Lane Medical Library

Male Infertility and Risk of Nonmalignant Chronic Diseases: A Systematic Review of the Epidemiological Evidence.

Semin Reprod Med. 2017 May;35(3):282-290

Authors: Glazer CH, Bonde JP, Eisenberg ML, Giwercman A, Hærvig KK, Rimborg S, Vassard D, Pinborg A, Schmidt L, Bräuner EV

PMID: 28658712 [PubMed - in process]

Rheological characterization of human brain tissue.

Acta Biomater. 2017 Jun 25;:

Authors: Budday S, Sommer G, Haybaeck J, Steinmann P, Holzapfel GA, Kuhl E

Abstract
The rheology of ultrasoft materials like the human brain is highly sensitive to regional and temporal variations and to the type of loading. While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior under various loading conditions remains insufficiently understood. Here we combine cyclic and relaxation testing under multiple loading conditions, shear, compression, and tension, to understand the rheology of four different regions of the human brain, the cortex, the basal ganglia, the corona radiata, and the corpus callosum. We establish a family of finite viscoelastic Ogden-type models and calibrate their parameters simultaneously for all loading conditions. We show that the model with only one viscoelastic mode and a constant viscosity captures the essential features of brain tissue: nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. With stiffnesses and time constants of μ∞=0.7kPa, μ1=2.0kPa, and τ1=9.7s in the gray matter cortex and μ∞=0.3kPa, μ1=0.9kPa and τ1=14.9s in the white matter corona radiata combined with negative parameters α∞ and α1, this five-parameter model naturally accounts for pre-conditioning and tissue softening. Increasing the number of viscoelastic modes improves the agreement between model and experiment, especially across the entire relaxation regime. Strikingly, two cycles of pre-conditioning decrease the gray matter stiffness by up to a factor three, while the white matter stiffness remains almost identical. These new insights allow us to better understand the rheology of different brain regions under mixed loading conditions. Our family of finite viscoelastic Ogden-type models for human brain tissue is simple to integrate into standard nonlinear finite element packages. Our simultaneous parameter identification of multiple loading modes can inform computational simulations under physiological conditions, especially at low to moderate strain rates. Understanding the rheology of the human brain will allow us to more accurately model the behavior of the brain during development and disease and predict outcomes of neurosurgical procedures.
STATEMENT OF SIGNIFICANCE: While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior at finite strains and under various loading conditions remains insufficiently understood. In this manuscript, we characterize the rheology of human brain tissue through a family of finite viscoelastic Ogdentype models and identify their parameters for multiple loading modes in four different regions of the brain. We show that even the simplest model of this family, with only one viscoelastic mode and five material parameters, naturally captures the essential features of brain tissue: its characteristic nonlinearity, pre-conditioning, hysteresis, and tensioncompression asymmetry. For the first time, we simultaneously identify a single parameter set for shear, compression, tension, shear relaxation, and compression relaxation loading. This parameter set is significant for computational simulations under physiological conditions, where loading is naturally of mixed mode nature. Understanding the rheology of the human brain will help us predict neurosurgical procedures, inform brain injury criteria, and improve the design of protective devices.

PMID: 28658600 [PubMed - as supplied by publisher]

Genetically Encoded Calcium Indicators for Fluorescence Imaging in the Moss Physcomitrella: GCaMP3 Provides a Bright New Look.

Plant Biotechnol J. 2017 Jun 28;:

Authors: Kleist TJ, Cartwright HN, Perera AM, Christianson ML, Lemaux PG, Luan S

Abstract
The moss Physcomitrella patens is emerging as a model organism due to the availability of established protocols for precise genome engineering by homologous recombination and a high-quality genome sequence (Rensing et al., 2008). Physcomitrella is an attractive system for cell biology and live cell imaging and has been used to investigate fundamental cellular processes such as tip growth, vesicle trafficking, and cytoskeletal dynamics (e.g., Furt et al., 2012). In each of these processes, calcium (Ca(2+) ) acts as an important signal to relay developmental and environmental cues. This article is protected by copyright. All rights reserved.

PMID: 28658532 [PubMed - as supplied by publisher]

The Evolving Story of Overlapping Surgery.

JAMA. 2017 Jun 28;:

Authors: Mello MM, Livingston EH

PMID: 28658474 [PubMed - as supplied by publisher]

Isotretinoin and Timing of Procedural Interventions: A Systematic Review With Consensus Recommendations.

JAMA Dermatol. 2017 Jun 28;:

Authors: Spring LK, Krakowski AC, Alam M, Bhatia A, Brauer J, Cohen J, Del Rosso JQ, Diaz L, Dover J, Eichenfield LF, Gurtner GC, Hanke CW, Jahnke MN, Kelly KM, Khetarpal S, Kinney MA, Levy ML, Leyden J, Longaker MT, Munavalli GS, Ozog DM, Prather H, Shumaker PR, Tanzi E, Torres A, Velez MW, Waldman AB, Yan AC, Zaenglein AL

Abstract
Importance: The notion that systemic isotretinoin taken within 6 to 12 months of cutaneous surgery contributes to abnormal scarring or delayed wound healing is widely taught and practiced; however, it is based on 3 small case series from the mid-1980s.
Objective: To evaluate the body of literature to provide evidence-based recommendations regarding the safety of procedural interventions performed either concurrently with, or immediately following the cessation of systemic isotretinoin therapy.
Evidence Review: A panel of national experts in pediatric dermatology, procedural/cosmetic dermatology, plastic surgery, scars, wound healing, acne, and isotretinoin was convened. A systematic PubMed review of English-language articles published from 1982 to 2017 was performed using the following search terms: isotretinoin, 13-cis-retinoic acid, Accutane, retinoids, acitretin, surgery, surgical, laser, ablative laser, nonablative laser, laser hair removal, chemical peel, dermabrasion, wound healing, safety, scarring, hypertrophic scar, and keloid. Evidence was graded, and expert consensus was obtained.
Findings: Thirty-two relevant publications reported 1485 procedures. There was insufficient evidence to support delaying manual dermabrasion, superficial chemical peels, cutaneous surgery, laser hair removal, and fractional ablative and nonablative laser procedures for patients currently receiving or having recently completed isotretinoin therapy. Based on the available literature, mechanical dermabrasion and fully ablative laser are not recommended in the setting of systemic isotretinoin treatment.
Conclusions and Relevance: Physicians and patients may have an evidence-based discussion regarding the known risk of cutaneous surgical procedures in the setting of systemic isotretinoin therapy. For some patients and some conditions, an informed decision may lead to earlier and potentially more effective interventions.

PMID: 28658462 [PubMed - as supplied by publisher]

The Fifth Vital Sign: Postoperative Pain Predicts 30-day Readmissions and Subsequent Emergency Department Visits.

Ann Surg. 2017 Jun 27;:

Authors: Hernandez-Boussard T, Graham LA, Desai K, Wahl TS, Aucoin E, Richman JS, Morris MS, Itani KM, Telford GL, Hawn MT

Abstract
OBJECTIVE: We hypothesized that inpatient postoperative pain trajectories are associated with 30-day inpatient readmission and emergency department (ED) visits.
BACKGROUND: Surgical readmissions have few known modifiable predictors. Pain experienced by patients may reflect surgical complications and/or inadequate or difficult symptom management.
METHODS: National Veterans Affairs Surgical Quality Improvement data on inpatient general, vascular, and orthopedic surgery from 2008 to 2014 were merged with laboratory, vital sign, health care utilization, and postoperative complications data. Six distinct postoperative inpatient patient-reported pain trajectories were identified: (1) persistently low, (2) mild, (3) moderate or (4) high trajectories, and (5) mild-to-low or (6) moderate-to-low trajectories based on postoperative pain scores. Regression models estimated the association between pain trajectories and postdischarge utilization while controlling for important patient and clinical variables.
RESULTS: Our sample included 211,231 surgeries-45.4% orthopedics, 37.0% general, and 17.6% vascular. Overall, the 30-day unplanned readmission rate was 10.8%, and 30-day ED utilization rate was 14.2%. Patients in the high pain trajectories had the highest rates of postdischarge readmissions and ED visits (14.4% and 16.3%, respectively, P < 0.001). In multivariable models, compared with the persistently low pain trajectory, there was a dose-dependent increase in postdischarge ED visits and readmission for pain-related diagnoses, but not postdischarge complications (χ trend P < 0.001).
CONCLUSIONS: Postoperative pain trajectories identify populations at risk for 30-day readmissions and ED visits, and do not seem to be mediated by postdischarge complications. Addressing pain control expectations before discharge may help reduce surgical readmissions in high pain categories.

PMID: 28657940 [PubMed - as supplied by publisher]

Machine Learning and Prediction in Medicine - Beyond the Peak of Inflated Expectations.

N Engl J Med. 2017 Jun 29;376(26):2507-2509

Authors: Chen JH, Asch SM

PMID: 28657867 [PubMed - in process]

Does the use of arteriovenous loops increase complications rates in posttraumatic microsurgical lower extremity reconstruction?-A matched-pair analysis.

Microsurgery. 2017 Jun 28;:

Authors: Momeni A, Lanni MA, Levin LS, Kovach SJ

Abstract
INTRODUCTION: The use of arteriovenous (AV) loops in microsurgical lower extremity reconstruction is a controversial topic. The objective of the present study was to assess the impact of AV loops on complication rates following microsurgical reconstruction of posttraumatic lower extremity defects.
PATIENTS AND METHODS: Patients who underwent free flap coverage of posttraumatic defects in combination with an AV loop (Group 1) were identified and matched for age, body mass index (BMI), tobacco use, defect location, and flap type with patients who underwent reconstruction without vein grafts (Group 2). Outcomes of interest included complication rate and flap loss rate.
RESULTS: Groups 1 and 2 consisted of 10 patients each with a mean age of 51 years (range, 21-79 years) and 47.3 years (range, 22-69 years), respectively (P = 0.596). No differences were noted regarding flap loss (P = 1.0), intraoperative (P = 0.474) or postoperative complication rate [surgical site infection (P = 1.0), bleeding (P = 1.0), delayed wound healing (P = 0.23), dehiscence (P = 0.58), and osseous non-union (P = 1.0)]. Only one flap loss was noted in Group 1. The only differences were increased operative time (P = 0.03) and increased length of stay (P = 0.009) in Group 1.
CONCLUSION: Our results suggest that utilization of vein grafts with creation of AV loops followed by single-stage division and free flap transfer for reconstruction of posttraumatic lower extremity defects achieve reconstructive outcomes similar to those obtained in patients in whom no vein grafts are necessary.

PMID: 28657669 [PubMed - as supplied by publisher]

Family Science Talk in Museums: Predicting Children's Engagement From Variations in Talk and Activity.

Child Dev. 2017 Jun 28;:

Authors: Callanan MA, Castañeda CL, Luce MR, Martin JL

Abstract
Children's developing reasoning skills are better understood within the context of their social and cultural lives. As part of a research-museum partnership, this article reports a study exploring science-relevant conversations of 82 families, with children between 3 and 11 years, while visiting a children's museum exhibit about mammoth bones, and in a focused one-on-one exploration of a "mystery object." Parents' use of a variety of types of science talk predicted children's conceptual engagement in the exhibit, but interestingly, different types of parent talk predicted children's engagement depending on the order of the two activities. The findings illustrate the importance of studying children's thinking in real-world contexts and inform creation of effective real-world science experiences for children and families.

PMID: 28657198 [PubMed - as supplied by publisher]

Joint genotype- and ancestry-based genome-wide association studies in admixed populations.

Genet Epidemiol. 2017 Jun 28;:

Authors: Szulc P, Bogdan M, Frommlet F, Tang H

Abstract
In genome-wide association studies (GWAS) genetic loci that influence complex traits are localized by inspecting associations between genotypes of genetic markers and the values of the trait of interest. On the other hand, admixture mapping, which is performed in case of populations consisting of a recent mix of two ancestral groups, relies on the ancestry information at each locus (locus-specific ancestry). Recently it has been proposed to jointly model genotype and locus-specific ancestry within the framework of single marker tests. Here, we extend this approach for population-based GWAS in the direction of multimarker models. A modified version of the Bayesian information criterion is developed for building a multilocus model that accounts for the differential correlation structure due to linkage disequilibrium (LD) and admixture LD. Simulation studies and a real data example illustrate the advantages of this new approach compared to single-marker analysis or modern model selection strategies based on separately analyzing genotype and ancestry data, as well as to single-marker analysis combining genotypic and ancestry information. Depending on the signal strength, our procedure automatically chooses whether genotypic or locus-specific ancestry markers are added to the model. This results in a good compromise between the power to detect causal mutations and the precision of their localization. The proposed method has been implemented in R and is available at http://www.math.uni.wroc.pl/~mbogdan/admixtures/.

PMID: 28657151 [PubMed - as supplied by publisher]

The dawn of automated insulin delivery: A new clinical framework to conceptualize insulin administration.

Pediatr Diabetes. 2017 Jun 27;:

Authors: Messer LH, Forlenza GP, Wadwa RP, Weinzimer SA, Sherr JL, Hood KK, Buckingham BA, Slover RH, Maahs DM

PMID: 28656656 [PubMed - as supplied by publisher]

Automatic renal segmentation for MR urography using 3D-GrabCut and random forests.

Magn Reson Med. 2017 Jun 27;:

Authors: Yoruk U, Hargreaves BA, Vasanawala SS

Abstract
PURPOSE: To introduce and evaluate a fully automated renal segmentation technique for glomerular filtration rate (GFR) assessment in children.
METHODS: An image segmentation method based on iterative graph cuts (GrabCut) was modified to work on time-resolved 3D dynamic contrast-enhanced MRI data sets. A random forest classifier was trained to further segment the renal tissue into cortex, medulla, and the collecting system. The algorithm was tested on 26 subjects and the segmentation results were compared to the manually drawn segmentation maps using the F1-score metric. A two-compartment model was used to estimate the GFR of each subject using both automatically and manually generated segmentation maps.
RESULTS: Segmentation maps generated automatically showed high similarity to the manually drawn maps for the whole-kidney (F1 = 0.93) and renal cortex (F1 = 0.86). GFR estimations using whole-kidney segmentation maps from the automatic method were highly correlated (Spearman's ρ = 0.99) to the GFR values obtained from manual maps. The mean GFR estimation error of the automatic method was 2.98 ± 0.66% with an average segmentation time of 45 s per patient.
CONCLUSION: The automatic segmentation method performs as well as the manual segmentation for GFR estimation and reduces the segmentation time from several hours to 45 s. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

PMID: 28656614 [PubMed - as supplied by publisher]

If I do not have enough water, then how could I bring additional water for toilet cleaning?! Addressing water scarcity to promote hygienic use of shared toilets in Dhaka, Bangladesh.

Trop Med Int Health. 2017 Jun 27;:

Authors: Saxton RE, Yeasmin F, Alam MU, Al-Masud A, Dutta NC, Yeasmin D, Luby SP, Unicomb L, Winch PJ

Abstract
OBJECTIVES: Provision of toilets is necessary but not sufficient to impact health as poor maintenance may impair toilet function and discourage their consistent use. Water in urban slums is both scarce and a prerequisite for toilet maintenance behaviors. We describe the development of behavior change communications and selection of low-cost water storage hardware to facilitate adequate flushing among users of shared toilets.
METHODS: We conducted 9 focus group discussions and 6 ranking exercises with adult users of shared toilets (50 females, 35 males), then designed and implemented 3 pilot interventions to facilitate regular flushing and improve hygienic conditions of shared toilets. We conducted follow-up assessments one and two months post-pilot including 9 in-depth interviews and 3 focus group discussions with adult residents (23 females, 15 males) and 3 landlords in the pilot communities.
RESULTS: Periodic water scarcity was common in the study communities. Residents felt embarrassed to carry water for flushing. Reserving water adjacent to the shared toilet enabled slum residents to flush regularly. Signs depicting rules for toilet use empowered residents and landlords to communicate these expectations for flushing to transient tenants. Residents in the pilot reported improvements in cleanliness and reduced odor inside toilet cubicles.
CONCLUSIONS: Our pilot demonstrates the potential efficacy of low-cost water storage and behavior change communications to improve maintenance of and user satisfaction with shared toilets in urban slum settings. This article is protected by copyright. All rights reserved.

PMID: 28656596 [PubMed - as supplied by publisher]

Relationship between subjective and actigraphy-measured sleep in 237 patients with metastatic colorectal cancer.

Qual Life Res. 2017 Jun 27;:

Authors: Palesh O, Haitz K, Lévi F, Bjarnason GA, Deguzman C, Alizeh I, Ulusakarya A, Packer MM, Innominato PF

Abstract
OBJECTIVE: Patients with cancers frequently experience sleep and circadian dysfunction. To date, only a few studies have used both a questionnaire and actigraphy for concomitant evaluation of sleep and circadian function in patients with cancer. We sought to evaluate objective sleep and circadian parameters in metastatic colon cancer (MCC) patients and their associations with symptoms and quality of life (QOL).
METHODS: Patients reported subjective sleep problems on the EORTC QLQ-C30. Sleep and circadian parameters were calculated using a wrist-actigraph that patients wore for 72 h.
RESULTS: 237 Patients with MCC (mean age: 60.4 years; range: 20.7-77.6; Male/Female ratio: 1.66) participated in this cross-sectional study. Subjective sleep problems were reported by 63.4% of patients (S+). No differences in any sleep parameters (sleep efficiency, sleep latency, total sleep time, total time in bed, wake after sleep onset, activity bathyphase) were observed between S+ and S- patients. However, S+ patients displayed a significantly worse circadian function than S- patients (96.4 vs 98.1%; p = 0.005). The presence of poor subjective sleep and objective circadian dysfunction negatively affected symptoms and QOL domains (p = 0.038).
CONCLUSIONS: Subjective report of sleep problems was not associated with worse objectively measured sleep parameters in patients with MCC although it was associated with disrupted circadian rest-activity rhythm and poorer QOL. These findings coincide with prior research in cancer patients in that an inconsistent relationship exists between subjective and objective sleep measurements on some sleep domains. This study supports the value of coupled evaluation of self-reported and objective measures of sleep and circadian function in cancer patients.

PMID: 28656534 [PubMed - as supplied by publisher]

Surgeon Design Interface for Patient-Specific Concentric Tube Robots.

Proc IEEE RAS EMBS Int Conf Biomed Robot Biomechatron. 2016 Jun;2016:41-48

Authors: Morimoto TK, Greer JD, Hsieh MH, Okamura AM

Abstract
Concentric tube robots have potential for use in a wide variety of surgical procedures due to their small size, dexterity, and ability to move in highly curved paths. Unlike most existing clinical robots, the design of these robots can be developed and manufactured on a patient- and procedure-specific basis. The design of concentric tube robots typically requires significant computation and optimization, and it remains unclear how the surgeon should be involved. We propose to use a virtual reality-based design environment for surgeons to easily and intuitively visualize and design a set of concentric tube robots for a specific patient and procedure. In this paper, we describe a novel patient-specific design process in the context of the virtual reality interface. We also show a resulting concentric tube robot design, created by a pediatric urologist to access a kidney stone in a pediatric patient.

PMID: 28656124 [PubMed - in process]

HBV/HCV Coinfection and Possible Reactivation of HBV Following DAA Use.

Gastroenterol Hepatol (N Y). 2017 May;13(5):292-295

Authors: Gish RG

PMID: 28656026 [PubMed - in process]

In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells.

Sci Signal. 2017 Jun 27;10(485):

Authors: Mukherjee S, Jensen H, Stewart W, Stewart D, Ray WC, Chen SY, Nolan GP, Lanier LL, Das J

Abstract
Natural killer (NK) cells perform immunosurveillance of virally infected and transformed cells, and their activation depends on the balance between signaling by inhibitory and activating receptors. Cytokine receptor signaling can synergize with activating receptor signaling to induce NK cell activation. We investigated the interplay between the signaling pathways stimulated by the cytokine interleukin-2 (IL-2) and the activating receptor NKG2D in immature (CD56(bright)) and mature (CD56(dim)) subsets of human primary NK cells using mass cytometry experiments and in silico modeling. Our analysis revealed that IL-2 changed the abundances of several key proteins, including NKG2D and the phosphatase CD45. Furthermore, we found differences in correlations between protein abundances, which were associated with the maturation state of the NK cells. The mass cytometry measurements also revealed that the signaling kinetics of key protein abundances induced by NKG2D stimulation depended on the maturation state and the pretreatment condition of the NK cells. Our in silico model, which described the multidimensional data with coupled first-order reactions, predicted that the increase in CD45 abundance was a major enhancer of NKG2D-mediated activation in IL-2-treated CD56(bright) NK cells but not in IL-2-treated CD56(dim) NK cells. This dependence on CD45 was verified by measurement of CD107a mobilization to the NK cell surface (a marker of activation). Our mathematical framework can be used to glean mechanisms underlying synergistic signaling pathways in other activated immune cells.

PMID: 28655861 [PubMed - in process]

Risk for Major Bleeding in Patients Receiving Ticagrelor Compared with Aspirin After TIA or Acute Ischemic Stroke in the SOCRATES Study.

Circulation. 2017 Jun 27;:

Authors: Easton JD, Aunes M, Albers GW, Amarenco P, Bokelund Singh S, Denison H, Evans SR, Held P, Jahreskog M, Jonasson J, Mimematsu K, Molina CA, Wang Y, Wong KSL, Johnston SC, SOCRATES Steering Committee and Investigators

Abstract
Background -Patients with minor acute ischemic stroke (AIS) or transient ischemic attack (TIA) are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial was the first trial with ticagrelor in patients with AIS or TIA, in which the efficacy and safety of ticagrelor were compared with aspirin. The main safety objective was assessment of PLATO-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods -An independent adjudication committee, blinded to study treatment, classified bleeds according to the PLATO, TIMI and GUSTO definitions. The definitions of ICrH and major bleeding excluded cerebral micro-bleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results -A total of 13,130 of 13,199 randomized patients received at least one dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (HR 0.83, 95% CI 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (four on ticagrelor and nine on aspirin) were hemorrhagic strokes and four (two in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in six and 13, traumatic in three and three, and procedural in three and two patients on ticagrelor and aspirin, respectively. In total, nine fatal bleeds occurred on ticagrelor and four on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independent of bleeding classification, PLATO, TIMI or GUSTO, the relative difference between treatments for major/severe bleedings was similar. Non-major bleeds were more common on ticagrelor. Conclusions -Antiplatelet therapy with ticagrelor in patients with AIS or TIA showed a similar bleeding profile as aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration -URL: http://www.clinicaltrials.gov Unique Identifier: NCT01994720.

PMID: 28655834 [PubMed - as supplied by publisher]

Isolation and Structure-function Characterization of a Signaling-active Rhodopsin-G protein Complex.

J Biol Chem. 2017 Jun 27;:

Authors: Gao Y, Westfield G, Erickson JW, Cerione RA, Skiniotis G, Ramachandran S

Abstract
The visual photo-transduction cascade is a prototypical G protein-coupled receptor (GPCR) signaling system, in which light-activated rhodopsin (Rho*) is the GPCR catalyzing the exchange of GDP for GTP on the heterotrimeric G protein transducin (GT). This results in the dissociation of GT into its component αT-GTP and β1γ1 subunit complex. Structural information for the Rho*-GT complex will be essential for understanding the molecular mechanism of visual photo-transduction. Moreover, it will shed light on how GPCRs selectively couple to and activate their G protein signaling partners. Here we report on the preparation of a stable detergent-solubilized complex between Rho* and a heterotrimer (GT*) comprising a GαT/Gαi1 chimera (αT*) and β1γ1 The complex was formed on native rod outer segment membranes upon light activation, solubilized in lauryl maltose neopentyl glycol (LMNG), and purified with a combination of affinity and size exclusion chromatography. We found that the complex is fully functional and that the stoichiometry of Rho* to GαT* is 1:1. The molecular weight of the complex was calculated from small angle X-ray scattering (SAXS) data and was in good agreement with a model consisting of one Rho* and one GT*. The complex was visualized by negative-stain electron microscopy (EM), which revealed an architecture similar to that of the β2 adrenergic receptor-GS complex including a flexible αT* helical domain. The stability and high yield of the purified complex should allow for further efforts toward obtaining a high-resolution structure of this important signaling complex.

PMID: 28655769 [PubMed - as supplied by publisher]

RBM25 is a global splicing factor promoting inclusion of alternatively spliced exons and is itself regulated by lysine mono-methylation.

J Biol Chem. 2017 Jun 27;:

Authors: Carlson SM, Soulette CM, Yang Z, Elias JE, Brooks AN, Gozani O

Abstract
In eukaryotes, pre-mRNA splicing removes non-coding intron sequences to produce mature mRNA. This removal is controlled in part by RNA-binding proteins that regulate alternative splicing decisions through interactions with the splicing machinery. RNA binding motif protein 25 (RBM25) is a putative splicing factor strongly conserved across eukaryotic lineages. However, the role of RBM25 in global splicing regulation and its cellular functions are unknown. Here we show that RBM25 is required for viability of multiple human cell lines, suggesting that it could play a key role in pre-mRNA splicing. Indeed, transcriptome-wide analysis of splicing events demonstrated that RBM25 regulates a large fraction of alternatively spliced exons throughout the human genome. Moreover, proteomic analysis indicated that RBM25 interacts with components of the early spliceosome and regulators of alternative splicing. Previously, we identified an RBM25 species that is mono-methylated at lysine 77 (RBM25K77me1), and here we used quantitative mass spectrometry to show that RBM25K77me1 is abundant in multiple human cell lines. We also identified a region of RBM25 spanning K77 that binds with high affinity to serine and arginine rich splicing factor 2 (SRSF2), a crucial protein in exon definition, but only when K77 is unmethylated. Together our findings uncover a pivotal role for RBM25 as an essential regulator of alternative splicing and reveal a new potential mechanism for regulation of pre-mRNA splicing by lysine methylation of a splicing factor.

PMID: 28655759 [PubMed - as supplied by publisher]

Structural and functional analysis of the GABARAP interaction motif (GIM).

EMBO Rep. 2017 Jun 27;:

Authors: Rogov VV, Stolz A, Ravicahandran AC, Rios-Szwed DO, Suzuki H, Kniss A, Löhr F, Wakatsuki S, Dötsch V, Dikic I, Dobson RC, McEwan DG

Abstract
Through the canonical LC3 interaction motif (LIR), [W/F/Y]-X1-X2-[I/L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of 30 known core LIR motifs towards individual LC3s and GABARAPs. From these, we define a G ABARAP I nteraction M otif (GIM) sequence ([W/F]-[V/I]-X2-V) that the adaptor protein PLEKHM1 tightly conforms to. Using biophysical and structural approaches, we show that the PLEKHM1-LIR is indeed 11-fold more specific for GABARAP than LC3B. Selective mutation of the X1 and X2 positions either completely abolished the interaction with all LC3 and GABARAPs or increased PLEKHM1-GIM selectivity 20-fold towards LC3B. Finally, we show that conversion of p62/SQSTM1, FUNDC1 and FIP200 LIRs into our newly defined GIM, by introducing two valine residues, enhances their interaction with endogenous GABARAP over LC3B. The identification of a GABARAP-specific interaction motif will aid the identification and characterization of the expanding array of autophagy receptor and adaptor proteins and their in vivo functions.

PMID: 28655748 [PubMed - as supplied by publisher]

Quality Measures in Orthopaedic Sports Medicine: A Systematic Review.

Arthroscopy. 2017 Jun 24;:

Authors: Abrams GD, Greenberg DR, Dragoo JL, Safran MR, Kamal RN

Abstract
PURPOSE: To report the current quality measures that are applicable to orthopaedic sports medicine physicians.
METHODS: Six databases were searched with a customized search term to identify quality measures relevant to orthopaedic sports medicine surgeons: MEDLINE/PubMed, EMBASE, the National Quality Forum (NQF) Quality Positioning System (QPS), the Agency for Healthcare Research and Quality (AHRQ) National Quality Measures Clearinghouse (NQMC), the Physician Quality Reporting System (PQRS) database, and the American Academy of Orthopaedic Surgeons (AAOS) website. Results were screened by 2 Board-certified orthopaedic surgeons with fellowship training in sports medicine and dichotomized based on sports medicine-specific or general orthopaedic (nonarthroplasty) categories. Hip and knee arthroplasty measures were excluded. Included quality measures were further categorized based on Donabedian's domains and the Center for Medicare and Medicaid (CMS) National Quality Strategy priorities.
RESULTS: A total of 1,292 quality measures were screened and 66 unique quality measures were included. A total of 47 were sports medicine-specific and 19 related to the general practice of orthopaedics for a fellowship-trained sports medicine specialist. Nineteen (29%) quality measures were collected within PQRS, with 5 of them relating to sports medicine and 14 relating to general orthopaedics. AAOS Clinical Practice Guidelines (CPGs) comprised 40 (60%) of the included measures and were all within sports medicine. Five (8%) additional measures were collected within AHRQ and 2 (3%) within NQF. Most quality measures consist of process rather than outcome or structural measures. No measures addressing concussions were identified.
CONCLUSIONS: There are many existing quality measures relating to the practice of orthopaedic sports medicine. Most quality measures are process measures described within PQRS or AAOS CPGs.
CLINICAL RELEVANCE: Knowledge of quality measures are important as they may be used to improve care, are increasingly being used to determine physician reimbursement, and can inform future quality measure development efforts.

PMID: 28655476 [PubMed - as supplied by publisher]

Systematic reviews: guidance relevant for studies of older people.

Age Ageing. 2017 Jun 24;:1-7

Authors: Shenkin SD, Harrison JK, Wilkinson T, Dodds RM, Ioannidis JPA

Abstract
Systematic reviews and meta-analyses are increasingly common. This article aims to provide guidance for people conducting systematic reviews relevant to the healthcare of older people. An awareness of these issues will also help people reading systematic reviews to determine whether the results will influence their clinical practice. It is essential that systematic reviews are performed by a team which includes the required technical and clinical expertise. Those performing reviews for the first time should ensure they have appropriate training and support. They must be planned and performed in a transparent and methodologically robust way: guidelines are available. The protocol should be written-and if possible published-before starting the review. Geriatricians will be interested in a table of baseline characteristics, which will help to determine if the studied samples or populations are similar to their patients. Reviews of studies of older people should consider how they will manage issues such as different age cut-offs; non-specific presentations; multiple predictors and outcomes; potential biases and confounders. Systematic reviews and meta-analyses may provide evidence to improve older people's care, or determine where new evidence is required. Newer methodologies, such as meta-analyses of individual level data, network meta-analyses and umbrella reviews, and realist synthesis, may improve the reliability and clinical utility of systematic reviews.

PMID: 28655142 [PubMed - as supplied by publisher]

A Localized Complex of Two Protein Oligomers Controls the Orientation of Cell Polarity.

MBio. 2017 Feb 28;8(1):

Authors: Perez AM, Mann TH, Lasker K, Ahrens DG, Eckart MR, Shapiro L

Abstract
Signaling hubs at bacterial cell poles establish cell polarity in the absence of membrane-bound compartments. In the asymmetrically dividing bacterium Caulobacter crescentus, cell polarity stems from the cell cycle-regulated localization and turnover of signaling protein complexes in these hubs, and yet the mechanisms that establish the identity of the two cell poles have not been established. Here, we recapitulate the tripartite assembly of a cell fate signaling complex that forms during the G1-S transition. Using in vivo and in vitro analyses of dynamic polar protein complex formation, we show that a polymeric cell polarity protein, SpmX, serves as a direct bridge between the PopZ polymeric network and the cell fate-directing DivJ histidine kinase. We demonstrate the direct binding between these three proteins and show that a polar microdomain spontaneously assembles when the three proteins are coexpressed heterologously in an Escherichia coli test system. The relative copy numbers of these proteins are essential for complex formation, as overexpression of SpmX in Caulobacter reorganizes the polarity of the cell, generating ectopic cell poles containing PopZ and DivJ. Hierarchical formation of higher-order SpmX oligomers nucleates new PopZ microdomain assemblies at the incipient lateral cell poles, driving localized outgrowth. By comparison to self-assembling protein networks and polar cell growth mechanisms in other bacterial species, we suggest that the cooligomeric PopZ-SpmX protein complex in Caulobacter illustrates a paradigm for coupling cell cycle progression to the controlled geometry of cell pole establishment.IMPORTANCE Lacking internal membrane-bound compartments, bacteria achieve subcellular organization by establishing self-assembling protein-based microdomains. The asymmetrically dividing bacterium Caulobacter crescentus uses one such microdomain to link cell cycle progression to morphogenesis, but the mechanism for the generation of this microdomain has remained unclear. Here, we demonstrate that the ordered assembly of this microdomain occurs via the polymeric network protein PopZ directly recruiting the polarity factor SpmX, which then recruits the histidine kinase DivJ to the developing cell pole. Further, we find that overexpression of the bridge protein SpmX in Caulobacter disrupts this ordered assembly, generating ectopic cell poles containing both PopZ and DivJ. Together, PopZ and SpmX assemble into a cooligomeric network that forms the basis for a polar microdomain that coordinates bacterial cell polarity.

PMID: 28246363 [PubMed - indexed for MEDLINE]

Toxoplasma DJ-1 Regulates Organelle Secretion by a Direct Interaction with Calcium-Dependent Protein Kinase 1.

MBio. 2017 Feb 28;8(1):

Authors: Child MA, Garland M, Foe I, Madzelan P, Treeck M, van der Linden WA, Oresic Bender K, Weerapana E, Wilson MA, Boothroyd JC, Reese ML, Bogyo M

Abstract
Human DJ-1 is a highly conserved and yet functionally enigmatic protein associated with a heritable form of Parkinson's disease. It has been suggested to be a redox-dependent regulatory scaffold, binding to proteins to modulate their function. Here we present the X-ray crystal structure of the Toxoplasma orthologue Toxoplasma gondii DJ-1 (TgDJ-1) at 2.1-Å resolution and show that it directly associates with calcium-dependent protein kinase 1 (CDPK1). The TgDJ-1 structure identifies an orthologously conserved arginine dyad that acts as a phospho-gatekeeper motif to control complex formation. We determined that the binding of TgDJ-1 to CDPK1 is sensitive to oxidation and calcium, and that this interaction potentiates CDPK1 kinase activity. Finally, we show that genetic deletion of TgDJ-1 results in upregulation of CDPK1 expression and that disruption of the CDPK1/TgDJ-1 complex in vivo prevents normal exocytosis of parasite virulence-associated organelles called micronemes. Overall, our data suggest that TgDJ-1 functions as a noncanonical kinase-regulatory scaffold that integrates multiple intracellular signals to tune microneme exocytosis in T. gondiiIMPORTANCE Apicomplexan parasites such as Toxoplasma and Plasmodium are obligate intracellular parasites that require the protective environment of a host cell in order to replicate and survive within a host organism. These parasites secrete effector proteins from specialized apical organelles to select and invade a chosen host cell. The secretion of these organelles is a tightly regulated process coordinated by endogenous small molecules and calcium-dependent protein kinases. We previously identified the Toxoplasma orthologue of the highly conserved protein DJ-1 as a regulator of microneme secretion, but the molecular basis for this was not known. We have now identified the molecular mechanism for how TgDJ-1 regulates microneme secretion. TgDJ-1 interacts with the kinase responsible for the secretion of these organelles (calcium-dependent kinase 1) and synergizes with calcium to potentiate kinase activity. This interaction is direct, phosphodependent, and necessary for the normal secretion of these important organelles.

PMID: 28246362 [PubMed - indexed for MEDLINE]

Minimally Important Differences in Patient or Proxy-Reported Outcome Studies Relevant to Children: A Systematic Review.

Pediatrics. 2017 Mar;139(3):

Authors: Ebrahim S, Vercammen K, Sivanand A, Guyatt GH, Carrasco-Labra A, Fernandes RM, Crawford MW, Nesrallah G, Johnston BC

Abstract
CONTEXT: No study has characterized and appraised all anchor-based minimally important differences (MIDs) associated with patient-reported outcome (PRO) instruments in pediatric studies.
OBJECTIVE: To complete a comprehensive systematic survey and appraisal of published anchor-based MIDs associated with PRO instruments used in children.
DATA SOURCES: Medline, Embase, and PsycINFO (1989 to February 11, 2015).
STUDY SELECTION: Studies reporting empirical ascertainment of anchor-based MIDs among PROs used in pediatric care.
DATA EXTRACTION: All pertinent data items related to the characteristics of PRO instruments, anchors, and MIDs.
RESULTS: Of 4179 unique citations, 30 studies (including 32 cohorts) proved eligible and reported on 28 unique PROs (8 generic, 13 disease-specific, 5 symptoms-specific, 2 function-specific), with 9 (32%) classified as patient-reported, 11 (39%) proxy-reported, and 8 (29%) both patient- and proxy-reported. Of the 30 studies, we rated 14 (44%) as providing highly credible estimates of the MID. Most cohorts (n = 20, 62%) recorded patients' direct response to the target PRO and the use of an independent standard of comparison (n = 25, 78%). Most, however, failed to effectively report measurement properties of the anchor (n = 24, 75%).
LIMITATIONS: We have not yet addressed the measurement properties of instrument to measure credibility; our search was restricted to 3 electronic sources, and we used a single data abstractor.
CONCLUSIONS: Our study found 28 PROs that have been developed for children, with fewer than half providing credible estimates. Clinicians, clinical trialists, systematic reviewers, and guideline developers seeking to effectively summarize and interpret results of studies addressing PROs in child health are likely to find our comprehensive compendium of MIDs of use, both in providing best estimates of MIDs and identifying credible estimates.

PMID: 28196931 [PubMed - indexed for MEDLINE]

Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis.

J Am Soc Nephrol. 2017 Jun;28(6):1933-1942

Authors: Block GA, Rosenbaum DP, Leonsson-Zachrisson M, Åstrand M, Johansson S, Knutsson M, Langkilde AM, Chertow GM

Abstract
Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebo-controlled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1- to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to <10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia.

PMID: 28159782 [PubMed - indexed for MEDLINE]

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia.

J Am Soc Nephrol. 2017 Jun;28(6):1851-1858

Authors: Fishbane S, Block GA, Loram L, Neylan J, Pergola PE, Uhlig K, Chertow GM

Abstract
Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral ferric citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to ferric citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the ferric citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the ferric citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with ferric citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral ferric citrate to be a safe and efficacious treatment for iron deficiency anemia.

PMID: 28082519 [PubMed - indexed for MEDLINE]

MSMBuilder: Statistical Models for Biomolecular Dynamics.

Biophys J. 2017 Jan 10;112(1):10-15

Authors: Harrigan MP, Sultan MM, Hernández CX, Husic BE, Eastman P, Schwantes CR, Beauchamp KA, McGibbon RT, Pande VS

Abstract
MSMBuilder is a software package for building statistical models of high-dimensional time-series data. It is designed with a particular focus on the analysis of atomistic simulations of biomolecular dynamics such as protein folding and conformational change. MSMBuilder is named for its ability to construct Markov state models (MSMs), a class of models that has gained favor among computational biophysicists. In addition to both well-established and newer MSM methods, the package includes complementary algorithms for understanding time-series data such as hidden Markov models and time-structure based independent component analysis. MSMBuilder boasts an easy to use command-line interface, as well as clear and consistent abstractions through its Python application programming interface. MSMBuilder was developed with careful consideration for compatibility with the broader machine learning community by following the design of scikit-learn. The package is used primarily by practitioners of molecular dynamics, but is just as applicable to other computational or experimental time-series measurements.

PMID: 28076801 [PubMed - indexed for MEDLINE]

BDNF Val66Met polymorphism moderates the link between child maltreatment and reappraisal ability.

Genes Brain Behav. 2017 Apr;16(4):419-426

Authors: Miu AC, Cărnuţă M, Vulturar R, Szekely-Copîndean RD, Bîlc MI, Chiş A, Cioară M, Fernandez KC, Szentágotai-Tătar A, Gross JJ

Abstract
Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype × child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis-stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self-report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype × child maltreatment interaction (B = -0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non-maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders.

PMID: 28009101 [PubMed - indexed for MEDLINE]

Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV.

Science. 2016 11 18;354(6314):865-869

Authors: Logan MM, Toma T, Thomas-Tran R, Du Bois J

Abstract
The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics.

PMID: 27856903 [PubMed - indexed for MEDLINE]

Toward a national, sustained U.S. ecosystem assessment.

Science. 2016 11 18;354(6314):838-839

Authors: Jackson ST, Duke CS, Hampton SE, Jacobs KL, Joppa LN, Kassam KS, Mooney HA, Ogden LA, Ruckelshaus M, Shogren JF

PMID: 27856870 [PubMed - indexed for MEDLINE]

Functional Analysis of Orai1 Concatemers Supports a Hexameric Stoichiometry for the CRAC Channel.

Biophys J. 2016 Nov 01;111(9):1897-1907

Authors: Yen M, Lokteva LA, Lewis RS

Abstract
Store-operated Ca(2+) entry occurs through the binding of the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 to Orai1, the pore-forming subunit of the Ca(2+) release-activated Ca(2+) (CRAC) channel. Although the essential steps leading to channel opening have been described, fundamental questions remain, including the functional stoichiometry of the CRAC channel. The crystal structure of Drosophila Orai indicates a hexameric stoichiometry, while studies of linked Orai1 concatemers and single-molecule photobleaching suggest that channels assemble as tetramers. We assessed CRAC channel stoichiometry by expressing hexameric concatemers of human Orai1 and comparing in detail their ionic currents to those of native CRAC channels and channels generated from monomeric Orai1 constructs. Cell surface biotinylation results indicated that Orai1 channels in the plasma membrane were assembled from intact hexameric polypeptides and not from truncated protein products. In addition, the L273D mutation depressed channel activity equally regardless of which Orai1 subunit in the concatemer carried the mutation. Thus, functional channels were generated from intact Orai1 hexamers in which all subunits contributed equally. These hexameric Orai1 channels displayed the biophysical fingerprint of native CRAC channels, including the distinguishing characteristics of gating (store-dependent activation, Ca(2+)-dependent inactivation, open probability), permeation (ion selectivity, affinity for Ca(2+) block, La(3+) sensitivity, unitary current magnitude), and pharmacology (enhancement and inhibition by 2-aminoethoxydiphenyl borate). Because permeation characteristics depend strongly on pore geometry, it is unlikely that hexameric and tetrameric pores would display identical Ca(2+) affinity, ion selectivity, and unitary current magnitude. Thus, based on the highly similar pore properties of the hexameric Orai1 concatemer and native CRAC channels, we conclude that the CRAC channel functions as a hexamer of Orai1 subunits.

PMID: 27806271 [PubMed - indexed for MEDLINE]

Scar Homogenization Versus Limited-Substrate Ablation in Patients With Nonischemic Cardiomyopathy and Ventricular Tachycardia.

J Am Coll Cardiol. 2016 Nov 01;68(18):1990-1998

Authors: Gökoğlan Y, Mohanty S, Gianni C, Santangeli P, Trivedi C, Güneş MF, Bai R, Al-Ahmad A, Gallinghouse GJ, Horton R, Hranitzky PM, Sanchez JE, Beheiry S, Hongo R, Lakkireddy D, Reddy M, Schweikert RA, Dello Russo A, Casella M, Tondo C, Burkhardt JD, Themistoclakis S, Di Biase L, Natale A

Abstract
BACKGROUND: Scar homogenization improves long-term ventricular arrhythmia-free survival compared with standard limited-substrate ablation in patients with post-infarction ventricular tachycardia (VT). Whether such benefit extends to patients with nonischemic cardiomyopathy and scar-related VT is unclear.
OBJECTIVES: The aim of this study was to assess the long-term efficacy of an endoepicardial scar homogenization approach compared with standard ablation in this population.
METHODS: Consecutive patients with dilated nonischemic cardiomyopathy (n = 93), scar-related VTs, and evidence of low-voltage regions on the basis of pre-defined criteria on electroanatomic mapping (i.e., bipolar voltage <1.5 mV) underwent either standard VT ablation (group 1 [n = 57]) or endoepicardial ablation of all abnormal potentials within the electroanatomic scar (group 2 [n = 36]). Acute procedural success was defined as noninducibility of any VT at the end of the procedure; long-term success was defined as freedom from any ventricular arrhythmia at follow-up.
RESULTS: Acute procedural success rates were 69.4% and 42.1% after scar homogenization and standard ablation, respectively (p = 0.01). During a mean follow-up period of 14 ± 2 months, single-procedure success rates were 63.9% after scar homogenization and 38.6% after standard ablation (p = 0.031). After multivariate analysis, scar homogenization and left ventricular ejection fraction were predictors of long-term success. During follow-up, the rehospitalization rate was significantly lower in the scar homogenization group (p = 0.035).
CONCLUSIONS: In patients with dilated nonischemic cardiomyopathy, scar-related VT, and evidence of low-voltage regions on electroanatomic mapping, endoepicardial homogenization of the scar significantly increased freedom from any recurrent ventricular arrhythmia compared with a standard limited-substrate ablation. However, the success rate with this approach appeared to be lower than previously reported with ischemic cardiomyopathy, presumably because of the septal and midmyocardial distribution of the scar in some patients.

PMID: 27788854 [PubMed - indexed for MEDLINE]

Left Atrial Appendage Isolation in Patients With Longstanding Persistent AF Undergoing Catheter Ablation: BELIEF Trial.

J Am Coll Cardiol. 2016 Nov 01;68(18):1929-1940

Authors: Di Biase L, Burkhardt JD, Mohanty P, Mohanty S, Sanchez JE, Trivedi C, Güneş M, Gökoğlan Y, Gianni C, Horton RP, Themistoclakis S, Gallinghouse GJ, Bailey S, Zagrodzky JD, Hongo RH, Beheiry S, Santangeli P, Casella M, Dello Russo A, Al-Ahmad A, Hranitzky P, Lakkireddy D, Tondo C, Natale A

Abstract
BACKGROUND: Longstanding persistent (LSP) atrial fibrillation (AF) is the most challenging type of AF. In addition to pulmonary vein isolation, substrate modification and triggers ablation have been reported to improve freedom from AF in patients with LSPAF.
OBJECTIVES: This study sought to assess whether the empirical electrical isolation of the left atrial appendage (LAA) could improve success at follow-up.
METHODS: This was an open-label, randomized study assessing the effectiveness of empirical electrical left atrial appendage isolation for the treatment of LSPAF. Patients were randomly assigned to undergo empirical electrical left atrial appendage isolation along with extensive ablation (group 1; n = 85) or extensive ablation alone (group 2; n = 88). Recurrence of atrial arrhythmias was the primary endpoint. Secondary endpoints included cardiac-related hospitalization, all-cause mortality, and stroke at follow-up.
RESULTS: Major clinical characteristics were not different between the 2 groups. At 12-month follow-up, 48 (56%) patients in group 1 and 25 (28%) in group 2 were recurrence free after a single procedure (unadjusted hazard ratio [HR] for recurrence with standard ablation: 1.92; 95% confidence interval [CI]: 1.3 to 2.9; log-rank p = 0.001). After adjusting for age, sex, and left atrial size, standard ablation was predictive of recurrence (HR: 2.22; 95% CI: 1.29 to 3.81; p = 0.004). During repeat procedures, empirical electrical left atrial appendage isolation was performed in all patients. After an average of 1.3 procedures, cumulative success at 24-month follow-up was reported in 65 (76%) in group 1 and in 49 (56%) in group 2 (unadjusted HR: 2.24; 95% CI: 1.3 to 3.8; log-rank p = 0.003).
CONCLUSIONS: This randomized study showed that both after a single procedure and after redo procedures in patients with LSPAF, empirical electrical isolation of the LAA improved long-term freedom from atrial arrhythmias without increasing complications. (Effect of Empirical Left Atrial Appendage Isolation on Long-term Procedure Outcome in Patients With Persistent or Longstanding Persistent Atrial Fibrillation Undergoing Catheter Ablation [BELIEF]; NCT01362738).

PMID: 27788847 [PubMed - indexed for MEDLINE]

The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease.

J Am Coll Cardiol. 2016 Oct 25;68(17):1898-1907

Authors: Jones WS, Roe MT, Antman EM, Pletcher MJ, Harrington RA, Rothman RL, Oetgen WJ, Rao SV, Krucoff MW, Curtis LH, Hernandez AF, Masoudi FA

Abstract
Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.

PMID: 27765193 [PubMed - indexed for MEDLINE]

Transcatheter Pulmonary Valve Replacement Reduces Tricuspid Regurgitation in Patients With Right Ventricular Volume/Pressure Overload.

J Am Coll Cardiol. 2016 Oct 04;68(14):1525-35

Authors: Jones TK, Rome JJ, Armstrong AK, Berger F, Hellenbrand WE, Cabalka AK, Benson LN, Balzer DT, Cheatham JP, Eicken A, McElhinney DB

Abstract
BACKGROUND: Tricuspid regurgitation (TR) is a common and important comorbidity in patients with postoperative right ventricular outflow tract (RVOT) obstruction or pulmonary regurgitation (PR). Transcatheter pulmonary valve replacement (TPVR) has become a useful tool in the management of postoperative RVOT obstruction and PR, but it is unknown whether relief of the right ventricular volume and/or pressure overload by TPVR will have a beneficial effect on TR, as is often seen with surgical pulmonary valve replacement.
OBJECTIVES: This study sought to assess the prevalence of and factors associated with significant TR in patients undergoing TPVR for RVOT obstruction or PR.
METHODS: Data were combined from 3 prospective multicenter trials of patients referred for TPVR. Follow-up data through 5 years post-implantation were analyzed.
RESULTS: Of 300 patients studied, 77 (25.6%) had moderate or severe TR at baseline. After TPVR, TR severity was improved in 65% of those patients, and more than one-half had mild TR or less TR at discharge. Of 13 patients with severe TR pre-implantation, only 1 had severe TR at 1-year follow-up and beyond. Moderate or severe baseline TR was associated with shorter freedom from RVOT reintervention after TPVR.
CONCLUSIONS: In this prospective multicenter study of post-operative patients with RVOT obstruction and/or PR, TR was common. In patients with significant baseline TR, TPVR resulted in clinically relevant acute reductions in TR that persisted over at least 5 years of follow-up. These observations support the application of TPVR therapy in patients with RVOT obstruction or PR who are anatomically suitable, even in the setting of significant concomitant TR.

PMID: 27687194 [PubMed - indexed for MEDLINE]

High Throughput Light Absorber Discovery, Part 2: Establishing Structure-Band Gap Energy Relationships.

ACS Comb Sci. 2016 Nov 14;18(11):682-688

Authors: Suram SK, Newhouse PF, Zhou L, Van Campen DG, Mehta A, Gregoire JM

Abstract
Combinatorial materials science strategies have accelerated materials development in a variety of fields, and we extend these strategies to enable structure-property mapping for light absorber materials, particularly in high order composition spaces. High throughput optical spectroscopy and synchrotron X-ray diffraction are combined to identify the optical properties of Bi-V-Fe oxides, leading to the identification of Bi4V1.5Fe0.5O10.5 as a light absorber with direct band gap near 2.7 eV. The strategic combination of experimental and data analysis techniques includes automated Tauc analysis to estimate band gap energies from the high throughput spectroscopy data, providing an automated platform for identifying new optical materials.

PMID: 27662502 [PubMed - indexed for MEDLINE]

Mapping Disparities in Access to Safe, Timely, and Essential Surgical Care in Zambia.

JAMA Surg. 2016 Nov 01;151(11):1064-1069

Authors: Esquivel MM, Uribe-Leitz T, Makasa E, Lishimpi K, Mwaba P, Bowman K, Weiser TG

Abstract
Importance: Surgical care is widely unavailable in developing countries; advocates recommend that countries evaluate and report on access to surgical care to improve availability and aid health planners in decision making.
Objective: To analyze the infrastructure, capacity, and availability of surgical care in Zambia to inform health policy priorities.
Design, Setting, and Participants: In this observational study, all hospitals providing surgical care were identified in cooperation with the Zambian Ministry of Health. On-site data collection was conducted from February 1 through August 30, 2011, with an adapted World Health Organization Global Initiative for Emergency and Essential Surgical Care survey. Data collection at each facility included interviews with hospital personnel and assessment of material resources. Data were geocoded and analyzed in a data visualization platform from March 1 to December 1, 2015. We analyzed time and distance to surgical services, as well as the proportion of the population living within 2 hours from a facility providing surgical care.
Main Outcomes and Measures: Surgical capacity, supplies, human resources, and infrastructure at each surgical facility, as well as the population living within 2 hours from a hospital providing surgical care.
Results: Data were collected from all 103 surgical facilities identified as providing surgical care. When including all surgical facilities (regardless of human resources and supplies), 14.9% of the population (2 166 460 of 14 500 000 people) lived more than 2 hours from surgical care. However, only 17 hospitals (16.5%) met the World Health Organization minimum standards of surgical safety; when limiting the analysis to these hospitals, 65.9% of the population (9 552 780 people) lived in an area that was more than 2 hours from a surgical facility. Geographic analysis of emergency and essential surgical care, defined as access to trauma care, obstetric care, and care of common abdominal emergencies, found that 80.7% of the population (11 704 700 people) lived in an area that was more than 2 hours from these surgical facilities.
Conclusions and Relevance: A large proportion of the population in Zambia does not have access to safe and timely surgical care; this percentage would change substantially if all surgical hospitals were adequately resourced. Geospatial visualization tools assist in the evaluation of surgical infrastructure in Zambia and can identify key areas for improvement.

PMID: 27580500 [PubMed - indexed for MEDLINE]

ABO blood group and risk of cancer: A register-based cohort study of 1.6 million blood donors.

Cancer Epidemiol. 2016 Oct;44:40-43

Authors: Vasan SK, Hwang J, Rostgaard K, Nyrén O, Ullum H, Pedersen OB, Erikstrup C, Melbye M, Hjalgrim H, Pawitan Y, Edgren G

Abstract
INTRODUCTION: The associations between ABO blood group and cancer risk have been studied repeatedly, but results have been variable. Consistent associations have only been reported for pancreatic and gastric cancers.
MATERIALS AND METHODS: We estimated associations between different ABO blood groups and site-specific cancer risk in a large cohort of healthy blood donors from Sweden and Denmark.
RESULTS: A total of 1.6 million donors were followed over 27 million person-years (20 million in Sweden and 7 million in Denmark). We observed 119,584 cancer cases. Blood groups A, AB and B were associated either with increased or decreased risk of cancer at 13 anatomical sites (p≤0.05), compared to blood group O. Consistent with assessment using a false discovery rate approach, significant associations with ABO blood group were observed for cancer of the pancreas, breast, and upper gastrointestinal tract (mouth, salivary glands, pharynx, esophageal adenocarcinoma and stomach).
DISCUSSION: Our study reconfirms the association between ABO blood group and cancer risk and exact underlying mechanisms involved needs further research.

PMID: 27459465 [PubMed - indexed for MEDLINE]

Randomized n-of-1 Trials: Quality Improvement, Research, or Both?

Pediatrics. 2016 Aug;138(2):

Authors: Samuel JP, Burgart A, Wootton SH, Magnus D, Lantos JD, Tyson JE

Abstract
The regulatory demarcations between clinical research and quality improvement (QI) are ambiguous and controversial. Some projects that were undertaken as a form of QI were deemed by regulatory agencies to be research and thus to require institutional review board approval. In the era of personalized medicine, some physicians may ask some patients to participate in n-of-1 trials in an effort to personalize and optimize each patient's medical treatment. Should such activities be considered research, QI, or just excellent personalized medicine? Experts in research, research regulation, and bioethics analyze these issues.

PMID: 27385811 [PubMed - indexed for MEDLINE]

Pediatric Resident Workload Intensity and Variability.

Pediatrics. 2016 Jul;138(1):

Authors: Was A, Blankenburg R, Park KT

Abstract
BACKGROUND: Research on resident workloads has focused primarily on the quantity of hours worked, rather than the content of those hours or the variability among residents. We hypothesize that there are statistically significant variations in resident workloads and better understanding of workload intensity could improve resident education.
METHODS: The Stanford Children's Health research database was queried for all electronic notes and orders written by pediatric residents from June 2012 to March 2014. The dataset was narrowed to ensure an accurate comparison among residents. A survey was used to determine residents' self-perceived workload intensity. Variability of total notes written and orders entered was analyzed by χ(2) test and a Monte Carlo simulation. Linear regression was used to analyze the correlation between note-writing and order-entry workload intensity.
RESULTS: A total of 20 280 notes and 112 214 orders were written by 26 pediatric interns during 6 core rotations between June 2012 and June 2013. Both order-entry and note-writing workload intensity showed highly significant (P < .001) variability among residents. "High workload" residents, defined as the top quartile of total workload intensity, wrote 91% more orders and 19% more notes than "low workload" residents in the bottom quartile. Statistically significant correlation was observed between note-writing and order-entry workload intensity (R(2) = 0.22; P = .02). There was no significant correlation between residents' self-perceived workload intensity and their objective workload.
CONCLUSIONS: Significant variations in workload exist among pediatric residents. This may contribute to heterogeneous educational opportunities, physician wellness, and quality of patient care.

PMID: 27358473 [PubMed - indexed for MEDLINE]

Transforming the care of atrial fibrillation with mobile health.

J Interv Card Electrophysiol. 2016 Oct;47(1):45-50

Authors: Turakhia MP, Kaiser DW

Abstract
Atrial fibrillation (AF) is a multifaceted and highly variable disease that is often difficult to manage within the traditional health-care model. The conventional model of regular or pre-scheduled appointments with physicians or allied health professionals is poorly suited to the unpredictable and often urgent clinical needs of patients with AF. Mobile health (mHealth) has the potential to dramatically transform the delivery and quality of AF care. In this brief review, we summarize the current limitations and evidence gaps in treating patients with AF. We then describe the current mHealth landscape, changes in telehealth coverage and reimbursement, and recent technological advances of smartphones, mobile applications, and connected wearable devices. We also describe important barriers and challenges, such as clinical management of large volumes of data, application of predictive analytics/machine learning, and the need for high-quality randomized clinical trials.

PMID: 27306552 [PubMed - indexed for MEDLINE]

Comparison of Clinical, Maternal, and Self Pubertal Assessments: Implications for Health Studies.

Pediatrics. 2016 Jul;138(1):

Authors: Terry MB, Goldberg M, Schechter S, Houghton LC, White ML, O'Toole K, Chung WK, Daly MB, Keegan TH, Andrulis IL, Bradbury AR, Schwartz L, Knight JA, John EM, Buys SS

Abstract
BACKGROUND: Most epidemiologic studies of puberty have only 1 source of pubertal development information (maternal, self or clinical). Interpretation of results across studies requires data on reliability and validity across sources.
METHODS: The LEGACY Girls Study, a 5-site prospective study of girls aged 6 to 13 years (n = 1040) collected information on breast and pubic hair development from mothers (for all daughters) and daughters (if ≥10 years) according to Tanner stage (T1-5) drawings. At 2 LEGACY sites, girls (n = 282) were also examined in the clinic by trained professionals. We assessed agreement (κ) and validity (sensitivity and specificity) with the clinical assessment (gold standard) for both the mothers' and daughters' assessment in the subcohort of 282. In the entire cohort, we examined the agreement between mothers and daughters.
RESULTS: Compared with clinical assessment, sensitivity of maternal assessment for breast development was 77.2 and specificity was 94.3. In girls aged ≥11 years, self-assessment had higher sensitivity and specificity than maternal report. Specificity for both mothers and self, but not sensitivity, was significantly lower for overweight girls. In the overall cohort, maternal and daughter agreement for breast development and pubic hair development (T2+ vs T1) were similar (0.66, [95% confidence interval 0.58-0.75] and 0.69 [95% confidence interval 0.61-0.77], respectively), but declined with age. Mothers were more likely to report a lower Tanner stage for both breast and pubic hair compared with self-assessments.
CONCLUSIONS: These differences in validity should be considered in studies measuring pubertal changes longitudinally when they do not have access to clinical assessments.

PMID: 27279647 [PubMed - indexed for MEDLINE]

Parent Health Literacy, Depression, and Risk for Pediatric Injury.

Pediatrics. 2016 Jul;138(1):

Authors: Cheng ER, Bauer NS, Downs SM, Sanders LM

Abstract
BACKGROUND: Population-wide research on the impact of parent health literacy to children's health outcomes is limited. We assessed the relationship of low parent health literacy to a range of pediatric health risks within a large cohort of primary care patients.
METHODS: Data were from 17 845 English- and Spanish-speaking parents of children aged ≤7 years presenting for well-child care. We used a 3-item screener to measure health literacy. Outcomes included secondhand smoke exposure, asthma treatment nonadherence, parent depression, child-rearing practices, injury prevention, and parent first-aid knowledge. We summarized study variables with descriptive statistics and then performed multivariable logistic regression to identify associations between low parent literacy and our dependent measures.
RESULTS: Mean child age was 4.8 years (SD 3.7); 36.5% of parent respondents had low health literacy. In models adjusted for child gender, race/ethnicity, insurance, age, and parent language preference, low parent health literacy was related to a range of pediatric health risks, including parent depression (adjusted odds ratio [AOR] 1.32; 95% confidence interval 1.18-1.48), firearm access (AOR 1.68; 1.49-1.89), not having a working smoke detector (AOR 3.54; 2.74-4.58), and lack of first-aid knowledge about choking (AOR 1.67; 1.44-1.93) and burns (AOR 1.45; 1.29-1.63). Children of parents with low health literacy were also more likely to watch >2 hours of television per day (AOR 1.27; 1.17-1.36).
CONCLUSIONS: Low parent health literacy is independently and significantly related to parent depression, child television viewing, and at-risk family behaviors associated with child injury. Use of low-literacy approaches to health-behavior interventions may be essential to address common child morbidities.

PMID: 27273749 [PubMed - indexed for MEDLINE]

Bottle Size and Weight Gain in Formula-Fed Infants.

Pediatrics. 2016 Jul;138(1):

Authors: Wood CT, Skinner AC, Yin HS, Rothman RL, Sanders LM, Delamater AM, Perrin EM

Abstract
BACKGROUND: Formula-fed infants may be at greater risk for overfeeding and rapid weight gain. Different size bottles are used for feeding infants, although little is known about whether bottle size is related to weight gain in bottle-fed infants.
METHODS: Data from the Greenlight Intervention Study, a cluster randomized trial to prevent childhood obesity at 4 pediatric resident clinics, were used to analyze the exposure to regular (<6 oz) or large (≥6 oz) bottle size at the 2-month visit on changes in weight, weight-for-age z score (WAZ), and weight-for-length z score (WLZ) at the 6-month visit. Using multivariable regression, we adjusted for potential confounders (birth weight, gender, age, weight measures at 2 months, parent race/ethnicity, education, household income and size, time between 2- and 6-month visits, and first child status).
RESULTS: Forty-five percent (n = 386; 41% black, 35% Hispanic, 23% white, 2% other) of infants at the 2-month visit were exclusively formula-fed, and 44% used large (≥6 oz) bottles. Infants whose parents fed with large bottles had 0.21 kg (95% confidence interval [CI]: 0.05 to 0.37) more weight change, 0.24 U (95% CI: 0.07 to 0.41) more change in WAZ, and 0.31 U (95% CI: 0.08 to 0.54) more change in WLZ during this period than infants fed with regular bottles.
CONCLUSIONS: Using a large bottle in early infancy independently contributed to greater weight gain and change in WLZ at the 6-month visit. Although growth in infancy is complex, bottle size may be a modifiable risk factor for rapid infant weight gain and later obesity among exclusively formula-fed infants.

PMID: 27273748 [PubMed - indexed for MEDLINE]

The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.

Nat Genet. 2016 Jun;48(6):648-56

Authors: Toriyama M, Lee C, Taylor SP, Duran I, Cohn DH, Bruel AL, Tabler JM, Drew K, Kelly MR, Kim S, Park TJ, Braun DA, Pierquin G, Biver A, Wagner K, Malfroot A, Panigrahi I, Franco B, Al-Lami HA, Yeung Y, Choi YJ, University of Washington Center for Mendelian Genomics, Duffourd Y, Faivre L, Rivière JB, Chen J, Liu KJ, Marcotte EM, Hildebrandt F, Thauvin-Robinet C, Krakow D, Jackson PK, Wallingford JB

Abstract
Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

PMID: 27158779 [PubMed - indexed for MEDLINE]

Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences.

Nat Genet. 2016 Jun;48(6):593-9

Authors: Poznik GD, Xue Y, Mendez FL, Willems TF, Massaia A, Wilson Sayres MA, Ayub Q, McCarthy SA, Narechania A, Kashin S, Chen Y, Banerjee R, Rodriguez-Flores JL, Cerezo M, Shao H, Gymrek M, Malhotra A, Louzada S, Desalle R, Ritchie GR, Cerveira E, Fitzgerald TW, Garrison E, Marcketta A, Mittelman D, Romanovitch M, Zhang C, Zheng-Bradley X, Abecasis GR, McCarroll SA, Flicek P, Underhill PA, Coin L, Zerbino DR, Yang F, Lee C, Clarke L, Auton A, Erlich Y, Handsaker RE, 1000 Genomes Project Consortium, Bustamante CD, Tyler-Smith C

Abstract
We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.

PMID: 27111036 [PubMed - indexed for MEDLINE]

Concerted genomic targeting of H3K27 demethylase REF6 and chromatin-remodeling ATPase BRM in Arabidopsis.

Nat Genet. 2016 Jun;48(6):687-93

Authors: Li C, Gu L, Gao L, Chen C, Wei CQ, Qiu Q, Chien CW, Wang S, Jiang L, Ai LF, Chen CY, Yang S, Nguyen V, Qi Y, Snyder MP, Burlingame AL, Kohalmi SE, Huang S, Cao X, Wang ZY, Wu K, Chen X, Cui Y

Abstract
SWI/SNF-type chromatin remodelers, such as BRAHMA (BRM), and H3K27 demethylases both have active roles in regulating gene expression at the chromatin level, but how they are recruited to specific genomic sites remains largely unknown. Here we show that RELATIVE OF EARLY FLOWERING 6 (REF6), a plant-unique H3K27 demethylase, targets genomic loci containing a CTCTGYTY motif via its zinc-finger (ZnF) domains and facilitates the recruitment of BRM. Genome-wide analyses showed that REF6 colocalizes with BRM at many genomic sites with the CTCTGYTY motif. Loss of REF6 results in decreased BRM occupancy at BRM-REF6 co-targets. Furthermore, REF6 directly binds to the CTCTGYTY motif in vitro, and deletion of the motif from a target gene renders it inaccessible to REF6 in vivo. Finally, we show that, when its ZnF domains are deleted, REF6 loses its genomic targeting ability. Thus, our work identifies a new genomic targeting mechanism for an H3K27 demethylase and demonstrates its key role in recruiting the BRM chromatin remodeler.

PMID: 27111034 [PubMed - indexed for MEDLINE]

Analysis of catheter contact force during atrial fibrillation ablation using the robotic navigation system: results from a randomized study.

J Interv Card Electrophysiol. 2016 Aug;46(2):97-103

Authors: Dello Russo A, Fassini G, Conti S, Casella M, Di Monaco A, Russo E, Riva S, Moltrasio M, Tundo F, De Martino G, Gallinghouse GJ, Di Biase L, Natale A, Tondo C

Abstract
PURPOSE: Contact with cardiac tissue is an important determinant of lesion efficacy during atrial fibrillation (AF) ablation. The Sensei X™ robotic navigation system (RNS) (Hansen Medical, Mountain View, CA, USA) has been validated for contact force (CF) sensing expressed in grams (g). The Thermocool® SmartTouch™ catheter enables the measurement of catheter tip CF and direction inside the heart. We aimed to investigate the catheter CF with and without RNS during pulmonary vein isolation (PVI) procedures.
METHODS: Eighty patients with symptomatic AF (56 males, age 63 ± 18) were enrolled in this study. Fifty-seven patients had paroxysmal AF and 23 early persistent AF. All procedures were performed with the Thermocool® SmartTouch™ ablation catheter. Forty patients were randomized to perform PVI with the Sensei X™ RNS (group 1), while in the other 40 patients (group 2), PVI was performed without the RNS.
RESULTS: AF ablation was performed successfully in all patients without complications, while contact force was kept in the established 10-40 g range. A significantly higher CF was documented on the PVs in group 1 compared to group 2. The 1-year freedom from AF recurrence was higher in group 1 compared to group 2 (90 vs. 65 %, p = 0.04). Moreover, a significant reduction of fluoroscopy time was noted in the RNS group (13 ± 10 vs. 20 ± 10 min, respectively, p = 0.05).
CONCLUSIONS: The Sensei X™ RNS permits a significantly higher CF during transcatheter AF ablation with a low rate of AF recurrence at clinical follow-up.

PMID: 26798037 [PubMed - indexed for MEDLINE]

Contrasting Frequencies and Effects of cis- and trans-Regulatory Mutations Affecting Gene Expression.

Mol Biol Evol. 2016 May;33(5):1131-46

Authors: Metzger BP, Duveau F, Yuan DC, Tryban S, Yang B, Wittkopp PJ

Abstract
Heritable differences in gene expression are caused by mutations in DNA sequences encoding cis-regulatory elements and trans-regulatory factors. These two classes of regulatory change differ in their relative contributions to expression differences in natural populations because of the combined effects of mutation and natural selection. Here, we investigate how new mutations create the regulatory variation upon which natural selection acts by quantifying the frequencies and effects of hundreds of new cis- and trans-acting mutations altering activity of the TDH3 promoter in the yeast Saccharomyces cerevisiae in the absence of natural selection. We find that cis-regulatory mutations have larger effects on expression than trans-regulatory mutations and that while trans-regulatory mutations are more common overall, cis- and trans-regulatory changes in expression are equally abundant when only the largest changes in expression are considered. In addition, we find that cis-regulatory mutations are skewed toward decreased expression while trans-regulatory mutations are skewed toward increased expression. We also measure the effects of cis- and trans-regulatory mutations on the variability in gene expression among genetically identical cells, a property of gene expression known as expression noise, finding that trans-regulatory mutations are much more likely to decrease expression noise than cis-regulatory mutations. Because new mutations are the raw material upon which natural selection acts, these differences in the frequencies and effects of cis- and trans-regulatory mutations should be considered in models of regulatory evolution.

PMID: 26782996 [PubMed - indexed for MEDLINE]

"Reverse Genomics" Predicts Function of Human Conserved Noncoding Elements.

Mol Biol Evol. 2016 May;33(5):1358-69

Authors: Marcovitz A, Jia R, Bejerano G

Abstract
Evolutionary changes in cis-regulatory elements are thought to play a key role in morphological and physiological diversity across animals. Many conserved noncoding elements (CNEs) function as cis-regulatory elements, controlling gene expression levels in different biological contexts. However, determining specific associations between CNEs and related phenotypes is a challenging task. Here, we present a computational "reverse genomics" approach that predicts the phenotypic functions of human CNEs. We identify thousands of human CNEs that were lost in at least two independent mammalian lineages (IL-CNEs), and match their evolutionary profiles against a diverse set of phenotypes recently annotated across multiple mammalian species. We identify 2,759 compelling associations between human CNEs and a diverse set of mammalian phenotypes. We discuss multiple CNEs, including a predicted ear element near BMP7, a pelvic CNE in FBN1, a brain morphology element in UBE4B, and an aquatic adaptation forelimb CNE near EGR2, and provide a full list of our predictions. As more genomes are sequenced and more traits are annotated across species, we expect our method to facilitate the interpretation of noncoding mutations in human disease and expedite the discovery of individual CNEs that play key roles in human evolution and development.

PMID: 26744417 [PubMed - indexed for MEDLINE]