Different Fractional Charges from Auto- and Cross-Correlation Noise in Quantum Hall States without Upstream Modes.

Fractional charges of anyons can be extracted from shot noise in two ways. One can use either the autocorrelation noise of the current in one drain or the cross-correlation noise between two drains on the two sides of the device. The former approach typically overestimates the charge. This may happen due to upstream edge modes. We propose a mechanism for the excess autocorrelation noise without upstream modes. It applies to systems with multiple copropagating edge modes and assumes that the noise is measured at a low but nonzero frequency.

[Design, implementation and evaluation of an educational approach for patients with PICC line and midline]. / Conception, réalisation et évaluation d'une démarche éducative auprès des patients porteurs de PICC line et midline.

OBJECTIVES: Design the competency framework and an interview guide for patients with PICC line or midline. Develop a patient satisfaction evaluation questionnaire. METHODS: A multidisciplinary team has developed a reference system for the skills of patients with PICC line or midline. The skills are classified in three categories: knowledge, know-how and attitudes. An interview guide was written in order to transmit the priority skills, determined beforehand, to the patient. A second multidisciplinary team designed a questionnaire to evaluate patient satisfaction. RESULTS: The competency framework includes nine competencies: four, knowledge-based; three, know-how-based and two, attitude-based. Among these competencies, five were considered to be priorities. The interview guide is a tool that allows care professionals to transmit the priority skills to patients. The satisfaction questionnaire explores the information received by the patient, the passage through the interventional technical platform, the end of the management before the return home, and the overall satisfaction of the patients with the course of the device placement. Over a 6-month period, 276 patients responded with a high satisfaction rate. CONCLUSIONS: The PICC line or midline patient's competency framework has made it possible to list all the skills that patients should acquire. The interview guide serves as a support for the care teams in the patient education process. This work could be used by other establishments to develop the educational process around these vascular access devices.

Thermal Interferometry of Anyons in Spin Liquids.

Aharonov-Bohm interferometry is the most direct probe of anyonic statistics in the quantum Hall effect. The technique involves oscillations of the electric current as a function of the magnetic field and is not applicable to Kitaev spin liquids and other systems without charged quasiparticles. Here, we establish a novel protocol, involving heat transport, for revealing fractional statistics even in the absence of charged excitations, as is the case in quantum spin liquids. Specifically, we demonstrate that heat transport in Kitaev spin liquids through two distinct interferometer's geometries, Fabry-Perot and Mach-Zehnder, exhibit drastically different behaviors. Therefore, we propose the use of heat transport interferometry as a probe of anyonic statistics in charge insulators.

Fractional charge and fractional statistics in the quantum Hall effects.

Quasiparticles with fractional charge and fractional statistics are key features of the fractional quantum Hall effect. We discuss in detail the definitions of fractional charge and statistics and the ways in which these properties may be observed. In addition to theoretical foundations, we review the present status of the experiments in the area. We also discuss the notions of non-Abelian statistics and attempts to find experimental evidence for the existence of non-Abelian quasiparticles in certain quantum Hall systems.

Thermal Equilibration on the Edges of Topological Liquids.

Thermal conductance has emerged as a powerful probe of topological order in the quantum Hall effect and beyond. The interpretation of experiments crucially depends on the ratio of the sample size and the equilibration length, on which energy exchange among contrapropagating chiral modes becomes significant. We show that at low temperatures the equilibration length diverges as 1/T^{2} for almost all Abelian and non-Abelian topological orders. A faster 1/T^{4} divergence is present on the edges of the non-Abelian PH-Pfaffian and negative-flux Read-Rezayi liquids. We address experimental consequences of the 1/T^{2} and 1/T^{4} laws in a sample, shorter than the equilibration length.

Consensus statement from 2nd International Conference on Controversies in Vitamin D.

The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling.

Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and three-dimensional (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in the wild-type mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.

Diagnostic validity and triage concordance of a physiotherapist compared to physicians' diagnoses for common knee disorders.

BACKGROUND: Emergence of more autonomous roles for physiotherapists warrants more evidence regarding their diagnostic capabilities. Therefore, we aimed to evaluate diagnostic and surgical triage concordance between a physiotherapist and expert physicians and to assess the diagnostic validity of the physiotherapist's musculoskeletal examination (ME) without imaging. METHODS: This is a prospective diagnostic study where 179 consecutive participants consulting for any knee complaint were independently diagnosed and triaged by two evaluators: a physiotherapist and one expert physician (orthopaedic surgeons or sport medicine physicians). The physiotherapist completed only a ME, while the physicians also had access to imaging to make their diagnosis. Raw agreement proportions and Cohen's kappa (k) were calculated to assess inter-rater agreement. Sensitivity (Se) and specificity (Sp), as well as positive and negative likelihood ratios (LR+/-) were calculated to assess the validity of the ME compared to the physicians' composite diagnosis. RESULTS: Primary knee diagnoses included anterior cruciate ligament injury (n = 8), meniscal injury (n = 36), patellofemoral pain (n = 45) and osteoarthritis (n = 79). Diagnostic inter-rater agreement between the physiotherapist and physicians was high (k = 0.89; 95% CI:0.83-0.94). Inter-rater agreement for triage recommendations of surgical candidates was good (k = 0.73; 95% CI:0.60-0.86). Se and Sp of the physiotherapist's ME ranged from 82.0 to 100.0% and 96.0 to 100.0% respectively and LR+/- ranged from 23.2 to 30.5 and from 0.03 to 0.09 respectively. CONCLUSIONS: There was high diagnostic agreement and good triage concordance between the physiotherapist and physicians. The ME without imaging may be sufficient to diagnose or exclude common knee disorders for a large proportion of patients. Replication in a larger study will be required as well as further assessment of innovative multidisciplinary care trajectories to improve care of patients with common musculoskeletal disorders.

Oncologist use and perception of large panel next-generation tumor sequencing.

BACKGROUND: Genomic profiling is increasingly incorporated into oncology research and the clinical care of cancer patients. We sought to determine physician perception and use of enterprise-scale clinical sequencing at our center, including whether testing changed management and the reasoning behind this decision-making. PATIENTS AND METHODS: All physicians who consented patients to MSK-IMPACT, a next-generation hybridization capture assay, in tumor types where molecular profiling is not routinely performed were asked to complete a questionnaire for each patient. Physician determination of genomic 'actionability' was compared to an expertly curated knowledgebase of somatic variants. Reported management decisions were compared to chart review. RESULTS: Responses were received from 146 physicians pertaining to 1932 patients diagnosed with 1 of 49 cancer types. Physicians indicated that sequencing altered management in 21% (331/1593) of patients in need of a treatment change. Among those in whom treatment was not altered, physicians indicated the presence of an actionable alteration in 55% (805/1474), however, only 45% (362/805) of these cases had a genomic variant annotated as actionable by expert curators. Further evaluation of these patients revealed that 66% (291/443) had a variant in a gene associated with biologic but not clinical evidence of actionability or a variant of unknown significance in a gene with at least one known actionable alteration. Of the cases annotated as actionable by experts, physicians identified an actionable alteration in 81% (362/445). In total, 13% (245/1932) of patients were enrolled to a genomically matched trial. CONCLUSION: Although physician and expert assessment differed, clinicians demonstrate substantial awareness of the genes associated with potential actionability and report using this knowledge to inform management in one in five patients. CLINICAL TRIAL NUMBER: NCT01775072.

Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers.

Background: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. Methods: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib. Results: We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1-2 and 50 mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60-84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%). Conclusion: This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients.

Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma.

Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.

Stabilization of the Particle-Hole Pfaffian Order by Landau-Level Mixing and Impurities That Break Particle-Hole Symmetry.

Numerical results suggest that the quantum Hall effect at ν=5/2 is described by the Pfaffian or anti-Pfaffian state in the absence of disorder and Landau-level mixing. Those states are incompatible with the observed transport properties of GaAs heterostructures, where disorder and Landau-level mixing are strong. We show that the recent proposal of a particle-hole (PH)-Pfaffian topological order by Son is consistent with all experiments. The absence of particle-hole symmetry at ν=5/2 is not an obstacle to the existence of the PH-Pfaffian order since the order is robust to symmetry breaking.

A Systematic Review of the Cervical Plexus Accessory Innervation and Its Role in Dental Anesthesia.

INTRODUCTION: Accessory innervation (AI) may account for the persistent sensation perceived after successful mandibular anesthesia in the adult patient. The purpose of this systematic review was to record the quality of evidence pertaining to the cervical plexus (CP) AI in dental anesthesia. MATERIALS AND METHODS: Electronic and manual searches were conducted using Ovid and Medline of articles published from 1922 to March of 2015. Studies written in any language were included as long as they involved: (i) humans, animals, and/or cadavers AND (ii) anatomical and/or research anesthetic-technique approaches and/or clinical approaches. Exclusion criteria were (i) maxillary buccal infiltration, (ii) no abstract/paper available, (iii) studies that do not comprise the description of the branches of the CP branches in dentistry and (iv) duplicated articles. The articles were reviewed and graded by levels of evidence (LOE) through a methodological scoring index (MSI). RESULTS: Forty-four out of 185 papers fulfilled the inclusion criteria. One randomized control trial, 3 comprehensive reviews, 1 cohort study, 5 case series/reports, 16 poor-quality cohort and case series/reports and 18 reviews/case, reports/expert opinions were found. Of the 44 publications, there were 4 LOE 1, 1 LOE 2, 5 LOE 3, 20 LOE 4 and 14 LOE 5 studies. CONCLUSIONS: The MSI helped to classify papers LOE in a standardized and objective approach. The objective evidence quality occurrence recorded was found to be LOE 4 (n = 20) > LOE 5 (n = 14) > LOE 3 (n = 5) > LOE 1 (n = 4) > LOE 2 (n = 1). The anatomy of the CP needs to be reexamined and understood in the anatomical literature.

The interpersonal theory of suicide and adolescent suicidal behavior.

BACKGROUND: Joiner's interpersonal theory of suicide (IPTS) proposes that suicide results from the combination of a perception of burdening others, social alienation, and the capability for self-harm. The theory gained some empirical support, however the overall model has yet to be tested. This study aimed to test the main predictions of IPTS in a large community sample of Israeli adolescents. METHOD: 1196 Israeli Jewish and Arab high-school pupils participating in the SEYLE project completed a self-report questionnaire measuring perceived burdensomeness, thwarted belongingness, health risk behaviors, and non-suicidal self-injury (risk variables), and suicidal ideation and suicide attempts (outcome measures). The data were tested in cross-sectional regression models. RESULTS: Consistent with IPTS, perceived burdensomeness was found to interact with thwarted belongingness, predicting suicidal ideation. Depression mediated most of the effect of thwarted belongingness and perceived burdensomeness on suicidal ideation. Acquired capability for self-harm, as measured by health risk behaviors and direct non-suicidal self-injurious behaviors, predicted suicide attempt. However, this mechanism operated independently from ideation rather than in interaction with it, at variance with IPTS-based predictions. LIMITATIONS: The cross-sectional design precludes conclusions about causality and directionality. Proxy measures were used to test the interpersonal theory constructs. CONCLUSION: The findings support some of the IPTS predictions but not all, and imply two separate pathways for suicidal behavior in adolescents: one related to internalizing psychopathology and the other to self-harm behaviors. This conceptualization has clinical implications for the differential identification of adolescents at risk for suicidal behavior and for the development of prevention strategies.

Observational determination of surface radiative forcing by CO2 from 2000 to 2010.

The climatic impact of CO2 and other greenhouse gases is usually quantified in terms of radiative forcing, calculated as the difference between estimates of the Earth's radiation field from pre-industrial and present-day concentrations of these gases. Radiative transfer models calculate that the increase in CO2 since 1750 corresponds to a global annual-mean radiative forcing at the tropopause of 1.82 ± 0.19 W m(-2) (ref. 2). However, despite widespread scientific discussion and modelling of the climate impacts of well-mixed greenhouse gases, there is little direct observational evidence of the radiative impact of increasing atmospheric CO2. Here we present observationally based evidence of clear-sky CO2 surface radiative forcing that is directly attributable to the increase, between 2000 and 2010, of 22 parts per million atmospheric CO2. The time series of this forcing at the two locations-the Southern Great Plains and the North Slope of Alaska-are derived from Atmospheric Emitted Radiance Interferometer spectra together with ancillary measurements and thoroughly corroborated radiative transfer calculations. The time series both show statistically significant trends of 0.2 W m(-2) per decade (with respective uncertainties of ±0.06 W m(-2) per decade and ±0.07 W m(-2) per decade) and have seasonal ranges of 0.1-0.2 W m(-2). This is approximately ten per cent of the trend in downwelling longwave radiation. These results confirm theoretical predictions of the atmospheric greenhouse effect due to anthropogenic emissions, and provide empirical evidence of how rising CO2 levels, mediated by temporal variations due to photosynthesis and respiration, are affecting the surface energy balance.

Report from a forum on US heart allocation policy.

Since the latest revision in US heart allocation policy (2006), the landscape and volume of transplant waitlists have changed considerably. Advances in mechanical circulatory support (MCS) prolong survival, but Status 1A mortality remains high. Several patient subgroups may be disadvantaged by current listing criteria and geographical disparity remains in waitlist time. This forum on US heart allocation policy was organized to discuss these issues and highlight concepts for consideration in the policy development process. A 25-question survey on heart allocation policy was conducted. Among attendees/respondents were 84 participants with clinical/published experience in heart transplant representing 51 US transplant centers, and OPTN/UNOS and SRTR representatives. The survey results and forum discussions demonstrated very strong interest in change to a further-tiered system, accounting for disadvantaged subgroups and lowering use of exceptions. However, a heart allocation score is not yet viable due to the long-term viability of variables (used in the score) in an ever-developing field. There is strong interest in more refined prioritization of patients with MCS complications, highly sensitized patients and those with severe arrhythmias or restrictive physiology. There is also strong interest in distribution by geographic boundaries modified according to population. Differences of opinion exist between small and large centers.

Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies.

BACKGROUND: The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. PATIENTS AND METHODS: Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS: Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. CONCLUSIONS: A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.

Rates of risk-reducing surgery in Israeli BRCA1 and BRCA2 mutation carriers.

The frequency of BRCA1 and BRCA2 mutations is higher in Israel than in almost all other countries. One strategy to reduce the burden of hereditary breast and ovarian cancers is to offer genetic testing followed by risk-reducing surgery (mastectomy and salpingo-oophorectomy) for mutation carriers. The extent to which Israeli women who carry mutations undergo these surgeries is not well characterized. Israeli women who are BRCA1 or BRCA2 mutation carriers and followed at a single high-risk clinic were asked to complete a questionnaire detailing their clinical histories at the time of genetic results disclosure and a follow-up questionnaire was completed 18 or more months thereafter. A total of 205 mutation carriers completed the questionnaires. Of 170 women with no cancer history, 84 (49%) had a risk-reducing bilateral salpingo-oophorectomy and 22 (13%) had a risk-reducing mastectomy. Five of 35 (14.3%) women with breast cancer opted for contralateral mastectomy. Approximately one half of Israeli women with a BRCA1 or BRCA2 mutation opt for risk-reducing oophorectomy, but the rate of risk-reducing mastectomy is only 13%.