination of advantages from different methods and outperforms these methods in the studied scenarios.
Comparison Of Multi-locus Sequence Typing software For next generation sequencing data
Authors: Page Andrew J. , Alikhan Nabil-Fareed , Carleton Heather A. , Seemann Torsten , Keane Jacqueline A. , Katz Lee S.
Published: March 2017

Multi-locus sequence typing (MLST) is a widely used method for categorising bacteria. Increasingly MLST is being performed using next generation sequencing data by reference labs and for clinical diagnostics. Many software applications have been developed to calculate sequence types from NGS data; however, there has been no comprehensive review to date on these methods. We have compared six of these applications against real and simulated data and present results on: 1. the accuracy of each method against traditional typing methods, 2. the performance on real outbreak datasets, 3. in the impact of contamination and varying depth of coverage, and 4. the computational resource requirements.

DATA SUMMARY

Simulated reads for datasets testing coverage and mixed samples have been deposited in Figshare; DOI:https://doi.org/10.6084/m9.figshare.4602301.vl

Outbreak databases are available from Github; url -https://github.com/WGS-standards-and-analysis/datasets

Docker containers used to run each of the applications are available from Github; url –https://tinyurl.com/z7ks2ft

Accession numbers for the data used in this paper are available in the Supplementary material.

We confirm all supporting data, code and protocols have been provided within the article or through supplementary data files. ☒

IMPACT STATEMENT

Sequence typing is rapidly transitioning from traditional sequencing methods to using whole genome sequencing. A number ofin silicoprediction methods have been developed on anad hocbasis and aim to replicate Multi-locus sequence typing (MLST). This is the first study to comprehensively evaluate multiple MLST software applications on real validated datasets and on common simulated difficult cases. It will give researchers a clearer understanding of the accuracy, limitations and computational performance of the methods they use, and will assist future researchers to choose the most appropriate method for their experimental goals.
Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data
Authors: Racle Julien , de Jonge Kaat , Baumgaertner Petra , Speiser Daniel E. , Gfeller David
Published: March 2017

Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research.
Probabilistic recovery of cryptic haplotypes from metagenomic data
Authors: Nicholls Samuel M. , Aubrey Wayne , de Grave Kurt , Schietgat Leander , Creevey Christopher J. , Clare Amanda
Published: March 2017

The cryptic diversity of microbial communities represent an untapped biotechnological resource for biomining, biorefining and synthetic biology. Revealing this information requires the recovery of the exact sequence of DNA bases (or “haplotype”) that constitutes the genes and genomes of every individual present. This is a computationally difficult problem complicated by the requirement for environmental sequencing approaches (metagenomics) due to the resistance of the constituent organisms to culturingin vitro.

Haplotypes are identified by their unique combination of DNA variants. However, standard approaches for working with metagenomic data require simplifications that violate assumptions in the process of identifying such variation. Furthermore, current haplotyping methods lack objective mechanisms for choosing between alternative haplotype reconstructions from microbial communities.

To address this, we have developed a novel probabilistic approach for reconstructing haplotypes from complex microbial communities and propose the “metahaplome” as a definition for the set of haplotypes for any particular genomic region of interest within a metagenomic dataset. Implemented in the twin software tools Hansel and Gretel, the algorithm performs incremental probabilistic haplotype recovery using Naive Bayes — an efficient and effective technique.

Our approach is capable of reconstructing the haplotypes with the highest likelihoods from metagenomic datasets withouta prioriknowledge or making assumptions of the distribution or number of variants. Additionally, the algorithm is robust to sequencing and alignment error without altering or discarding observed variation and uses all available evidence from aligned reads. We validate our approach using synthetic metahaplomes constructed from sets of real genes, and demonstrate its capability using metagenomic data from a complex HIV-1 strain mix. The results show that the likelihood framework can allow recovery from microbial communities of cryptic functional isoforms of genes with 100% accuracy.
Variation of the meiotic recombination landscape and properties over a broad evolutionary distance in yeasts
Authors: Brion Christian , Legrand Sylvain , Peter Jackson , Caradec Claudia , Pflieger David , Hou Jing , Friedrich Anne , Llorente Bertrand , Schacherer Joseph
Published: March 2017

Meiotic recombination is a major factor of genome evolution, deeply characterized in only a few model species, notably the yeastSaccharomyces cerevisiae.Consequently, little is known about variations of its properties across species. In this respect, we explored the recombination landscape ofLachancea kluyveri,a protoploid yeast species that diverged from theSaccharomycesgenus more than 100 million years ago and we found striking differences withS. cerevisiae.These variations include a lower recombination rate, a higher frequency of chromosomes segregating without any crossover and the absence of recombination on the chromosome arm containing the sex locus. In addition, although well conserved within theSaccharomycesclade, theS. cerevisiaerecombination hotspots are not conserved over a broader evolutionary distance. Finally and strikingly, we found evidence of frequent reversion of meiotic commitment to mitotic growth allowing allele shuffling without meiosis completion. Identification of this major but underestimated evolutionary phenomenon illustrates the relevance of exploring non-model species.

Author summary

Meiotic recombination promotes accurate chromosome segregation and genetic diversity. To date, the mechanisms and rules lying behind recombination were dissected using model organisms such as the budding yeastSaccharomyces cerevisiae. To assess the conservation and variation of this process over a broad evolutionary distance, we explored the meiotic recombination landscape inLachancea kluyveri,a budding yeast species that diverged fromS. cerevisiaemore than 100 million years ago. The meiotic recombination map we generated revealed that the meiotic recombination landscape and properties significantly vary across distantly related yeast species, supporting that recombination hotspots conservation across yeast species is likely associated to the conservation of synteny. Finally, the frequent meiotic reversions we observed led us to re-evaluate their evolutionary importance.
mRNA and long non-coding RNA expression profiles in rats reveal inflammatory features in sepsis-associated encephalopathy
Authors: Sun WenChong , Pei Ling , Liang Zuodi
Published: March 2017

Background

Sepsis-associated encephalopathy (SAE) is related to cognitive sequelae in patients in the intensive care unit (ICU) and can have serious impacts on quality of life after recovery. Although various pathogenic pathways are involved in SAE development, little is known concerning the global role of long non-coding RNAs (lncRNAs) in SAE.

Methods

Herein, we employed transcriptome sequencing approaches to characterize the effects of lipopolysaccharide (LPS) on lncRNA expression patterns in brain tissue isolated from Sprague-Dawley (SD) rats with and without SAE. We performed high-throughput transcriptome sequencing after LPS was intraperitoneally injected and predicted targets and functions using bioinformatics tools. Subsequently, we explored the results in detail according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses.

Results

LncRNAs were differentially expressed in brain tissue after LPS treatment. After 6 h of LPS exposure, expression of 400 lncRNAs were significantly changed, including an increase in 316 lncRNAs and a decrease in 84 lncRNAs. In addition, 155 mRNAs were differentially expressed, with 84 up-regulated and 71 down-regulated. At 24 h post-treatment, expression of 117 lncRNAs and 57 mRNAs was consistently elevated, while expression of 79 lncRNAs and 21 mRNAs was decreased (change > 1.5-fold; p < 0.05). We demonstrated for the first time that differentially expressed lncRNAs were predicted to be enriched in a post-chaperonin tubulin folding pathway (GO : 007023), which is closely related to the key step in the tubulin folding process.

Interestingly, the predicted pathway (KEGG 04360: axon guidance) was significantly changed under the same conditions. These results reveal that LPS might influence the construction and polarization of microtubules, which exert predominant roles in synaptogenesis and related biofunctions in the rodent central nervous system (CNS).

Conclusions

An inventory of LPS-modulated expression profiles from the rodent CNS is an important step toward understanding the function of mRNAs, including lncRNAs, and suggests that microtubule malformation and dysfunction may be involved in SAE pathogenesis.
Increased pericarp cell length underlies a major QTL for grain weight in hexaploid wheat
Authors: Brinton Jemima , Simmonds James , Minter Francesca , Leverington-Waite Michelle , Snape John , Uauy Cristobal
Published: March 2017

Crop yields must increase to address food insecurity. Grain weight, determined by grain length and width, is an important yield component, but our understanding of the underlying genes and mechanisms is limited.

We used genetic mapping and near isogenic lines (NILs) to identify, validate and fine map a major quantitative trait loci (QTL) on wheat chromosome 5A associated with grain weight. Detailed phenotypic characterisation of developing and mature grains from the NILs was performed.

We identified a stable and robust QTL associated with a 6.9 % increase in grain weight. The positive interval leads to 4.0 % longer grains, with differences first visible twelve days post fertilization. This grain length effect was fine-mapped to a 4.3 cM interval. The locus also has a pleiotropic effect on grain width (1.5 %) during late grain development that determines the relative magnitude of the grain weight increase. Positive NILs have increased maternal pericarp cell length, an effect which is independent of absolute grain length.

These results provide direct genetic evidence that pericarp cell length affects final grain size and weight in polyploid wheat. We propose that combining genes which control distinct biological mechanisms, such as cell expansion and proliferation, will enhance crop yields.
Intracellular Sodium Regulates Opioid Signalling in Peripheral Neurons
Authors: Kanellopoulos Alexandros H. , Zhao Jing , Emery Edward C. , Wood John N
Published: March 2017

Opioid receptors signal more effectively in sensory neurons from pain-free mice lacking the voltagegated sodium channel Nav1.7. Type-A GPCRs are known to be regulated through a specific sodium binding site, the occupancy of which diminishes agonist binding. We have used an electrophysiological assay of Protein Kinase A activity to examine the role of intracellular sodium on opioid signalling. Phosphorylation of sodium channel Nav1.8 by activation of Protein Kinase A with db-cAMP is unaffected by altered intracellular sodium. By contrast, there is a dose-dependent inhibition of fentanyl action on Nav1.8 currents when intracellular sodium is increased from 0 mM to 20 mM. Fentanyl shows a 50% loss of activity and 80-fold increase in EC50with 20 mM intracellular sodium. These data demonstrate that altered intracellular sodium levels modulate opioid receptor signalling.