Safety and efficacy of the next generation Resolute Onyx zotarolimus-eluting stent: Primary outcome of the RESOLUTE ONYX core trial

Abstract

Objectives

To assess the safety and efficacy of the novel Resolute (R-) Onyx drug-eluting stent (DES).

Background

The R-Onyx DES consists of a composite wire with an outer shell of cobalt chromium alloy and a platinum-iridium inner core to enhance radiopacity, with thinner, swaged struts and modified stent geometry compared with the predicate Resolute DES, resulting in a slightly lower total drug load in most sizes.

Methods

This was a prospective, single-arm non-inferiority trial compared with a historical control. Patients with stable angina/ischemia and up to 2 de novo target lesions ≤35 mm long with reference vessel diameter (RVD) of 2.25–4.2 mm were enrolled. The primary endpoint was late lumen loss at 8-month follow-up. Propensity-score adjusted outcomes from the single-arm RESOLUTE-US trial served as the control.

Results

Seventy-five patients (85 lesions) were enrolled. Mean patient age was 66 ± 9 years, 73% were male, and 32% had diabetes. Mean lesion length was 14.28 ± 6.68 mm, mean RVD was 2.57 ± 0.48 mm, and 86% of lesions were class B2/C. In-stent late lumen loss at 8 months was 0.24 ± 0.39 mm with R-Onyx DES compared with 0.36 ± 0.52 mm with Resolute DES (P < 0.001 for noninferiority, P = 0.029 for superiority). At 8 months, clinically driven target lesion revascularization occurred in 3 patients (4.0%) and target lesion failure occurred in 5 patients (6.7%).

Conclusions

In-stent late lumen loss is non-inferior, and appears to be superior, with the thin-strut novel composite wire R-Onyx DES compared with Resolute DES. Continued evolution of stent design can improve angiographic outcomes in complex lesions, even in the current era of next-generation DES.

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Comparative outcomes of transcatheter aortic valve replacement in African American and Caucasian patients with severe aortic stenosis

Abstract

Background

Racial disparities in cardiovascular care have been extensively investigated. The introduction of transcatheter aortic valve replacement (TAVR) revolutionized the treatment of aortic stenosis (AS) in the last decade. Whether a racial disparity in the utilization and outcome of TAVR exists is unknown.

Methods

We utilized the nationwide inpatient sample (NIS) to compare utilization rates, and in-hospital outcomes of Caucasians and African American (AA) patients who underwent TAVR between August 2011 and December 2014.

Results

A total of 7,176 patients (6870 Caucasians, 95.7%) and (306 AAs, 4.3%) were included in this analysis. Among patients who underwent aortic valve replacement between 2011 and 2014, the rates of TAVR utilization increased from 0.32% to 7.6% in AAs and from 0.4% to 8.8% in Caucasians. In propensity-matched cohorts of patients (n = 300 Caucasians and n = 300 AAs), in-hospital mortality was similar (3.7% and 3.3%, respectively, P = 0.99). Also, rates of key complications including stroke, permanent pacemaker implantation (PPMI), vascular complications, acute kidney injury, new dialysis, blood transfusion, and tamponade were similar in both races. There was also no significant difference between Caucasians and AAs with regards to length of stay, cost of hospitalization, and intermediate care facility utilization.

Conclusions

There was no significant difference in the utilization rates, in-hospital outcomes, and cost of TAVR between Caucasians and AA patients in contemporary US practice. Further comparative studies of surgical and TAVR in AAs and other racial minorities are warranted.

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IJMS, Vol. 18, Pages 2047: Podocalyxin-Like Protein 1 Regulates TAZ Signaling and Stemness Properties in Colon Cancer

IJMS, Vol. 18, Pages 2047: Podocalyxin-Like Protein 1 Regulates TAZ Signaling and Stemness Properties in Colon Cancer

International Journal of Molecular Sciences doi: 10.3390/ijms18102047

Authors: Wen-Ying Lee Chih-Chia Kuo Bo-Xing Lin Chia-Hsiung Cheng Ku-Chung Chen Cheng-Wei Lin

Colon cancer is the third most common cancer in the world and the second most common cause of cancer-related mortality. Molecular biomarkers for colon cancer have undergone vigorous discovery and validation. Recent studies reported that overexpression of podocalyxin-like protein 1 (PODXL) is associated with distant metastasis and poor prognosis across several types of malignancies. Its role and underlying molecular mechanism, however, are not yet fully understood. In the present study, we revealed that the Hippo transducer, the transcriptional coactivator with PDZ-binding motif (TAZ), acts as a downstream mediator of PODXL in colon cancer. Inhibition of PODXL resulted in the suppression of TAZ signaling and the downregulation of Hippo downstream genes. Moreover, PODXL plays a critical role in cancer stemness, invasiveness, and sensitivity to chemotherapies in colon cancer HCT15 cells. Notably, expression of PODXL showed a positive correlation with stem-like and epithelial-mesenchymal transition (EMT) core signatures, and was associated with poor survival outcomes in patients with colon cancer. These findings provide novel insights into the molecular mechanism of PODXL-mediated tumorigenesis in colon cancer.

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IJMS, Vol. 18, Pages 2046: Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis

IJMS, Vol. 18, Pages 2046: Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis

International Journal of Molecular Sciences doi: 10.3390/ijms18102046

Authors: Christoffer Soendergaard Peter Kvist Peter Thygesen Mats Reslow Ole Nielsen John Kopchick Thomas Holm

Growth hormone (GH) resistance may develop as a consequence of inflammation during conditions such as inflammatory bowel disease, encompassing ulcerative colitis (UC). However, the specific role of the GH–insulin growth factor (IGF)-1-axis and/or the functional consequences of GH resistance in this condition are unclear. In situ hybridization targeting the GH receptor (GHR) and relevant transcriptional analyses were performed in patients with UC and in IL-10 knock-out mice with piroxicam accelerated colitis (PAC). Using cultured primary epithelial cells, the effects of inflammation on the molecular mechanisms governing GH resistance was verified. Also, the therapeutic potential of GH on mucosal healing was tested in the PAC model. Inflammation induced intestinal GH resistance in UC and experimental colitis by down-regulating GHR expression and up-regulating suppressor of cytokine signalling (SOCS) proteins. These effects are driven by pro-inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) as confirmed using primary epithelial cells. Treatment of experimental colitis with GH increased IGF-1 and body weight of the mice, but had no effects on colonic inflammation or mucosal healing. The high transcriptional similarity between UC and experimental colitis accentuates the formation of intestinal GH resistance during inflammation. Inflammation-induced GH resistance not only impairs general growth but induces a state of local resistance, which potentially impairs the actions of GH on mucosal healing during colitis when using long-acting GH therapy.

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IJMS, Vol. 18, Pages 2048: Deciphering the Role of B Cells in Multiple Sclerosis—Towards Specific Targeting of Pathogenic Function

IJMS, Vol. 18, Pages 2048: Deciphering the Role of B Cells in Multiple Sclerosis—Towards Specific Targeting of Pathogenic Function

International Journal of Molecular Sciences doi: 10.3390/ijms18102048

Authors: Klaus Lehmann-Horn Silke Kinzel Martin Weber

B cells, plasma cells and antibodies may play a key role in the pathogenesis of multiple sclerosis (MS). This notion is supported by various immunological changes observed in MS patients, such as activation and pro-inflammatory differentiation of peripheral blood B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement. In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody—ocrelizumab—is currently in the process of being approved for treatment of MS. In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components. We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS.

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Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats

Abstract

The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber–Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2.5 mg/kg) of the aromatase inhibitor letrozole. We also assessed the effect of letrozole on synaptic plasticity at the PF synapse in vitro, using cerebellar slices from male rats. We found that letrozole acutely impaired both gain increases and decreases adaptation of the VOR without altering basal ocular-motor performance. Moreover, letrozole prevented long-term potentiation at the PF synapse (PF-LTP) without affecting long-term depression (PF-LTD). Thus, in male rats neurosteroid E2 has a relevant impact on VOR adaptation and affects exclusively PF-LTP. These findings suggest that E2 might regulate changes in VOR adaptation by acting locally on cerebellar and extra-cerebellar synaptic plasticity sites.

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Cells, Vol. 6, Pages 32: Use of Human Neurons Derived via Cellular Reprogramming Methods to Study Host-Parasite Interactions of Toxoplasma gondii in Neurons

Cells, Vol. 6, Pages 32: Use of Human Neurons Derived via Cellular Reprogramming Methods to Study Host-Parasite Interactions of Toxoplasma gondii in Neurons

Cells doi: 10.3390/cells6040032

Authors: Sandra Halonen

Toxoplasma gondii is an intracellular protozoan parasite, with approximately one-third of the worlds' population chronically infected. In chronically infected individuals, the parasite resides in tissue cysts in neurons in the brain. The chronic infection in immunocompetant individuals has traditionally been considered to be asymptomatic, but increasing evidence indicates that chronic infection is associated with diverse neurological disorders such as schizophrenia, cryptogenic epilepsy, and Parkinson's Disease. The mechanisms by which the parasite exerts affects on behavior and other neuronal functions are not understood. Human neurons derived from cellular reprogramming methods offer the opportunity to develop better human neuronal models to study T. gondii in neurons. Results from two studies using human neurons derived via cellular reprogramming methods indicate these human neuronal models provide better in vitro models to study the effects of T. gondii on neurons and neurological functions. In this review, an overview of the current neural reprogramming methods will be given, followed by a summary of the studies using human induced pluripotent stem cell (hiPSC)-derived neurons and induced neurons (iNs) to study T. gondii in neurons. The potential of these neural reprogramming methods for further study of the host-parasite interactions of T. gondii in neurons will be discussed.

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IJERPH, Vol. 14, Pages 1106: Agricultural Capacity to Increase the Production of Select Fruits and Vegetables in the US: A Geospatial Modeling Analysis

IJERPH, Vol. 14, Pages 1106: Agricultural Capacity to Increase the Production of Select Fruits and Vegetables in the US: A Geospatial Modeling Analysis

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph14101106

Authors: Zach Conrad Christian Peters Kenneth Chui Lisa Jahns Timothy Griffin

The capacity of US agriculture to increase the output of specific foods to accommodate increased demand is not well documented. This research uses geospatial modeling to examine the capacity of the US agricultural landbase to increase the per capita availability of an example set of nutrient-dense fruits and vegetables. These fruits and vegetables were selected based on nutrient content and an increasing trend of domestic production and consumption. Geographic information system models were parameterized to identify agricultural land areas meeting crop-specific growing requirements for monthly precipitation and temperature; soil depth and type; cropland availability; and proximity to existing production centers. The results of these analyses demonstrate that crop production can be expanded by nearly 144,000 ha within existing national production centers, generating an additional 0.05 cup-equivalents of fruits and vegetables per capita per day, representing a 1.7% increase above current total F&amp;V availability. Expanding the size of national crop production centers can further increase the availability of all F&amp;V by 2.5%–5.4%, which is still less than the recommended amount. Challenges to increasing F&amp;V production in the US include lack of labor availability, barriers to adoption among producers, and threats to crop yields from environmental concerns.

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IJERPH, Vol. 14, Pages 1103: Association between Long-Term Exposure to Particulate Matter Air Pollution and Mortality in a South Korean National Cohort: Comparison across Different Exposure Assessment Approaches

IJERPH, Vol. 14, Pages 1103: Association between Long-Term Exposure to Particulate Matter Air Pollution and Mortality in a South Korean National Cohort: Comparison across Different Exposure Assessment Approaches

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph14101103

Authors: Ok-Jin Kim Sun-Young Kim Ho Kim

Increasing numbers of cohort studies have reported that long-term exposure to ambient particulate matter is associated with mortality. However, there has been little evidence from Asian countries. We aimed to explore the association between long-term exposure to particulate matter with a diameter ≤10 µm (PM10) and mortality in South Korea, using a nationwide population-based cohort and an improved exposure assessment (EA) incorporating time-varying concentrations and residential addresses (EA1). We also compared the association across different EA approaches. We used information from 275,337 people who underwent health screening from 2002 to 2006 and who had follow-up data for 12 years in the National Health Insurance Service-National Sample Cohort. Individual exposures were computed as 5-year averages using predicted residential district-specific annual-average PM10 concentrations for 2002–2006. We estimated hazard ratios (HRs) of non-accidental and five cause-specific mortalities per 10 µg/m3 increase in PM10 using the Cox proportional hazards model. Then, we compared the association of EA1 with three other approaches based on time-varying concentrations and/or addresses: predictions in each year and addresses at baseline (EA2); predictions at baseline and addresses in each year (EA3); and predictions and addresses at baseline (EA4). We found a marginal association between long-term PM10 and non-accidental mortality. The HRs of five cause-specific mortalities were mostly higher than that of non-accidental mortality, but statistically insignificant. In the comparison between EA approaches, the HRs of EA1 were similar to those of EA2 but higher than EA3 and EA4. Our findings confirmed the association between long-term exposure to PM10 and mortality based on a population-representative cohort in South Korea, and suggested the importance of assessing individual exposure incorporating air pollution changes over time.

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Dental Robot fits first Dental Implant without any Human involvement

In a first of its kind, a Dental Robot system named Yomi has successfully carried out the procedure of placing two Dental Implants in a patients mouth without much human involvement. The success of this procedure has opened up a whole new field in Dentistry – Dental Robotics which can be the thing for the [...]

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Retrospective biomonitoring of mercury and other elements in museum feathers of common kestrel Falco tinnunculus using instrumental neutron activation analysis (INAA)

Abstract

This study examines the potential to use instrumental neutron activation analysis (INAA) to explore temporal and geographical variation in exposure to heavy metals and other selected elements in common kestrel Falco tinnunculus using feathers from a natural history collection. The study gathered samples of two breast feathers from each of 16 adult male kestrel specimens from Naturalis Biodiversity Centre, collected in The Netherlands between 1901 and 2001. Feather samples were analysed for more than 50 elements, using INAA at the Reactor Institute Delft. Results (in mg/kg dw) were transformed into ratios of milligram of element per millimetre of feather length. The distribution of the mass fractions and ratios was plotted for each element against time and by geographical area. Observed mass fractions and/or ratios are discussed for selected elements (Hg, Cd, Zn, Pt, Pd, Se, Al, Rb, As, Sb, Cr, V, Cl, Br) known to have, at certain concentrations, adverse effects on raptors. Some samples show mass fractions of certain elements (Cr, Cd, Se, As) above levels known to have adverse effects. We conclude that the analysis of museum feathers using INAA provides reference values for concentrations of selected elements, including those of high societal concern such as Hg and Cd, against which to assess concentrations of these elements in feathers of present-day living raptor populations.

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Cognitive performance in mid-stage Parkinson’s disease: functional connectivity under chronic antiparkinson treatment

Abstract

Cognitive impairment in Parkinson's disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.

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Cardiovascular Research turns the spotlight onto the right ventricle

This month's issue of Cardiovascular Research is dedicated to the right ventricle. As introduced by the guest editors, this has long been considered the 'lesser' ventricle. A PubMed search for 'left ventricle' (LV) shows 25 217 publications since 2010, whereas a search for 'right ventricle' (RV) results in 21 684 publications in the same time period. However, most documents include both terms, so if we compare the publications that exclusively cover the 'left ventricle' we get 6 270 documents, and in contrast there are only 2 737 publications specifically on the 'right ventricle'.

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Dr Patrick Baeuerle, MPM Capital, talks with young scientists

Check the interview here: Opportunities for discovery research in industry and in the private sector

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RNA in the spotlight: the dawn of RNA therapeutics in the treatment of human disease

Professor Konstantinos Stellos previously contributed to Cardiovascular Research OnLife¹⁴; more information on his work can be found at http://ift.tt/2xATGHC.

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Treatment strategies for the right heart in pulmonary hypertension

Abstract

The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wall stress since this is the main determinant of changes to the ventricle. Secondly, we discuss treatment strategies targeting the detrimental consequences of increased RV wall stress. To reduce wall stress, afterload reduction is the essential. Additionally, preload to the ventricle can be reduced by diuretics, by atrial septostomy, and potentially by mechanical ventricular support. Secondary to ventricular wall stress, left-to-right asynchrony, altered myocardial energy metabolism, and neurohumoral activation will occur. These may be targeted by optimising RV contraction with pacing, by iron supplement, by angiogenesis and improving mitochondrial function, and by neurohumoral modulation, respectively. We conclude that several treatment strategies for the right heart are available; however, evidence is still limited and further research is needed before clinical application can be recommended.

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A focus on the greatness of the lesser circulation: spotlight issue on the right ventricle

What is the motivation behind a special issue on the right ventricle? William Harvey's assertion in 1628 that '(mother nature) would not have added the right ventricle for the sole purpose of nourishing the lungs, but to propel blood through the lungs into the cavity of the LV'¹ celebrated the marvel of human physiology in which all constituents have an important function. The right ventricle (RV) is of critical importance. The circulation is composed of a single continuous circuit in which there are only two intrinsic contractile pumps; the RV that provides the pressure necessary to augment flow through the pulmonary circulation and the left ventricle (LV) that provides the pressure adequate to perfuse the organs and muscles of the body. The statement that cardiac output is only as good as the worst ventricle reflects upon the fact that neither ventricle can fully compensate for the failure of the other. Put simply, if the RV is only able to pump 2 L/min of cardiac output, then even the best functioning LV will be constrained to 2 L of output. Thus, the RV shoulders significant responsibility in meeting the metabolic requirements of the body under a vast array of physiological settings. Just as for the LV, the RV needs to augment cardiac output at times of increased metabolic need, such as exercise or illness and it must cope with changes in load. There are also a range of pathologies that can affect the structure and function of the RV directly, or indirectly via increases in volume or pressure load.

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Origins and consequences of congenital heart defects affecting the right ventricle

Abstract

Congenital heart disease is a major health issue, accounting for a third of all congenital defects. Improved early surgical management has led to a growing population of adults with congenital heart disease, including patients with defects affecting the right ventricle, which are often classified as severe. Defects affecting the right ventricle often cause right ventricular volume or pressure overload and affected patients are at high risk for complications such as heart failure and sudden death. Recent insights into the developmental mechanisms and distinct developmental origins of the left ventricle, right ventricle, and the outflow tract have shed light on the common features and distinct problems arising in specific defects. Here, we provide a comprehensive overview of the current knowledge on the development into the normal and congenitally malformed right heart and the clinical consequences of several congenital heart defects affecting the right ventricle.

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The overloaded right heart and ventricular interdependence

Abstract

The right and the left ventricle are interdependent as both structures are nested within the pericardium, have the septum in common and are encircled with common myocardial fibres. Therefore, right ventricular volume or pressure overloading affects left ventricular function, and this in turn may affect the right ventricle. In normal subjects at rest, right ventricular function has negligible interaction with left ventricular function. However, the right ventricle contributes significantly to the normal cardiac output response to exercise. In patients with right ventricular volume overload without pulmonary hypertension, left ventricular diastolic compliance is decreased and ejection fraction depressed but without intrinsic alteration in contractility. In patients with right ventricular pressure overload, left ventricular compliance is decreased with initial preservation of left ventricular ejection fraction, but with eventual left ventricular atrophic remodelling and altered systolic function. Breathing affects ventricular interdependence, in healthy subjects during exercise and in patients with lung diseases and altered respiratory system mechanics. Inspiration increases right ventricular volumes and decreases left ventricular volumes. Expiration decreases both right and left ventricular volumes. The presence of an intact pericardium enhances ventricular diastolic interdependence but has negligible effect on ventricular systolic interdependence. On the other hand, systolic interdependence is enhanced by a stiff right ventricular free wall, and decreased by a stiff septum. Recent imaging studies have shown that both diastolic and systolic ventricular interactions are negatively affected by right ventricular regional inhomogeneity and prolongation of contraction, which occur along with an increase in pulmonary artery pressure. The clinical relevance of these observations is being explored.

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Exercise and the right ventricle: a potential Achilles’ heel

Abstract

Exercise is associated with unequivocal health benefits and results in many structural and functional changes of the myocardium that enhance performance and prevent heart failure. However, intense exercise also presents a significant hemodynamic challenge in which the right-sided heart chambers are exposed to a disproportionate increase in afterload and wall stress that can manifest as myocardial fatigue or even damage if intense exercise is sustained for prolonged periods. This review focuses on the physiological factors that result in a disproportionate load on the right ventricle during exercise and the long-term consequences. The changes in cardiac structure and function that define 'athlete's heart' disproportionately affect the right-sided heart chambers and this can raise important diagnostic overlap with some cardiac pathologies, particularly some inherited cardiomyopathies. The interaction between exercise and arrhythmogenic right ventricular cardiomyopathy (ARVC) will be highlighted as an important example of how hemodynamic stressors can combine with deficiencies in cardiac structural elements to cause cardiac dysfunction predisposing to arrhythmias. The extent to which extreme exercise can cause adverse remodelling in the absence of a genetic predisposition remains controversial. In the athlete with profound changes in heart structure, it can be extremely challenging to determine whether common symptoms such as palpitations may be a marker of more sinister arrhythmias. This review discusses some of the techniques that have recently been proposed to identify pathology in these circumstances. Finally, we will discuss recent evidence defining the role of exercise restriction as a therapeutic intervention in individuals predisposed to arrhythmogenic cardiomyopathy.

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Role of cardiac inflammation in right ventricular failure

Abstract

Right ventricular failure (RVF) is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH). Although the exact pathophysiology underlying RVF remains unclear, inflammation may play an important role, as it does in left heart failure. Perivascular pulmonary artery and systemic inflammation is relatively well studied and known to contribute to the initiation and maintenance of the pulmonary vascular insult in PAH. However, less attention has been paid to the role of cardiac inflammation in RVF and PAH. Consistent with many other types of heart failure, cardiac inflammation, triggered by systemic and local stressors, has been shown in RVF patients as well as in RVF animal models. RV inflammation likely contributes to impaired RV contractility, maladaptive remodelling and a vicious circle between RV and pulmonary vascular injury. Although the potential to improve RV function through anti-inflammatory therapy has not been tested, this approach has been applied clinically in left ventricular failure patients, with variable success. Because inflammation plays a dual role in the development of both pulmonary vascular pathology and RVF, anti-inflammatory therapies may have a potential double benefit in patients with PAH and associated RVF.

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Combining computer modelling and cardiac imaging to understand right ventricular pump function

Abstract

Right ventricular (RV) dysfunction is a strong predictor of outcome in heart failure and is a key determinant of exercise capacity. Despite these crucial findings, the RV remains understudied in the clinical, experimental, and computer modelling literature. This review outlines how recent advances in using computer modelling and cardiac imaging synergistically help to understand RV function in health and disease. We begin by highlighting the complexity of interactions that make modelling the RV both challenging and necessary, and then summarize the multiscale modelling approaches used to date to simulate RV pump function in the context of these interactions. We go on to demonstrate how these modelling approaches in combination with cardiac imaging have improved understanding of RV pump function in pulmonary arterial hypertension, arrhythmogenic right ventricular cardiomyopathy, dyssynchronous heart failure and cardiac resynchronization therapy, hypoplastic left heart syndrome, and repaired tetralogy of Fallot. We conclude with a perspective on key issues to be addressed by computational models of the RV in the near future.

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MicroRNAs in right ventricular remodelling

Abstract

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases.

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Fibroblasts and the extracellular matrix in right ventricular disease

Abstract

Right ventricular failure predicts adverse outcome in patients with pulmonary hypertension (PH), and in subjects with left ventricular heart failure and is associated with interstitial fibrosis. This review manuscript discusses the cellular effectors and molecular mechanisms implicated in right ventricular fibrosis. The right ventricular interstitium contains vascular cells, fibroblasts, and immune cells, enmeshed in a collagen-based matrix. Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins. Mechanosensitive transduction of adrenergic signalling and stimulation of the renin–angiotensin–aldosterone cascade trigger the activation of right ventricular fibroblasts. Inflammatory cytokines and chemokines may contribute to expansion and activation of macrophages that may serve as a source of fibrogenic growth factors, such as transforming growth factor (TGF)-β. Endothelin-1, TGF-βs, and matricellular proteins co-operate to activate cardiac myofibroblasts, and promote synthesis of matrix proteins. In comparison with the left ventricle, the RV tolerates well volume overload and ischemia; whether the right ventricular interstitial cells and matrix are implicated in these favourable responses remains unknown. Expansion of fibroblasts and extracellular matrix protein deposition are prominent features of arrhythmogenic right ventricular cardiomyopathies and may be implicated in the pathogenesis of arrhythmic events. Prevailing conceptual paradigms on right ventricular remodelling are based on extrapolation of findings in models of left ventricular injury. Considering the unique embryologic, morphological, and physiologic properties of the RV and the clinical significance of right ventricular failure, there is a need further to dissect RV-specific mechanisms of fibrosis and interstitial remodelling.

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Arrhythmogenic cardiomyopathy: pathology, genetics, and concepts in pathogenesis

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a rare, heritable heart disease characterized by fibro-fatty replacement of the myocardium and a high degree of electric instability. It was first thought to be a congenital disorder, but is now regarded as a dystrophic heart muscle disease that develops over time. There is no curative treatment and current treatment strategies focus on attenuating the symptoms, slowing disease progression, and preventing life-threatening arrhythmias and sudden cardiac death. Identification of mutations in genes encoding desmosomal proteins and in other genes has led to insights into the disease pathogenesis and greatly facilitated identification of family members at risk. The disease phenotype is, however, highly variable and characterized by incomplete penetrance. Although the reasons are still poorly understood, sex, endurance exercise and a gene-dosage effect seem to play a role in these phenomena. The discovery of the genes and mutations implicated in ACM has allowed animal and cellular models to be generated, enabling researchers to start unravelling it's underlying molecular mechanisms. Observations in humans and in animal models suggest that reduced cell–cell adhesion affects gap junction and ion channel remodelling at the intercalated disc, and along with impaired desmosomal function, these can lead to perturbations in signalling cascades like the Wnt/β-catenin and Hippo/YAP pathways. Perturbations of these pathways are also thought to lead to fibro-fatty replacement. A better understanding of the molecular processes may lead to new therapies that target specific pathways involved in ACM.

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RV pressure overload: from hypertrophy to failure

Abstract

In pulmonary arterial hypertension (PAH), right ventricular (RV) adaptation is essential to overcome the chronic increases in RV pressure overload. Ultimately, RV compensatory mechanisms are not sufficient and patients succumb to RV failure. The processes underlying the transition of RV adaptation to RV failure are not well understood. In this review, we propose that important insights in RV adaptation processes can be obtained by comparing different etiologies of PAH, namely patients with PAH secondary to Eisenmenger syndrome, patients with PAH secondary to systemic sclerosis and patients where no cause is identified: idiopathic PAH. Although the amount of RV afterload does not differ between these patient groups, their prognosis is distinctly different. We will show that an adaptive RV phenotype, as is observed in Eisenmenger patients, coincides with RV hypertrophy, increased RV contractility, low RV fibrosis and low RV diastolic stiffness. Whereas a phenotype of RV failure, as is observed in patients with PAH-secondary to systemic sclerosis, is characterized by impaired contractile reserve, RV fibrosis and RV diastolic stiffness.

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The patterns of birthmarks suggest a novel population of melanocyte precursors arising around the time of gastrulation

Abstract

Systematic work in the mouse and chicken has mapped out two neural crest-derived pathways of melanocyte precursor migration. With these in mind, this study reappraises the patterns of congenital pigmentary disorders in humans, and identifies three recurrent patterns consistent across genetically-different diseases. Only two of these are seen in diseases known to be melanocyte cell-autonomous. The segmental pattern correlates well with the classical dorsolateral population from animal studies, demonstrating respect of the midline, craniocaudal axial mixing, unilateral migration and involvement of key epidermally-derived structures. Importantly however, the melanocyte precursors responsible for the non-segmental pattern, which demonstrates circular, bilateral migration centred on the midline, and not involving key epidermally-derived structures, have not been identified previously. We propose that this population originates around the time of gastrulation, most likely within the mesoderm, and ultimately resides within the dermis. Whether it contributes to mature melanocytes in non-disease states is not known, however parallels with the patterns of acquired vitiligo would suggest that it does. The third pattern, hypo- or hyper-pigmented fine and whorled Blaschko's lines, is proposed to be non-cell-autonomous.

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Complete mitochondrial genome of Porzana fusca and Porzana pusilla and phylogenetic relationship of 16 Rallidae species

Abstract

The complete mitochondrial genome sequences of Porzana fusca and Porzana pusilla were determined. The two avian species share a high degree of homology in terms of mitochondrial genome organization and gene arrangement. Their corresponding mitochondrial genomes are 16,935 and 16,978 bp and consist of 37 genes and a control region. Their PCGs were both 11,365 bp long and have similar structure. Their tRNA gene sequences could be folded into canonical cloverleaf secondary structure, except for tRNA^{Ser (AGY)}, which lost its "DHU" arm. Based on the concatenated nucleotide sequences of the complete mitochondrial DNA genes of 16 Rallidae species, reconstruction of phylogenetic trees and analysis of the molecular clock of P. fusca and P. pusilla indicated that these species from a sister group, which in turn are sister group to Rallina eurizonoides. The genus Gallirallus is a sister group to genus Lewinia, and these groups in turn are sister groups to genus Porphyrio. Moreover, molecular clock analyses suggested that the basal divergence of Rallidae could be traced back to 40.47 (41.46‒39.45) million years ago (Mya), and the divergence of Porzana occurred approximately 5.80 (15.16‒0.79) Mya.

Graphical abstract

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A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease

Abstract

Background: Consistent evidence at high levels of water arsenic (≥100 µg/l), and growing evidence at low-moderate levels (<100 µg/l), support a link with cardiovascular disease (CVD). The shape of the dose-response across low-moderate and high levels of arsenic in drinking water is uncertain and critical for risk assessment.Methods: We conducted a systematic review of general population epidemiological studies of arsenic and incident clinical CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories. In a dose-response meta-analysis, we estimated the pooled association between log-transformed water arsenic (log-linear) and restricted cubic splines of log-transformed water arsenic (non-linear) and the relative risk of each CVD endpoint.Results: Twelve studies (pooled N = 408 945) conducted at high (N = 7) and low-moderate (N = 5) levels of water arsenic met inclusion criteria, and 11 studies were included in the meta-analysis. Compared with 10 µg/l, the estimated pooled relative risks [95% confidence interval (CI)] for 20 µg/l water arsenic, based on a log-linear model, were 1.09 (1.03, 1.14) (N = 2) for CVD incidence, 1.07 (1.01, 1.14) (N = 6) for CVD mortality, 1.11 (1.05, 1.17) (N = 4) for CHD incidence, 1.16 (1.07, 1.26) (N = 6) for CHD mortality, 1.08 (0.99, 1.17) (N = 2) for stroke incidence and 1.06 (0.93, 1.20) (N = 6) for stroke mortality. We found no evidence of non-linearity, although these tests had low statistical power.Conclusions: Although limited by the small number of studies, this analysis supports quantitatively including CVD in inorganic arsenic risk assessment, and strengthens the evidence for an association between arsenic and CVD across low-moderate to high levels.

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A pooled analysis of dietary sugar/carbohydrate intake and esophageal and gastric cardia adenocarcinoma incidence and survival in the USA

Abstract

Background: During the past 40 years, esophageal/gastric cardia adenocarcinoma (EA/GCA) incidence increased in Westernized countries, but survival remained low. A parallel increase in sugar intake, which may facilitate carcinogenesis by promoting hyperglycaemia, led us to examine sugar/carbohydrate intake in association with EA/GCA incidence and survival.Methods: We pooled 500 EA cases, 529 GCA cases and 2027 controls from two US population-based case-control studies with cases followed for vital status. Dietary intake, assessed by study-specific food frequency questionnaires, was harmonized and pooled to estimate 12 measures of sugar/carbohydrate intake. Multivariable-adjusted odds ratios (ORs) and hazard ratios [95% confidence intervals (CIs)] were calculated using multinomial logistic regression and Cox proportional hazards regression, respectively.Results: EA incidence was increased by 51–58% in association with sucrose (OR_Q5vs.Q1 = 1.51, 95% CI = 1.01–2.27), sweetened desserts/beverages (OR_Q5vs.Q1 = 1.55, 95% CI = 1.06–2.27) and the dietary glycaemic index (OR_Q5vs.Q1 = 1.58, 95% CI = 1.13–2.21). Body mass index (BMI) and gastro-esophageal reflux disease (GERD) modified these associations (Pmultiplicative-_interaction ≤ 0.05). For associations with sucrose and sweetened desserts/beverages, respectively, the OR was elevated for BMI < 25 (OR_{Q4–5vs.Q1–3} = 1.79, 95% CI = 1.26–2.56 and OR_{Q4–5vs.Q1–3} = 1.45, 95% CI = 1.03–2.06), but not BMI ≥ 25 (OR_{Q4–5vs.Q1–3} = 1.05, 95% CI = 0.76–1.44 and OR_{Q4–5vs.Q1–3} = 0.85, 95% CI = 0.62–1.16). The EA-glycaemic index association was elevated for BMI ≥ 25 (OR_{Q4–5vs.Q1–3} = 1.38, 95% CI = 1.03–1.85), but not BMI < 25 (OR_{Q4–5vs.Q1–3} = 0.88, 95% CI = 0.62–1.24). The sucrose-EA association OR for GERD < weekly was 1.58 (95% CI = 1.16–2.14), but for GERD ≥ weekly was 1.01 (95% CI = 0.70–1.47). Sugar/carbohydrate measures were not associated with GCA incidence or EA/GCA survival.Conclusions: If confirmed, limiting intake of sucrose (e.g. table sugar), sweetened desserts/beverages, and foods that contribute to a high glycaemic index, may be plausible EA risk reduction strategies.

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Comparison of the role of HHIP SNPs in susceptibility to chronic obstructive pulmonary disease between Chinese Han and Mongolian populations

Publication date: 30 December 2017
Source:Gene, Volume 637
Author(s): Guihua Xu, Xiaoyu Gao, Sainan Zhang, Yan Wang, Mingjing Ding, Wenyan Liu, Jie Shen, Dejun Sun
The contribution of risk alleles to chronic obstructive pulmonary disease (COPD) may vary between populations. This study aimed to investigate the role of single nucleotide polymorphisms (SNPs) in HHIP on COPD susceptibility in the Chinese Mongolian and Han populations from Inner Mongolia autonomous region. In this case-control study, five SNPs in HHIP gene were detected in 700 COPD patients (350 Chinese Han and 350 Chinese Mongolian) and 700 healthy controls (350 Chinese Han and 350 Chinese Mongolian). The genotype, the association with COPD, and the differences between Chinese Han and Mongolian populations were evaluated using the chi-squared (χ²) test, genetic models, and logistic analysis. The minor allele C in SNP rs10519717 was associated with COPD in Mongolian (Odds ration (OR)=1.401, 95% confidence interval (CI): 1.110–1.769, P=0.044); however, not in the Han. The CC genotype in SNP rs10519717 was a risk factor for COPD in Mongolian (OR=2.667, 95% CI: 1.479–4.809, P=0.044); however, the TC genotype in Han played the same role (OR=1.396, 95% CI: 1.018–1.915, P=0.044). The GG genotype in SNP rs13147758 was protective in the Han (OR=0.546, 95% CI: 0.332–0.897, P=0.017). The homozygote of the minor alleles in SNPs rs12504628, rs1828591, and rs13118928 had a protective role in the both of COPD populations. For the minor allele distribution, the differences between the Han and Mongolian were presented only in the case group for rs12504628 (P=0.003), rs13147758 (P=0.002), rs1828591 (P=0.001), and rs13118928 (P=0.002); for the genotypes, differences was presented at the frequency of the minor allele homozygote in rs13147758 (P=0.048), rs10519717 (P=0.027), rs1828591 (P=0.041), and rs13118928 (P=0.044) in Mongolian. Our findings suggested that HHIP rs10519717 might be associated with susceptibility of Mongolian COPD. For the other SNPs, the differences between the two populations were represented by minor allele distribution and frequency of the minor allele homozygotes.



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Clinical and molecular characterization of two Chinese patients with Type 2 congenital generalized lipodystrophy

Publication date: 30 December 2017
Source:Gene, Volume 637
Author(s): Ruimin Chen, Xin Yuan, Jian Wang, Ying Zhang
BackgroundType 2 congenital generalized lipodystrophy (CGL2, OMIM 269700) is a rare autosomal recessive disease, characterized by the generalized absence of adipose tissue at birth or in early infancy. Pathogenic variants in BSCL2 gene have been reported to be responsible for CGL2. The aim of this study is to analyze the clinical and genetic characteristics of two Chinese patients with CGL2, and with particular focus on the BSCL2 gene sequence variants.MethodsMedical history, clinical manifestations, physical examination, laboratory data, and ultrasonography findings were analyzed for the two patients with CGL2. Blood samples from both families were obtained for genetic testing. Next generation sequencing for the 2742-gene inherited disease panel were conducted.ResultsTwo patients had similar physical appearances including a conspicuous generalized lack of body fat since birth, extreme muscularity, face with empty cheeks, hirsutism and skin hyperpigmentation especially around necks and armpits; both had intellectual disability, alone with psycho-behavioral issues including tantrum and aggression. One patient exhibited multiple signs of overgrowth such as advanced bone age and macropenis. Laboratory data revealed hypertriglyceridemia, hypercholesterolemia, and low high-density lipoprotein cholesterol concentration. Ultrasound showed hepatomegaly in both patients and renal hypertrophy in patient 2. Echocardiography exams were normal. Both were treated with low-fat, high-carbohydrate diet. Molecular testing confirmed the clinical diagnosis of CGL, specifically CGL2 by detecting a homozygous variant (c.782dupG/p.Ile262Hisfs*12) in BSCL2 gene in patient 1, and compound heterozygous mutations (c. 713G>A/p.Gly238Asp and c.782dupG/p.Ile262Hisfs*12) in patient 2.ConclusionWe describe two patients with classic clinical manifestations of CGL2 confirmed by genetic sequence analysis. A novel variant in BSCL2 gene was detected in one patient (c.713G>A/p.Gly238Asp).



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Design, virtual screening, molecular docking and molecular dynamics studies of novel urushiol derivatives as potential HDAC2 selective inhibitors

Publication date: 30 December 2017
Source:Gene, Volume 637
Author(s): Hao Zhou, Chengzhang Wang, Jianzhong Ye, Hongxia Chen, Ran Tao
Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The binding affinity toward HDAC2 of the compounds was screened by Glide docking. The best scoring compounds were processed further with molecular docking, MD simulations and binding free energy studies to analyze the binding modes and mechanisms. Six compounds, 21, 23, 10, 19, 9 and 30, gave Glide scores of −7.9 to −8.5, which revealed that introducing F, Cl, triazole, benzamido, formamido, hydroxyl or nitro substituents onto the benzene ring could increase binding affinity significantly. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC2 and that His145, His146, Gly154, Glu103, His183, Asp104, Tyr308 and Phe155 contributed favorably to the binding. MD simulations and binding free energy studies showed that all complexes possessed good stability as characterized by low RMSDs; low RMSFs of residues, moderate hydrogen bonding and zinc ion coordination; and low values of binding free energies. van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the promising potential of urushiol derivatives as potent HDAC2 binding lead compounds.

Graphical abstract

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Insights of Lr28 mediated wheat leaf rust resistance: Transcriptomic approach

Publication date: 30 December 2017
Source:Gene, Volume 637
Author(s): Dharmendra Singh, Dhananjay Kumar, Lopamudra Satapathy, Jyoti Pathak, Saket Chandra, Adnan Riaz, Govindraj Bhaganagre, Raman Dhariwal, Manish Kumar, Kumble Vinod Prabhu, Harindra Singh Balyan, Pushpendra Kumar Gupta, Kunal Mukhopadhyay
Leaf rust is a fungal disease that causes severe yield losses in wheat. Resistant varieties with major and quantitative resistance genes are the most effective method to control the disease. However, the main problem is inadequate information for understanding resistance mechanism and its usefulness. This paper presents Lr28 mediated genome-wide response of known and unknown genes during wheat–Puccinia triticina interaction. In this study, we prepared Serial Analysis of Gene Expression (SAGE) libraries using seedling wheat mRNA for infected and mock conditions. The libraries were sequenced on Sequencing by Oligonucleotide Ligation and Detection (SOLiD) system generating 37–48 million reads. After mapping and gene expression analysis of ~6–12 million trimmed reads/library, we revealed five major categories comprised of Lr28 controlled transcripts in resistant (+Lr28) isoline (39), transcripts specific to susceptible (−Lr28) isoline (785), transcripts specific to hypersensitive-response (HR) (375), transcripts specific for basal-defense (153) and transcripts for establishment of pathogen (1616). We estimated the impact of specific genes and pathways through mapping on plant resistant gene database (PRGdb), reactive oxygen species (ROS) and phytohormone database. Functional annotation results revealed, receptor binding, homeostatic processes and cytoskeletal components as the major discriminating factors between susceptibility and resistance. We validated 28 key genes using qRT-PCR and found positive results. These findings were projected on hypothetical interaction model to demonstrate interaction mechanism. The study might have significant impact on future rust-resistance breeding through knowledge based smart genetic selection of quantitative resistance genes besides major effect R-gene.



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Transcriptome profiling of the Plutella xylostella (Lepidoptera: Plutellidae) ovary reveals genes involved in oogenesis

Publication date: 30 December 2017
Source:Gene, Volume 637
Author(s): Lu Peng, Lei Wang, Yi-Fan Yang, Ming-Min Zou, Wei-Yi He, Yue Wang, Qing Wang, Liette Vasseur, Min-Sheng You
BackgroundAs a specialized organ, the insect ovary performs valuable functions by ensuring fecundity and population survival. Oogenesis is the complex physiological process resulting in the production of mature eggs, which are involved in epigenetic programming, germ cell behavior, cell cycle regulation, etc. Identification of the genes involved in ovary development and oogenesis is critical to better understand the reproductive biology and screening for the potential molecular targets in Plutella xylostella, a worldwide destructive pest of economically major crops.ResultsBased on transcriptome sequencing, a total of 7.88Gb clean nucleotides was obtained, with 19,934 genes and 1861 new transcripts being identified. Expression profiling indicated that 61.7% of the genes were expressed (FPKM≥1) in the P. xylostella ovary. GO annotation showed that the pathways of multicellular organism reproduction and multicellular organism reproduction process, as well as gamete generation and chorion were significantly enriched. Processes that were most likely relevant to reproduction included the spliceosome, ubiquitin mediated proteolysis, endocytosis, PI3K-Akt signaling pathway, insulin signaling pathway, cAMP signaling pathway, and focal adhesion were identified in the top 20 'highly represented' KEGG pathways. Functional genes involved in oogenesis were further analyzed and validated by qRT-PCR to show their potential predominant roles in P. xylostella reproduction.ConclusionsOur newly developed P. xylostella ovary transcriptome provides an overview of the gene expression profiling in this specialized tissue and the functional gene network closely related to the ovary development and oogenesis. This is the first genome-wide transcriptome dataset of P. xylostella ovary that includes a subset of functionally activated genes. This global approach will be the basis for further studies on molecular mechanisms of P. xylostella reproduction aimed at screening potential molecular targets for integrated pest management.



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The positive effects of habit reversal treatment of scratching in children with atopic dermatitis: A randomised controlled study

Abstract

Background

Scratching and itch are common clinical signs of atopic dermatitis (AD). Studies of adult patients have shown that a decrease in scratching behaviour results in regression of inflammation and improved healing of the skin.

Objectives

This study aimed to investigate whether a modified habit reversal treatment (HR) protocol could be used for the treatment of scratching in children to improve skin status.

Methods

The study is a single-blind, randomised controlled trial of 39 patients who started with registration a week before randomisation into one of two groups (intervention, control). The participants in the intervention group received a habit-breaking therapy of their scratching behaviour (i.e. HR) in addition to a potent steroid (mometasone furoate), whereas the patients in the control group received the steroid alone. The patients were assessed by an independent dermatologist after the first week of registration (baseline assessment) and then after three and eight weeks post-treatment. The primary efficacy variable was a change in objective SCORAD (SCORing Atopic Dermatitis).

Results

At the end of the three-week treatment period, the change in mean objective SCORAD was significantly (p=0.027) higher in the intervention group -31.9 (SD 9.5) compared with the control group -23.8 (SD 10.1). After the eight-week follow-up, the change in mean objective SCORAD was significantly (p=0.0038) higher in the intervention group -31.7 (SD 10.4) than in the control group -19.7 (SD 9.4).

Conclusions

The treatment of scratching with the HR method in combination with a potent steroid was found to significantly improve skin status after 3 and 11 weeks.

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EAACI Guidelines on Allergen Immunotherapy: Allergic Rhinoconjunctivitis

Abstract

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology and it may have a disease modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergy Immunotherapy". It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass-tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

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Correlation between direction and severity of temporomandibular joint disc displacement and reduction ability during mouth opening

Abstract

Background

The most common temporomandibular joint (TMJ) internal derangement is an abnormal relationship of the disc with respect to the mandibular condyle, articular eminence, and glenoid fossa – disc displacement.

Objective

The aim of our study is to analyse the correlation between partial/complete disc displacement in the intercuspal position (IP) and its reduction in the open mouth position (OMP) in both oblique-sagittal and coronal plane on magnetic resonance imaging (MRI) in patients with temporomandibular disorders.

Materials and methods

Multi-section MRI analysis of 382 TMJs was conducted in 191 patients with disc displacement according to RDC/TMD criteria (148 women, 43 men; aged 14-60 years). The disc position was evaluated on all oblique sagittal and coronal images in the IP and the OMP.

Results

Univariate logistic regression analysis showed that the severity of disc displacement in the sagittal plane is a statistically significant predictor of reduction ability during mouth opening (B=3,118; p<0.001). Moreover, the severity of disc displacement in both planes is also a significant predictor of disc reduction in OMP (B=2,200; p<0.05).

Conclusions

Reduction ability during mouth opening is associated with the severity of disc displacement in IP, in both sagittal and coronal plane. Multi-section analysis of all MR images allows distinguishing the correct disc position from disc displacement and can improve the ability to distinguish between various stages of TMJ internal derangement.

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A systematic review and meta-analysis of three-unit fixed dental prostheses: are the results of two abutment implants comparable to the results of two abutment teeth?

Summary

The purpose of the systematic review and meta-analysis was to compare the performance of three-unit bridges on teeth with three-unit bridges on implants, evaluating survival of the bridges, survival of the teeth or implants, condition of the hard and soft tissues surrounding the supports, complications and patient-reported outcome measures after a mean observation period of at least 1 year. A literature search was conducted using a combination of the search terms: fixed partial denture and fixed dental prostheses. An electronic search for data published until January 2017 was undertaken using the Medline, Embase and Cochrane Library databases. Eligibility criteria included clinical human studies, either randomized or not, interventional or observational, which evaluated the results of three-unit FDPs (fixed dental prostheses) on either two implants or two abutment teeth. The search identified 1686 unique references. After applying eligibility criteria 66 articles were included in the analysis. A total of 1973 three-unit FDPs were supported by teeth, and 765 were implant-supported. No significant differences were found either in the survival of the supporting abutments (P=0.52; 99% versus 98.7% survival per year) or in the survival of the prostheses (P=0.34; 96.4% versus 97.4% survival per year). Both treatments show an almost equally low complication rate, but there is a low level of reporting of hard and soft tissue conditions and patient-reported outcome measures. It is concluded that implant-supported three-unit FDPs seem to be a reliable treatment with survival rates not significantly different from the results of teeth-supported three-unit FDPs.

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Dyadic interdependence of psychosocial outcomes among haematological cancer survivors and their support persons

Abstract

Purpose

This study aimed to explore the dyadic relationships between unmet need, depression, and anxiety in people diagnosed with haematological cancer and their support persons.

Methods

Adult survivors (18 years+) who had been diagnosed with a haematological cancer were recruited to a cross-sectional mailed survey via five state cancer registries in Australia. Participating survivors invited a support person to also complete a survey. Structural equation modelling was used to explore the relationships among survivor and support person self-reported depression, anxiety, and unmet needs.

Results

Of the 4299 eligible haematological cancer survivors contacted by the registries, 1511 (35%) returned a completed survey as did 1004 support persons. There were 787 dyads with complete data. After adjusting for age, gender, rurality, cancer type, and whether the support person was a relative, positive correlations were found between survivor and support person scores for depression (p = 0.0029) and unmet needs (p < 0.001), but not anxiety scores (p = 0.075). Survivor unmet needs were significantly related to support person depression (p = 0.0036). Support person unmet needs were significantly related to a higher depression score for survivors (p = 0.0067). Greater support person unmet needs were significantly related to a higher anxiety score for survivors (p = 0.0083). Survivor unmet needs did not have a significant relationship to support person anxiety (p = 0.78).

Conclusion

Unmet needs may mediate the interdependence of psychosocial experiences for survivors and support persons, although a longitudinal study is required to confirm causality. Addressing unmet needs may be a potential target for improving outcomes for both groups.

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Association between bone scan index and activities of daily living in patients with advanced non-small cell lung cancer: methodological issues in cross-sectional study

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Changes in light-, moderate-, and vigorous-intensity physical activity and changes in depressive symptoms in breast cancer survivors: a prospective observational study

Abstract

Purpose

Despite the recommendations for cancer survivors to engage in either moderate or vigorous physical activity, light-intensity physical activity may also have beneficial effects on mental health. The purpose of this study was to examine the associations between light, moderate, and vigorous physical activity and depressive symptoms in breast cancer survivors over 1 year post-treatment.

Methods

Participants (N = 201) were a sample of breast cancer survivors who self-reported depressive symptoms and wore an accelerometer for seven consecutive days to measure physical activity, on five occasions every 3 months post-treatment for cancer.

Results

Based on the results of hierarchical linear modeling, relative to others (i.e., between-person effects) and to oneself (i.e., within-person effects), higher levels of light- and moderate-intensity physical activity, but not vigorous-intensity physical activity, were associated with lower scores of depressive symptoms.

Conclusions

In the first year post-treatment, increases in light- and moderate-intensity physical activity, but not vigorous-intensity physical activity, were associated with lower scores of depressive symptoms in relation to other study participants (i.e., between-person effects) and when participants were compared to their own typical levels of physical activity (i.e., within-person effects). The findings may have implications for physical activity recommendations following treatment for breast cancer as light-intensity physical activity may play a role in mitigating depressive symptoms over the first year.

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Longitudinal perceptions of the side effects of chemotherapy in patients with gynecological cancer

Abstract

Purpose

This study aimed to assess the incidence and difference of side effects among six courses of chemotherapy (C/T) in gynecological cancer patients.

Methods

The study period was from Sep. 2010 to Dec. 2011 at the Kaohsiung Veterans General Hospital in Taiwan. The treating protocols, courses, and drugs of C/T in patient were considered according to the different malignant cancers and clinical conditions. The patient data of age, marriage status, education, religion, and experiences of C/T were collected. The patients' or their families' reported side effects of C/T were recorded daily from the beginning of C/T to the 10th day after C/T in each cycle and every course of C/T.

Results

Total 89 patients enrolled into the study received total 450 courses of C/T. The mean age was 54.52 ± 11.02. Ovarian cancer was the most common malignant disease (64.0%). The most often combination of drugs used was Taxol and carboplatin (40.9%). Patients complained peripheral numbness of limbs, with the highest incidence of 58.6%. The side effects with incidence about 50% were decreased fatigue (55.0%) and hair loss (49.9%). Other side effects with different levels of incidence were also noticed, such as lack of appetite, changes in taste, and muscle ache. The incidences of peripheral limb numbness and hair loss were increased with following courses of C/T. The high incidence of fatigue did not show variation between different courses of C/T.

Conclusion

This study revealed the incidence of side effects and occurrence timing during C/T in patients with gynecological cancer. These data provide substantial information to patients and their families to understand the potential side effects of C/T courses, which might increase their compliance in receiving adjuvant C/T. Relieving the side effects in C/T would be important to improve their quality of daily life and treatment willingness.

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Can complications in febrile neutropenia be predicted? Report from a developing country

Abstract

Purpose

Febrile neutropenia (FN) is an important cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). We aimed to look at complications in febrile neutropenia and to derive a risk model for developing complications from the variables predicting complications.

Methods

Children on treatment for ALL, presenting with FN, were prospectively enrolled over a period of 1 year. Their clinical presentation, course during hospital stay, and outcomes were recorded. Complications recorded included septic shock, pneumonia requiring invasive or non-invasive ventilation, renal failure, neutropenic enterocolitis, encephalopathy, congestive heart failure, and bleeding manifestations.

Results

There were 320 episodes of FN among 176 patients. Complications occurred during 73 (22.8%) episodes. Time since last chemotherapy ≤7 days [OR 2.2 (1–4.5)], clinical focus of infection [OR 2.7 (1.3–5.5)], undernutrition [OR 2.5 (1.1–5.5)], absolute neutrophil count (ANC) ≤ 100/μL [OR 2.8 (1.3–5.9)], and C-reactive protein (CRP) > 60 mg/L at admission [OR 13.3 (5.2–33.8)] were independent predictors of complications. A risk model (total score = 13) was developed based on these predictors. Children with score of ≥7 had 17.2 (7.7–38.6) odds of developing complications as compared to those with score <7. Score of <7 predicted children at lower risk of complications [sensitivity 88% (78.2–93.8%), specificity 72.5% (65.7–78.4%), PPV 53.6% (44.3–62.6%), NPV 94.4% (89.3–97.1%)].

Conclusions

Complications during febrile neutropenia are high in a developing country setup. A risk score model based on identified risk factors can possibly help in recognizing low-risk febrile neutropenic children at admission.

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Management of infection during chemotherapy for acute leukemia in Japan: a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group

Abstract

Purpose

We performed a nationwide questionnaire-based survey to evaluate the current clinical practices of infectious complications during chemotherapy for acute leukemia in Japan.

Methods

We e-mailed a questionnaire to member institutions of the Japan Adult Leukemia Study Group in September, 2013. The questionnaire consisted of 50 multiple-choice questions covering therapeutic environment, antimicrobial prophylaxis, screening test during neutropenia, empirical therapy for febrile neutropenia, and the use of granulocyte-colony stimulating factor. The results were compared to those of previous surveys conducted in 2001 and 2007, and also to the recommendations described in the guidelines.

Results

Usable responses were received from 141 out of 222 (63.5%) institutions. Chemotherapy for acute myeloid leukemia was performed in protective environment in 90% of the institutions, which increased compared to previous survey (76%). Fluoroquinolones and fluconazole were the most commonly used antimicrobial agents for antibacterial and antifungal prophylaxis, followed by sulfamethoxazole-trimethoprim and itraconazole, respectively. In empirical therapy for febrile neutropenia, monotherapy with β-lactum antibiotics was the first-line therapy in most of the institutions. While empirical antifungal therapy was adopted for persistent fever in more than half of the institutions, preemptive/presumptive therapy was also used in approximately 40% of the institutions. Most of the clinicians were reluctant to use granulocyte-colony stimulating factor routinely in chemotherapy for acute myeloid leukemia.

Conclusions

This study clarified the current clinical practices of infectious complications during chemotherapy for acute leukemia and would provide important information for the development of a suitable guideline in Japan.

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Illness perception is a strong parameter on anxiety and depression scores in early-stage breast cancer survivors: a single-center cross-sectional study of Turkish patients

Abstract

Background

Illness perception has been suggested to have a significant effect on anxiety and depression in cancer patients. In this cross-sectional study, we aimed to evaluate this on Turkish breast cancer patients with follow-up periods up to 12 years.

Patients and methods

A total of 225 patients (with 6 months to 12 years follow-up) were recruited in this cross-sectional study. The patients were divided into three groups of follow-up: 6 months–2 years, 2–5 years, and >5 years. Beck Depression Inventory, Beck Anxiety Inventory, Duke–University of North Carolina Functional Social Support Questionnaire, and Brief Illness Perception Questionnaire were used to assess the depression, anxiety, functional social support (FSS), and illness perception, respectively. Statistical significance of the associations was analyzed using Spearman correlation, Student's t, Mann–Whitney U, and ANOVA tests.

Results

Rates of moderate–severe anxiety and depression scores were not correlated with follow-up period and disease stage, whereas all these parameters were associated significantly with FSS and age. Parameters of illness perception were also not correlated with follow-up period and stage of disease. However, illness perception scores were noticeably better with increments in FSS. Also, the parameters of illness perception were strongly associated with the depression/anxiety score.

Conclusion

Illness perception is an important determinant of the depression/anxiety score in Turkish breast cancer patients.

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Author’s response

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Effectiveness of a standardized patient education program on therapy-related side effects and unplanned therapy interruptions in oral cancer therapy: a cluster-randomized controlled trial

Abstract

Purpose

Oral agents for cancer treatment are increasingly prescribed due to their benefits. However, oral cancer medications are difficult to handle and have a considerable potential for side effects. This type of therapy requires a high level of self-management competence by the patient. A standardized patient education program provided by physicians and oncology nurses may positively influence the handling of oral agents. The aim of the study was to evaluate the impact of a standardized patient education program provided by specially trained oncology nurses on therapy management regarding side effects and unplanned therapy interruptions.

Methods

One hundred sixty-five patients from 28 office-based oncology practices from all over Germany participated in this cluster-randomized controlled study. Patients of both intervention (n = 111) and standard care groups (n = 54) received the usual oncologist counseling; in addition, the patients from the intervention group (k = 17 practices) received an education from specially trained oncology nurses. The time of observation was 3 months per patient.

Results

The patients of the intervention group reported fewer side effects (skin rash, pain, fatigue, nausea, vomiting). Patients in the standard care group interrupted the therapy more frequently without informing their oncologist, compared to the intervention group.

Conclusions

Patients benefit from a standardized patient education program provided by specially trained oncology nurses. They tend to handle side effects and critical situations better.

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A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I

Abstract

Purpose

Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Given that extensive animal data suggest that minocycline may prevent chemotherapy-induced neurotoxicity, the purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and the P-APS.

Methods

Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks and were randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a matching placebo. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy to measure P-APS and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment, to measure CIPN.

Results

Forty-seven patients were randomized. There were no remarkable differences noted between the minocycline and placebo groups for the overall sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components, which evaluate tingling, numbness and shooting/burning pain in hands and feet. However, patients taking minocycline had a significant reduction in the daily average pain score attributed to P-APS (p = 0.02). Not only were no increased toxicities reported with minocycline, but there was a significant reduction in fatigue (p = 0.02).

Conclusions

Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted.

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Timing to antibiotic therapy in septic oncologic patients presenting without hypotension

Abstract

Purpose

Sepsis accounts for only 2% of the hospitalizations worldwide but more than 17% of total in-hospital mortality. Inappropriate antimicrobial selection and delays in appropriate therapy have been associated with reduced survival in severe sepsis and septic shock. No studies to date have exclusively targeted septic oncologic patients without hypotension.

Methods

This study was a retrospective chart review of 100 adult cancer patients presenting to the emergency department with sepsis without hypotension. We investigated the effect of time to appropriate antibiotics on in-hospital mortality and hospital length of stay. It was hypothesized that increased time to antibiotic administration would worsen patient outcomes including in-hospital mortality and length of stay.

Results

Each 1-h delay in administration of appropriate antibiotic therapy increased the odds of in-hospital mortality by 16% (adjusted OR 1.16. 95% CI 1.04–1.34, p = 0.04). Time to appropriate antibiotics had no effect on hospital length of stay.

Conclusions

Time to appropriate antibiotics and in-hospital mortality were associated in this population of adult oncologic patients with sepsis without hypotension. Clinicians in the emergency department should strive to ensure the timely administration of a complete and appropriate empiric antibiotic regimen in septic patients with active cancer even in the absence of hypotension.

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The influence of unmet supportive care needs on anxiety and depression during cancer treatment and beyond: a longitudinal study of survivors of haematological cancers

Abstract

Objectives

This paper aims to examine the cross-sectional and longitudinal associations between patient-reported unmet needs and anxiety and depression for survivors of diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM).

Methods

In a longitudinal study design, self-reported data were collected through telephone interviews at two time points approximately 7 (T1) and 15 (T2) months post-diagnosis. The sample was recruited through the population-based Victorian Cancer Registry. At T1 and T2, the study outcomes, anxiety and depression, were assessed using the Hospital Anxiety and Depression Scale (HADS) and unmet needs were measured using the Supportive Care Needs Survey (SCNS-SF34). Questions related to social/family problems, relationship problems and financial problems were also asked. A three-step multivariable hierarchical logistic regression analysis examined the relative role of T1 anxiety and depression, T1 and T2 unmet needs and other psychosocial factors with T2 anxiety and depression.

Results

Both cross-sectional and longitudinal associations were observed between unmet needs and psychological distress. T2 anxiety was associated with T1 anxiety (OR 4.75, 95% CI 1.86–11.09), T2 psychological needs (OR 1.68, 95% CI 1.34–2.11) and with T1 social problems (OR 2.33, 95% CI 1.03–5.05) in multivariate analysis. T2 depression was associated with both T1 (OR 1.28, 95% CI 1.06–1.57) and T2 psychological needs (OR 1.35, 95% CI 1.06–1.70), T2 physical needs (OR 1.89, 95% CI 1.27–2.81) and T1 depression (OR 4.52, 95% CI 1.88–10.86).

Conclusions

Unmet needs that manifest following diagnosis and treatment may persist into early survivorship and contribute to psychological distress. Addressing these needs during treatment may diminish the risk of current and future anxiety and depression.

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Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology

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Optimal clinical assessment strategies for chemotherapy-induced peripheral neuropathy (CIPN): a systematic review and Delphi survey

Abstract

Background/purpose

Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent side effect of the treatment of cancer. Despite this frequent complication, there has been no comprehensive review and quality appraisal of CIPN assessments. The purpose of this study is to provide a definitive quality appraisal of CIPN assessment strategies for clinical use.

Methods

Relevant studies were identified through database searches of Medline, Embase, CINAHL, and Cochrane. CIPN assessment strategies from included articles were extracted and initially rated by an oncologist and neurophysiologist according to criteria related to assessment depth, comprehensiveness, appropriateness, and reliability. The six highest scoring assessment strategies were the focus of a two-round Delphi survey of a working party of 32 physicians, nurses, and consumers to achieve consensus on the highest rated assessments for each criterion.

Results

The database search yielded 117 distinct CIPN assessments that were extracted from 2373 articles. Three patient-reported outcome surveys and three clinician-based assessments were included in the Delphi survey. No consensus was generated regarding the best overall CIPN assessment, although good (≥70%) consensus was achieved regarding the best assessment within each criterion. The Participant Neurotoxicity Questionnaire (PNQ) was rated the highest overall and patient-reported outcome (PRO) assessment, while the Total Neuropathy Score clinical version (TNSc) was the highest rated clinician-based assessment.

Conclusions

A diverse range of CIPN assessments currently exists. While several assessments assess CIPN symptoms with adequate comprehensiveness, depth, language, and feasibility, the consensus 'gold standard' clinical assessment remains to be established.

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Needs assessment of primary care physicians in the management of chronic pain in cancer survivors

Abstract

Introduction

Cancer patients live longer with effective anti-cancer therapy and supportive care. About 30% of cancer survivors (non-palliative cancer patients who completed treatment) suffer from chronic pain, which will be managed by their primary care physician (PCP). The aim of this study was to assess practice patterns and treatment barriers in the management of chronic pain in cancer survivors among PCPs.

Methods

A survey using a 16-item questionnaire was sent to PCPs across Canada.

Results

A total of 162 responses were collected. The majority of participants were in group (59%) or solo (33%) practice, with an average of 25 years of clinical experience. Seventy-one percent of PCPs were practicing in communities of 10,000 to 100,000 people. Respondents were treating approximately 10 cancer survivors with chronic pain per month. The majority of PCPs (59%) reported having "little knowledge" or "some understanding" of chronic pain management in cancer survivors. They did not usually refer these patients to other specialists. Patient comorbidities (79%), pain medication side effects (78%), previous pain treatment (76%), effect of pain on daily functioning (75%), and drug interactions (71%) were identified as factors that guided PCP treatment choices. Major barriers included medication cost (54%), concerns about opioid abuse (51%), and patient non-compliance (46%). PCPs indicated that treatment guidelines (74%) and knowledge of pharmacological (64%) and non-pharmacological (62%) treatment options would help their chronic pain management.

Conclusion

Most PCPs report a lack of knowledge in the management of chronic pain in cancer survivors but are keen to receive medical education on treatment options and clinical practice guidelines.

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An update in symptom clusters using the Edmonton Symptom Assessment System in a palliative radiotherapy clinic

Abstract

Purpose

To identify symptom clusters in advanced cancer patients attending a palliative radiotherapy clinic using the Edmonton Symptom Assessment System (ESAS).

Methods

Principal component analysis (PCA), exploratory factor analysis (EFA), and hierarchical cluster analysis (HCA) were used to identify symptom clusters among the nine ESAS items using scores from each patient's first visit.

Results

ESAS scores from 182 patients were analyzed. The PCA identified three symptom clusters (cluster 1: depression-anxiety-well-being, cluster 2: pain-tiredness-drowsiness, cluster 3: nausea-dyspnea-loss of appetite). The EFA identified two clusters (cluster 1: tiredness-drowsiness-loss of appetite-well-being-pain-nausea-dyspnea, cluster 2: depression-anxiety). The HCA identified three clusters similar to the PCA with an exception of the loss of appetite item being classified under cluster 1 rather than 3. Two to three symptom clusters were identified using three analytical methods, with similar patterns reported in the literature. Particular groups of items co-occurred consistently across all three analyses: depression and anxiety; nausea and dyspnea; as well as pain, tiredness, and drowsiness.

Conclusion

Three similar symptom clusters were identified in our patient population using the PCA and HCA; whereas, the EFA produced two clusters: one physical and one psychological cluster. Given the implications of symptom clusters in the management of quality of life, clinicians should be aware of these clusters to aid in the palliative treatment of patients.

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Long-term follow-up of the potential benefits of early nutritional intervention in adults with upper gastrointestinal cancer: a pilot randomised trial

Abstract

Purpose

This study aimed to evaluate the long-term survival of all patients who participated in a pilot randomised trial of an early nutritional intervention for adults with upper gastrointestinal cancer. It also sought to identify factors that predicted patient mortality.

Methods

All participants (n = 21) who were randomised into the original study were followed for a maximum of 5 years and 2 months (final follow-up April 2016). The primary outcome measure was time from date of recruitment until date of death, ascertained by the Victorian Cancer Registry and/or Monash Health Scanned Medical Records. Secondary analyses were conducted to identify factors that adversely affected survival.

Results

At the end of the follow-up period, three patients were alive in the nutrition intervention group whilst only two patients were living from the standard care group. Visual evaluation of the Kaplan-Meier survival curves demonstrated a possible survival benefit from being exposed to the intervention between 6 months and 1.4 years post-recruitment, though this benefit dissipated soon after. The intervention was not associated with increased survival in univariate analyses, but was after adjustment for other factors found to adversely impact on survival (adjusted hazard ratio 0.12 (95% CI 0.02–0.72) p = 0.02). These factors were being a smoker (14.2 (1.43 to 140.67), p = 0.02); low baseline physical functioning (1.11 (1.01 to 1.21), p = 0.03); high baseline fatigue (1.09 (1.02–1.16), p = 0.007); and high baseline dyspnoea (1.08 (1.02–1.13), p = 0.003).

Conclusion

Early and intensive nutrition intervention may increase the survival of people with upper gastrointestinal cancer.

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Logical Paradoxes and Paradoxical Constellations in Medicolegal Assessment

Abstract

In medicolegal contexts, the expert is confronted with a number of apparent or seemingly paradox constellations that are mostly not even explicit to the assessor involved, yet when they occur, they may have a profound effect on the shaping of the expert's opinion and, subsequently, on the outcome of litigation. Because the paradoxes in this forensic work have not been made explicit for the most part in the field, it can be assumed that forensic experts themselves are often unaware of paradoxical situations and logical incoherence to be found in many cases. Difficulties to positively diagnose somatoform and dissociative disorders in disability claimants and compensation-seeking litigants are among the most prominent of these paradoxes. For example, in these diagnoses, presumably unconscious core motives and an involuntarily, unconsciously distorted symptom presentation (both being central for the diagnosis) might contrast with conscious symptom magnification and pursuit of monetary interests on the part of the complainant (external incentives in the form of disability or compensation seeking). Other paradoxes discussed in more detail are linked with symptom validity assessment in forensic psychology. Logical dilemmas and paradoxes, if not placed at the forefront in forensic psychological evaluations, potentially undermine the quality of forensic determinations.

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