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Purpose Fatigue is a distressing symptom commonly reported among pediatric patients with primary immunodeficiency (PID). However, the relationship between fatigue and disease activity is currently unknown. Methods In this cross-sectional study, we examined the prevalence of severe fatigue, the effect of fatigue on health-related quality of life (HRQoL), and the effects of disease activity and comorbidity on fatigue severity among pediatric patients 2–18 years of age with PID. Fatigue and HRQoL were assessed using the pediatric quality of life inventory multidimensional fatigue scale (PedsQL MFS) and generic core scales (PedsQL GCS), respectively. Linear regression analyses and an analysis of covariance were used to compare the fatigue scores with the scores obtained from a healthy control group. Data were adjusted for age and sex. Results Of the 91 eligible patients, 79 were assessed (87% participation rate), with a mean age of 10.4 ± 4.4 years. Pediatric patients with PID reported significantly higher fatigue levels compared to healthy peers, with an 18.9% prevalence of severe fatigue. Moreover, higher fatigue levels were inversely associated with HRQoL in all domains and directly associated with school absences. We found that severe fatigue was comparable between common variable immunodeficiency (CVID), combined immunodeficiency (CID), and selective immunoglobulin A deficiency (SIgAD) patients, but was not reported in the X-linked agammaglobulinemia (XLA) patients studied. Finally, fatigue severity was not significantly associated with disease activity or comorbidity. Conclusions Nearly 20% of pediatric patients with PID reported experiencing severe fatigue, and fatigue was reported among a wide range of PID subcategories. In addition, severe fatigue negatively affected the patient’s quality of life and daily functioning, but was not associated with disease activity or comorbidity. Thus, targeting severe fatigue might be a promising strategy for improving the overall well-being and quality of life of pediatric patients with PID.

This paper aims to enhance our understanding of the relationship between organizations' strategic orientation (i.e., instrumental, equidistant, and stewardship) and their innovational strategy (i.e., organizational ambidexterity and open innovation), and this relationship's influence on their sustainability performance. We expected organizations' strategic orientation to influence their innovational strategy and exhibit better corporate sustainability. We focused on 12 different multinational organizations in the Eurozone and found that inbound open innovation acts as a driver for corporate sustainability while simultaneously positively enabling organizations to pursue both financial and social initiatives. After suggesting open innovation as a new corporate sustainability antecedent, we only found empirical evidence of inbound open innovation. However, we would suggest that if organizations incorporated outbound open innovation in their strategy, they could likely improve their corporate sustainability. Also, we found that achieving an equidistant or stewardship orientation paves the way for sustainability to become an integral part of an organization's innovational culture and actualizes the organization's strategic behavior. Our findings further contribute to a deeper understanding of organizations' characteristics as their sustainability commitment grows and as they move from an instrumental to a stewardship orientation and implement an open innovational strategy.

Many adolescents worldwide (indirectly) grow up with a chronic disease, which may impact their functioning and wellbeing. The objective of this study is to assess whether adolescents with a (family member with a) chronic disease differ from their healthy counterparts in terms of psychosocial functioning. Data from the Dutch 2013 HBSC-survey were used, including 7168 adolescents (Meanage = 13.7, SD = 1.57, 50.5% female). Participants indicated whether they or one of their family members had a long-term (> 3 months) disease or disability (mental/physical) and were categorized into four groups based on disease presence (none, other, self, both). Psychosocial functioning was assessed in terms of life satisfaction, self-rated health, psychosomatic health, mental health problems, support, substance use, physical exercise, screen time, and school liking. Chronically diseased adolescents (n = 162) reported lower life satisfaction, self-rated and psychosomatic health, more mental health problems, lower peer support, more substance use, and less physical exercise compared to healthy peers. Chronically diseased adolescents who also had a family member with a chronic disease (n = 74) showed comparable outcomes on these life domains, although they did not differ from their healthy peers regarding peer support, substance use, and physical activity. Healthy adolescents with a chronically diseased family member (n = 737) reported significantly lower life satisfaction, self-rated and psychosomatic health, more mental health problems, and less family support compared to healthy peers who grew up in healthy families; however, they reported more positive outcomes than adolescents who had a chronic disease themselves.Conclusion: Having a (family member with a) chronic disease is associated with impaired psychosocial functioning on various life domains. Our findings aid in understanding the psychosocial associates of chronic disease and imply that caregivers should be observant of psychosocial problems among vulnerable adolescents to provide appropriate guidance. What is Known:• Adolescents who grow up with a (family member with a) chronic disease encounter numerous challenges that may be related to poorer developmental outcomes on the long term. What is New:• This study adds a comprehensive overview of the psychosocial functioning of adolescents with a (family member with a) chronic disease, as compared to healthy counterparts that grow up in a healthy family.

Background Increasing pressure threatens to overwhelm primary care services, affecting the quality of care and their role as gatekeepers to specialised care services. This study investigated healthcare users’ acceptability of – and the effectiveness of – an e-consultation system in primary care services. Methods Seven GP practices in East-Midlands, all of whom use online consultation system participated in the study, with a retrospective review being undertaken of 189 electronic patients’ records (age range of 18–76 years) over 5 months. The focus was on the electronic records of patients who accessed the service for five different conditions identified as presenting common conditions seen by the GPs practices. Statistical analysis was done using SPSS to perform an exploratory data analysis and descriptive statistics. Results The results showed a positive reception of the online consultation platform, with an average satisfaction score of 4.15 (most likely to recommend score = 5). Given the nature of the conditions, 47.6% of patients had experienced a previous episode of the health condition they were seeking consultation for, and a total of 72% had existing comorbidities. Follow-up activity occurred for 87.3% of patients, 66.1% of which included at least one follow-up visit for the same condition as the initial online consultation. Conclusion The results suggest that online consultation is convenient for patients, and it also has the potential to relieve pressure placed on primary care services. Although a number of challenges were identified, such as patient verification, this study gives insight into – and enhances our understanding of – the use of online GP consultations.

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19, This study has been funded by the Austrian Forum against Cancer, which covered in part expenses for interaction between authors and for secretarial support.

Apoptosis induction by death receptor (DR)-specific agonistic antibodies is a potentially effective antitumor therapy. Nonetheless, to date, all conventional DR-targeting antibodies that induce apoptosis via FcγR-dependent DR clustering failed to show clinical efficacy. HexaBody-DR5/DR5 (GEN1029) has been developed to overcome full FcγR dependence. HexaBody-DR5/DR5 is a mixture of 2 noncompeting DR5-specific immunoglobulin G1 (IgG1) antibodies, each with an E430G mutation in the Fc domain. This mutation enhances Fc-Fc interactions, resulting in antibody hexamerization, followed by FcγR-independent clustering of DR5 molecules. This unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent preclinical antitumor activity in various solid cancers. In this study, we explored the preclinical activity of HexaBody-DR5/DR5 in multiple myeloma (MM), because MM cells are known to express DR5. In bone marrow samples from 48 MM patients, HexaBody-DR5/DR5 induced potent cytotoxicity of primary MM cells. Importantly, HexaBody-DR5/DR5 mediated the highest cytotoxic activity in samples from relapsed/refractory MM patients, including those who are refractory to daratumumab. This improved cytotoxic activity was observed only in patients who received their last anti-MM treatment

Background Previous studies have reported a negative psychological and mental health impact of the COVID-19 pandemic. This impact is likely to be stronger for people with autism as they are at heightened risk of mental health problems and because the pandemic directly affects social functioning and everyday routines. We therefore examined COVID-19 pandemic-related changes in mental health, the impact of the pandemic on their social life and routines, satisfaction with pandemic-related information and tips, and participants’ wishes for guidance. Methods We used a mixed-method approach, collecting quantitative and qualitative survey data from adults with and without autism across three European countries: Belgium, the Netherlands, and the UK (N = 1044). Results We found an increase in depression and anxiety symptoms in response to the pandemic for both the non-autism and the autism group, which was greater for adults with autism. Furthermore, adults with autism showed a greater increase in worries about their pets, work, getting medication and food, and their own safety/security. They felt more relieved from social stress, yet experienced the loss of social contact as difficult. Adults with autism also felt more stressed about the loss of routines. Pleasant changes noted by adults with autism were the increase in solidarity and reduced sensory and social overload. Adults with autism frequently reported problems with cancellation of guidance due to the pandemic and expressed their wish for (more) autism-specific information and advice. Limitations Our sample is likely to reflect some degree of selection bias, and longitudinal studies are needed to determine long-term effects. Conclusions Results highlight the psychological burden of the pandemic on adults with autism and shed light on how to support them during this COVID-19 pandemic, which is especially important now that the pandemic is likely to have a prolonged course. There is a need for accessible, affordable (continued) support from health services. Guidance may focus on the maintenance of a social network, and adjusting routines to the rapid ongoing changes. Finally, we may learn from the COVID-19 pandemic-related changes experienced as pleasant by adults with autism to build a more autism-friendly society post-pandemic.

ObjectiveOpportunities to participate in daily life have improved considerably for children with chronic disease. Nevertheless, they still face challenges associated with their ever-present illness affecting every aspect of their lives. To best help these children, we aimed to assess the child’s own perspective on participation and the main considerations that affect participation in a stable phase of disease.MethodsQualitative study design was applied. Semistructured, indepth interviews were conducted and analysed by a general inductive approach using constant comparison, coding and categorisation. Children 8–18 years old with a chronic disease were recruited from a cohort study involving cystic fibrosis, autoimmune disease and post-treatment paediatric cancer.Results31 of the 56 (55%) invited patients participated. From the perspective of children with chronic disease, participation is considered more than merely engaging in activities; rather, they view having a sense of belonging, the ability to affect social interactions and the capacity to keep up with peers as key elements of full participation. Some children typically placed a higher priority on participation, whereas other children typically placed a higher priority on their current and/or future needs, both weighing the costs and benefits of their choices and using disclosure as a strategy.ConclusionsEnabling full participation from the child’s perspective will help realise patient-centred care, ultimately helping children self-manage their participation. Caregivers can stimulate this participation by evaluating with children how to achieve a sense of belonging, active involvement and a role within a peer group. This requires active collaboration between children, healthcare providers and caregivers.

Contains fulltext : 240012.pdf (Publisher’s version ) (Open Access) Many adolescents in residential care have experienced traumatic events and suffer from posttraumatic stress. Prolonged activation of neurobiological stress systems as the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis can result in long-lasting maladaptive alternations. This study investigated the effectiveness of Muse, a game-based meditation intervention, on the sympathetic nervous system (SNS), parasympathetic nervous system (PNS), and cortisol basal activity and reactivity to acute stress among adolescents with posttraumatic symptoms in residential care. The intervention consisted of two gameplay sessions a week, for 6 consecutive weeks. Seventy-seven adolescents with clinical levels of posttraumatic symptoms (10-18 years old) received either Muse as an addition to treatment as usual (n = 40) or treatment as usual alone (n = 37). We expected reduced basal activity for the SNS and cortisol and increased basal activity for the PNS. As for the response to acute stress, we expected decreased PNS and increased HPA axis reactivity. The Muse group exhibited lower basal activity for the SNS and increased HPA reactivity to acute stress. There were no differences between conditions on SNS and HPA axis activity during rest and on SNS and PNS reactivity to acute stress. Game-based meditation therapy is a promising intervention for the treatment of adolescents with posttraumatic symptoms in residential care. Implications for clinical relevance and trauma-focused treatment purposes are discussed. 8 p.

B-cell maturation antigen (BCMA)-targeting bispecific antibodies and bispecific T-cell engagers (BiTEs) redirect T-cells to BCMA-expressing multiple myeloma (MM) cells. These MM cells are subsequently eliminated via various mechanisms of action including the release of granzymes and perforins. Several phase 1, dose-escalation studies show pronounced activity of BCMA-targeting bispecific antibodies, including teclistamab, AMG420 and CC-93269, in heavily pretreated MM patients. Cytokine release syndrome is the most common adverse event, which can be adequately managed with tocilizumab or steroids. Several clinical trials are currently evaluating combination therapy with a BCMA-specific bispecific antibody, based on preclinical findings showing that immunomodulatory drugs or CD38-targeting antibodies enhance the activity of bispecific antibodies. In addition, bispecific antibodies, targeting other MM cell surface antigens (i. e. GPRC5D, CD38 and FcRH5), are also evaluated in early phase clinical trials. Such bispecific antibodies, targeting other antigens, may be given to patients with low baseline BCMA expression, disease with substantial heterogeneity in BCMA expression, following prior BCMA-targeted therapy, or combined with BCMA bispecific antibodies to prevent development of antigen escape.

This study focuses on understanding the inner psychological (intrinsic) motivations that influence local business leaders in adopting CSR behaviours. The inner motivations are hereby considered as the mind-sets of individuals, the human capacity to interpret reality. According to the constructive developmental theories, individuals experience several stages of consciousness development, as a consequence of their deeper understanding of reality, wisdom and ego awareness. More specifically, building upon the Action Logics framework of Rooke and Torbert (2005), it can be considered what type of action logics relate to advanced forms of CSR behaviours. One of the main contributions of this study to the leadership and CSR literature is to describe each action logics as specific intrinsic motivation and clarify empirically the relationship between action logics of local business leaders and different stages of CSR behaviours, in a specific local context. An inductive research strategy is applied. Nine local business leaders participated in this research and triangulation was applied based on in-depth interviews, observations and company reports to determine CSR behaviours and how they are related to action logics. Template analysis was used for coding the findings. The study resulted in four distinctive patterns about the relationships between action logics and CSR behaviours. The study indicates that: (1) Higher action logics are needed to be engaged in more advanced stages of CSR practices; (2) It is at the achiever action logic level when leaders start moving towards advanced stages of CSR behaviours; (3) Lower action logics cannot induce advanced stages of CSR behaviours; (4) Business leaders with higher action logics can still apply practices of the full range of CSR stages. Based on these findings this paper provides recommendations for future research and managerial practice.

Background Internet-based cognitive behavior therapy (I-CBT) for adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been shown to be effective in a randomized controlled trial (RCT; Fatigue in Teenagers on the Internet [FITNET]). FITNET can cause a significant reduction in fatigue and disability. Objective We aimed to investigate whether FITNET treatment implemented in routine clinical care (IMP-FITNET) was as effective, using the outcomes of the FITNET RCT as the benchmark. Methods Outcomes of CFS/ME adolescents who started IMP-FITNET between October 2012 and March 2018 as part of routine clinical care were compared to the outcomes in the FITNET RCT. The primary outcome was fatigue severity assessed posttreatment. The secondary outcomes were self-reported physical functioning, school attendance, and recovery rates. Clinically relevant deterioration was assessed posttreatment, and for this outcome, a face-to-face CBT trial was used as the benchmark. The attitude of therapists toward the usability of IMP-FITNET was assessed through semistructured interviews. The number of face-to-face consultations during IMP-FITNET was registered. Results Of the 384 referred adolescents with CFS/ME, 244 (63.5%) started IMP-FITNET, 84 (21.9%) started face-to-face CBT, and 56 (14.6%) were not eligible for CBT. Posttreatment scores for fatigue severity (mean 26.0, SD 13.8), physical functioning (mean 88.2, SD 15.0), and full school attendance (mean 84.3, SD 26.5) fell within the 95% CIs of the FITNET RCT. Deterioration of fatigue and physical functioning after IMP-FITNET was observed at rates of 1.2% (n=3) and 4.1% (n=10), respectively, which is comparable to a waiting list condition (fatigue: 1.2% vs 5.7%, χ21=3.5, P=.06; physical functioning: 4.1% vs 11.4%, χ21=3.3, P=.07). Moreover, 41 (16.8%) IMP-FITNET patients made use of face-to-face consultations. Conclusions IMP-FITNET is an effective and safe treatment for adolescents with CFS/ME in routine clinical care.

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumab-refractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR ≥15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.

Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice. ispartof: LEUKEMIA vol:35 issue:1 pages:31-44 ispartof: location:England status: published

PURPOSE: The purposes of this study were to assess whether mental well-being has changed after introduction of the lockdown measures compared with that before, whether this change differs between boys and girls, and whether this change is associated with COVID-19-related concerns. METHODS: This is a two-wave prospective study among Dutch adolescents using data collected up to one year before the COVID-19 pandemic (n = 224) and 5-8 weeks after the first introduction of lockdown measures (n = 158). Mental well-being was assessed by three indicators: life satisfaction, internalizing symptoms, and psychosomatic health. General linear model repeated-measures analysis of variance was used to assess whether mental well-being has changed and if this differed by sex. Univariate linear regressions were used to assess associations between COVID-19-related concerns and a change in mental well-being. RESULTS: Life satisfaction decreased (I·2p = .079, p < .001), but no change in internalizing symptoms was observed (I·2p = .014, p = .14), and psychosomatic health increased (I·2p = .194, p < .001) after the introduction of lockdown measures. Boys scored significantly better on all mental health indicators compared with girls at baseline and follow-up. However, boys' life satisfaction significantly decreased at the follow-up (I·2p = .038, p = .015), whereas girls' life satisfaction did not change. Concerns about COVID-19 were significantly associated with a lower life satisfaction and more internalizing symptoms. CONCLUSIONS: Adolescents', especially boys', life satisfaction decreased during the lockdown. They reported no change in internalizing symptoms and an improved psychosomatic health. Adolescents' mental well-being is expected to vary during the COVID-19 pandemic and should continue to be monitored.

Objective Growing up with a chronic disease comes with challenges, such as coping with fatigue. Many adolescents are severely fatigued, though its associated factors exhibit considerable interpersonal and longitudinal variation. We assessed whether PROfeel, a combination of a smartphone-based ecological momentary assessment (EMA) method using the internet, followed by a face-to-face dialogue and personalized advice for improvement of symptoms or tailor treatment based on a dynamic network analysis report, was feasible and useful. Study design Feasibility study in fatigued outpatient adolescents 12–18 years of age with cystic fibrosis, autoimmune disease, post-cancer treatment, or with medically unexplained fatigue. Participants were assessed at baseline to personalize EMA questions. EMA was conducted via smartphone notifications five times per day for approximately six weeks. Hereby, data was collected via the internet. The EMA results were translated into a personalized report, discussed with the participant, and subsequently translated into a personalized advice. Afterwards, semi-structured interviews on feasibility and usefulness were held. Results Fifty-seven adolescents were assessed (mean age 16.2 y ± 1.6, 16% male). Adolescents deemed the smartphone-based EMA feasible, with the app being used for an average of 49 days. Forty-two percent of the notifications were answered and 85% of the participants would recommend the app to other adolescents. The personalized report was deemed useful and comprehensible and 95% recognized themselves in the personalized report, with 64% rating improved insight in their symptoms and subsequent steps towards an approach to reduce one's fatigue as good or very good. Conclusions PROfeel was found to be highly feasible and useful for fatigued adolescents with a chronic condition. This innovative method has clinical relevance through bringing a patient's daily life into the clinical conversation., Highlights • Fatigued adolescents with a chronic condition could use insight in their symptoms. • Fatigue and associated factors were measured via ecological momentary assessments. • Data were analyzed with dynamic network analyses, leading to personalized feedback. • This combination of assessment and feedback (PROfeel), was feasible and useful. • This innovative method brings a patient's daily life into the clinical conversation.

Background: A subset of patients with breast cancer is vulnerable to treatment-related cognitive problems. However, relatively little is known about the cognitive effects of endocrine treatment and the novel cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors in the metastatic setting. Research on possible cognitive effects of these therapies is needed, since cognitive impairment can affect role functioning, independence and quality of life. Trial design: The current study is a side study of the SONIA (Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer) trial: a multicenter, randomized phase III study. The side study is an observational study with nine months of follow-up, comparing two intervention groups (first line non-steroidal aromatase inhibitor + CDK4/6 inhibition vs. single agent non-steroidal aromatase inhibitor) and a reference group of people without a history of cancer. Cognition will be measured at start of treatment (T0) and nine months later (T1), using the Amsterdam Cognition Scan, a validated online neuropsychological test battery that is completed at home without supervision. It includes tests of among others attention, memory, and executive functioning, and two questionnaires on anxiety and depression, and fatigue. Specific aims: The main objective is to evaluate if there is a difference in cognitive functioning over time in patients with metastatic breast cancer who will undergo first line endocrine treatment + CDK4/6 inhibition vs. endocrine treatment alone. Eligibility criteria: All patients who participate in the main SONIA study will be eligible for participation: adult women (≥ 18 years of age) with proven diagnosis of hormone receptor-positive, human epidermal growth factor receptor 2 negative adenocarcinoma of the breast with evidence of loco-regional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent, for whom chemotherapy is not clinically indicated and who have not received any prior systemic anti-cancer therapy for metastatic disease. Participants in the reference group are patients’ female relatives/friends without a history of cancer and without neurological/psychiatric symptoms influencing cognition, who have a sufficient level of Dutch and access to a computer with internet. Statistical methods: We will use a mixed effects modeling approach to examine changes in cognition from baseline to follow-up between the two intervention groups and the reference group, adjusting for non-ignorable drop-out patterns. The primary endpoint will be the change from baseline to follow-up on the total score of cognition. Present accrual and target accrual: With an accrual period of 21 months and 9 months of follow-up, inclusion of 260 patients is required. In addition, our already existing reference group (n=157) will be expanded by recruiting participants’ female relatives/friends without a history of cancer. As of June 2019, 435 patients have enrolled in the main SONIA study. Target accrual is 1050 patients. Contact information Study coordinator: Philippe Lee Meeuw Kjoe, Netherlands Cancer Institute, p.lee.meeuw.kjoe@nki.nl PI: Elsken van der Wall, MD, PhD, UMC Utrecht Cancer Center, E.vanderWall@umcutrecht.nl PI: Sanne Schagen, PhD, Netherlands Cancer Institute, s.schagen@nki.nl Citation Format: Philippe Lee Meeuw Kjoe, Elsken van der Wall, Inge Konings, Agnes Jager, Gabe Sonke, Annemiek van Ommen-Nijhof, Sanne Schagen. Evaluation of cognitive functioning in patients with metastatic breast cancer treated with endocrine or combined therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-06.

Contains fulltext : 214790.pdf (Publisher’s version ) (Closed access) The aim of the current study was to compare levels of oxytocin, cortisol, and testosterone in adolescents with either autism spectrum disorder (ASD), or oppositional defiant disorder (ODD)/conduct disorder (CD), and in typically developing individuals (TDI), and relate hormone levels to severity and subtype of aggression and callous-unemotional (CU) traits. Saliva concentrations of oxytocin, cortisol, and testosterone were assessed in 114 male participants (N = 49 ASD, N = 37 ODD/CD, N = 28 TDI,) aged 12-19 years (M = 15.4 years, SD = 1.9). The ASD and the ODD/CD groups had significantly lower levels of oxytocin than the TDI group, and the ODD/CD group had significantly higher levels of testosterone than the ASD group. There were no group effects on cortisol levels. Group differences remained for oxytocin after correcting for the influence of CU traits, but were not significant after controlling for aggression. Results for testosterone became non-significant after correction for either CU traits or aggression. Across groups, higher levels of CU traits were related to higher levels of cortisol and testosterone, however, proactive and reactive aggression were unrelated to all three hormonal levels. The current findings show that, regardless of cognitive ability or comorbid disorders, the diagnostic groups (ASD, ODD/CD) differ from each other by their hormonal levels, with the ASD group characterized by relative low level of oxytocin, and the ODD/CD group by a relative low level of oxytocin and high level of testosterone. These group effects were partly driven by differences in CU traits between the groups. 15 p.

Background Machine learning (ML) allows the exploration and progressive improvement of very complex high-dimensional data patterns that can be utilised to optimise specific classification and prediction tasks, outperforming traditional statistical approaches. An enormous acceleration of ready-to-use tools and artificial intelligence (AI) applications, shaped by the emergence, refinement, and application of powerful ML algorithms in several areas of knowledge, is ongoing. Although such progress has begun to permeate the medical sciences and clinical medicine, implementation in cardiovascular medicine and research is still in its infancy. Objectives To lay out the theoretical framework, purpose, and structure of a novel AI consortium. Methods We have established a new Dutch research consortium, the CVON-AI, supported by the Netherlands Heart Foundation, to catalyse and facilitate the development and utilisation of AI solutions for existing and emerging cardiovascular research initiatives and to raise AI awareness in the cardiovascular research community. CVON-AI will connect to previously established CVON consortia and apply a cloud-based AI platform to supplement their planned traditional data-analysis approach. Results A pilot experiment on the CVON-AI cloud was conducted using cardiac magnetic resonance data. It demonstrated the feasibility of the platform and documented excellent correlation between AI-generated ventricular function estimates as compared to expert manual annotations. The resulting AI solution was then integrated in a web application. Conclusion CVON-AI is a new consortium meant to facilitate the implementation and raise awareness of AI in cardiovascular research in the Netherlands. CVON-AI will create an accessible cloud-based platform for cardiovascular researchers, demonstrate the clinical applicability of AI, optimise the analytical methodology of other ongoing CVON consortia, and promote AI awareness through education and training.

Aim: This review aimed to provide a comprehensive overview of the psychosocial developmental trajectory of various diseases during childhood and adolescence. Methods: Studies of Dutch young adults aged 18-35 years, who had grown up with a chronic disease, were included if the Course of Life Questionnaire had been used to assess psychosocial developmental milestones in three domains: social, autonomy and psychosexual. Differences between the disease groups and the general population were presented as Cohen's d and odds ratios. Results: We included 17 studies comprising 1899 young adults, who had grown up with 18 different paediatric diseases. Psychosocial development was delayed in all three questionnaire domains. Remarkable findings with regard to specific milestones were as follows: less participation in sports clubs in the social domain, less likely to have had paid jobs in the autonomy domain and later sexual intimacy in the psychosexual domain. End-stage renal disease, galactosaemia (males), childhood cancer and orthotopic liver transplants were the most affected disease groups. Conclusion: Children and adolescents with chronic diseases risked delays in psychosocial development. This should be addressed by healthcare providers, along with the physical aspects of diseases, and they should focus on the optimal psychosocial development of the patient.

Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients.

Background Although fatigue is a prevalent distressing symptom in children and adolescents with Pediatric Rheumatic Conditions (PRCs), intervention studies designed for reducing fatigue in PRCs are limited. Aim To systematically review evidence regarding the efficacy of interventions intended to reduce fatigue in patients with PRCs. Methods Comprehensive electronic searches were performed in PubMed/ MEDLINE, Embase, Web of Science and Cinahl. The risk of bias was assessed using the ‘Revised Cochrane risk-of-bias tool for randomized trials’ and ‘Quality Assessment Tool for Before-After Studies With No Control Group’ for respectively studies with and without a control group. Results Ten out of 418 studies were included with a total of 240 participants (age range 5–23 years). Interventions included land-based and aquatic-based exercise therapy, prednisolone, vitamin-D and creatine supplementation, psychological therapy and a transition program into an adult rheumatology program. Fatigue was assessed with self-reported questionnaires in all included studies. Land-based exercise therapy was effective in one pre-post intervention study, whereas not effective in two randomized controlled trials. Aquatic-based exercise therapy was found more effective than land-based exercise therapy. Two placebo-controlled studies showed a significant positive effect in reducing subjective fatigue with prednisolone and vitamin-D. Creatine was not found effective. Cognitive therapy was effective in one pre-post intervention study, while one RCT did not show an effect in reducing fatigue. A transition program based on health education showed a small reducing effect, however, it was not clear if this was a significant effect. Six studies showed a high risk of bias, three studies a moderate risk, and one study had a low risk of bias. Conclusions Insufficient evidence is provided to substantiate the efficacy of current interventions to reduce fatigue in PRCs. The low number of studies, non-comparable interventions, risk of bias, and inconclusive outcomes of the included studies denote future research should focus on intervention studies aimed at the treatment of fatigue in children and adolescents with PRCs. Identification of possible underlying biological and psychosocial mechanisms as possible treatment targets to reduce complaints of fatigue in children and adolescents with PRCs is warranted.

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Objectives To assess whether adolescents with asthma experience a lower mental well-being and lower general health than their peers without asthma.Study design Data from the Prevention and Incidence of Asthma and Mite Allergy study were used. At the ages of 11, 14, 17, and 20 years, 2651, 2522, 2094, and 2206 participants, respectively, completed questionnaires. Their parents completed questionnaires at the ages of 11 (n = 2660), 14 (n = 2338), and 17 years (n = 1872). Asthma was defined according to the Mechanisms of the Development of Allergy criteria. Mental well-being was measured using the Mental Health Index-5 and was reported by the adolescents. General health, measured on a 4-point Likert scale, was reported by the adolescents and their parents. We estimated associations of asthma with mental wellbeing and perceived general health using generalized estimating equations.Results At ages 11, 14, 17, and 20 years, 6.7%, 6.9%, 5.0%, and 6.6%, respectively, of the adolescents had asthma. Adolescents with asthma did not score differently on the Mental Health Index than their peers without asthma. Adolescents with asthma were less likely to experience good or excellent health than their peers without asthma (aOR, 0.37; 95% CI, 0.26-0.51 for intermittent asthma and 0.33; 95% CI, 0.25-0.41 for persistent asthma). These results remain similar across the different ages.Conclusions The mental well-being of adolescents with asthma is similar to that of their peers without asthma, although adolescents with asthma are less likely to perceive a good or excellent general health.

Background Fatigue is common among adults living with human immunodeficiency virus (HIV) as well as children with a chronic disease (CCD). Fatigue can have disastrous effects on health status, including health related quality of life (HRQOL). Even so, fatigue is underexplored in children and adolescents perinatally infected with HIV (PHIV+) in the Netherlands. The objective of this observational study is to explore fatigue in PHIV+ and its association with their HRQOL. Methods We measured HRQOL and fatigue using the Pediatric Quality of Life Inventory™ (PedsQL 4.0) and the PedsQL Multidimensional Fatigue Scale (MFS). The PedsQL MFS encompasses three subscales: general fatigue, sleep/rest fatigue and cognitive fatigue, and a total fatigue score. We compared outcomes of PHIV+ children and adolescents in the Amsterdam University Medical Centre with three groups: 1) HIV-uninfected controls (HIV-) matched for age, sex, region of birth, socioeconomic status and adoption status, 2) CCD, and 3) the general Dutch population. Within the PHIV+ group we explored associations between fatigue and HRQOL. Results We enrolled 14 PHIV+ (median age 10.2 years [IQR 9.2–11.4]) and 14 HIV-. Compared to CCD, PHIV+ significantly reported less general fatigue (mean difference 13.0, 95% CI 1.3 to 24.8). PHIV+ did not score significantly different on any of the other PedsQL MFS scales compared to HIV-, CCD or the general Dutch population. PHIV children scored relatively low on the cognitive fatigue scale in comparison to HIV-uninfected matched controls, CCD and the general population, although these differences did not reach significance. Among PHIV+, a lower score on total fatigue, general fatigue and cognitive fatigue was associated with a lower HRQOL score. Conclusions The results of this study suggest that PHIV children and adolescents do not experience more symptoms of fatigue than their healthy peers. However, PHIV children and adolescents may be more likely to experience cognitive fatigue. Fatigue in PHIV also appears to be associated with children’s HRQOL. Further research should confirm these exploratory findings.

ObjectiveTo determine: (1) which biological/lifestyle, psychological and/or social factors are associated with fatigue among children with a chronic disease and (2) how much each of these factors contributes to explaining variance in fatigue.Design and settingThis was a cross-sectional study across two children’s hospitals.PatientsWe included children aged 8–18 years who visited the outpatient clinic with cystic fibrosis, an autoimmune disease or postcancer treatment.Main outcome measuresFatigue was assessed using the PedsQL Multidimensional Fatigue Scale. Generic biological/lifestyle, psychological and social factors were assessed using clinical assessment tools and questionnaires. Multiple linear regression analyses were used to test the associations between these factors and fatigue. Finally, a multivariable regression model was used to determine which factor(s) have the strongest effect on fatigue.ResultsA total of 434 out of 902 children were included (48% participation rate), with a median age of 14.5 years; 42% were male. Among these 434 children, 21.8% were severely fatigued. Together, all biopsychosocial factors explained 74.6% of the variance in fatigue. More fatigue was uniquely associated with poorer physical functioning, more depressive symptoms, more pressure at school, poorer social functioning and older age.ConclusionsFatigue among children with a chronic disease is multidimensional. Multiple generic biological/lifestyle, psychological and social factors were strongly associated with fatigue, explaining 58.4%; 65.8% and 50.0% of the variance in fatigue, respectively. Altogether, almost three-quarters of the variance in fatigue was explained by this biopsychosocial model. Thus, when assessing and treating fatigue, a transdiagnostic approach is preferred, taking into account biological, psychological and social factors.

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab’s effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8+ versus CD4+ T cells. The expansion of CD8+ T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38+ regulatory T cells. This study confirms daratumumab’s immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

PURPOSE Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex). METHODS Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years. RESULTS The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age > 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or > 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles. CONCLUSION Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance.

The history of CSR in the Netherlands can be characterized by a regularly changing focus and leadership oscillating between government and business. At the beginning of the twentieth century, the first focus of attention in what we now call sustainability was social issues. The government took the first step with a law to improve the social well-being of the population, but the major follow-up steps were taken by a few leaders within the business community. It was then the government in the 1980s that asked companies to give attention to the environmental effects of their actions. However, the role of the government in that area became increasingly passive over time, and the business community took the lead. Recently, the Dutch government has again grabbed the steering wheel by establishing very ambitious goals in the field of energy and with regard to a circular economy. Moreover, it is becoming increasingly clear that there can no longer be any question of leaders and followers: the government and the business community are now working intensively together to achieve the intended goals. This is not only within the Netherlands but increasingly across national borders. In this contribution, we describe these developments regarding Corporate Social Responsibility (CSR) in the Netherlands, and highlight what is special about the CSR activities in the Netherlands by outlining some individual cases, and explain the background to these activities.

Contains fulltext : 234328.pdf (Publisher’s version ) (Open Access) Alterations in neurobiological stress systems such as the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis contribute to the development and maintenance of psychological and behavioral problems after traumatic experiences. Investigating neurobiological parameters and how these relate to each other may provide insight into the complex mechanisms at play. Whereas the preponderance of studies focuses on either the ANS or the HPA axis separately, the current study is the first to evaluate relations between posttraumatic stress and both basal activity during rest and stress reactivity of the ANS as well as the HPA axis in a sample of traumatized adolescents and healthy controls. The traumatized sample (n = 77), based on clinical levels of posttraumatic stress, was a convenience sample that was recruited within residential institutions, was compared to a healthy control sample (n = 48) recruited within the general community. For the ANS, we expected increased SNS and decreased PNS activity during rest and increased SNS and decreased PNS reactivity to social stress among traumatized adolescents compared to healthy controls. Regarding the HPA axis, we expected increased basal cortisol levels and decreased cortisol reactivity to stress in the traumatized sample. Compared to healthy controls, traumatized adolescents exhibited significantly higher sympathetic and lower parasympathetic activation during rest and increased sympathetic reactivity to acute stress (ANS parameters). Outcomes on the HPA axis (i.e. cortisol) indicated that traumatized adolescents showed increased cortisol levels during rest and blunted cortisol reactivity to acute stress. Implications for clinical relevance and trauma-focused treatment purposes are discussed. 12 p.

Objectives Treatment non-adherence is more frequent among difficult-to-treat (D2T) than among non-D2T RA patients. Perceptions of non-adherence may differ. We aimed to thematically structure and prioritize barriers to (i.e. causes and reasons for non-adherence) and facilitators of optimal adherence from the patients’ and rheumatologists’ perspectives. Methods Patients’ perceptions were identified in semi-structured in-depth interviews. Experts selected representative statements regarding 40 barriers and 40 facilitators. Twenty D2T and 20 non-D2T RA patients sorted these statements during two card-sorting tasks: first, by order of content similarity and, second, content applicability. Additionally, 20 rheumatologists sorted the statements by order of content applicability to the general RA population. The similarity sorting was used as input for hierarchical cluster analysis. The applicability sorting was analysed using descriptive statistics, prioritized and the results compared between D2T RA patients, non-D2T RA patients and rheumatologists. Results Nine clusters of barriers were identified, related to the healthcare system, treatment safety/efficacy, treatment regimen and patient behaviour. D2T RA patients prioritized adverse events and doubts about effectiveness as the most important barriers. Doubts about effectiveness were more important to D2T than to non-D2T RA patients (P = 0.02). Seven clusters of facilitators were identified, related to the healthcare system and directly to the patient. All RA patients and rheumatologists prioritized a good relationship with the healthcare professional and treatment information as the most helpful facilitators. Conclusions D2T RA patients, non-D2T RA patients and rheumatologists prioritized perceptions of non-adherence largely similarly. The structured overviews of barriers and facilitators provided in this study may guide improvement of adherence.

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Plastic waste accumulating in the global ocean is an increasingly threatening environmental issue. To date, the floating and thus most visible fraction of ocean plastic pollution has been mapped at global scale. Yet, large knowledge gaps exist in our current understanding of the transport and transformation processes of positively buoyant plastic debris at the sea surface. Observations at sea typically report an apparent scarcity of microplastics (500 µm) and mesoplastics (0.5–5 cm) in the surface waters of the eastern North Pacific Ocean using data from 1136 040 plastic fragments collected by 679 neuston trawl deployments between 2015 and 2019. Our results reveal that the apparent microplastic scarcity is not uniformly distributed across the region. Instead, we show that the relative abundance of floating microplastics increases from the outside to the inside of the North Pacific Garbage Patch. We hypothesize that this observation could be explained by (i) a spatially variable microplastic removal due to spatial differences in ocean productivity, (ii) a differential dispersal of micro- vs. mesoplastics with a preferential accumulation of microplastics in the subtropical gyre, and/or (iii) the timescales associated with transport and fragmentation of plastic objects at the ocean surface with older, more degraded, floating plastic accumulation in subtropical gyres. The results presented here highlight that global estimates of the accumulation and removal of positively buoyant microplastics need to consider spatial aspects such as variations in ocean productivity, the dominant physical transport processes in a given area, as well as the time needed for a plastic object to reach the specific offshore location.

Simple Summary Monoclonal antibody (mAb) therapy has been an important addition to the therapeutic arsenal in B-cell malignancies. MAbs can induce cytotoxicity against B-cell malignancies by antibody effector functions mediated via their fragment crystallizable (Fc) region. In order to enhance the anti-tumor potential of antibodies, various Fc-engineering strategies have been developed. In this review we summarize the well-established as well as recently developed Fc-engineering strategies which are aimed to increase Fc-effector function and to enhance the anti-tumor potency of mAbs. In addition, the increased number of Fc-engineered mAbs in (pre-)clinical development asks for a clear overview describing the specific type of Fc-engineering, their antigen and disease target, and the current developmental stage, which we aimed to provide in this review. Abstract Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).

Background Many adolescents in residential care have been exposed to prolonged traumatic experiences such as violence, neglect, or abuse. Consequently, they suffer from posttraumatic stress. This not only negatively affects psychological and behavioral outcomes (eg, increased anxiety, depression, and aggression) but also has adverse effects on physiological outcomes, in particular on their neurobiological stress systems. Although current evidence-based treatment options are effective, they have their limitations. An alternative to traditional trauma treatment is meditation-based treatment that focuses on stress regulation and relaxation. Muse is a game-based meditation intervention that makes use of adolescents’ intrinsic motivation. The neurofeedback element reinforces relaxation abilities. Objective This paper describes the protocol for a randomized controlled trial in which the goal is to examine the effectiveness of Muse (InteraXon Inc) in reducing posttraumatic stress and normalizing neurobiological stress systems in a sample of traumatized adolescents in residential care. Methods This will be a multicenter, multi-informant, and multimethod randomized controlled trial. Participants will be adolescents (N=80), aged 10 to 18 years, with clinical levels of posttraumatic symptoms, who are randomized to receive either the Muse therapy sessions and treatment as usual (intervention) or treatment as usual alone (control). Data will be collected at 3 measurement instances: pretest (T1), posttest (T2), and at 2-month follow-up. Primary outcomes will be posttraumatic symptoms (self-report and mentor report) and stress (self-report) at posttest. Secondary outcomes will be neurobiological stress parameters under both resting and acute stress conditions, and anxiety, depression, and aggression at posttest. Secondary outcomes also include all measures at 2-month follow-up: posttraumatic symptoms, stress, anxiety, depression aggression, and neurobiological resting parameters. Results The medical-ethical committee Arnhem-Nijmegen (NL58674.091.16) approved the trial on November 15, 2017. The study was registered on December 2, 2017. Participant enrollment started in January 2018, and the results of the study are expected to be published in spring or summer 2021. Conclusions Study results will demonstrate whether game-based meditation therapy improves posttraumatic stress and neurobiological stress systems, and whether it is more effective than treatment as usual alone for traumatized adolescents. Trial Registration Netherlands Trial Register NL6689 (NTR6859); https://www.trialregister.nl/trial/6689 International Registered Report Identifier (IRRID) DERR1-10.2196/19881

Aim Oligometastatic breast cancer (OMBC) is a disease-entity with potential for long-term remission in selected patients. Those with truly limited metastatic load (rather than occult widespread metastatic disease) may benefit from multimodality treatment including local ablative therapy of distant metastases. In this systematic review, we studied factors associated with long-term survival in patients with OMBC. Methods Eligible studies included patients with OMBC who received a combination of local and systemic therapy as multimodal approach and reported overall survival (OS) or progression-free survival (PFS), or both. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of each included study. Independent prognostic factors for OS and/or PFS are summarized. Results Of 1271 screened abstracts, 317 papers were full-text screened and twenty studies were included. Eleven of twenty studies were classified as acceptable quality. Definition of OMBC varied between studies and mostly incorporated the number and/or location of metastases. The 5-year OS ranged between 30 and 79% and 5-year PFS ranged between 25 and 57%. Twelve studies evaluated prognostic factors for OS and/or PFS in multivariable models. A solitary metastasis, >24 months interval between primary tumor and OMBC, no or limited involved axillary lymph nodes at primary diagnosis, and hormone-receptor positivity were associated with better outcome. HER2-positivity was associated with worse outcome, but only few patients received anti-HER2 therapy. Conclusions OMBC patients with a solitary distant metastasis and >24 months disease-free interval have the best OS and may be optimal candidates to consider a multidisciplinary approach.

Buffalo-derived Theileria parva can ‘break through’ the immunity induced by the infection and treatment vaccination method (ITM) in cattle. However, no such ‘breakthroughs’ have been reported in northern Tanzania where there has been long and widespread ITM use in pastoralist cattle, and the Cape buffalo (Syncerus caffer) is also present. We studied the exposure of vaccinated and unvaccinated cattle in northern Tanzania to buffalo-derived T. parva using p67 gene polymorphisms and compared this to its distribution in vaccinated cattle exposed to buffalo-derived T. parva in central Kenya, where vaccine ‘breakthroughs’ have been reported. Additionally, we analysed the CD8+ T cell target antigen Tp2 for positive selection. Our results showed that 10% of the p67 sequences from Tanzanian cattle (n = 39) had a buffalo type p67 (allele 4), an allele that is rare among East African isolates studied so far. The percentage of buffalo-derived p67 alleles observed in Kenyan cattle comprised 19% of the parasites (n = 36), with two different p67 alleles (2 and 3) of presumptive buffalo origin. The Tp2 protein was generally conserved with only three Tp2 variants from Tanzania (n = 33) and five from Kenya (n = 40). Two Tanzanian Tp2 variants and two Kenyan Tp2 variants were identical to variants present in the trivalent Muguga vaccine. Tp2 evolutionary analysis did not show evidence for positive selection within previously mapped epitope coding sites. The p67 data indicates that some ITM-vaccinated cattle are protected against disease induced by a buffalo-derived T. parva challenge in northern Tanzania and suggests that the parasite genotype may represent one factor explaining this.

PurposeOrganizational change involves optimizing a firm’s sustainability performance. The purpose of this paper is to explore how strategic orientations concerning the interface between business and society influence organizations’ sustainability performance. To explain how different strategic orientations – especially stewardship and instrumental orientations – impact sustainability performance, dynamic managerial capability theory is explored.Design/methodology/approachOurs is an inductive, qualitative study based on the template analysis of interviews conducted among sustainability managers from stock-listed multinational corporations headquartered in the Eurozone.FindingsCorporations with a stewardship orientation develop different dynamic managerial capabilities underlying sustainability performance than corporations that apply a more instrumental orientation. Results also show an “in-between” position: an equidistant orientation.Research limitations/implicationsThis study proves the emergence of different dynamic managerial capabilities that depend on companies’ strategic orientation, but follow-up research based on appreciative inquiry is needed to investigate the development of these capabilities over time.Practical implicationsFor achieving a higher level of sustainability performance, a stewardship orientation offers a stronger foundation than an instrumental orientation. Also companies with an equidistant orientation have a better sustainability performance than companies with an instrumental orientation, but based on a more central corporate level. The strategic orientation must be grounded in the development of fitting dynamic managerial capabilities that include an emphasis on shared cognition of long-term objectives, inclusion of stakeholders and setting objectives. Also strong internal and external ties, leadership of the CEO, educational background and how to deal with lack of knowledge are important aspects of managerial social and human capital.Social implicationsDue to its focus on the sustainability performance of companies and the identification of the supporting dynamic managerial capabilities, this paper is socially highly relevant.Originality/valuePrevious research has focused on strategic orientation, but little to no research has investigated how various strategic orientations toward the interface between business and society impact sustainability performance or what role dynamic managerial capabilities might play in the related change process.

Antibodies targeting CD38 are rapidly changing the treatment landscape of multiple myeloma (MM). CD38−directed antibodies have several mechanisms of action. Fc−dependent immune effector mechanisms include complement-dependent cytotoxicity (CDC), antibody−dependent cell−mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis. In addition, direct effects and immunomodulatory effects contribute to the efficacy of CD38−directed antibodies. Daratumumab, the first−in−class anti−CD38 monoclonal antibody, is now part of standard treatment regimens of both newly diagnosed as well as relapsed/refractory MM patients. The FDA has recently approved isatuximab in combination with pomalidomide and dexamethasone for relapsed/refractory MM patients after at least two prior therapies. Further, the other CD38−targeting antibodies (i.e., MOR202 and TAK-079) are increasingly used in clinical trials. The shift to front-line treatment of daratumumab will lead to an increase in patients refractory to CD38 antibody therapy already after first−line treatment. Therefore, it is important to gain insight into the mechanisms of resistance to CD38−targeting antibodies in MM, and to develop strategies to overcome this resistance. In the current review, we will briefly describe the most important clinical data and mechanisms of action and will focus in depth on the current knowledge on mechanisms of resistance to CD38-targeting antibodies and potential strategies to overcome this.

Bicuspid aortic valve (BAV) is the most frequent congenital cardiac abnormality leading to premature aortic valve apparatus dysfunction and is often associated with aortopathy. Therefore, current guidelines recommend a surgical aortic valve replacement (SAVR), even if many patients are deemed inoperable owing to their comorbidities and require alternatives such as transcatheter aortic valve replacement (TAVR). However, BAV variations remain challenging for procedural success. Therefore, the latest development in different imaging modalities (echocardiography, multislice-computertomographie, cardiovascular magnetic resonance) allows in-depth analysis for preprocedural risk stratification, follow up, and patient selection. Furthermore, we shed light on the latest developments in pre- and periprocedural fusion imaging as well as on current and future treatment options.

Purpose This paper aims to clarify the relationship between the voting and engagement behaviour of institutional investors, i.e. institutional investor stewardship behaviour, and the enactment of stewardship by corporate boards. In doing so, this paper contributes to the evaluation of contemporary corporate governance systems and provides recommendations for the redesign of these systems. Design/methodology/approach This paper is based on a qualitative exploratory descriptive research study into assumed, prescribed and the actual behaviour of institutional investors. Their behaviour is explored through a survey and in-depth interviews with global institutional investors. Findings The prescription of institutional investor stewardship behaviour and the exploration of actual behaviour from an investors’ perspective led to the conclusion that assumed institutional investor stewardship exists variously as either “in form” (i.e. measured by compliance to the relevant corporate governance code) or “in substance” (i.e. the actual behaviour from the investors and investee companies’ perspective). The results suggest that that institutional investors’ actual stewardship behaviour as global investors requires a nuanced conclusion about the existence of institutional investor stewardship. Research limitations/implications Although the number of semi-structured interviews with institutional investors was limited to just 14, these interviewees represent the majority share in terms of market capitalisation of Dutch listed companies. Additional research could clarify the perspective of other investors, such as pension funds and private investors. Practical implications The outcome of this research can serve as input for corporate governance reforms in the preambles of governance codes and the prescribed principles and best practice provisions of corporate governance and stewardship codes. This research identifies opportunities for further academic research to enrich the understanding of the role of institutional investors in enacting corporate stewardship. Social implications This paper contributes to furthering the understanding of the mechanisms by which institutional investors, through their behaviour, contribute to enacting stewardship through their corporate boards. This is an important part of the corporate social responsibility of institutional investors. It also triggers a dialogue about the social and environmental impacts of stock listed companies. Originality/value This paper fulfils an identified need to develop knowledge about new paradigms and offers a more integrated approach to corporate governance reforms in terms of the role of institutional shareholders in the promotion of good corporate governance.

An introduction is presented in which the author comments on the articles in this issue, including one on leadership in corporate social responsibility, one on employee cynicism, and one on ethical leadership.

INTRODUCTION: Multiple myeloma (MM) is generally an incurable hematological malignancy with heterogeneous overall survival rates ranging from a few months to more than 10 years. Survival is especially poor for patients who developed disease that is refractory to immunomodulatory drugs and proteasome inhibitors. Areas covered: This review will discuss the importance of CD38-targeting antibodies for the treatment of MM patients to improve their outcome. Expert commentary: Intense immuno-oncological laboratory research has resulted in the development of functionally active monoclonal antibodies against cell surface markers present on MM cells. In this respect, CD38-targeting antibodies such as daratumumab, MOR202, and isatuximab, have high single agent activity in heavily pretreated MM patients by virtue of their pleiotropic mechanisms of action including Fc-dependent effector mechanisms and immunomodulatory activities. Importantly, CD38-targeting antibodies are well tolerated, with infusion reactions as most frequent adverse event. Altogether, this makes them attractive combination partners with other anti-MM agents. Daratumumab is already approved as monotherapy and in combination with lenalidomide-dexamethasone as well as bortezomib-dexamethasone in pretreated MM patients. Furthermore, results from studies evaluating CD38-targeting antibodies in newly diagnosed MM patients are also promising, indicating that CD38-targeting antibodies will be broadly used in MM, resulting in further improvements in survival.

My search strategies are messy; what does this mean? Is it a sign of intelligent quick and dirty searching? I sure hope so, but is it? That patent searching is an art after all? Could be, but it's probably only an art when conducted by the unconsciously competent ones among us and that brings me to the question: am I unconsciously incompetent or unconsciously competent? I am going to investigate this by taking a look at what my drivers are when I conduct searches: these drivers are the requirements of the client and my personal objectives which combined translate into a set of general objectives that I seem to use for most of my searches (primarily novelty and validity searches). These general objectives in turn determine how I tackle searching in practice. It turns out that I basically break every search rule there is.