bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships as Medicine: Quality of the Physician–Patient Relationship Determines Physician Influence on Treatment Recommendation Adherence
Authors: Orom Heather , Underwood Willie , Cheng Zinan , Homish D. Lynn , Scott I'Yanna
Published: December 2016

Objective

To determine whether quality of physician–patient relationships influences uptake of physician treatment recommendations in men with clinically localized prostate cancer (PCa).

Study Setting

Data were collected July 2010 to August 2014 at two cancer centers and three community facilities.

Study Design

Analyses were prospective and cross‐sectional. We modeled associations between quality of the patient–physician relationship and influence of physician recommendations on treatment choice using generalized estimating equations (GEE).

Data Collection

Data were collected via survey and medical record abstraction.

Principal Findings

Participants (N = 1166) were 14.7 percent minority; 37.1 percent had low‐, 47.5 percent had intermediate‐, and 15.4 percent had high‐risk PCa. Those reporting a better physician–patient relationship perceived that their physician's treatment recommendation was more influential (RR = 1.05, 95 percent CI = 1.04–1.05, p < .001) and were more likely to choose the recommended treatment (OR = 2.92, 95 percent CI = 2.39, 3.58, p < .001). A pattern of interactions emerged indicating that quality of the physician–patient relationship was more strongly associated with influence of recommendations for more, versus less aggressive treatment in those with low‐risk, but not intermediate‐risk disease.

Conclusions

Prioritizing quality of the physician–patient relationship through training, practice change, and patient feedback may increase adherence. However, strategies need to align with efforts to reduce physician recommendations for inefficacious treatments to prevent overtreatment.
Changes in Attenuated Total Reflection Fourier Transform Infrared Spectra as Blood Dries Out
Authors: Zhang Yinming , Wang Qi , Li Bing , Wang Zhijun , Li Chengzhi , Yao Yao , Huang Ping , Wang Zhenyuan
Published: December 2016

The time since deposition (TSD) of a bloodstain is a valuable piece of evidence for forensic scientists to determine the time at which a crime took place. The objective of this study was to determine whether attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy could be used to estimate the TSD of a bloodstain in a relatively early period (from 0 min to the time required for the bloodstain to dry out). For this purpose, we used ATR‐FTIR to study the variation in absorbance at certain wavelengths as rat and human blood sample dried out. The absorbance at 3308/cm (A3308) was found to have a close correlation with the TSD during this time period, and the changes in A3308 during the drying of rat and human blood drops under the same controlled conditions showed similar results. The current study indicates that ATR‐FTIR spectroscopy has potential as a tool for estimating TSD at early time periods of blood deposition.
Severe Retinal Hemorrhages with Retinoschisis in Infants are Not Pathognomonic for Abusive Head Trauma
Authors: Shuman Mark J. , Hutchins Kenneth D.
Published: December 2016

The combination of subdural hemorrhage (SDH), retinal hemorrhage (RH), and encephalopathy, or the presence of severe retinal hemorrhages alone in infants, is often attributed to and has been stated to be pathognomonic for abusive head trauma (AHT) or shaken baby syndrome. These beliefs have been challenged, because the same constellation of findings has been identified in accidental head injuries and natural diseases, and most if not all of the studies that support the concept of diagnostic specificity have serious flaws in their methodology. Presented here are two cases of severe retinal hemorrhages with retinoschisis associated with subdural hemorrhage in a natural disease and with severe cerebral edema in an accidental head injury. These cases challenge the dogma that severe retinal hemorrhages with retinoschisis are pathognomonic for AHT.
Death Due to Decapitation in Two Motorcyclists: A Description of a Unique Case and a Brief Review of the Literature
Authors: Osculati Antonio , Visonà Silvia D. , Della Chiesa Laura , Navarra Filippo , Calbi Andrea , Andrello Luisa
Published: December 2016

Deaths due to decapitation, especially related to traffic accidents, are rarely found in forensic practice. The present case involves a man and a woman who died from decapitation due to an unusual mechanism while they were riding on a motorbike down a mountain road. The autopsy, which was completed as a physics study, allowed the accident to be reconstructed as follows: A plastic cable that had detached from a timber‐transporting machine whipped the road and hit the two motorcyclists. The impact resulted in the complete severing of both riders’ heads. Involving different scientists in this accident investigation was crucial to understanding the dynamics of the accident. In fact, in addition to scene inspection and autopsy, a physics study was carried out on the cable and the clamp involved, which led to an explanation for the abrupt movement of the cable and, thus, to a thorough reconstruction of the accident.
Self‐Embedding Behavior in Adults: A Report of Two Cases and a Systematic Review
Authors: Mannarino Victor S. , Pereira Débora C. S. , Gurgel Wagner S. , Costa Carolina B. F. , Valença Alexandre M. , Fontenelle Leonardo F. , Mendlowicz Mauro V.
Published: December 2016

Self‐embedding behavior (SEB) is the repeated insertion of sharp objects, such as needles or pins, into the soft tissues of abdomen, limbs, and other body parts. In this study, two cases of SEB were reported and the scientific worldwide literature reviewed. Thirty‐two cases of SEB were identified through systematic searches in the main bibliographic databases. Mean age was 35 years (SD = 8.97). Just over two‐thirds of the patients were female. Although the number of embedded objects could be as high as 200, major clinical and surgical complications were uncommon and mortality was null. Patients with SEB presented three major diagnoses: psychotic (25%), personality (21.9%), and factitious (28.1%) disorders. The practice of SEB largely went undetected as the patients themselves did not bring it to the attention of family members or physicians and usually denied they have engaged in SEB. A high level of suspicion is required to avoid a missed diagnosis.
PRISM vs. CFSR Precipitation Data Effects on Calibration and Validation of SWAT Models
Authors: Radcliffe D.E. , Mukundan R.
Published: December 2016

Precipitation is one of the most important drivers in watershed models. Our objective was to compare two sources of interpolated precipitation data in terms of their effect on calibration and validation of two Soil and Water Assessment Tool (SWAT) models. One model was a suburban watershed in metropolitan Atlanta, Georgia. The precipitation sources were Parameter‐elevation Relationships on Independent Slopes Model (PRISM) data on a 4‐km grid and climate forecast system reanalysis (CFSR) data on a 38‐km grid. The PRISM data resulted in a better fit to the calibration data (Nash Sutcliffe efficiency [NSE] = 0.64, Kling‐Gupta efficiency [KGE] = 0.74, p‐factor = 0.84, and r‐factor = 0.43) than the CFSR data (NSE = 0.47, KGE = 0.53, p‐factor = 0.67, and r‐factor = 0.39). Validation results were similar. Sensitive parameters were similar in both the PRISM and CFSR models, but fitted values indicated more rapid groundwater flow to the streams with the PRISM data. The same comparison was made in the Big Creek watershed located approximately 1,000 km away, in central Louisiana. Results were similar with a more responsive groundwater system indicating PRISM data may produce better predictions of streamflow because of a more accurate estimate of rainfall within a watershed or because of a denser grid. Our study implies PRISM is providing a better estimate than CFSR of precipitation within a watershed when rain gauge data are not available, resulting in more accurate simulations of streamflows at the watershed outlet. Editor's note: This paper is part of the featured series on SWAT Applications for Emerging Hydrologic and Water Quality Challenges. See the February 2017 issue for the introduction and background to the series.
Obesity, weight change, and chronic kidney disease in patients with type 2 diabetes mellitus: A longitudinal study in Taiwan
Authors: Chung Hsin‐Fang , Al Mamun Abdullah , Huang Meng‐Chuan , Long Kurt Z. , Huang Ya‐Fang , Shin Shyi‐Jang , Hwang Shang‐Jyh , Hsu Chih‐Cheng
Published: December 2016

Background

The aim of the present study was to investigate relationships between the risk of chronic kidney disease (CKD) and obesity and weight changes in Asian patients with type 2 diabetes.

Methods

At baseline (2003–05), 1187 diabetic patients aged 30–70 years were recruited to the study, with follow‐up surveys completed in 2008, 2009, and 2010. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2; body mass index (BMI) was categorised as normal (18.5–22.9 kg/m2), overweight (23–27.4 kg/m2), or obese (≥27.5 kg/m2); waist circumference (WC) ≥80 cm for women and ≥90 cm for men was taken to indicate abdominal obesity. Changes in weight and WC were calculated from baseline to each follow‐up survey. Relative risk (RR) and 95% confidence intervals (CIs) of CKD were estimated. To estimate the risk for incident CKD, associations were examined in patients without CKD at baseline (n = 881).

Results

Over 7 years of follow‐up, obesity (RR 1.48; 95% CI 1.08–2.04; P = 0.015) and high WC (RR 1.23; 95% CI 1.00–1.52; P = 0.049) were associated with CKD after adjusting for covariates. Among participants without CKD at baseline, those who gained >10% weight (RR 1.43; 95% CI 1.07–1.90; P = 0.015) and in whom WC increased >15% (RR 1.37; 95% CI 1.01–1.85; P = 0.045) had a higher risk of incident CKD than those who remained stable (±5% changes in weight or WC).

Conclusions

Diabetic patients who are obese and those with excessive central fat were more likely to have CKD. Large weight gain (>10%) and increases in WC (>15%) independently predicted incident CKD.
What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus
Authors: Chan Wing B. , Luk Andrea , Chow Wing S. , Yeung Vincent T.F.
Published: December 2016

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short‐acting, prandial, and long‐acting GLP‐1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short‐acting prandial GLP‐1RA lixisenatide, with a focus on treatment of Asian patients with T2DM.
Previous malignancy is an independent predictor of follow‐up mortality after percutaneous treatment of mitral valve regurgitation by means of MitraClip
Authors: Öner Alper , Ince Hüseyin , Paranskaya Liliya , Schröder Guido , Sherif Mohammad , Thiele Olga , Neuhausen Alla , Kische Stephan , Ortak Jasmin , D′Ancona Giuseppe
Published: December 2016

Aims

To investigate the prognostic burden of previously diagnosed and treated malignancies in candidates for percutaneous mitral valve repair (MVR) with MitraClip.

Methods and Results

A total of 165 patients underwent MVR and 19 (11.5%) had been previously treated for malignancy and considered healed with life expectancy over 1 year at time of percutaneous MVR. There was a significant trend for an increased overall risk profile (euroSCORE II 14.0±11.4 vs 10.0±6.7, P=.01) in patients with a previous diagnosis of neoplasia. Moreover, neoplastic patients had lower device success rates (78.9% vs 97.3%; P=.001), longer hospitalization (12.3±10.6 vs 7.5±4.9 days, P=.001), and higher 30‐day mortality (10.5% vs 2.7%, P=.09). Kaplan‐Meier overall estimated 1‐, 2‐, 3‐, and 4‐year survival of the overall cohort was 72%, 61%, 48%, and 44%, respectively. Estimated 1‐ and 2‐year survival were 44.4% and 22.2 % in patients with previous neoplasia and 75.3% and 65% in the remaining patients (P<.0001). Median survival was 312 days in the neoplastic group (CI 95%: 182.6‐441.4 days) and 1209 days in the remaining patients (CI 95%: 758.8‐1659.2 days) (P<.0001). At Cox regression, the strongest determinant for mortality was an anamnesis for neoplasia (HR 2.4, 95% CI 1.4‐4.3, P=.001).

Conclusions

Previous neoplasm is a significant independent predictor of increased mortality after MVR with MitraClip. This association is even stronger than that of other cardiac and overall comorbidities and should be kept into consideration when referring patients for treatment.
Soil inoculum density of Verticillium dahliae and Verticillium wilt of olive in Lebanon
Authors: Habib W. , Choueiri E. , Baroudy F. , Tabet D. , Gerges E. , Saab C. , Nigro F.
Published: December 2016

In the Mediterranean basin, Verticillium Wilt of Olive (VWO) is diffused throughout its range of cultivation, causing severe yield losses and tree mortality. The disease was reported in almost all the Mediterranean and Middle East countries, and in Lebanon it is of increasing significance also on many valuable crops. The disease has already been reported on potato, peach and almond in the Bekaa valley; however, to date no information is available about the incidence of VWO and the inoculum density of Verticillium dahliae microsclerotia in soil of the main agricultural areas of Lebanon. Results from the present investigations demonstrate a high V. dahliae frequency in soils (75.3%), coupled with a mean soil inoculum density of 17.0 MS g−1, clearly indicating a great impact on the production of susceptible hosts in Lebanon, mainly in Bekaa region. Molecular method to assess the microsclerotia inoculum density in soil allowed the detection of a higher frequency of infested soils, as compared with the traditional plating, thus confirming its higher sensitivity. The overall Verticillium wilt prevalence in the inspected olive orchards was 46.2%, and the frequency of V. dahliae‐infected trees was 25.7%. The widespread presence of V. dahliae in all olive growing areas of Lebanon enforces the adoption of measures aimed at reducing the soil inoculum density before any new olive plantation, and the use of strong phytosanitary regulations to improve the certification schemes of propagating material.
Detection of Fomitiporia torreyae and Fulviformes umbrinellus by multiplex loop‐mediated isothermal amplification (mLAMP) for diagnosis of Japanese pear dwarf
Authors: Fukuta S. , Nagai H. , Suzuki R. , Matsumoto Y. , Kato S. , Saka N. , Horikawa H. , Kato S. , Miyake N.
Published: December 2016

Japanese pear dwarf, caused by the fungi Fomitiporia torreyae or Fulviformes umbrinellus, is one of the most important diseases affecting Japanese pear (Pyrus pyrifolia var. culta). To diagnose this disease, a multiplex loop‐mediated isothermal amplification (mLAMP) reaction using primer sets designed from the rDNA internal transcribed spacer (ITS) sequences of F. torreyae and F. umbrinellus was developed. The optimal conditions for simultaneous detection of the two pathogens were investigated. The best results were obtained at a reaction temperature of 65°C and a primer ratio of 1:1.5 (F. torreyae : F. umbrinellus). Fluorescently labelled mLAMP amplicons were precipitated using polyethyleneimine. As a result, multiplex detection was enabled by the fluorescent colour of precipitate under ultraviolet light. The detection limit of mLAMP was 100 fg of genomic DNA, which was 10 times more sensitive than the polymerase chain reaction (PCR) method. The mLAMP assay was applied to Japanese pear trunk samples from Aichi Prefecture, Japan, and the results were compared with those obtained using PCR. As a result, mLAMP was observed to be effective for the specific detection of F. torreyae or F. umbrinellus.
H1‐antihistamines Reduce Progression to Anaphylaxis Among Emergency Department Patients With Allergic Reactions
Authors: Kawano Takahisa , Scheuermeyer Frank X. , Gibo Koichiro , Stenstrom Robert , Rowe Brian , Grafstein Eric , Grunau Brian
Published: December 2016

Objectives

H1‐antihistamines (H1a) can be used to treat emergency department (ED) patients with allergic reactions; however, this is inconsistently done, likely because there is no evidence that this therapy has an impact on serious outcomes. Among ED patients initially presenting with allergic reactions, we investigated whether H1a were associated with lower rates of progression to anaphylaxis.

Methods

This was a retrospective cohort study conducted at two urban Canadian EDs from April 1, 2007, to March 31, 2012. We included consecutive adult patients with allergic reactions while excluding those presenting with anaphylaxis, according to prespecified criteria. The primary outcome was the proportion of patients who subsequently developed anaphylaxis during medical care, either by emergency medical services (EMS) or in the ED. A prespecified subgroup analysis excluded patients who received H1a prior to EMS or ED contact. We compared those who received H1a and those who did not and used multivariable regression and propensity score adjustment techniques to compare outcomes.

Results

Of 2,376 overall patients included, 1,880 (79.1%) were managed with H1a. Of the latter group, 36 of 1,880 (1.9%) developed anaphylaxis, compared to 17 of 496 (3.4%) in the non–H1a‐treated group (adjusted odds ratio [AOR] = 0.34, 95% confidence interval [CI] = 0.17–0.70; number needed to treat [NNT] to benefit = 44.74, 95% CI = 35.36–99.67). In the subgroup analysis of 1,717 patients who did not receive H1a prior to EMS or ED contact, a similar association was observed (AOR = 0.26, 95% CI = 0.10–0.50; NNT to benefit 38.20, 95% CI = 32.58–55.24).

Conclusions

Among ED patient with allergic reactions, H1a administration was associated with a lower likelihood of progression to anaphylaxis. These data indicate that early H1a treatment in the ED or prehospital setting may decrease progression to anaphylaxis.
Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia
Authors: Paillère‐Martinot M.‐L. , Galinowski A. , Plaze M. , Andoh J. , Bartrés‐Faz D. , Bellivier F. , Lefaucheur J.‐P. , Rivière D. , Gallarda T. , Martinot J.‐L. , Artiges E.
Published: December 2016

Objective

Repetitive transcranial magnetic stimulation (rTMS) over the left temporo‐parietal region has been proposed as a treatment for resistant auditory verbal hallucinations (AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology.

Method

Twenty‐seven patients with schizophrenia and medication‐resistant AVH participated to a randomized, double‐blind, placebo‐controlled, add‐on rTMS study. The stimulation targeted a language‐perception area individually determined using functional magnetic resonance imaging and a language recognition task. AVH were assessed using the hallucination subscale of the Scale for the Assessment of Positive Symptoms (SAPS). The spatial location of AVH was assessed using the Psychotic Symptom Rating Scales.

Results

A significant improvement in SAPS hallucination subscale score was observed in both actively treated and placebo‐treated groups with no difference between both modalities. Patients with external AVH were significantly more improved than patients with internal AVH, with both modalities.

Conclusions

A marked placebo effect of rTMS was observed in patients with resistant AVH. Patients with prominent external AVH may be more likely to benefit from both active and placebo interventions. Cortical effects related to non‐magnetic stimulation of the auditory cortex are suggested.
Targeting and transforming major depression
Authors: Parker G. , Paterson A. , McCraw S. , Hadzi‐Pavlovic D.
Published: December 2016

Objective

To detail limitations to the construct of ‘major depression’, argue for repositioning it as a proxy for ‘clinical depression’ and then operationalize it and its principal constituent depressive subtypes, while preserving the DSM criteria‐based format.

Method

We summarize limitations to major depression being viewed as a diagnostic entity. Data from 391 clinically depressed patients were analysed to identify high‐prevalence non‐specific depressive symptoms to define ‘clinical depression’ as well as the features showing specificity to a melancholic depressive subtype.

Results

We identified a set of high‐prevalence and generalized symptoms for defining clinical depression and with many being current criteria for major depression. We also developed a refined set of melancholic features and with their underlying distributions generating two classes that correlated strongly with clinical diagnoses of a melancholic or non‐melancholic depression, thus validating its capacity to so differentiate. We append criteria sets for diagnosing clinical depression and its principal diagnostic subtypes (psychotic, melancholic and non‐melancholic).

Conclusion

This heuristic study reframes and modifies major depression's criteria set to define a domain of clinical depression with additional criteria and then allowing the delineation of three diagnostic subtypes. If this paradigm shift is accepted and further refined, greater precision in diagnosis, treatment and research would be anticipated.
Alcohol use disorder and divorce: evidence for a genetic correlation in a population‐based Swedish sample
Authors: Salvatore Jessica E. , Larsson Lönn Sara , Sundquist Jan , Lichtenstein Paul , Sundquist Kristina , Kendler Kenneth S.
Published: December 2016

Aims

We tested the association between alcohol use disorder (AUD) and divorce; estimated the genetic and environmental influences on divorce; estimated how much genetic and environmental influences accounted for covariance between AUD and divorce; and estimated latent genetic and environmental correlations between AUD and divorce. We tested sex differences in these effects.

Design

We identified twin and sibling pairs with AUD and divorce information in Swedish national registers. We described the association between AUD and divorce using tetrachorics and used twin and sibling models to estimate genetic and environmental influences on divorce, on the covariance between AUD and divorce and the latent genetic and environmental correlations between AUD and divorce.

Setting

Sweden.

Participants

A total of 670 836 individuals (53% male) born 1940–1965.

Measurements

Life‐time measures of AUD and divorce.

Findings

AUD and divorce were related strongly (males: rtet = +0.44, 95% CI = 0.43, 0.45; females rtet = +0.37, 95% CI = 0.36, 0.38). Genetic factors accounted for a modest proportion of the variance in divorce (males: 21.3%, 95% CI = 7.6, 28.5; females: 31.0%, 95% CI = 18.8, 37.1). Genetic factors accounted for most of the covariance between AUD and divorce (males: 52.0%, 95% CI = 48.8, 67.9; females: 53.74%, 95% CI = 17.6, 54.5), followed by non‐shared environmental factors (males: 45.0%, 95% CI = 37.5, 54.9; females: 41.6%, 95% CI = 40.3, 60.2). Shared environmental factors accounted for a negligible proportion of the covariance (males: 3.0%, 95% CI = −3.0, 13.5; females: 4.75%, 95% CI = 0.0, 6.6). The AUD–divorce genetic correlations were high (males: rA = +0.76, 95% CI = 0.53, 0.90; females +0.52, 95% CI = 0.24, 0.67). The non‐shared environmental correlations were modest (males: rE = +0.32, 95% CI = 0.31, 0.40; females: +0.27, 95% CI = 0.27, 0.36).

Conclusions

Divorce and alcohol use disorder are correlated strongly in the Swedish population, and the heritability of divorce is consistent with previous studies. Covariation between AUD and divorce results from overlapping genetic and non‐shared environmental factors. Latent genetic and non‐shared environmental correlations for alcohol use disorder and divorce are high and moderate.
Approach to hypersensitivity reactions from intravenous iron preparations
Authors: Morales Mateluna C. A. , Scherer Hofmeier K. , Bircher A. J.
Published: December 2016

Hypersensitivity reactions (HSRs) to intravenous iron preparations (IVIPs) are well known. With newer preparations, HSRs have become rarer; however, severe reactions may still occur. We retrospectively reviewed records of patients evaluated for HSRs to IVIPs, to determine the safety of controlled re‐administration (CRA). Allergological work‐up included a detailed history, skin prick tests (SPTs) with IVIP, and basophil activation tests (BATs) in some patients. CRA with an IVIP was carried out if indicated. Thirty‐one patients with mild to severe reactions were evaluated. SPTs and BATs were negative in all patients tested. Eighteen CRAs in 15 patients were performed. Twelve patients tolerated the procedure, including three with a previous grade IV HSR. Two developed urticaria and one developed urticaria and dyspnea. The pathophysiology of HSRs to IVIPs remains currently unclear. SPTs and BATs provided no additional information. However, in appropriate situations, CRA under surveillance can be safely performed in most patients.
Anticoagulation in patients at high risk of stroke without documented atrial fibrillation. Time for a paradigm shift?
Authors: Bayés de Luna Antoni , Baranchuk Adrian , Martínez‐Sellés Manuel , Platonov Pyotr G.
Published: December 2016

Atrial fibrillation (AF) is currently considered a risk factor for stroke. Depending on the severity of clinical factors (risk scores) a recommendation for full anticoagulation is made. Although AF is most certainly a risk factor for ischemic stroke, it is not necessarily the direct cause of it. The causality of association between AF and ischemic stroke is questioned by the reported lack of temporal relation between stroke events and AF paroxysms (or atrial high‐rate episodes detected by devices). In different studies, only 2% of patients had subclinical AF > 6 minutes in duration at the time of stroke or systemic embolism. Is it time to consider AF only one more factor of endothelial disarray rather than the main contributor to stroke? In this “opinion paper” we propose to consider not only clinical variables predicting AF/stroke but also electrocardiographic markers of atrial fibrosis, as we postulate this as a strong indicator of risk of AF/stroke. We ask if it is time to change the paradigm and to consider, in some special situations, to protect patients (preventing stroke) who have no evidence of AF.
Postnatal systemic inflammation and neuro‐ophthalmologic dysfunctions in extremely low gestational age children
Authors: Holm Mari , Austeng Dordi , Fichorova Raina N. , Allred Elizabeth N. , Kuban Karl C. , O'Shea T. Michael , Dammann Olaf , Leviton Alan ,   the ELGAN Study Investigators
Published: December 2016

Aim

Compared to infants born at term, children born very preterm are at increased risk of visual dysfunctions and neonatal systemic inflammation. Here, we explore whether these two propensities are related.

Methods

As part of the ELGAN study, the concentrations of 16 mediators of inflammation were measured in blood obtained on postnatal days 1, 7, 14, 21 and 28 from 1062 children born before the 28th week of gestation. Presence of visual field deficit, strabismus and/or impaired visual fixation was recorded at age two. The concentrations of each protein were divided into quartiles within gestational week categories. We calculated odds ratios with 99% confidence intervals for having each disorder comparing children with concentration in the top quartile of each protein to children whose concentration was in the lower quartiles on the corresponding day. Analyses were adjusted for gestational age and birth weight Z‐score.

Results

Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation. No association was found between strabismus and any inflammatory mediator.

Conclusion

None of the three neuro‐ophthalmologic dysfunctions assessed at two years appears to be associated with systemic inflammation measured the first four postnatal weeks.
The Impact of the FMA Guidelines on Non‐GAAP Earnings Disclosures
Authors: Rainsbury Elizabeth A.
Published: December 2016

In 2012 the New Zealand Financial Markets Authority (FMA) introduced guidelines for the disclosure of non‐GAAP financial information. This study investigates the effect of those guidelines on New Zealand listed companies. The findings show that, despite not being mandatory, these guidelines are modifying corporate disclosure behaviour. Companies have improved the way in which they disclose non‐GAAP earnings information and there has been a reduction in the emphasis given to non‐GAAP earnings compared with the emphasis given to audited statutory profit. However, the study also highlights areas for improvement, including the depth of explanation of non‐GAAP earnings calculations and adjustments, and concern about multiple adjusted earnings figures to explain performance.
Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties
Authors: Okkerse Pieter , Hay Justin L. , Sitsen Elske , Dahan Albert , Klaassen Erica , Houghton William , Groeneveld Geert Jan
Published: December 2016

Aim

Xen2174 is a synthetic 13‐amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects.

Methods

This was a randomized, blinded, placebo‐controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks).

Results

Twenty‐five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration–time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post‐lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg–placebo (95% confidence interval), 22.2% (−5.0%, 57.1%); P = 0.1131].

Conclusions

At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed.
Metabolic Response to Olanzapine in Healthy Chinese Subjects with rs7093146 Polymorphism in Transcription Factor 7‐like 2 Gene (TCF7L2): A Prospective Study
Authors: Li Qing , Guo Dong , Yang Hong , Ye Zhi , Huang Jin , Shu Yan
Published: December 2016

Olanzapine is a widely used atypical antipsychotic with significant weight gain and other metabolic side effects. The locus of the transcription factor 7‐like 2 (TCF7L2) gene is strongly associated with type 2 diabetes (T2D). The goal of this study was to determine whether polymorphic TCF7L2 is involved in the susceptibility to the metabolic changes associated with the atypical antipsychotic agents (AAPs). In this study, a parallel clinical study with 3‐day consecutive administration of olanzapine (10 mg/day) was conducted in 17 healthy subjects with a genotype of TCF7L2 rs7903146 CC (N = 10) or CT (N = 7). Olanzapine caused rapid metabolic changes including body‐weight gain, increased triglycerides level and reduced HDL‐cholesterol level in the healthy subjects. rs7093146 T carriers (CT) were found to have greater AUC0–2 hr of insulin during OGTT compared to those (CC) bearing only reference alleles before and after olanzapine treatment. However, the triglyceride level in the subjects with the CT genotype was found to be significantly lower than that in the subjects with CC genotype. Moreover, a significant interaction between the effect by genotype and that by olanzapine treatment on triglyceride level was identified. Acute olanzapine treatment also significantly caused total protein, albumin and haemoglobin decrease and uric acid increase in the healthy subjects. In conclusion, even acute olanzapine treatment induces significant and rapid metabolic changes, and TCF7L2 polymorphism is a genetic risk factor of olanzapine‐associated metabolic side effects.
TP53 mutations predict decitabine‐induced complete responses in patients with myelodysplastic syndromes
Authors: Chang Chun‐Kang , Zhao You‐Shan , Xu Feng , Guo Juan , Zhang Zheng , He Qi , Wu Dong , Wu Ling‐Yun , Su Ji‐Ying , Song Lu‐Xi , Xiao Chao , Li Xiao
Published: December 2016

To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post‐DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine‐induced complete responses in patients with MDS. DAC‐induced responses may result from partial suppression of malignant clones containing mutated TP53 genes.
Interim assessment of liver damage in patients with sickle cell disease using new non‐invasive techniques
Authors: Drasar Emma , Fitzpatrick Emer , Gardner Kate , Awogbade Moji , Dhawan Anil , Bomford Adrian , Suddle Abid , Thein Swee L.
Published: December 2016

We explored transient elastography (TE) and enhanced liver fibrosis (ELF™) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSβ0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6·8 vs. 5·3, P < 0·0001 and ELF, 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0·24, P = 0·004; ELF: r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin (TE: r = −0·25, P = 0·002; ELF: r = −0·25 P = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P < 0·0001, total blood transfusion units, β = 0·25, P < 0·0001 and LIC β = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies.
Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics
Authors: Tasian Sarah K. , Hunger Stephen P.
Published: December 2016

Major advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia (ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia‐associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (i) underlying biological and clinical characteristics, and (ii) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies.
The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma
Authors: Chihara Dai , Fanale Michelle A. , Miranda Roberto N. , Noorani Mansoor , Westin Jason R. , Nastoupil Loretta J. , Hagemeister Fredrick B. , Fayad Luis E. , Romaguera Jorge E. , Samaniego Felipe , Turturro Francesco , Lee Hun J. , Neelapu Sattva S. , Rodriguez M. Alma , Wang Michael , Fowler Nathan H. , Davis Richard E. , Medeiros L. Jeffrey , Hosing Chitra , Nieto Yago L. , Oki Yasuhiro
Published: December 2016

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL‐NOS) and angioimmunoblastic T‐cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL‐NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL‐NOS, 105 AITL) experienced progression/relapse. In patients with PTCL‐NOS, the median durations of FFS1, FFS2 and FFS3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL, they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.
Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd‐line therapy for relapsed and refractory multiple myeloma – a phase II trial
Authors: Mey Ulrich J. M. , Brugger Wolfram , Schwarb Heike , Pederiva Stefanie , Schwarzer Andreas , Dechow Tobias , Jehner Paul , Rauh Jacqueline , Taverna Christian J. , Schmid Mathias , Schmidt‐Hieber Martin , Doerfel Steffen , Fischer Natalie , Ruefer Axel , Ziske Carsten , Knauf Wolfgang , Cathomas Richard , von Moos Roger , Hitz Felicitas , Sauter Rafael , Hiendlmeyer Elke , Cantoni Nathan , Bargetzi Mario , Driessen Christoph
Published: December 2016

The combination of lenalidomide (Revlimid®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose‐limiting haematotoxicity restricted its use in extensively pre‐treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46–83]) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28‐day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol‐defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.
Importance and outcome relevance of central pathology review in prostatectomy specimens: data from the SAKK 09/10 randomized trial on prostate cancer
Authors: Ghadjar Pirus , Hayoz Stefanie , Genitsch Vera , Zwahlen Daniel R. , Hölscher Tobias , Gut Philipp , Guckenberger Matthias , Hildebrandt Guido , Müller Arndt‐Christian , Putora Paul M. , Papachristofilou Alexandros , Stalder Lukas , Biaggi‐Rudolf Christine , Sumila Marcin , Kranzbühler Helmut , Najafi Yousef , Ost Piet , Azinwi Ngwa C. , Reuter Christiane , Bodis Stephan , Khanfir Kaouthar , Budach Volker , Aebersold Daniel M. , Thalmann George N. ,   the Swiss Group for Clinical Cancer Research (SAKK)
Published: December 2016

Objective

To conduct a central pathology review within a randomized clinical trial on salvage radiation therapy (RT) in the presence of biochemical recurrence after prostatectomy to assess whether this results in changes in histopathological prognostic factors, such as Gleason score.

Patients and Methods

A total of 350 patients were randomized and specimens from 279 patients (80%) were centrally reviewed by a dedicated genitourinary pathologist. Gleason score, tumour classification and resection margin status were reassessed and compared with the results of local pathology review. Agreement was assessed using contingency tables and Cohen's kappa coefficient. The association between other histopathological features (e.g. largest diameter of carcinoma) and rapid biochemical progression (up to 6 months after salvage RT) was also investigated.

Results

There was good concordance between central and local pathology review for seminal vesicle invasion (pT3b: 91%; κ = 0.95 [95% confidence interval {CI} 0.89, 1.00]), extraprostatic extension (pT3a/b: 94%; κ = 0.82 [95% CI 0.75, 0.89]) and positive surgical margin (PSM) status (87%; κ = 0.7 [95% CI 0.62, 0.79]). The rate of agreement was lower for Gleason score (78%; κ = 0.61 [95% CI 0.52, 0.70]). The median (range) largest diameter of carcinoma was 16 (3–38) mm. A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma (odds ratio [OR] 2.04 [95% CI 1.30, 3.20]; P = 0.002), resection margin status (OR 0.36 [95% CI 0.18, 0.72]; P = 0.004) and Gleason score (OR 1.55 [95% CI 1.00, 2.42]; P = 0.05) remained associated with rapid progression after salvage RT after backward selection.

Conclusion

The results of the central pathology analyses showed concordance between central and local pathology review with regard to seminal vesicle invasion, extraprostatic extension and PSM status, but a lower rate of agreement for Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT.
Reality bites: Managing identity ambiguity in an advertising agency
Authors: Round Heather , Styhre Alexander
Published: December 2016

Creative industries provide a challenging environment for management, especially given the ambiguities inherent in these environments and the need to balance creative work with mundane, yet supportive practices of organizations. Within these environments there are a large number of individuals with high identity needs such as the Creatives, and management must thus balance the needs of these Creatives with those of other organizational actors, including those responsible for allegedly ‘non‐creative’ processes. This paper examines an Australian advertising agency and demonstrates how individuals and groups within the organization handle ambiguities and tensions inherent to their work. The case study shows how management provides structures and support in order to allow for heedful interactions between two oppositional dimensions of the environment. Therefore managerial action and instituted processes serve to strike a balance between the creative and non‐creative work and to guide individuals and groups towards meaningful outcomes.
Neddylated Cullin 3 is required for vascular endothelial‐cadherin‐mediated endothelial barrier function
Authors: Sakaue Tomohisa , Fujisaki Ayako , Nakayama Hironao , Maekawa Masashi , Hiyoshi Hiromi , Kubota Eiji , Joh Takashi , Izutani Hironori , Higashiyama Shigeki
Published: December 2016

Vascular endothelial (VE)‐cadherin, a major endothelial adhesion molecule, regulates vascular permeability, and increased vascular permeability has been observed in several cancers. The aim of this study was to elucidate the role of the NEDD8‐Cullin E3 ligase, in maintaining barrier permeability. To this end, we investigated the effects of the inhibition of Cullin E3 ligases, by using inhibitors and knockdown techniques in HUVECs. Furthermore, we analyzed the mRNA and protein levels of the ligases by quantitative RT‐PCR and Western blotting, respectively. The results revealed that NEDD8‐conjugated Cullin 3 is required for VE‐cadherin‐mediated endothelial barrier functions. Treatment of HUVECs with MLN4924, a chemical inhibitor of the NEDD8‐activating enzyme, led to high vascular permeability due to impaired cell–cell contact. Similar results were obtained when HUVECs were treated with siRNA directed against Cullin 3, one of the target substrates of NEDD8. Immunocytochemical staining showed that both treatments equally depleted VE‐cadherin protein localized at the cell–cell borders. However, quantitative RT‐PCR showed that there was no significant difference in the VE‐cadherin mRNA levels between the treatment and control groups. In addition, cycloheximide chase assay revealed that the half‐life of VE‐cadherin protein was dramatically reduced by Cullin 3 depletion. Together, these findings suggest that neddylated Cullin 3 plays a crucial role in endothelial cell barrier function by regulating VE‐cadherin.