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Child abuse among adolescents in China has been documented and can lead to a whole range of psychological and behavioural problems. This study examined whether male and female adolescents would differ in level of child abuse, emotional processing difficulties, alexithymia, psychological symptoms and behavioural problems, and whether the pattern of association between these variables would vary depending on gender. Eight hundred adolescents were recruited from China and completed the Childhood Trauma Questionnaire, Emotional Processing Scale, Toronto Alexithymia Scale, General Health Questionnaire, and Prediction Test of Problem Children. Male adolescents reported significantly higher levels of emotional and physical neglect, and external oriented thinking style than female adolescents. Females reported significantly more anxiety symptoms and problems with learning than males. For males, child abuse was associated with emotional processing difficulties which were associated with alexithymia. In turn, alexithymia was associated with both psychological and behavioural problems. For females, the same association was established for predicting behavioural problems but not psychological symptoms. Male and female adolescents differed in level of child abuse, alexithymia, psychological symptoms and behavioural problems. These psychological constructs were connected in a specific pattern to trigger psychological and behavioural problems for male adolescents whereas for females, different patterns were involved.

This study investigated whether rejection sensitivity (RS), shyness and unsociability would positively correlate with Posttraumatic Stress Disorder (PTSD) and psychiatric co-morbidity and whether shyness and unsociability would mediate the impact of RS on distress outcomes. Four hundred and one adolescents from three middle schools in China completed a demographic questionnaire, Children's Rejection Sensitivity Questionnaire, Children's Shyness Questionnaire, Child Social Preference Scale, Posttraumatic Stress Disorder Checklist for DSM-5, and the General Health Questionnaire-28. The results showed that RS and shyness were mostly correlated with PTSD and psychiatric co-morbidity whereas unsociability was not and therefore not a mediator. Shyness, on the other hand, mediated the impact of angry RS and anxious RS on PTSD, as well as anxious RS on psychiatric co-morbidity. To conclude, the severity of PTSD along with other psychological difficulties tends to increase for those who are shy and sensitive to rejection.

Objectives: Posttraumatic stress disorder (PTSD) symptoms following past trauma could lead to psychological distress. Little is known, however, about the roles of defense mechanisms and alexithymia may play in the process. The current study aimed to examine the potential impact of alexithymia and defense mechanisms on the relationship between past trauma and distress among Chinese university students., Method: 455 university students completed a set of questionnaires: PTSD Checklists for DSM-5, Toronto Alexithymia Scale (TAS-20), Defense Style Questionnaire, and General Health Questionnaire-28., Results: PTSD following past trauma was associated with increased psychological distress. Alexithymia and defenses (especially immature defense) mediated the path between PTSD and psychological co-morbidities., Conclusion: Following past trauma, people developed PTSD and other psychological symptoms. The severity of these distress symptoms was influenced by the way they defended themselves psychologically, and their ability to identify, express, and process distressing emotions., (Copyright © 2020 Fang, Chung and Wang.)

Since November 2018, Blood Advances has published American Society of Hematology (ASH) clinical practice guidelines on venous thromboembolism, immune thrombocytopenia, and sickle cell disease. More ASH guidelines on these and other topics are forthcoming. These guidelines have been developed using consistent processes, methods, terminology, and presentation formats. In this article, we describe how patients, clinicians, policymakers, researchers, and others may use ASH guidelines and the many related derivates by describing how to interpret information and how to apply it to clinical decision-making. Also, by exploring how these documents are developed, we aim to clarify their limitations and possible inappropriate usage., (© 2020 by The American Society of Hematology.)

Gas-phase ion/ion chemistry was coupled to ion mobility/mass spectrometry analysis to correlate the structure of gaseous ubiquitin to its solution structures with selective covalent structural probes. Collision cross section (CCS) distributions were measured to ensure the ubiquitin ions were not unfolded when they were introduced to the gas phase. Aqueous solutions stabilizing the native state of ubiquitin yielded folded ubiquitin structures with CCS values consistent with previously published literature. Denaturing solutions favored several families of unfolded conformations for most of the charge states evaluated. Gas-phase covalent labeling via ion/ion reactions was followed by collision-induced dissociation of the intact, labeled protein to determine which residues were labeled. Ubiquitin 5 + and 6 + electrosprayed from aqueous conditions were covalently modified preferentially at the lysine 29 and arginine 54 positions, indicating that elements of three-dimensional structure were maintained in the gas phase. On the other hand, most ubiquitin ions produced in denaturing conditions were labeled at various other lysine residues, likely due to the availability of additional sites following methanol- and low-pH-induced unfolding. These data support the conservation of ubiquitin structural elements in the gas phase. The research presented here provides the basis for residue-specific characterization of biomolecules in the gas phase.

Introduction: Implant treatments and peri-implant maintenance continue apace, while the evidence for implant maintenance and home hygiene continues to be developed. Information sources for dental practitioners and patients in peri-implant health maintenance and disease management are generally not known. This study investigated the implant maintenance topics taught, the discipline backgrounds of convenors and presenters and information delivery methods within implant dentistry teaching in Australia., Materials and Methods: An online survey was distributed to 56 convenors of implant dentistry and maintenance education programmes in Australia, garnering responses from 24 individuals which outlined 43 different education programmes., Results: Lectures were the main delivery method for implant maintenance information across the different course types. Peri-implant diagnostics were generally taught according to current literature recommendations, but coverage varied in topics where the evidence is yet to be established (eg home hygiene, professional maintenance and implant review). Some educators reported awareness of limitations in their programmes., Conclusion: Implant dentistry education programmes in Australia vary widely in teaching implant maintenance, coverage of which should be current and evidence-based at all education levels. The structure of implant dentistry teaching at the continuing professional development level requires further development., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Previous costing and resource estimates for cancer have not been complete owing to lack of comprehensive data on cancer-related medication and radiation treatment. Our objective was to calculate the mean overall costs per patient of cancer-related medications and radiation, as well as by disease subtype and stage, in the first year after diagnosis for the 4 most prevalent cancers in Ontario., Methods: We conducted a retrospective cohort study using provincial health administrative databases to identify population health system resources and costs for all patients diagnosed with breast, colorectal, lung or prostate cancer between Jan. 1, 2010, and Dec. 31, 2015 in Ontario. The primary outcome measure was the overall average cost per patient in the 365 days after diagnosis for cancer-related medications and radiation treatment, calculated with the use of 2 novel costing algorithms. We determined the cost by disease, disease subtype and stage as secondary outcomes., Results: There were 168 316 Ontarians diagnosed with cancer during the study period, 50 141 with breast cancer, 38 108 with colorectal cancer, 34 809 with lung cancer and 45 258 with prostate cancer. The mean per-patient cost for cancer-related medications was $8167 (95% confidence interval [CI] $8023-$8311), $6568 (95% CI $6446-$6691), $2900 (95% CI $2816-$2984) and $1211 (95% CI $1175-$1247) for breast, colorectal, lung and prostate cancer, respectively. The corresponding mean radiation treatment costs were $18 529 (95% CI $18 415-$18 643), $15 177 (95% CI $14 899-$15 456), $10 818 (95% CI $10 669-$10 966) and $16 887 (95% CI $16 648-$17 125). In general, stage III and IV cancers were the most expensive stages for both medications and radiation across all 4 disease sites., Interpretation: Our work updates previous costing estimates to help understand costs and resources critical to health care system planning in a single-payer system. More refined costing estimates are useful as inputs to allow for more robust health economic modelling and health care system planning., Competing Interests: Competing interests: Natalie Coburn receives salary support from Cancer Care Ontario and the Sherif and MaryLou Hanna Chair in Surgical Oncology at the Sunnybrook Research Institute. No other competing interests were declared., (Copyright 2020, Joule Inc. or its licensors.)

This study examined the inter-relationship between posttraumatic stress disorder (PTSD) from past trauma, psychiatric co-morbidity, trauma centrality and posttraumatic growth (PTG) among Chinese adolescents. Nine hundred and forty-eight Chinese adolescents (M = 462, F = 486) were recruited from two secondary schools. They completed the Posttraumatic Stress Disorder Checklist for DSM-5, the Centrality of Events Scale, the Posttraumatic Growth Inventory, the General Health Questionnaire-28, and the Educational Stress Scale for Adolescents. After controlling for demographic variables and levels of academic stress, structural equation modeling showed that PTSD was positively associated with trauma centrality and psychiatric co-morbidity but negatively associated with posttraumatic growth. Trauma centrality mediated the impacts of PTSD on posttraumatic growth and psychiatric co-morbidity. To conclude, PTSD from past trauma could impact adolescents' ways of perceiving positive aspects of their trauma and psychological well-being. Such impact, however, was influenced by the changes in their self-concept., (Copyright © 2020 Elsevier B.V. All rights reserved.)

PTSD has profound personal, social and economic impact. Understanding factors that influence strong recovery is a priority for informing the use of limited treatment resources. This study follows up a preliminary finding from Hoelterhoff and Cheung Chung, Psychiatr Q, 88, 635-651, [30] which found that death anxiety is related to PTSD and suggested that self-efficacy may mediate this relationship. Specifically, this study examined self-efficacy as a protective factor in the context of people who have experienced a life-threatening event. 109 undergraduate university students completed self-report questionnaires on, self-efficacy, death anxiety, trauma and well-being as well as a number of demographic factors. Self-efficacy was found that to be significantly and inversely related to death anxiety and psychiatric co-morbidity, but not PTSD. Results were discussed in light of literature regarding death anxiety. It seems that self-efficacy is related to death anxiety and well-being; however, it interacts with these processes independently and not as a mediating factor. More research is needed to understand coping mechanisms that help develop resilience against the negative effects of death anxiety against PTSD and minimize its detrimental impact on mental health.

Background: Restricted mean survival time (RMST) overcomes limitations of current measures of survival benefits because it directly captures information of the entire area under Kaplan-Meier survival curves. Using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit), we quantified the magnitude of survival benefits of recent oncology drugs and compared immunotherapies with nonimmunotherapies., Methods: Kaplan-Meier curves were extracted from phase II/III randomized controlled trials used by the FDA for oncology drug approvals from January 2011 through November 2017 with overall survival (OS) or progression-free survival (PFS) as primary endpoints. RMST differences, ratios, and their 95% confidence intervals were meta-analyzed to estimate absolute and relative survival benefits of contemporary oncology drugs and to compare immunotherapies with nonimmunotherapies. Meta-regression was conducted to adjust for potential confounders., Results: Ninety-four trials with a total of 51,639 patients were included. Overall absolute survival benefits (RMST differences) were 1.55 months for OS (95% CI, 1.32-1.77) and 2.99 months for PFS (95% CI, 2.65-3.33). Overall relative survival benefits (RMST ratios) were 1.11 for OS (95% CI, 1.09-1.13) and 1.42 for PFS (95% CI, 1.36-1.48). Immunotherapy absolute PFS benefit was less than that of nonimmunotherapy (1.56 vs 3.23 months), whereas immunotherapy absolute OS benefit was larger than that of nonimmunotherapy by 0.59 months (2.02 vs 1.43 months). Adjusted OS RMST difference was 0.91 months greater for immunotherapy than for nonimmunotherapy after adjusting for confounders., Conclusions: Absolute survival benefits of recent oncology drugs are modest. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. Routine reporting and use of RMST may help patients, physicians, and payers make more informed and responsible decisions regarding the care of patients with cancer.

Background: Several strategies are available for the initial treatment of advanced-stage Hodgkin lymphoma, but the optimal strategy in terms of cost-effectiveness is unclear. The aim of this study was to compare the quality-adjusted effectiveness and costs of five modern treatment options for transplantation-eligible patients with newly diagnosed advanced-stage Hodgkin lymphoma., Methods: A Markov decision-analytic model was developed using a 20-year time horizon. Five of the most common treatment approaches were selected based on clinical experience and expert opinion: (1) six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), including data from the HD2000 trial, Viviani and colleagues, and EORTC trial; (2) six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; from the HD15 trial or PET-adapted as in the HD18 trial, two initial cycles of BEACOPP followed by four additional cycles for patients with a positive PET and either two or four additional cycles of BEACOPP for patients with a negative PET); (3) PET-adapted escalation (as in the RATHL trial, two cycles of standard ABVD chemotherapy followed by an additional four cycles of ABVD or AVD in PET-negative patients and four cycles of BEACOPP in PET-positive patients); (4) six cycles of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A-AVD) or ABVD as in the Echelon-1 trial; and (5) PET-adapted de-escalation (as in the AHL2011 trial, two cycles of BEACOPP followed by PET2 scan; PET-positive patients received two additional BEACOPP cycles and PET-negative patients received two cycles of ABVD; at PET4, PET-negative patients completed two further cycles of either ABVD or BEACOPP depending on what they received after PET2, and PET-positive patients received salvage therapy). Note that all uses of BEACOPP in these strategies were BEACOPP escalated . The randomised groups of interest from these studies comprised 4255 patients enrolled between April, 2000, and January, 2016. Baseline probability estimates and utilities were derived from the included trials in addition to a systematic review of published studies. A Canadian public health payer's perspective was considered (CAN$1=US$0·74) and adjusted for inflation for 2018. All costs and benefits were discounted by 1·5% per year because life-years now are more valuable than future potential life-years., Findings: Probabilistic analyses (10 000 simulations) showed that, for a willingness-to-pay threshold of CAN$50 000, a PET-adapted de-escalation strategy based on AHL2011 was more cost-effective 87% of the time. This strategy had the highest number of life-years (14·6 years [95% CI 13·7-15·1]) and quality-adjusted life years (13·2 years [95% CI 10·2-14·4]), and the lowest direct costs ($53 129 [95% CI 31 914-94 446]) compared with the other treatment regimens. Sensitivity analyses showed that the model was robust to key variables, including probability of treatment-related mortality, relapse, frequency of secondary malignancy, death from secondary malignancy, and probability of infertility after BEACOPP., Interpretation: Our results suggest that, when considering cost, effectiveness, and short and long-term toxicities, the preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the PET-adapted de-escalation regimen starting with BEACOPP and de-escalating to ABVD as appropriate. Although our findings do not provide an absolute best treatment approach for clinicians to follow for all patients, they can contribute to shared decision making between patients and treating physicians., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Despite advances in the management of hematologic malignancies, a significant proportion of patients die of their disease. We used administrative databases in Ontario, Canada (between 2005 and 2013) to determine the number of days spent at home in the last 6 months of life. We studied the predictors of the median number of days at home (DAH) using quantile regression. For the 11,127 patients with hematologic malignancies who died, the median number of DAH in the last 6 months was 156 days. Patients with acute leukemias ( p  < .0001), women ( p  < .0001), and those requiring transfusions ( p  < .0001) spent the fewest DAH. Patients assessed by palliative care prior to their last 6 months were likely to spend more time at home ( p  < .0001). Providing additional supports for patients nearing the end of life, including earlier access to palliative care and continued transfusion support, may increase the likelihood that patients can die at home.

Background: Paclitaxel is an important chemotherapeutic agent for the treatment of breast cancer. Paclitaxel-induced peripheral neuropathy (PIPN) is a major dose-limiting toxicity that can persist into survivorship. While not all survivors develop PIPN, for those who do, it has a substantial negative impact on their functional status and quality of life. No interventions are available to treat PIPN. In our previous studies, we identified that the HIF-1 signaling pathway (H1SP) was perturbed between breast cancer survivors with and without PIPN. Preclinical studies suggest that the H1SP is involved in the development of bortezomib-induced and diabetic peripheral neuropathy, and sciatic nerve injury. The purpose of this study was to identify H1SP genes that have both differential methylation and differential gene expression between breast cancer survivors with and without PIPN., Methods: A multi-staged integrated analysis was performed. In peripheral blood, methylation was assayed using microarray and gene expression was assayed using RNA-seq. Candidate genes in the H1SP having both differentially methylation and differential expression were identified between survivors who received paclitaxel and did (n = 25) and did not (n = 25) develop PIPN. Then, candidate genes were evaluated for differential methylation and differential expression in public data sets of preclinical models of PIPN and sciatic nerve injury., Results: Eight candidate genes were identified as both differential methylation and differential expression in survivors. Of the eight homologs identified, one was found to be differential expression in both PIPN and "normal" mice dorsal root ganglia; three were differential methylation in sciatic nerve injury versus sham rats in both pre-frontal cortex and T-cells; and two were differential methylation in sciatic nerve injury versus sham rats in the pre-frontal cortex., Conclusions: This study is the first to evaluate for methylation in cancer survivors with chronic PIPN. The findings provide evidence that the expression of H1SP genes associated with chronic PIPN in cancer survivors may be regulated by epigenetic mechanisms and suggests genes for validation as potential therapeutic targets.

Background: Clinical benefit scores (CBS) are key elements of the ASCO Value Framework (ASCO-VF) and are weighted based on a hierarchy of efficacy endpoints: hazard ratio for death (HR OS), median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, the other endpoints serve as "surrogates" to calculate CBS. CBS are computed from PFS or RR in 39.6% of randomized controlled trials. This study examined whether surrogate-derived CBS offer unbiased scoring compared with HR OS-derived CBS., Methods: Using the ASCO-VF, CBS for advanced disease settings were computed for randomized controlled trials of oncology drug approvals by the FDA, European Medicines Agency, and Health Canada in January 2006 through December 2017. Mean differences of surrogate-derived CBS minus HR OS-derived CBS assessed the tendency of surrogate-derived CBS to overestimate or underestimate clinical benefit. Spearman's correlation evaluated the association between surrogate- and HR OS-derived CBS. Mean absolute error assessed the average difference between surrogate-derived CBS relative to HR OS-derived CBS., Results: CBS derived from mOS, HR PFS, mPFS, and RR overestimated HR OS-derived CBS in 58%, 68%, 77%, and 55% of pairs and overall by an average of 5.62 (n=90), 6.86 (n=110), 29.81 (n=101), and 3.58 (n=108), respectively. Correlation coefficients were 0.80 (95% CI, 0.70-0.86), 0.38 (0.20-0.53), 0.20 (0.00-0.38), and 0.01 (-0.18 to 0.19) for mOS-, HR PFS-, mPFS-, and RR-derived CBS, respectively, and mean absolute errors were 11.32, 12.34, 40.40, and 18.63, respectively., Conclusions: Based on the ASCO-VF algorithm, HR PFS-, mPFS-, and RR-derived CBS are suboptimal surrogates, because they were shown to be biased and poorly correlated to HR OS-derived CBS. Despite lower weighting than OS in the ASCO-VF algorithm, PFS still overestimated CBS. Simple rescaling of surrogate endpoints may not improve their validity within the ASCO-VF given their poor correlations with HR OS-derived CBS.

This study examined 1) the relationship between posttraumatic stress disorder (PTSD) from past trauma, interpersonal sensitivity and psychiatric co-morbidity, and 2) whether cognitive emotion regulation strategies would mediate the impact of PTSD on specific distress outcomes. Four hundred seventy-five Kazakh students (F = 336, M = 139) participated in the study and completed a demographic page, Posttraumatic Stress Diagnostic Scale for DSM-5, General Health Questionnaire-28, Interpersonal Sensitivity Measure and Cognitive Emotion Regulation Questionnaire. The results showed that 71% reported that they had experienced at least one trauma throughout their lifespan, of whom 39% met the criteria for full-PTSD. Controlling for age and university majors, PTSD was associated with interpersonal sensitivity and psychiatric co-morbidity. Cognitive emotion regulation strategies were correlated with specific distress outcomes. Whilst positive reappraisal and refocusing on planning were associated with interpersonal sensitivity, self-blame and putting the trauma into perspective were associated with psychiatric co-morbidity. Self-blame mediated the impact of PTSD on psychiatric co-morbidity. To conclude, trauma can heighten levels of sensitivity in interpersonal interaction and psychological symptoms. Having specific thoughts about the trauma can impact on specific psychological reactions. Blaming oneself for the trauma can influence its impact on the severity of psychological symptoms.

Cancer treatment and management have become increasingly economically burdensome. Consequently, to help with planning health service delivery, it is vital to understand the associated costs. Administrative databases can be used to help understand and generate real-world system-level costs. Using databases to generate costs can take one of two approaches: top-down or bottom-up. Top-down approaches disaggregate the total health care spending from a global health care budget by sector and provider. A bottom-up approach begins with individual-level health care use and its costs, which are then aggregated., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: NC has received salary support from Cancer Care Ontario as the Clinical Lead in Patient Reported Outcomes and Symptom Management; WKE has received fees as an advisory board member for AbbVie, Astellas, Bristol–Myers Squibb, Eisai, Gilead, Lilly, Takeda, and Merck, and has received consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene, Janssen, Lilly, Roche, Servier, and Sanofi Genzyme. NM, SYC, NL, SJS, FES, CD, NJLH, CCE, MC, and NL have no conflicts to disclose., (2019 Multimed Inc.)

Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited., Competing Interests: Conflict of interest: C.H.T. Bui has nothing to disclose. Conflict of interest: M.M.T. Ng has nothing to disclose. Conflict of interest: M.C. Cheung has nothing to disclose. Conflict of interest: K-C. Ng has nothing to disclose. Conflict of interest: M.P.K. Chan has nothing to disclose. Conflict of interest: L.L.Y. Chan has nothing to disclose. Conflict of interest: J.H.M. Fong has nothing to disclose. Conflict of interest: J.M. Nicholls has nothing to disclose. Conflict of interest: J.S.M. Peiris reports grants from the Research Grants Council of the Hong Kong SAR and the US National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study. Conflict of interest: R.W.Y Chan reports grants from the Research Fund Secretariat, Food and Health Bureau, Hong Kong Special Administrative Region, during the conduct of the study. Conflict of interest: M.C.W. Chan reports grants from the Research Grants Council of the Hong Kong SAR and the US National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study., (Copyright ©ERS 2019.)

The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Traditional glass molding involves infrared heating; however, the thermal cycle time is long. A molding technique based on three-dimensional carbide-bonded graphene (CBG) has been developed to mold boron silicon glass. This CBG coating on a wafer silicon die can serve as a thin-film resistance heater to heat up the sample surface very rapidly with a relatively low applied voltage. To improve the precision temperature control in hot embossing so as to enhance the process quality, a heating system with lower energy consumption, shorter cycle time, and much more precision control is proposed. We have used COMSOL to simulate the whole heating process, and the heating behavior of a CBG-coated silicon wafer was experimentally investigated. The results showed that the repeatability of the heating system is stable, and it is suitable for precision glass hot embossing. Finally, an example of a precisely fabricated microlens array (Schott P-SK57) is embossed by using this novel heating system.

Background: The soaring costs of anti-cancer drugs pose a threat to the sustainability of cancer care. The pricing strategy chosen by manufacturers can impact the costs of oral anti-cancer drugs during dose modifications, but this issue remains under-recognized in the literature. In general, with the flat pricing strategy, there is a single fixed price for each tablet regardless of dosage strength, whereas with linear pricing, the price of each tablet increases with its dose. We hypothesize that flat pricing will have increased drug costs compared to linear pricing during dose reductions since the cost remains fixed despite decreased dose requirements. This practice may have significant financial implications considering the high costs, extensive utilization, and frequent occurence of dose reductions with anti-cancer drugs.  METHODS: Oral anti-cancer drugs reviewed by the pan-Canadian Oncology Drug Review program between 2011 and 2018 were identified. The cost per mg and cost per 28-day cycle were calculated for dose levels -2 to +2. The percent change in cost per mg and cost per cycle during dose modifications from the standard dose were calculated. We conducted Mann-Whitney U and Fisher-exact tests to compare the association between drug costs during dose reductions and pricing strategy., Results: In this study, 30 oral anti-cancer drugs for use in 41 indications were analyzed; 44% of drugs used linear pricing and 56% used flat pricing. Dose reductions increased the mean cost per mg for drugs with linear pricing by 14.7% (range: 0%-50%) at dose level -1 and 17.2% (range: 0%-50%) at dose level -2 and flat pricing by 60.8% (range: 19%-100%) at dose level -1 and 99.1% (range: 0%-300%) at dose level -2. The cost per mg was significantly increased in drugs using flat pricing compared to linear pricing when dose reduction to either level -1 (P = 0.010) or level -2 (P = 0.006) occurred. The mean cost per cycle was decreased for drugs using linear pricing by 20.9% (range: -40% to 0%) at dose level -1 and 48.7% (range: -60% to -25%) at dose level -2 and flat pricing by 0.8% (range -6% to 0%) at dose level -1 and 11.0% (range: -50% to 100%) at dose level -2. The cost per cycle was significantly decreased in drugs with linear pricing compared to flat pricing when the standard dose is reduced to either dose level -1 (P = 0.005) or dose level -2 (P = 0.026)., Conclusions: Overall, flat pricing had significantly greater costs compared to linear pricing during dose reductions of anti-cancer drugs. While there is a general expectation that the cost of drugs should decrease with dose reduction, drugs with flat pricing were generally found to have increased cost per mg and no change in the cost per cycle. The resultant increased spending on drug acquisition (despite purchasing lower doses) lead to financial wastage, which has significant implications on cost-effectiveness considerations and budgets. Future economic evaluations should take into consideration the hidden costs associated with dose reductions of flat priced drugs., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The association between obesity and survival in non-Hodgkin lymphoma is unclear. Using the Ontario Cancer Registry we conducted a retrospective analysis of incident cases of aggressive-histology B-cell lymphoma treated with a rituximab-containing regimen with curative intent between 2008-2016. 6246 patients were included. On multivariable analysis the rate of all-cause mortality was lower for the overweight body mass index (BMI 25-29.9 kg/m 2 ) (HR 0.85; 95%CI 0.77-0.95) and obese BMI (≥30 kg/m 2 ) (HR 0.75; 95%CI 0.67-0.85) groups compared to the normal weight group (18.5-24.9 kg/m 2 ). Binomial logistic regression analysis revealed a lower odds ratio (OR) of admission to hospital during treatment in the overweight (OR 0.84; 95%CI 0.75-0.95) compared to normal weight BMI group. In the largest cohort to date of aggressive-histology B-cell lymphoma patients treated with rituximab, increased BMI is associated with a survival advantage, and the magnitude of this effect increases from overweight to obese BMI.

Purpose: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL., Patients and Methods: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety., Results: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%)., Conclusion: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

Purpose: To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others., Methods: ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations., Results: The literature search identified 124 relevant studies to inform the evidence base for this guideline., Recommendations: Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.

The purpose of this project was to utilize pharmacists and pharmacy students to perform comprehensive medication reconciliation by telephone prior to a patient's office visit with their primary care physician, to address any medication issues. The project's aims were to decrease polypharmacy, improve the accuracy of medication reconciliation, and to allow more time for the physician to meet with the patient. Patients were called prior to appointment and a thorough medication reconciliation was conducted including verification of current prescription medications, over-the-counter medications, and herbal supplements. A total of 21 patients were enrolled in the study, and in 36% of patients, the number of medications decreased after the intervention. However, overall, the average number of medications used by patients increased from an average of 8.9 to 9.5 medications ( P = .39). All patients included in the study had at least one medication change in the electronic medical record system. Most of the changes were to add medications that were not on the medication list or to remove medications on the list that the patient was no longer taking. This study demonstrated improved accuracy with pharmacist/pharmacy student involvement in the medication reconciliation process.

We investigated GDP (gemcitabine, 1000 mg/m 2 IV d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m 2 IV d1) combined with romidepsin on days 1 and 8 every 21 days to a maximum of six cycles in a standard 3 + 3, phase I dose escalation trial for patients with relapsed/refractory peripheral T-cell (PTCL) or diffuse large B-cell (DLBCL) lymphoma (NCT01846390). After treating four patients, gemcitabine and romidepsin were given on days 1 and 15 every 28 days. On the 21-day schedule at 6 mg/m 2 romidepsin, there were three dose-limiting toxicities (DLTs) among four patients. On the 28-day schedule, there were no DLTs at the 6, 8, or 10 mg/m 2 dose. At 12 mg/m 2 , there were four observed grade 3 DLTs among six evaluable patients. Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m 2 if given on a day 1, 15 every 28 days schedule.

Purpose: Quality end-of-life care (EoLC) is a key aspect of oncology. Days at home in the last 6 months of life represents a novel, patient-driven quality indicator of EoLC. We measured days at home in a large population of patients with cancer in Ontario, Canada. Trends over time and predictors of more or less time at home were also determined., Methods: We conducted a population-based retrospective study using health administrative data linked by unique, encoded identifiers and analyzed at the ICES. Quantile regression was used to determine significant predictors of more or less time at home., Results: Of 72,987 patients who died of cancer in Ontario, Canada and met our inclusion criteria, the median number of days spent at home in the last 6 months of life was 164 (interquartile range [IQR], 144 to 175 days) of a possible 180 days. Patients with hematologic cancers spent significantly fewer days at home (156; IQR, 134 to 170 days). The strongest predictors of more time at home were male sex (+2.87 days relative to female sex; CI, 2.43 to 3.31 days) and receipt of palliative care before the last 6 months of life (+2.38 days; CI, 1.95 to 2.08 days). Additional predictors included income, age, cancer type, comorbidity burden, and health region. The majority of patients (69.7%) did not die at home., Conclusion: Days at home in the last 6 months of life, obtained from administrative data, can be used as a measure of quality EoLC. Predictors of days at home may prove valuable targets for future policy intervention.

Background: The vegetative state (VS)/unresponsive wakefulness syndrome (UWS) denotes brain-injured, awake patients who are seemingly without awareness. Still, up to 15% of these patients show signs of covert consciousness when examined by functional magnetic resonance imaging (fMRI) or EEG, which is known as cognitive motor dissociation (CMD). Experts often prefer the term unresponsive wakefulness syndrome to avoid the negative connotations associated with vegetative state and to highlight the possibility for CMD. However, the perception of VS/UWS by the public has never been studied systematically., Methods: Using an online crowdsourcing platform, we recruited 1,297 lay people from 32 countries. We investigated if vegetative state and unresponsive wakefulness syndrome might have a different influence on attitudes towards VS/UWS and the concept of CMD., Results: Participants randomized to be inquired about the vegetative state believed that CMD was less plausible (mean estimated frequency in unresponsive patients 38.07% ± SD 25.15) than participants randomized to unresponsive wakefulness syndrome (42.29% ± SD 26.63; Cohen's d 0.164; p  = 0.016). Attitudes towards treatment withdrawal were similar. Most participants preferred unresponsive wakefulness syndrome (60.05%), although a sizeable minority favored vegetative state (24.21%; difference 35.84%, 95% CI 29.36 to 41.87; p  < 0.0001). Searches on PubMed and Google Trends revealed that unresponsive wakefulness syndrome is increasingly used by academics but not lay people., Discussion: Simply replacing vegetative state with unresponsive wakefulness syndrome may not be fully appropriate given that one of four prefer the first term. We suggest that physicians take advantage of the controversy around the terminology to explain relatives the concept of CMD and its ethical implications., Competing Interests: The authors declare there are no competing interests.

This study examined the impact of bombing on posttraumatic stress disorder (PTSD) and psychiatric co-morbidity over time, whether this relationship was mediated by shattered world assumptions and altered self-capacities, and whether the mediational effects were moderated by attachment style and crisis support among Iraqi civilians. One hundred and fifty-nine Iraqi civilians completed questionnaires measuring the aforementioned psychological constructs. Bombing exposure was associated with PTSD and psychiatric co-morbidity over time; 87% and 77% met the criteria for PTSD at baseline and five months respectively. Shattered world assumptions and altered self-capacities mediated the impact of bombing exposure on PTSD and psychiatric co-morbidity over time. The mediational effect for shattered world assumptions was not moderated by attachment style and crisis support. However, the mediational effect for altered self-capacities was moderated by fearful attachment and a medium level of crisis support. To conclude, following bombing, Iraqi civilians' assumptions about the world and others can change. These changes can have long term effects on psychological distress but are not influenced by childhood attachment experiences or the amount of crisis support received. Bombing can also change civilians' perceptions of internal capacities like emotional regulation, particularly those with fearful attachment who rely on crisis support to some extent., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study compared the severity of chronic idiopathic urticaria (CIU) and psychiatric symptoms between patients with different levels of posttraumatic stress disorder (PTSD) and investigated a model depicting the interrelationship between PTSD from past trauma, personality traits, coping strategies, CIU severity and psychiatric symptom severity. One hundred CIU and 60 allergy patients participated in the study, completing measures on PTSD, psychiatric symptoms, personality traits and coping strategies. The results showed that for CIU patients, 7%, 40 and 34% met the diagnostic criteria for no-PTSD, partial-PTSD and full-PTSD respectively whereas for allergy patients, 15%, 45 and 18% met the same criteria. Apart from CIU, psychiatric symptom severity differed significantly between diagnostic groups. PTSD was associated with coping strategies which were in turn associated with CIU severity and psychiatric symptom severity. PTSD was not significantly associated with personality. Emotion-focused coping mediated PTSD and CIU severity, PTSD and psychiatric symptom severity and neuroticism and CIU severity. To conclude, psychiatric symptom severity varies depending on the level of PTSD among CIU patients. Neurotic patients with a high level of PTSD from past trauma show raised CIU and psychiatric symptom severity when using emotion-focused coping strategies.

This study examined 1) the link between PTSD from past trauma, interpersonal sensitivity and psychiatric co-morbidity, 2) mediational effects of alexithymia on 1), and 3) moderated mediational effects with emotional expressivity as the moderator. Five hundred and fifteen Kazakh students completed the Posttraumatic Stress Diagnostic Scale, General Health Questionnaire-28, Toronto Alexithymia Scale-20, Berkeley Expressivity Questionnaire and Interpersonal Sensitivity Measure. The results showed that 28% met the criteria for full-PTSD. Controlling for academic year, age and university major, PTSD from past trauma was significantly correlated with interpersonal sensitivity and psychiatric co-morbidity. Alexithymia mediated the impact of PTSD on interpersonal sensitivity and psychiatric co-morbidity. Alexithymia, however, did not interact with type of emotional expressivity to influence outcomes. Moderated mediational effects were not found. To conclude, following trauma, Kazakh students can experience heightened levels of interpersonal sensitivity and psychological symptoms. These problems are particularly severe for those who have difficulty getting in touch with their emotions.

Background: We examined how conditional market approval of cancer pharmaceuticals by Health Canada (hc) affects public funding recommendations by the pan-Canadian Oncology Review (pcodr). We were also interested to see how often hc conditions are enforced., Methods: Health Canada and pcodr databases for 2010-2017 were analyzed for patterns in hc conditional authorization and post-authorization reviews of cancer drugs and for correlation with pcodr reimbursement recommendations., Results: Between 2010 and 2017, pcodr reviewed 105 unique drug-indication pairings; 21% ( n = 22) had conditional hc authorization. In all cases, conditional authorization was given on the basis of preliminary data in a surrogate endpoint and was contingent on further data showing benefit in more robust outcome measures (for example, overall survival). Of those 22 drugs, 36% did not have updated data, 36% had updated data that met hc conditions, and 27% had data that met some, but not all, conditions. During the period considered, hc never revoked conditional authorization for failure to meet conditions. None of the 22 drugs was given an unconditional positive recommendation for public reimbursement by pcodr. A conditional recommendation was given to 11 of the drugs (50%), and reimbursement was not recommended for 6 drugs (27%) because of insufficient evidence., Conclusions: One fifth of the cancer drugs reviewed for public reimbursement in Canada were conditionally authorized by hc based on preliminary data. Conditional authorization was associated with a recommendation against public funding by pcodr. No drugs had their conditional market authorization revoked for failure to meet conditions, suggesting that a more robust hc reappraisal framework is needed., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conf licts of interest, and we declare the following interests: NP, AC, MET, KKWC, and MCC are members of the pan-Canadian Oncology Drug Review (pcodr) Expert Review Committee (perc), a committee that convenes under the auspices of the Canadian Agency for Drugs and Technologies in Health. The Canadian Agency for Drugs and Technologies in Health is an independent, not-for-profit organization established in 1989 by the federal, provincial, and territorial governments.

There is an ongoing debate about whether emotional responses to artworks are similar to those produced by the commercial stimuli experienced in everyday life. In this study, we evaluated the emotional responses to the visual art and commercial stimuli by using electroencephalography (EEG) to obtain an objective measure of emotional responses of the brain, namely the frontal alpha asymmetry. Positive frontal alpha asymmetry suggests positive emotional responses, and vice versa. The visual art stimuli consisted of 80 artistic and naturally colored paintings whereas the commercial stimuli consisted of 80 different window displays of fashion collections. The results revealed that positive frontal alpha asymmetry was elicited when the participants judged the visual art stimuli as either beautiful or not beautiful. For the commercial stimuli, positive frontal alpha asymmetry was observed when they were considered as beautiful, whereas negative frontal alpha asymmetry was exhibited toward those perceived as not beautiful. These findings suggest more positive emotional responses to the visual art stimuli, regardless of their aesthetics. However, favorable emotional responses were only elicited toward the commercial stimuli regarded as beautiful. The implications for the creative and aesthetic design of the commercial stimuli in Chinese society in influencing consumers' emotional responses are discussed.

Past traumatic events are distressing experiences which can result in the emergence of posttraumatic stress disorders (PTSD) and other psychological symptoms among university students. However, little is known as to whether or not cognitive distortion and alexithymia would influence the severity of these distress outcomes. This study examined a cognitive-emotional framework depicting potential roles that cognitive distortion and alexithymia could play in influencing the relationship between past trauma and psychiatric co-morbidities among university students in China. One thousand one hundred and eleven participants completed the PTSD Checklist for DSM-5, Cognitive Distortion Scale (CDS), Toronto Alexithymia Scale (TAS-20), and General Health Questionnaire (GHQ-28). Results indicated that PTSD following past trauma was significantly associated with increased psychiatric co-morbidities after controlling for covariates. Both alexithymia and distorted cognition mediated the association between PTSD and psychiatric co-morbidities. To conclude, university students can develop PTSD from past trauma and other mental health problems. The severity of psychological distress can be influenced by their distorted perceptions of themselves, the world, and the future, as well as their ability to identify, describe, and express distressing emotions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Research groups are increasingly utilizing value frameworks, but little is known of their reliability. To assess framework concordance and interrater reliability between two major value frameworks currently in use, we identified all previously published datasets containing both scores from the American Society of Clinical Oncology Value Framework (ASCO-VF) and grades from the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The intraclass correlation coefficient (ICC) was used to assess interrater reliability. Four eligible studies contained drugs evaluated by both value frameworks, resulting in a dataset of 39 grades/scores for discrete drug indications. ICC was 0.82 (95% confidence interval = 0.70 to 0.90) for ASCO-VF and 0.88 (95% confidence interval = 0.80 to 0.93) for ESMO-MCBS. Absolute concordance was found to be 5% for ASCO-VF and 44% for ESMO-MCBS, increasing to 74% and 80% when deviations within 20 points and 1 grade were considered, respectively. Interrater reliability of ASCO-VF and ESMO-MCBS is, therefore, near perfect, while absolute concordance is poor. This has implications when considering framework outputs in drug funding or treatment decision making.

It has been documented that trauma centrality is associated with posttraumatic stress disorder (PTSD) and psychiatric co-morbidity among Syrian refugees. Whether age would influence the levels of the above constructs and the association between trauma centrality and distress outcomes is unclear. This study compared age differences in 1) the levels of trauma centrality, posttraumatic stress disorder and psychiatric co-morbidity, and 2) models depicting the association between trauma centrality and distress outcomes among Syrian refugees. One thousand one hundred and ninety-seven refugees completed the Centrality of Event Scale, Harvard Trauma Questionnaire and General Health Questionnaire-28. Age groups were divided into young, middle-aged adults and adults of 45 or above. No significant group differences were found in the proportion of refugees meeting the diagnostic criteria for PTSD. Controlling for demographic variables, all subscales of trauma centrality and psychiatric co-morbidity were significantly different between groups. Young adults reported significantly less trauma centrality and psychiatric co-morbidity than the other groups. Multiple-indicator multiple-cause modelling showed that trauma centrality was significantly correlated with PTSD and psychiatric co-morbidity. Multi-group analysis showed the model for the young adult group to be significantly different from the middle-aged group model. To conclude, age did not seem to influence the severity of PTSD among Syrian refugees. The war had a less severe impact on young adults' sense of self and other psychological problems than those who were older. The way in which young and middle-aged adults responded to distress varied depending on environment and personal characteristics.

Background: Cancer screening aims to detect malignant disease early in its natural history when interventions might improve patient outcomes. Such benefits are unclear when screening occurs for patients with an existing high risk of death. Our aim was to study the extent of routine cancer screening for a new primary cancer in patients with existing metastatic cancer., Methods: We used administrative databases from Ontario to identify a retrospective cohort of adults of eligible screening age (≥ 50 yr) who had a diagnosis of stage IV (metastatic) colorectal, lung, breast or prostate cancer between 2007 and 2012. We calculated the cumulative incidence of cancer screening over time for colorectal and breast cancer., Results: Among the 20 992 patients with metastatic lung, breast or prostate cancer, 2.9%, 6.3% and 13.3% of patients, respectively, underwent testing for colorectal cancer within 1 year of cancer diagnosis. Within 3 years of diagnosis, rates reached 4.1%, 12.3% and 27.5%, respectively (8.5% of all patients). Incidence of colorectal cancer testing was higher among patients who received their diagnoses more recently compared with patients with diagnoses from earlier time periods ( p = 0.0143). Among the 10 034 women with metastatic lung or colorectal cancer, 8.7% and 8.0% of patients, respectively, underwent breast cancer screening within 1 year of cancer diagnosis. Within 3 years of diagnosis, screening rates reached 10.2% and 13.1%, respectively., Interpretation: Our findings indicate excessive rates of cancer screening among patients with metastatic cancer who are unlikely to benefit. Further studies are warranted to identify predictors for screening, resource implications, potential and real harms borne by patients, and the impact of a recent Choosing Wisely statement recommending against the practice., Competing Interests: Competing interests: Jill Tinmouth was the lead scientist for the ColonCancerCheck program at Cancer Care Ontario. No other competing interests were declared., (Copyright 2018, Joule Inc. or its licensors.)

Background: There is evidence suggesting that posttraumatic stress disorder (PTSD) symptom severity and CIU severity are linked and partially mediated by the high-anxious defense mechanism. What is unclear is whether emotional suppression, as a defense serving the opposite purpose for high-anxious defense, can also act as a mediator and whether this mediational effect is partly influenced by time since trauma and trauma type., Aims: To investigate whether emotional suppression mediated the links between PTSD and CIU symptom severities, and PTSD and psychiatric co-morbid symptom severities. It then examined whether the mediating effect would be moderated by how long ago the trauma occurred and trauma type., Methods: One hundred CIU patients were compared with 60 allergy patients. They completed questionnaires measuring PTSD, psychiatric co-morbidity and emotional suppression., Results: Suppressing depression mediated the relationship between PTSD and psychiatric co-morbidity. How long ago the trauma occurred and trauma type moderated the mediational effect of suppressing depression., Conclusions: Following a past trauma, CIU patients may develop PTSD symptoms which influence their psychological well-being through using different levels of emotional suppression, especially suppressing depression. The levels depend on the severity of PTSD symptoms, trauma history and whether they experienced interpersonal traumas.

Background: Relationship dissolution is a distressing experience which can result in the emergence of posttraumatic stress (i.e. post-dissolution PTSS) and other psychological symptoms among college students. Little is known, however, whether posttraumatic stress cognitions and interpersonal dependency may influence the severity of these distress outcomes., Aims: This study examined the interrelationship between posttraumatic stress symptoms (PTSS), posttraumatic stress cognitions, interpersonal dependency and psychological co-morbidities following relationship dissolution., Methods: One hundred and eighty college students (M = 69, F = 111) who had experienced relationship dissolution completed the Posttraumatic Stress Diagnostic Scale, Posttraumatic Stress Cognition Inventory, Interpersonal Dependency Inventory and General Health Questionnaire-28., Results: Posttraumatic stress symptoms following relationship dissolution (post-dissolution PTSS) were associated with increased psychological co-morbidities. Negative view of oneself and self-blame mediated between PTSS and psychological co-morbidities. Assertion of autonomy moderated the mediational effects of negative cognitions on psychological co-morbidities., Conclusions: People can develop PTSSs and other psychological symptoms following the dissolution of a romantic relationship. Their concept of self and tendency to seek independence and control played a key role in determining the severity of distress symptoms.

Monolayer graphene exhibits extraordinary properties owing to the unique, regular arrangement of atoms in it. However, graphene is usually modified for specific applications, which introduces disorder. This article presents details of graphene structure, including sp 2 hybridization, critical parameters of the unit cell, formation of σ and π bonds, electronic band structure, edge orientations, and the number and stacking order of graphene layers. We also discuss topics related to the creation and configuration of disorders in graphene, such as corrugations, topological defects, vacancies, adatoms and sp 3 -defects. The effects of these disorders on the electrical, thermal, chemical and mechanical properties of graphene are analyzed subsequently. Finally, we review previous work on the modulation of structural defects in graphene for specific applications.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) has emerged as a coronavirus infection of humans in the past 5 years. Though confined to certain geographical regions of the world, infection has been associated with a case fatality rate of 35%, and this mortality may be higher in ventilated patients. As there are few readily available animal models that accurately mimic human disease, it has been a challenge to ethically determine what optimum treatment strategies can be used for this disease. We used in-vitro and human ex-vivo explant cultures to investigate the effect of two immunomodulatory agents, interferon alpha and cyclosporine, singly and in combination, on MERS-CoV replication. In both culture systems the combined treatment was more effective than either agent used alone in reducing MERS-CoV replication. PCR SuperArray analysis showed that the reduction of virus replication was associated with a greater induction of interferon stimulated genes. As these therapeutic agents are already licensed for clinical use, it may be relevant to investigate their use for therapy of human MERS-CoV infection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7-12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6-19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML., (© 2018 John Wiley & Sons Ltd.)

To examine the prevalence of PTSD following homicide and investigate the relationship between PTSD from past traumas, defense styles and PTSD following homicide and psychiatric co-morbidity. 167 male homicide perpetrators participated in the study and completed the Posttraumatic Stress Diagnostic Scale, the General Health Questionnaire-28 and the Defense Styles Questionnaire. 45% met the criteria for PTSD following homicide and 55% for no-PTSD. With the number of times for imprisonment adjusted, regression analyses showed that immature defense style was associated with PTSD following homicide with the severity of PTSD from past traumas as a moderator. Neurotic and immature defense styles and PTSD from past trauma were significantly and independently associated with psychiatric co-morbidity. Homicide perpetrators could develop PTSD following homicide. The severity of PTSD from past traumas could affect PTSD following homicide and other psychological problems, and influence the effect of using immature defense against PTSD from homicide. Past trauma, immature and neurotic defense styles had a unique and specific pattern of influence on psychological symptoms, other than trauma symptoms.

Purpose: The purpose of this study was to determine if clinical benefits of novel anticancer drugs, measured by the ASCO Value Framework and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale, have increased over time in parallel with increasing costs., Methods: Anticancer drugs from phase III randomized controlled trials cited for clinical efficacy evidence in drug approvals between January 2006 to December 2015 were identified and scored using both frameworks. For each drug, the monthly price and incremental anticancer drug costs were calculated. Relationships between cost and year of approval were examined using generalized linear regressions models. Ordinary least square models were used to evaluate relationships between ASCO and ESMO scores and year of approval. Spearman correlation coefficients between costs and clinical benefit scores were calculated., Results: In total, 42 randomized controlled trials were included. Both monthly prices and incremental anticancer drug costs were significantly associated with year of approval and showed an average annual increase of 9% and 21%, respectively. The predicted mean incremental anticancer drug cost increased from $30,447 in 2006 to $161,141 in 2015 (greater than five-fold increase). Both ASCO and ESMO scores were not statistically associated with year of approval or correlated with monthly prices or incremental anticancer drug costs., Conclusion: Over the past decade, costs of novel oncology drugs have increased, while clinical benefits of these medications have not experienced a proportional positive change. The incremental anticancer drug costs have increased at a much greater rate than monthly prices, indicating that the increase in anticancer drug costs may be higher than commonly reported.

Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5-year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio-immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio-immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow-up of 48 months (range 3-84 months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: In the United States, certain minority groups have been shown to have inferior cancer outcomes compared with the white majority population. However, to the authors' knowledge, the majority of research has not separated ethnicity from immigration status. The objective of the current study was to determine the impact of ethnicity, independent of immigration status, on cancer outcomes in Chinese and South Asian populations in Ontario, Canada., Methods: The authors conducted a population-based retrospective cohort study using administrative databases in Ontario, Canada. Incident cancer cases were captured in Canadian-born Chinese and South Asian individuals, Chinese and South Asian immigrants, and the general Ontario reference population (non-Chinese/non-South Asian and non-immigrant) between 2000 and 2012. Subjects were followed until death (all-cause and cancer-specific), and Cox proportional hazard models were used to estimate the impact of Chinese and South Asian ethnicity on cancer outcomes after adjusting for explanatory variables., Results: A total of 423,678 cancer cases were identified; at total of 6631 cases were identified in Canadian-born Chinese individuals and 2752 cases in Canadian-born South Asian individuals. After adjustment, the rate of all-cause mortality was lower for Canadian-born Chinese (hazard ratio [HR], 0.829; 95% confidence interval [95% CI], 0.795-0.865), Canadian-born South Asian (HR, 0.856; 95% CI, 0.797-0.919), and Chinese immigrant (recent immigrant: HR, 0.661 [95% CI, 0.610-0.716] and non-recent immigrant: HR, 0.853 [95% CI, 0.803-0.906]) populations compared with the general Ontario population. A similar effect was found for cancer-specific mortality., Conclusions: Chinese and South Asian ethnic groups appear to have lower cancer mortalities compared with the general Ontario population. After removing the well-documented protective effect of immigration, Chinese and South Asian ethnicities were found to be associated with a cancer survival advantage in Ontario, Canada. Cancer 2018;124:1473-82. © 2018 American Cancer Society., (© 2018 American Cancer Society.)