bluuebunny/crossref_metadata_2025 huggingface dataset:
Older Adult Attendance in Cardiac Rehabilitation
Authors: Zullo Melissa D. , Dolansky Mary A. , Josephson Richard A. , Cheruvu Vinay K.
Published: July 2017

Purpose:

Older adults who use postacute care (PAC) after hospitalization for myocardial infarction (MI) are often overlooked as cardiac rehabilitation (CR) candidates because of physical limitations. This research describes the impact of functional status and PAC, including inpatient rehabilitation facility (IRF), skilled nursing facility (SNF), or home health care (HHC), on CR initiation in Medicare beneficiaries discharged from the hospital following an index MI.

Methods:

The Chronic Condition Warehouse database of Medicare beneficiaries discharged to PAC following index MI in 2008 (n = 63 092) was used for this retrospective study. Functional status at PAC discharge was described as dependent, needed assistance, needed supervision, or independent. Logistic regression examined factors associated with CR initiation.

Results:

CR was initiated by 3% and 21% of beneficiaries discharged from PAC as dependent or independent, respectively. Beneficiaries who were dependent, needed assistance, or needed supervision were 78% (95% CI, 0.18-0.28), 60% (0.32-0.49), and 51% (0.41-0.57) less likely to initiate CR compared with independent beneficiaries. Those who had used IRF were 40% more likely to initiate CR compared with those who had used HHC, with no difference observed between those who had used SNF compared with HHC.

Conclusions:

Functional status at PAC discharge was strongly associated with CR initiation. Beneficiary initiation of CR was at proportions corresponding to the level of independence. Beneficiaries discharged from PAC as independent initiated CR at rates slightly higher than non-PAC users, and those discharged from IRF were more likely to initiate CR. These findings are promising and more targeted recruitment from PAC may increase CR initiation and completion, resulting in continued improvement in functional status.
Sustaining multistakeholder alliances
Authors: D’Aunno Thomas , Hearld Larry , Alexander Jeffrey A.
Published: July 2017

Background:

Multistakeholder alliances that bring together diverse organizations to work on community-level health issues are playing an increasingly prominent role in the U.S. health care system. Yet, these alliances by their nature are fragile. In particular, low barriers to exit make alliances particularly vulnerable to disruption if key stakeholders leave. What factors are linked to the sustainability of alliances? One way to approach this question is to examine the perceptions of alliance participants, whose on-going involvement in alliances likely will matter much to their sustainability.

Purpose:

This study addresses the question: “Under what conditions do participants in alliances consider that their alliances are well positioned for the future, will perform well over time, and will be able to deal effectively with future challenges?”

Methods:

We draw on cross-sectional survey data collected in the summer of 2015 from a total number of 638 participants in 15 alliances that participated in the Robert Wood Johnson Foundation’s Aligning Forces for Quality program.

Results:

Results from regression analyses indicate that alliance participants are more likely to view their alliances as sustainable when they (a) share a common vision, goals, and strategies for the alliance and (b) perceive that the alliance has performed effectively in the past.

Practice Implications:

Leaders of multistakeholder alliances may need to ensure that alliances are collective efforts that build success one step at a time: to the extent that participants believe they share a vision and strategies and have had some prior success working together, the more likely they are to view the alliance as sustainable.
OUTCOMES OF PATIENTS WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION TREATED WITH ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR THREE OR MORE YEARS
Authors: Qin Vivian L. , Young Jason , Silva Fabiana Q. , Conti Felipe F. , Singh Rishi P.
Published: July 2017

Purpose:

To summarize the findings of long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy (≥36 months) in patients with exudative age-related macular degeneration.

Methods:

Studies reporting long-term outcomes (≥36 months) of anti-VEGF therapy (n = 11) were identified and analyzed for changes in visual acuity (VA), optical coherence tomography, and safety findings.

Results:

Six prospective extension studies of Phase 3 clinical trials and five retrospective evaluation studies were identified. The largest improvements in VA with anti-VEGF treatment were found in Years 1 to 2 after treatment initiation. In five studies, VA ultimately declined below patients' pretreatment initial baseline; in three studies, VA ultimately returned to patients' baseline; in three studies, VA decreased but ultimately remained improved over patients' baseline. There was a trend demonstrating that a higher frequency of intravitreous injections showed a better maintenance in VA. Rates of adverse events were similar to previous registration studies of anti-VEGF drugs.

Conclusion:

The body of evidence to date regarding long-term anti-VEGF treatment indicates a variable course at greater than 36 months follow-up and seems to be dependent on the treatment protocol. Consistent dosing with fluid-free interval is suggested to maintain VA gains in patients with exudative age-related macular degeneration. There is no evidence suggesting that there are additional adverse events from long-term anti-VEGF use.
QUANTITATIVE ANALYSIS OF THE INNER RETINAL LAYER THICKNESSES IN AGE-RELATED MACULAR DEGENERATION USING CORRECTED OPTICAL COHERENCE TOMOGRAPHY SEGMENTATION
Authors: Muftuoglu Ilkay Kilic , Ramkumar Hema L. , Bartsch Dirk-Uwe , Meshi Amit , Gaber Raouf , Freeman William R.
Published: June 2017

Purpose:

To characterize inner retinal damage in patients with dry age-related macular degeneration (AMD) using high-resolution spectral domain optical coherence tomography images.

Methods:

Sixty eyes of 60 patients with AMD were categorized using the Age-Related Eye Disease Study (AREDS) severity scale. Spectral domain optical coherence tomography images of these patients were quantified by manually correcting the segmentation of each retinal layer, including the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer to ensure accurate delineation of layers. The mean ganglion cell complex thickness values (ganglion cell layer + inner plexiform layer + retinal nerve fiber layer) were compared with 30 eyes of 30 healthy subjects.

Results:

Ninety percent of eyes (81 eyes) required manual correction of segmentation. Compared with healthy subjects, mean ganglion cell complex thicknesses significantly decreased in more advanced dry AMD eyes, and this decrease was predominantly related to a change in inner plexiform layer thickness. There was no significant difference in thickness-related measurements between milder dry AMD (AREDS-2) eyes and healthy eyes (P > 0.05).

Conclusion:

In patients with dry AMD, automatic optical coherence tomography segmentation algorithms may be erroneous. As the severity of dry AMD increases, the inner plexiform layer layer becomes thinned, suggesting that transsynaptic degeneration may be occurring, as the photoreceptor layer is affected by AMD.
NOVEL PATIENT POSITIONING APPARATUS FOR RETINAL SURGERY IN A CASE OF SEVERE KYPHOSIS
Authors: Iaboni Douglas S. M. , Seamone Mark E. , Stairs Mary S. , O'Brien Daniel M. , Bisson M. Sheldon , Gupta R. Rishi
Published: June 2017

Purpose:

To describe a novel patient positioning apparatus for intraocular surgery capable of accommodating patients with thoracic kyphosis.

Methods:

Case report.

Results:

A 60-year-old man presented with a macula-off retinal detachment and severe ankylosing spondylitis. The patient was scheduled for combined pars plana vitrectomy and scleral buckle. Because of the patient's severe kyphosis, a custom-designed positioning apparatus was built. The setup involved a canvas with 10 sewn-on straps and a Skytron operating table with strap inserts. Padding and blankets were also used to secure the patient comfortably in the Trendelenburg position. Surgery was uncomplicated and retinal detachment repair was successfully performed.

Conclusion:

To the authors' knowledge, this is the first report detailing a vest-like support apparatus for patients with thoracic kyphosis used in vitreoretinal surgery. This apparatus can be prepared using any conventional operating table, and it offers an effective approach to intraocular surgery for patients who cannot lie flat.
Influenza-associated Encephalitis/Encephalopathy Identified by the Australian Childhood Encephalitis Study 2013–2015
Authors: Britton Philip N. , Dale Russell C. , Blyth Christopher C. , Macartney Kristine , Crawford Nigel W. , Marshall Helen , Clark Julia E. , Elliott Elizabeth J. , Webster Richard I. , Cheng Allen C. , Booy Robert , Jones Cheryl A.
Published: June 2017

Background:

Influenza-associated encephalitis/encephalopathy (IAE) is an important cause of acute encephalitis syndrome in children. IAE includes a series of clinicoradiologic syndromes or acute encephalopathy syndromes that have been infrequently reported outside East Asia. We aimed to describe cases of IAE identified by the Australian Childhood Encephalitis study.

Methods:

Children ≤ 14 years of age with suspected encephalitis were prospectively identified in 5 hospitals in Australia. Demographic, clinical, laboratory, imaging, and outcome at discharge data were reviewed by an expert panel and cases were categorized by using predetermined case definitions. We extracted cases associated with laboratory identification of influenza virus for this analysis; among these cases, specific IAE syndromes were identified where clinical and radiologic features were consistent with descriptions in the published literature.

Results:

We identified 13 cases of IAE during 3 southern hemisphere influenza seasons at 5 tertiary children’s hospitals in Australia; 8 children with specific acute encephalopathy syndromes including: acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late diffusion restriction, mild encephalopathy with reversible splenial lesion, and hemiconvulsion-hemiplegia syndrome. Use of influenza-specific antiviral therapy and prior influenza vaccination were infrequent. In contrast, death or significant neurologic morbidity occurred in 7 of the 13 children (54%).

Conclusions:

The conditions comprising IAE are heterogeneous with varied clinical features, magnetic resonance imaging changes, and outcomes. Overall, outcome of IAE is poor emphasizing the need for optimized prevention, early recognition, and empiric management.
Neuroborreliosis in Swedish Children: A Population-based Study on Incidence and Clinical Characteristics
Authors: Södermark Liv , Sigurdsson Vignir , Näs Wilhelmina , Wall Pernilla , Trollfors Birger
Published: June 2017

Background:

Borrelia burgdorferi is a common cause of bacterial meningitis, but there are very few studies on incidence in Europe. The aim of this study was to report the incidence and symptoms of neuroborreliosis in Swedish children.

Methods:

Medical records of children (< 15 years) treated for neuroborreliosis 2002–2014 were studied retrospectively. The patients were identified in the computerized registers of discharge diagnoses at the Departments of Pediatrics and Infectious Diseases in Gothenburg, Borås, Trollhättan and Halmstad using International Classification of Diseases 10 diagnosis codes G51.0, G01.9 and/or A69.1. Of those, patients with symptoms compatible with neuroborreliosis and a white blood cell count in cerebrospinal fluid ≥ 7 cells/mm3 with ≥ 80% mononuclear cells were included. Only children living in the city of Gothenburg and 10 surrounding municipalities were included.

Results:

Five hundred forty-eight children were included. The median age was 7 (1–14) years. The total incidence for the 13-year-period was 2.8/10,000 and remained unchanged during the period. The incidence was significantly higher in rural (4.0/10,000) than in urban municipalities (2.1/10,000). The most common presenting symptoms were headache (n = 335), fatigue (n = 330) and cranial nerve palsies (n = 329). The median duration of symptoms before admittance was 4.0 days for facial palsy and 14.0 days for other symptoms (P < 0.001). The median white blood cell count in cerebrospinal fluid was 129 (7–1069) cells/mm3.

Conclusions:

This study is the largest so far in a pediatric population. The incidence of neuroborreliosis was higher than in previous European reports. This might be explained by increased Borrelia awareness, the distribution of tick population in Sweden, and the possibility that Swedish children more frequently play outdoors.
Proactive Safety Management in Trauma Care: Applying the Human Factors Analysis and Classification System
Authors: Cohen Tara N. , Cabrera Jennifer S. , Litzinger Tracy L. , Captain Kevin A. , Fabian Michael A. , Miles Steven G. , Reeves Scott T. , Shappell Scott A. , Boquet Albert J.
Published: July 2017

Introduction:

This article examines the reliability of the Human Factors Analysis and Classification System (HFACS) for classifying observational human factors data collected prospectively in a trauma resuscitation center.

Methods:

Three trained human factors analysts individually categorized 1,137 workflow disruptions identified in a previously collected data set involving 65 observed trauma care cases using the HFACS framework.

Results:

Results revealed that the framework was substantially reliable overall (κ = 0.680); agreement increased when only the preconditions for unsafe acts were investigated (κ = 0.757). Findings of the analysis also revealed that the preconditions for unsafe acts category was most highly populated (91.95%), consisting mainly of failures involving communication, coordination, and planning.

Conclusion:

This study helps validate the use of HFACS as a tool for classifying observational data in a variety of medical domains. By identifying preconditions for unsafe acts, health care professionals may be able to construct a more robust safety management system that may provide a better understanding of the types of threats that can impact patient safety.
Low-Intensity Pulsed Ultrasound Therapy for a Symptomatic Persistent Olecranon Physis in an Adolescent Baseball Pitcher
Authors: Botwin Kenneth , McMillen Thurston , Botwin Ariel
Published: June 2017

A 15-year-old competitive right-handed high school baseball pitcher experienced an acute onset of right elbow pain when throwing. He initially treated it conservatively with rest alone for 3 months, but on return to throwing, he was still experiencing pain. Radiographs revealed that he had a persistent olecranon physis. He proceeded with a trial of low-intensity pulsed ultrasound therapy and attained radiographic evidence of bony union at 7 months postinjury, thus avoiding surgical intervention. He returned to pitching competitively 9 months after injury without elbow pain. This is the first reported case of using ultrasound bone stimulation for treatment of a symptomatic persistent olecranon physis in a baseball pitcher.
Multidisciplinary Assessment of 100 Athletes With Groin Pain Using the Doha Agreement: High Prevalence of Adductor-Related Groin Pain in Conjunction With Multiple Causes
Authors: Taylor Rachel , Vuckovic Zarko , Mosler Andrea , Agricola Rintje , Otten Roald , Jacobsen Philipp , Holmich Per , Weir Adam
Published: June 2017

Objective:

To examine the prevalence of different causes of groin pain in athletes using the recent Doha consensus classification of terminology and definitions of groin pain in athletes.

Design:

Descriptive epidemiological study.

Setting:

Multidisciplinary sports groin pain clinic at Aspetar Orthopedic and Sports Medicine Hospital, Doha, Qatar.

Patients:

The clinical records of 100 consecutive athletes with complaints of groin pain who attended the multidisciplinary sports groin pain clinic between January and December 2014 were analyzed.

Main Outcome Measures:

The causes of groin pain were categorized according to terminology and definitions agreed upon at the Doha consensus meeting on groin pain classification in athletes. The classification system has 3 main subheadings; defined clinical entities for groin pain (adductor-related, iliopsoas-related, inguinal-related, and pubic-related groin pain), hip-related groin pain, and other causes of groin pain in athletes.

Results:

The majority of athletes were male (98%) soccer players (60%). Multiple causes for groin pain were found in 44% of the athletes. Adductor-related groin pain was the most prevalent defined clinical entity (61% of athletes), and pubic-related groin pain was the least prevalent (4% of athletes).

Conclusions:

Adductor-related groin pain is the most commonly occurring clinical entity in this athlete population in mainly kicking and change of direction sports and frequently, multiple causes are found.

Clinical Relevance:

This is the first study to use the Doha agreement classification system and highlights the prevalence of adductor-related groin pain and that often multiple clinical entities contribute to an athlete's groin pain. Consequently, prevention programs should be implemented with these factors in mind.
Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model
Authors: Thomsen Anna M. , Gulinello Maria E. , Wen Jing , Schmiegelow Kjeld , Cole Peter D.
Published: June 2017

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 μM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.
Assuring Sustainable Gains in Interdisciplinary Performance Improvement: Creating a Shared Mental Model During Operating Room to Cardiac ICU Handoff
Authors: Riley Christine M. , Merritt Amber D. , Mize Justine M. , Schuette Jennifer J. , Berger John T.
Published: June 2017

Objective:

To understand sustainability and assure long-term gains in multidisciplinary performance improvement using an operating room to cardiac ICU handoff process focused on creation of a shared mental model.

Design:

Performance improvement cohort project with pre- and postintervention assessments spanning a 4-year period.

Setting:

Twenty-six bed pediatric cardiac ICU in a tertiary care children’s hospital.

Patients:

Cardiac surgery patients admitted to cardiac ICU from the operating room following cardiac surgery.

Interventions:

An interdisciplinary workgroup overhauled our handoff process in 2010. The new algorithm emphasized role delineation, standardized communication, and creation of a shared mental model. Our “I-5” mnemonic allowed validation and verification of a shared mental model between multidisciplinary teams. Staff orientation and practice guidelines were revised to incorporate the new process, visual aids were distributed and posted at each patient’s bedside, and lapses/audit data were discussed in multidisciplinary forum.

Measurements and Main Results:

Audits assessing equipment and information transfer during handoff were performed 8 weeks following implementation (n = 29), repeated at 1 year (n = 37), 3 years (n = 15), and 4 years (n = 50). Staff surveys prior to implementation, at 8 weeks, and 4 years postintervention assessed satisfaction. Comprehensiveness of information transfer improved in the 4 years following implementation, and staff satisfaction was maintained. At 4 years, discussion of all elements of information transfer was 94%, increased from 85% 8 weeks following implementation and discussion of four or more information elements was 100% increased from 93%. Of the 73% of staff who completed the survey at 4 years, 91% agreed that they received all necessary information, and 87% agreed that the handoff resulted in a shared mental model.

Conclusions:

Our methods were effective in creating and sustaining high levels of staff communication and adherence to the new process, thus achieving sustainable gains. Performance improvement initiatives require proactive interdisciplinary maintenance to be successful long term.
Liver Preservation by Aortic Perfusion Alone Compared With Preservation by Aortic Perfusion and Additional Arterial Ex Situ Back-Table Perfusion With Histidine-Tryptophan-Ketoglutarate Solution: A Prospective, Randomized, Controlled, Multicenter Study
Authors: Otto Gerd , Heise Michael , Thies Jochen , Pitton Michael , Schneider Jens , Kaiser Gernot , Neuhaus Peter , Kollmar Otto , Barthels Michael , Geks Josef , Bechstein Wolf Otto , Hellinger Achim , Klempnauer Jürgen , Padberg Winfried , Frühauf Nils , Ebbing Andre , Mauer Dietmar , Schneider Astrid , Kwiecien Robert , Kronfeld Kai
Published: June 2017

Background

Arterial ex situ back-table perfusion (BP) reportedly reduces ischemic-type biliary lesion after liver transplantation. We aimed to verify these findings in a prospective investigation.

Methods

Our prospective, randomized, controlled, multicenter study involved livers retrieved from patients in 2 German regions, and compared the outcomes of standard aortic perfusion to those of aortic perfusion combined with arterial ex situ BP. The primary endpoint was the incidence of ischemic-type biliary lesions over a follow-up of 2 years after liver transplantation, whereas secondary endpoints included 2-year graft survival, initial graft damage as reflected by transaminase levels, and functional biliary parameters at 6 months after transplantation.

Results

A total of 75 livers preserved via standard aortic perfusion and 75 preserved via standard aortic perfusion plus arterial BP were treated using a standardized protocol. The incidence of clinically apparent biliary lesions after liver transplantation (n = 9 for both groups; P = 0.947), the 2-year graft survival rate (standard aortic perfusion, 74%; standard aortic perfusion plus arterial BP, 68%; P = 0.34), and incidence of initial graft injury did not differ between the 2 perfusion modes. Although 33 of the 77 patients with cholangiography workups exhibited injured bile ducts, only 10 had clinical symptoms.

Conclusions

Contrary to previous findings, the present study indicated that additional ex situ BP did not prevent ischemic-type biliary lesions or ischemia-reperfusion injury after liver transplantation. Moreover, there was considerable discrepancy between cholangiography findings regarding bile duct changes and clinically apparent cholangiopathy after transplantation, which should be considered when assessing ischemic-type biliary lesions.
Optical atomic phase reference and timing
Authors: Hollberg L. , Cornell E. H. , Abdelrahmann A.
Published: June 2017

Atomic clocks based on laser-cooled atoms have made tremendous advances in both accuracy and stability. However, advanced clocks have not found their way into widespread use because there has been little need for such high performance in real-world/commercial applications. The drive in the commercial world favours smaller, lower-power, more robust compact atomic clocks that function well in real-world non-laboratory environments. Although the high-performance atomic frequency references are useful to test Einstein's special relativity more precisely, there are not compelling scientific arguments to expect a breakdown in special relativity. On the other hand, the dynamics of gravity, evidenced by the recent spectacular results in experimental detection of gravity waves by the LIGO Scientific Collaboration, shows dramatically that there is new physics to be seen and understood in space–time science. Those systems require strain measurements at less than or equal to 10
−20
. As we discuss here, cold atom optical frequency references are still many orders of magnitude away from the frequency stability that should be achievable with narrow-linewidth quantum transitions and large numbers of very cold atoms, and they may be able to achieve levels of phase stability, Δ
Φ
/
Φ
total
 ≤ 10
−20
, that could make an important impact in gravity wave science.

This article is part of the themed issue ‘Quantum technology for the 21st century’.
Sparse Bursts Optimize Information Transmission in a Multiplexed Neural Code
Authors: Naud Richard , Sprekeler Henning
Published: July 2017

Many cortical neurons combine the information ascending and descending the cortical hierarchy. In the classical view, this information is combined nonlinearly to give rise to a single firing rate output, which collapses all input streams into one. We propose that neurons can simultaneously represent multiple input streams by using a novel code that distinguishes single spikes and bursts at the level of a neural ensemble. Using computational simulations constrained by experimental data, we show that cortical neurons are well suited to generate such multiplexing. Interestingly, this neural code maximizes information for short and sparse bursts, a regime consistent with in vivo recordings. It also suggests specific connectivity patterns that allows to demultiplex this information. These connectivity patterns can be used by the nervous system to maintain optimal multiplexing. Contrary to firing rate coding, our findings indicate that a single neural ensemble can communicate multiple independent signals to different targets.
Combining Ensemble Learning Techniques and G-Computation to Investigate Chemical Mixtures in Environmental Epidemiology Studies
Authors: Oulhote Youssef , Bind Marie-Abele , Coull Brent , Patel Chirag J , Grandjean Philippe
Published: July 2017

Background

Although biomonitoring studies demonstrate that the general population experiences exposure to multiple chemicals, most environmental epidemiology studies consider each chemical separately when assessing adverse effects of environmental exposures. Hence, the critical need for novel approaches to handle multiple correlated exposures.

Methods

We propose a novel approach using the G-formula, a maximum likelihood-based substitution estimator, combined with an ensemble learning technique (i.e. SuperLearner) to infer causal effect estimates for a multi-pollutant mixture. We simulated four continuous outcomes from real data on 5 correlated exposures under four exposure-response relationships with increasing complexity and 500 replications. The first simulated exposure-response was generated as a linear function depending on two exposures; the second was based on a univariate nonlinear exposure-response relationship; the third was generated as a linear exposure-response relationship depending on two exposures and their interaction; the fourth simulation was based on a non-linear exposure-response relationship with an effect modification by sex and a linear relationship with a second exposure. We assessed the method based on its predictive performance (Minimum Square error [MSE]), its ability to detect the true predictors and interactions (i.e. false discovery proportion, sensitivity), and its bias. We compared the method with generalized linear and additive models, elastic net, random forests, and Extreme gradient boosting. Finally, we reconstructed the exposure-response relationships and developed a toolbox for interactions visualization using individual conditional expectations.

Results

The proposed method yielded the best average MSE across all the scenarios, and was therefore able to adapt to the true underlying structure of the data. The method succeeded to detect the true predictors and interactions, and was less biased in all the scenarios. Finally, we could correctly reconstruct the exposure-response relationships in all the simulations.

Conclusions

This is the first approach combining ensemble learning techniques and causal inference to unravel the effects of chemical mixtures and their interactions in epidemiological studies. Additional developments including high dimensional exposure data, and testing for detection of low to moderate associations will be carried out in future developments.
LINE-1 and the cell cycle: protein localization and functional dynamics
Authors: Mita Paolo , Wudzinska Aleksandra , Sun Xiaoji , Andrade Joshua , Nayak Shruti , Kahler David J. , Badri Sana , LaCava John , Ueberheide Beatrix , Yun Chi Y. , Fenyo David , Boeke Jef D.
Published: July 2017

LINE-1/L1 retrotransposon sequences comprise 17% of the human genome. Among the many classes of mobile genetic elements, L1 is the only autonomous retrotransposon that still drives human genomic plasticity today. Through its co-evolution with the human genome, L1 has intertwined itself with host cell biology to aid its proliferation. However, a clear understanding of L1’s lifecycle and the processes involved in restricting its insertion and its intragenomic spreading remains elusive. Here we identify modes of L1 proteins’ entrance into the nucleus, a necessary step for L1 proliferation. Using functional, biochemical, and imaging approaches, we also show a clear cell cycle bias for L1 retrotransposition that peaks during the S phase. Our observations provide a basis for novel interpretations about the nature of nuclear and cytoplasmic L1 ribonucleoproteins (RNPs) and the potential role of DNA replication in L1 retrotransposition.
Multi-BRCT domain protein Brc1 links Rhp18/Rad18 and γH2A to maintain genome stability during S-phase
Authors: Reubens Michael C. , Rozenzhak Sophie , Russell Paul
Published: June 2017

DNA replication involves the inherent risk of genome instability, as replisomes invariably encounter DNA lesions or other structures that stall or collapse replication forks during S-phase. In the fission yeastSchizosaccharomyces pombe, the multi-BRCT domain protein Brc1, which is related to budding yeast Rtt107 and mammalian PTIP, plays an important role in maintaining genome integrity and cell viability when cells experience replication stress. The C-terminal pair of BRCT domains in Brc1 were previously shown to bind phospho-histone H2A (γH2A) formed by Rad3/ATR checkpoint kinase at DNA lesions; however, the putative scaffold interactions involving the N-terminal BRCT domains 1-4 of Brc1 have remained obscure. Here we show that these domains bind Rhp18/Rad18, which is an E3 ubiquitin protein ligase that has crucial functions in postreplication repair. A missense allele in BRCT domain 4 of Brc1 disrupts binding to Rhp18 and causes sensitivity to replication stress. Brc1 binding to Rhp18 and γH2A are required for the Brc1-overexpression suppression ofsmc6-74,which impairs the Smc5/6 structural maintenance of chromosomes complex required for chromosome integrity and repair of collapsed replication forks. From these findings we propose that Brc1 provides scaffolding functions linking γH2A, Rhp18, and Smc5/6 complex at damaged replication forks.
CLAPO syndrome: Identification of somatic activatingPIK3CAmutations and delineation of the natural history and phenotype
Authors: Rodriguez-Laguna Lara , Ibañez Kristina , Gordo Gema , Garcia-Minaur Sixto , Santos-Simarro Fernando , Agra Noelia , Vallespín Elena , Fernández-Montaño Victoria E , Martín-Arenas Rubén , del Pozo Ángela , Gonzalez-Pecellín Héctor , Mena Rocío , Rueda-Arenas Inmaculada , Gomez María V. , Villaverde Cristina , Bustamante Ana , Ayuso Carmen , Ruiz-Perez Víctor L. , Nevado Julián , Lapunzina Pablo , Lopez-Gutierrez Juan C. , Martinez-Glez Victor
Published: June 2017

Background

CLAPO syndrome is a rare vascular disorder characterized by Capillary malformation of the lower lip, Lymphatic malformation predominant on the face and neck, Asymmetry, and Partial/generalized Overgrowth. Although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.

Subjects and methods

We clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from nine patients using high-throughput, deep sequencing.

Results

We identified five activating mutations in thePIK3CAgene in affected tissues from six of the nine patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.

Conclusions

We describe for the first time the presence of somatic activatingPIK3CAmutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.
A compendium of co-regulated protein complexes in breast cancer reveals collateral loss events
Authors: Ryan Colm J. , Kennedy Susan , Bajrami Ilirjana , Matallanas David , Lord Christopher J.
Published: June 2017

Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and composition varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 258 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or over-expressed in specific breast cancer subtypes. We found that mutation or deletion of one subunit of a complex was often associated with a collateral reduction in protein expression of additional complex members. This collateral loss phenomenon was evident from proteomic, but not transcriptomic, profiles suggesting post-transcriptional control. Mutation of the tumor suppressor E-cadherin (CDH1)was associated with a collateral loss of members of the adherens junction complex, an effect we validated using an engineered model of E-cadherin loss.
Activation of somatostatin interneurons by nicotinic modulator Lypd6 enhances plasticity and functional recovery in the adult mouse visual cortex
Authors: Sadahiro Masato , Demars Michael P. , Burman Poromendro , Yevoo Priscilla , Zimmer Andreas , Morishita Hirofumi
Published: June 2017

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period – rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood.

Significance Statement

The decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical SST interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors (nAChRs), enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.
A Bayesian Framework for Multiple Trait Colocalization from Summary Association Statistics
Authors: Giambartolomei Claudia , Zhenli Liu Jimmy , Zhang Wen , Hauberg Mads , Shi Huwenbo , Boocock James , Pickrell Joe , Jaffe Andrew E. ,   the CommonMind Consortium, Pasaniuc Bogdan , Roussos Panos
Published: June 2017

Motivation

Most genetic variants implicated in complex diseases by genome-wide association studies (GWAS) are non-coding, making it challenging to understand the causative genes involved in disease. Integrating external information such as quantitative trait locus (QTL) mapping of molecular traits (e.g., expression, methylation) is a powerful approach to identify the subset of GWAS signals explained by regulatory effects. In particular, expression QTLs (eQTLs) help pinpoint the responsible gene among the GWAS regions that harbor many genes, while methylation QTLs (mQTLs) help identify the epigenetic mechanisms that impact gene expression which in turn affect disease risk. In this work we proposemultiple-trait-coloc(moloc), a Bayesian statistical framework that integrates GWAS summary data with multiple molecular QTL data to identify regulatory effects at GWAS risk loci.

Results

We appliedmolocto schizophrenia (SCZ) and eQTL/mQTL data derived from human brain tissue and identified 52 candidate genes that influence SCZ through methylation. Our method can be applied to any GWAS and relevant functional data to help prioritize disease associated genes.

Availability

molocis available for download as an R package (https://github.com/clagiamba/moloc). We also developed a web site to visualize the biological findings (icahn.mssm.edu/moloc). The browser allows searches by gene, methylation probe, and scenario of interest.

Contact

claudia.giambartolomei@gmail.com

Supplementary information

Supplementary data are available atBioinformaticsonline.
Novel ‘housekeeping’ genes and an unusually heterogeneous distribution of transporter expression profiles in human tissues and cell lines, assessed using the Gini coefficient
Authors: O’Hagan Steve , Muelas Marina Wright , Day Philip J. , Lundberg Emma , Kell Douglas B.
Published: June 2017

We analyse two comprehensive transcriptome datasets from human tissues and human-derived cell lines in terms of the expression profiles of the SLC and ABC families of membrane transporters. The Gini index (coefficient) characterises inequalities of distributions, and is used in a novel way to describe the distribution of the expression of each transporter among the different tissues and cell lines. In many cases, transporters exhibit extremely high Gini coefficients, even when their supposed substrates might be expected to be available to all tissues, indicating a much higher degree of specialisation than is usually assumed. This is consistent with divergent evolution from a more restricted set of ancestors. Similar trends hold true for the expression profiles of transporters in different cell lines, suggesting that cell lines exhibit largely similar transport behaviour to that of tissues. By contrast, the Gini coefficients for ABC transporters tend to be larger in cell lines than in tissues, implying that some kind of a selection process has taken place. In particular, with some exceptions such as olfactory receptors and genes involved in keratin production, transporter genes are significantly more heterogeneously expressed than are most non-transporter genes. The Gini index also allows us to determine those transcripts with the most stable expression; these often differ significantly from the ‘housekeeping’ genes commonly used for normalisation in transcriptomics and qPCR studies. The lowest four in tissues are FAM32A, ABCB7, MRPL21 and PCBP1, while the lowest three in cell lines are SF3B2, NXF1 and RBM45. PCBP1 is both reasonably highly expressed and has a low Gini coefficient in both tissues and cell lines, and is an excellent novel housekeeping gene. Overall, our analyses provide novel opportunities for the normalisation of genome-wide expression profiling data.
Alertness fluctuations during task performance modulate cortical evoked responses to transcranial magnetic stimulation
Authors: Noreika Valdas , Kamke Marc R. , Canales-Johnson Andrés , Chennu Srivas , Bekinschtein Tristan A. , Mattingley Jason B.
Published: June 2017

Transcranial magnetic stimulation (TMS) has been widely used in human cognitive neuroscience to examine the causal role of distinct cortical areas in perceptual, cognitive and motor functions. However, it is widely acknowledged that the effects of focal cortical stimulation on behaviour can vary substantially between participants and even from trial to trial within individuals. Here we asked whether spontaneous fluctuations in alertness can account for the variability in behavioural and neurophysiological responses to TMS. We combined single-pulse TMS with neural recording via electroencephalography (EEG) to quantify changes in motor and cortical reactivity with fluctuating levels of alertness defined objectively on the basis of ongoing brain activity. We observed rapid, non-linear changes in TMS-evoked neural responses – specifically, motor evoked potentials and TMS-evoked cortical potentials – as EEG activity indicated decreasing levels of alertness, even while participants remained awake and responsive in the behavioural task.

IMPACT STATEMENT

A substantial proportion of inter-trial variability in neurophysiological responses to TMS is due to spontaneous fluctuations in alertness, which should be controlled for during experimental and clinical applications of TMS.
Regulation of somatosensory mechanotransduction by Annexin A6
Authors: Raouf Ramin , Lolignier Stéphane , Sexton Jane E. , Millet Queensta , Santana-Varela Sonia , Biller Anna , Fuller Alice M. , Pereira Vanessa , Choudhary Jyoti , Collins Mark , Moss Stephen E. , Tordo Julie , Linden Michael , Wood John N
Published: June 2017

Sensory neuron mechanically-activated slowly adapting currents have been linked to noxious mechanosensation. We identified a Conotoxin, Noxious Mechanosensation Blocker -1, that blocks such currents selectively and inhibits mechanical pain Using an active biotinylated form of the toxin we identified 67 binding proteins in sensory neurons and sensory neuron-derived cell lines using mass spectrometry. Annexin A6 was the most frequently identified binding protein. Annexin A6 knockout mice showed an enhanced sensitivity to mechanical stimuli. An increase in rapidly adapting currents was observed in sensory neurons alongside a decrease in slowly adapting currents. Conversely, overexpression of Annexin A6 in sensory neurons inhibited rapidly adapting currents and augmented slowly adapting currents. Furthermore, co-expression of Annexin A6 with Piezo2 led to an inhibition of Piezo-mediated rapidly adapting currents. AAV-mediated overexpression of Annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis. These data demonstrate a modulatory role for Annexin A6 in somatosensory mechanotransduction.
On the dynamics of reproductive values and phenotypic traits in class-structured populations
Authors: Lion Sébastien
Published: June 2017

In natural populations, individuals of a given genotype may belong to different classes. Such classes can for instance represent different age groups, developmental stages, or habitats. Class structure has important evolutionary consequences because the fitness of individuals with the same genetic background may vary depending on their class. As a result, demographic transitions between classes can cause fluctuations that need to be removed when estimating selection on a trait. Intrinsic differences between classes are classically taken into account by weighting individuals by class-specific reproductive values, defined as the relative contribution of individuals in a given class to the future of the population. These reproductive values are generally constant weights calculated from a constant projection matrix. Here, I show, for large populations and clonal reproduction, that reproductive values can be defined as time-dependent weights satisfying dynamical demographic equations that only depend on the average between-class transition rates over all genotypes. Using these time-dependent demographic reproductive values yields a simple Price equation where the non-selective effects of between-class transitions are removed from the dynamics of the trait. This generalises previous theory to a large class of ecological scenarios, taking into account densitydependence, ecological feedbacks and arbitrary distributions of the trait. I discuss the role of reproductive values for prospective and retrospective analyses of the dynamics of phenotypic traits.

Note on this version

Compared to the previous version of the manuscript, some changes have been made to improve the readability and structure of the text, and to clarify the connections with the existing literature. One reviewer pointed out inconsistencies in some of the numerical simulations, and in the mutation term in appendix A2, which have now been fixed. When checking the calculations, I have also identified a missing term in the equation for the dynamics of individual reproductive values. The new equation makes much more sense. Additional results are also presented, in particular for discrete-time models and populations with a continuous age structure, for which Fisher’s original definition of reproductive value can be recovered.