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Heidi A van Vugt,1,2,* Anne Meike Boels,1,* Inge de Weerdt,2 Eelco JP de Koning,3 Guy EHM Rutten1 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3508 GA Utrecht, Utrecht, the Netherlands; 2Dutch Diabetes Federation, Amersfoort 3818 LE, the Netherlands; 3Department of Medicine, Leiden University Medical Center, 2300 RC Leiden, the Netherlands *These authors contributed equally to this work Aim: This study explored the relationship between insulin use and patient activation (a person’s internal readiness and capabilities to undertake health-promoting actions) in individuals with type 2 diabetes mellitus and aimed to identify demographic, clinical and psychosocial factors involved in patient activation.Methods: In this cross-sectional study, baseline data from a Dutch nationwide study were analyzed. Patient activation was assessed with the Patient Activation Measure 13. A linear mixed model was used to take clustering into account.Results: In total, 1,189 persons were included (310 of whom were on insulin), enrolled via 47 general practices and six hospitals. Their mean Patient Activation Measure 13 score was 59±12. We found no association between insulin therapy and patient activation. In the multivariable analysis, individuals with a better health status, very good or very poor social support (vs good social support), individuals who felt they had greater control over their illness and those with a better subjective understanding of their illness showed higher patient activation. Individuals with a lower educational level and those who expected their illness to continue showed a lower activation level.Conclusion: Patient activation does not differ between individuals with type 2 diabetes mellitus on insulin therapy and those on other therapies.Keywords: provider–patient communication, patient participation in health care, social support, patient activation, insulin therapy, psychological aspects, self-management

Abstract Background The number of patients with diabetes is increasing. BeweegKuur (Dutch for 'Exercise Therapy') is a Dutch lifestyle intervention which aims to effectively and feasibly promote physical activity and better dietary behaviour in primary health care to prevent diabetes. Methods The goal of this paper is to present the development process and the contents of the intervention, using a model of systematic health promotion planning. The intervention consists of a 1-year programme for diabetic and prediabetic patients. Patients are referred by their general practitioner (GP) to a lifestyle advisor (LSA), usually the practice nurse or a physiotherapist. Based on specific inclusion criteria and in close collaboration with the patient, an individual exercise programme is designed and supervised by the LSA. This programme can be attended at existing local exercise facilities or (temporarily) under the supervision of a specialized exercise coach or physiotherapist. All participants are also referred to a dietician and receive diet-related group education. In the first pilot year (2008), the BeweegKuur programme was implemented in 7 regions in the Netherlands (19 GP practices and health centres), while 14 regions (41 GP practices and health centres) participated during the second year. The aim is to implement BeweegKuur in all regions of the Netherlands by 2012. Discussion The BeweegKuur programme was systematically developed in an evidence- and practice-based process. Formative monitoring studies and (controlled) effectiveness studies are needed to examine the diffusion process and the effectiveness and cost-effectiveness of the intervention.

Bispecific T cell engagers (bsTCEs) hold great promise for cancer treatment but face challenges due to the induction of cytokine release syndrome (CRS), on-target off-tumor toxicity, and the engagement of immunosuppressive regulatory T cells that limit efficacy. The development of Vγ9Vδ2-T cell engagers may overcome these challenges by combining high therapeutic efficacy with limited toxicity. By linking a CD1d-specific single-domain antibody (VHH) to a Vδ2-TCR-specific VHH, we create a bsTCE with trispecific properties, which engages not only Vγ9Vδ2-T cells but also type 1 NKT cells to CD1d + tumors and triggers robust proinflammatory cytokine production, effector cell expansion, and target cell lysis in vitro. We show that CD1d is expressed by the majority of patient MM, (myelo)monocytic AML, and CLL cells and that the bsTCE triggers type 1 NKT and Vγ9Vδ2-T cell-mediated antitumor activity against these patient tumor cells and improves survival in in vivo AML, MM, and T-ALL mouse models. Evaluation of a surrogate CD1d-γδ bsTCE in NHPs shows Vγ9Vδ2-T cell engagement and excellent tolerability. Based on these results, CD1d-Vδ2 bsTCE (LAVA-051) is now evaluated in a phase 1/2a study in patients with therapy refractory CLL, MM, or AML., Competing Interests: Declaration of interests J.M.R., V.I.G., F.S.v.d.B., B.W., R.C.R., A.E.P.A., T.R., P.W.H.I.P., and H.J.v.d.V. are employees of LAVA Therapeutics, a company that develops bispecific gamma-delta T cell engagers, and own LAVA Therapeutics shares and/or stock options. R.L., T.D.d.G., P.W.H.I.P., and H.J.v.d.V. are named inventors on international patent application WO2020/060,405 ("Dual acting CD1d immunoglobulin"), which partially relates to the work described in this paper. T.D.d.G. is a consultant for and a shareholder of LAVA Therapeutics. A.P.K. is a consultant for LAVA Therapeutics. R.L., M.J., M.V., and I.d.W. were funded by a LAVA Therapeutics grant to Amsterdam UMC., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Although considerable progress has been made with autologous T cell-based therapy in B-cell malignancies, application in chronic lymphocytic leukemia (CLL) lags behind due to disappointing response rates as well as substantial toxicity that is of particular concern in the elderly CLL population. Vγ9Vδ2-T cells form a conserved T-cell subset with strong intrinsic immunotherapeutic potential, largely because of their capacity to be triggered by phosphoantigens that can be overproduced by CLL and other malignant cells. Specific activation of Vγ9Vδ2-T cells by a bispecific antibody may improve the efficacy and toxicity of autologous T-cell-based therapy in CLL., Experimental Design: We evaluated CD1d expression in a cohort of 78 untreated patients with CLL and generated and functionally characterized a CD1d-specific Vγ9Vδ2-T cell engager based on single-domain antibodies (VHH)., Results: CD1d was expressed by CLL in the majority of patients, particularly in patients with advanced disease. The CD1d-specific Vγ9Vδ2-T cell engager induced robust activation and degranulation of Vγ9Vδ2-T cells, enabling Vγ9Vδ2-T cells from patients with CLL to lyse autologous leukemic cells at low effector-to-target ratios. Expression of CD1d on CLL cells is upregulated by all-trans retinoic acid, and sensitizes the malignant cells to bispecific VHH-induced lysis. Furthermore, we provide evidence that the Vγ9Vδ2-T cell receptor retains responsiveness to phosphoantigens when the bispecific VHH is bound, and aminobisphosphonates can therefore enhance bispecific Vγ9Vδ2-T cell engager-mediated tumor-specific killing., Conclusions: Collectively, our data demonstrate the immunotherapeutic potential of this novel CD1d-specific Vγ9Vδ2-T cell engager in CLL., (©2021 American Association for Cancer Research.)

Novel T cell-based therapies for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), are thought to have strong potential. Progress, however, has been hampered by low efficacy and high toxicity. Tumor targeting by Vγ9Vδ2 T cells, a conserved T-cell subset with potent intrinsic antitumor properties, mediated by a bispecific antibody represents a novel approach promising high efficacy with limited toxicity. Here, we describe the generation of a bispecific Vγ9Vδ2 T-cell engager directed against CD40, which, due to its overexpression and biological footprint in malignant B cells, represents an attractive target. The CD40-targeting moiety of the bispecific antibody was selected because it can prevent CD40L-induced prosurvival signaling and reduce CD40-mediated resistance of CLL cells to venetoclax. Selective activation of Vγ9Vδ2 T cells in the presence of CD40 + tumor cells induced potent Vγ9Vδ2 T-cell degranulation, cytotoxicity against CLL and MM cells in vitro , and in vivo control of MM in a xenograft model. The CD40-bispecific γδ T-cell engager demonstrated lysis of leukemic cells by autologous Vγ9Vδ2 T cells present in patient-derived samples. Taken together, our CD40 bispecific γδ T-cell engager increased the sensitivity of leukemic cells to apoptosis and induced a potent Vγ9Vδ2 T cell-dependent antileukemic response. It may, therefore, represent a potential candidate for the development of novel treatments for B-cell malignancies., (©2020 American Association for Cancer Research.)

Acquired T cell dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), and is linked to an increased risk of infections, but also reduced immune surveillance and disappointing responses to autologous T cell-based immunotherapy. The mechanisms of T cell dysfunction in CLL are not well understood. Studying immunity against chronic viruses allows for detailed analysis of the effect of CLL on T cells chronically exposed to a specific antigen. Cytomegalovirus (CMV) reactivations are rare in CLL, which corroborates with preserved CMV-specific T cell function. Epstein-Barr virus (EBV) is another herpesvirus that results in chronic infection, but unlike CMV, is characterized by subclinical reactivations in CLL patients. Since both herpesviruses induce strong CD8 + T cell responses, but have different clinical outcomes, studying these specific T cells may shed light on the mechanisms of CLL-induced T cell dysfunction. We first analyzed the phenotype of EBV-specific CD8 + T cells in CLL and healthy controls, and found that in CLL EBV-specific CD8 + T cells are in an advanced differentiation state with higher expression of inhibitory receptors. Secondly, CLL-derived EBV-specific CD8 + T cells show reduced cytotoxic potential, in contrast to CMV-specific T cells. Finally, we performed transcriptome analysis to visualize differential modulation by CLL of these T cell subsets. While T cell activation and differentiation genes are unaffected, in EBV-specific T cells expression of genes involved in synapse formation and T cell exhaustion is altered. Our findings on the heterogeneity of antigen specific T cell function in CLL aids in understanding immune-dysregulation in this disease., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction, which may underlie the hampered efficacy of cellular immunotherapy. Most data on dampened immune responses in CLL come from studies investigating CLL and T cell interactions. Natural killer (NK) cells may be an attractive alternative source of effector cells in immunotherapy in CLL, provided that functionality is retained within the CLL micro-environment. Despite their important role in anti-tumor responses, NK cells are not extensively characterized in CLL. Here, we studied the expression of activating and inhibitory receptors on CLL-derived and healthy control (HC) NK cells, and their functional response towards several stimuli. NK cells from CLL patients have an increased maturation stage, with an expansion of NKG2C + NK cells in CMV seropositive individuals. The cytotoxicity receptor NKG2D is downregulated, and the killing capacity through this receptor was markedly reduced in CLL-derived NK cells. In contrast, activation via CD16 (FCγRIII) led to adequate activation and functional responses in CLL-derived NK cells. These findings indicate that NK cells in CLL are not intrinsically defect and still perform effector functions upon adequate activating signaling. Clinical relevance of this finding was shown by treatment with novel nanobody-Fc constructs, which induced cytotoxic responses in both CLL- and HC-derived NK cells via CD16. Our results show that NK cells, in contrast to the T cell compartment, retain their function within the CLL micro-environment, provided that they receive an adequate activating signal. These findings warrant future studies on NK cell mediated immunotherapeutic strategies in CLL., Competing Interests: The authors declare no conflicts of interests., (Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Despite the emergence of small molecule inhibitors, current treatment strategies for chronic lymphocytic leukemia (CLL) are not curative, and the search for new therapeutic modalities continues. Prosurvival signaling derived from the microenvironment is often mediated via JAK signaling. However, whether JAK inhibitors are useful in CLL therapy has not been studied extensively. JAK inhibitors are valuable therapeutic agents in myelofibrosis and show promising results in graft-versus-host-disease. However, JAK inhibition is associated with an increased infection risk, presumably because of the effect on other immune cells, a feature shared with other kinase inhibitors used for CLL treatment, such as the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We compared functional effects of the JAK1/2 inhibitors momelotinib and ruxolitinib, the BTK inhibitors ibrutinib and tirabrutinib, and PI3Kδ inhibitor idelalisib on malignant CLL cells but also on healthy human T, B, and NK lymphocytes. We found several interesting differences among the inhibitors, apart from expected and well-known effects. Momelotinib but not ruxolitinib blocked cytokine-induced proliferation of CLL cells. Momelotinib also reduced BCR signaling, in contrast to ruxolitinib, indicating that these JAK inhibitors in fact have a distinct target spectrum. In contrast to tirabrutinib, ibrutinib had inhibitory effects on T cell activation, probably because of ITK inhibition. Remarkably, both BTK inhibitors stimulated IFN-γ production in a mixed lymphocyte reaction. Collectively, our results demonstrate that kinase inhibitors directed at identical targets may have differential effects on lymphocyte function. Their unique profile could be strategically employed to balance desired versus unwanted lymphocyte inhibition., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (T regs ) and CLL supportive follicular T helper (T fh ) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8 + T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. T fh cell, T reg , and PD-1 + CD8 + T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells., (© 2019 by The American Society of Hematology.)

The efficacy of autologous (αβ) T-cell-based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex-independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T-cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (T H 1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib., (© 2018 by The American Society of Hematology.)

Objective: We assessed both from a patient and provider perspective the usefulness and added value of a consultation model that facilitates person-centered diabetes care., Research Design and Methods: The model consists of 1 ) inventory of disease and patient-related factors; 2 ) setting personal goals; 3 ) choosing treatment; and 4 ) determination of required care. It was implemented in 47 general practices and 6 hospital outpatient clinics. Providers were trained, and patients were recommended to prepare their visit. All filled out a questionnaire after every consultation. Differences between primary and secondary care practices and between physician-led and nurse-led consultations were analyzed., Results: Seventy-four physicians and thirty-one nurses participated, reporting on 1,366 consultations with type 2 diabetes patients. According to providers, the model was applicable in 72.4% (nurses 79.3% vs. physicians 68.5%, P < 0.001). Physicians more often had a consultation time <25 min (80.4% vs. 56.9%, P < 0.001). According to providers, two of three patients spoke more than half of the consultation time (outpatient clinics 75.2% vs. general practices 66.6%, P = 0.002; nurses 73.2% vs. physicians 64.4%, P = 0.001). Providers stated that person-related factors often determined treatment goals. Almost all patients (94.4%) reported that they made shared decisions; they felt more involved than before (with physicians 45.1% vs. with nurses 33.6%, P < 0.001) and rated the consultation 8.6 of 10. After physician-led consultations, 52.5% reported that the consultation was better than before (nurse visit 33.7%, P < 0.001)., Conclusions: A consultation model to facilitate person-centered care seems well applicable and results in more patient involvement, including shared decision making, and is appreciated by a substantial number of patients., (© 2018 by the American Diabetes Association.)

The use of novel B-cell receptor signaling inhibitors results in high response rates and long progression-free survival in patients with indolent B-cell malignancies, such as chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinemia. Ibrutinib, the first-in-class inhibitor of Bruton tyrosine kinase, and idelalisib, the first-in-class inhibitor of phosphatidylinositol 3-kinase δ , have recently been approved for the treatment of several indolent B-cell malignancies. These drugs are especially being used for previously unmet needs, i.e., for patients with relapsed or refractory disease, high-risk cytogenetic or molecular abnormalities, or with comorbidities. Treatment with ibrutinib and idelalisib is generally well tolerated, even by elderly patients. However, the use of these drugs may come with toxicities that are distinct from the side effects of immunochemotherapy. In this review we discuss the most commonly reported and/or most clinically relevant adverse events associated with these B-cell receptor inhibitors, with special emphasis on recommendations for their management., (Copyright© 2017 Ferrata Storti Foundation.)

Diabetes care is shifting from disease management to personalised care. Internationally, diabetes care providers are advised to integrate the patient's preferences, wishes and possibilities into diabetes care in order to improve its efficiency. The Dutch Diabetes Federation has developed a specifically patient-centred conversation model that can be systematically applied. At an annual appraisal, the physician and the patient make decisions on the treatment goals to set, and on the treatment and professional support needed to achieve these goals. In this way person-centred and efficient care may become reality. The first results of a pilot study are promising. Currently the applicability and added value of the model are being tested on a large scale. The model is more broadly applicable, which means this could be a new perspective for everyone with a chronic disease.

Background: The worldwide epidemic of type 2 diabetes (T2DM) underlines the need for diabetes prevention strategies. In this study the feasibility and effectiveness of a nurse led lifestyle program for subjects with impaired fasting glucose (IFG) is assessed., Methods: A cluster randomized clinical trial in 26 primary care practices in the Netherlands included 366 participants older than 45 years with newly diagnosed IFG and motivated to change their lifestyle (intervention group, n = 197; usual care group, n = 169). The one-year intervention, consisting of four to five individual nurse-led consultations, was directed at improving physical activity and dietary habits. The primary outcome measure was body mass index (BMI). Linear and logistic multilevel analyses and a process evaluation were performed., Results: Both groups showed small reductions in BMI at 1 and 2 years, but differences between groups were not significant. At both 1 and 2-year follow-up the number of participants physically active for at least 30 minutes at least five days a week was significantly improved in the intervention group compared to the usual care group (intervention group vs. usual care group: OR1year = 3.53; 95 % CI = 1.69-7.37 and OR2years = 1.97; 95 % CI = 1.22-3.20, respectively). The total drop-out rate was 24 %. Process evaluation revealed that participants in the intervention group received fewer consultations than advised, while some practice nurses and participants considered the RM protocol too intensive., Conclusions: This relatively simple lifestyle program in subjects with IFG resulted in a significant improvement in reported physical activity, but not in BMI. Despite its simplicity, some participants still considered the intervention too intensive. This viewpoint could be related to poor motivation and an absence of disease burden due to IFG, such that participants do not feel a need for behavioural change. Although the intervention provided some benefit, its wider use cannot be advised., Trial Registration: Current Controlled Trials ISRCTN41209683 , date of registration 16/10/2013h  .

Background: Over the past decade, the National Action program Diabetes (NAD) was implemented in the Netherlands. Its aim was to introduce the Care Standard (CS) for diabetes by means of a specific implementation plan and piloting in several regions. This study aimed to provide insight into the implementation of the NAD as, coupled with the introduction of the CS, it may function as an example for similar approaches in other countries., Methods: A series of quantitative studies (participants 2010: N = 1726, participants 2013: N = 1370 & participants pilot regions 2013: N = 168) and qualitative studies (participants 2010: N = 18 and participants 2013: N = 4) was conducted among health care professionals (HCPs). In addition, two quantitative studies were conducted among type 1 and 2 patients (participants 2010: N = 573; participants 2013: N = 5056)., Results: Overall, positive changes in diabetes care were detected in the period 2010 - 2013. In 2013 significantly more HCPs were familiar with the CS (43.7 versus 37.6 %) and more HCPs perceived themselves to be working largely or completely in accordance with the CS (89.2 versus 79.0 %) than in 2010. A comparison of the results in specific pilot regions with the rest of the country revealed that HCPs in these regions scored significantly more positively on implementation and appreciation of the CS. This positive trend was reflected by the high levels of reported patient satisfaction and involvement in treatment. HCPs who were in possession of the CS had significantly better scores on the implementation of several elements of the CS than HCPs who were not in possession of the CS., Conclusion: The CS has become more prominent and embedded in daily health care practice. In retrospect the CS has provided momentum for the realization of various processes relating to the wider implementation of standards to improve the care for people with other chronic diseases in the Netherlands. Experiences with the NAD and CS underline the need to move towards an integrated multidisciplinary approach of diabetes care worldwide.

This study examined how Dutch type 1 and type 2 diabetes patients' perceived autonomy support, as well as their perceived competence and treatment self-regulation, are associated with their diabetes self-care activities (healthy diet, physical activity, monitoring blood glucose, medication use) and general diabetes control. A cross-sectional questionnaire study was conducted among 143 type 1 diabetics and 384 type 2 diabetics. Overall, participants felt competent, supported in their autonomy, and perceived to autonomously self-regulate their diabetes. Our results underline the importance of perceived competence in type 1 and 2 diabetics, as this was strongly associated with adhering to a healthy diet and general diabetes control. Our findings also emphasize the need for autonomy supportive health care professionals in diabetes care. Interestingly, perceived competence partially mediated the influence of autonomy support on general diabetes control.

Objective: The aim of this study was to assess the associations between type 2 diabetes patients' mastery and perceived autonomy support and their self-management skills and health-related quality of life (HRQOL)., Methods: A cross-sectional questionnaire survey was conducted among 3352 patients with type 2 diabetes. Key variables were assessed with validated questionnaires., Results: Patients' mastery and perceived autonomy support correlated positively with their self-management skills (r=0.34, p<0.001; r=0.37, p<0.001) and HRQOL (r=0.37, p<0.001; r=0.15, p<0.001). In the linear regression analysis, mastery and perceived autonomy support were positive correlates of self-management (β=0.23; p<0.001; β=0.25; p<0.001). Patients with more physical or psychological complications had significantly lower scores on mastery, perceived autonomy support, self-management and HRQOL., Conclusion: Our results indicate the importance of mastery in relation to diabetes patients' perceived autonomy support, self-management skills and HRQOL., Practice Implications: Since a greater sense of mastery is likely to increase patients' autonomous motivation to cope with their disease, interventions can aim to influence patients' motivational regulation. In addition, we confirmed the need for autonomy support to improve patients' self-management skills. Professionals can be trained to be autonomy-supportive, which relates to person-centered approaches such as motivational interviewing (MI)., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Ibrutinib, an orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL., Methods: In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients., Findings: Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia., Interpretation: The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination., Funding: Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Effective diabetes prevention strategies that can be implemented in daily practice, without huge amounts of money and a lot of personnel are needed. The Dutch Diabetes Federation developed a protocol for coaching people with impaired fasting glucose (IFG; according to WHO criteria: 6.1 to 6.9 mmol/l) to a sustainable healthy lifestyle change: 'the road map towards diabetes prevention' (abbreviated: Road Map: RM). This protocol is applied within a primary health care setting by a general practitioner and a practice nurse. The feasibility and (cost-) effectiveness of care provided according to the RM protocol will be evaluated., Methods/design: A cluster randomised clinical trial is performed, with randomisation at the level of the general practices. Both opportunistic screening and active case finding took place among clients with high risk factors for diabetes. After IFG is diagnosed, motivated people in the intervention practices receive 3-4 consultations by the practice nurse within one year. During these consultations they are coached to increase the level of physical activity and healthy dietary habits. If necessary, participants are referred to a dietician, physiotherapist, lifestyle programs and/or local sports activities. The control group receives care as usual. The primary outcome measure in this study is change in Body Mass Index (BMI). Secondary outcome measures are waist circumference, physical activity, total and saturated fat intake, systolic blood pressure, blood glucose, total cholesterol, HDL cholesterol, triglycerides and behaviour determinants like risk perception, perceived knowledge and motivation. Based on a sample size calculation 120 people in each group are needed. Measurements are performed at baseline, and after one (post-intervention) and two years follow up. Anthropometrics and biochemical parameters are assessed in the practices and physical activity, food intake and their determinants by a validated questionnaire. The cost-effectiveness is estimated by using the Chronic Disease Model (CDM). Feasibility will be tested by interviews among health care professionals., Discussion: The results of the study will provide valuable information for both health care professionals and policy makers. If this study shows the RM to be both effective and cost-effective the protocol can be implemented on a large scale., Trial Registration: ISRCTN41209683. Ethical approval number: NL31342.075.10.

Chronic lymphocytic leukemia (CLL) is still incurable, with considerable resistance to the standard therapy. CLL cells receive anti-apoptotic and pro-proliferation stimuli in lymph nodes and bone marrow, mainly through B cell receptor activation and TNF-receptor family ligation. In recent years, the focus for finding new drugs has shifted to blocking signals from the microenvironment. Novel therapeutical agents interfere with these microenvironmental interactions, and include inhibitors of kinases Syk, Btk and PI3Kδ. In this review we will focus on the microenvironmental interactions of CLL and the role of tyrosine kinases. Furthermore, early results from clinical trials with kinase inhibitors are discussed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Although experts claim that computer-tailored interventions provided over the Internet have great potential to promote health behavior change, few studies have tested the efficacy of computer-tailored lifestyle interventions online-delivered over the Internet., Purpose: To evaluate the short-term (1 month) efficacy of an Internet-delivered, computer-tailored lifestyle intervention targeting saturated fat intake, physical activity (PA), and smoking cessation, and to evaluate exposure to the intervention., Methods: A pretest-posttest randomized controlled trial with an intervention group and a no intervention waiting list control group was conducted. Self-reported behavior and determinants were assessed at baseline and 1 month follow-up. Exposure to the intervention was monitored through server registrations. The data were analyzed using multiple linear and logistic regression analysis., Results: The intervention resulted in a significantly lower self-reported saturated fat intake (b = -0.76, p < 0.01) and a higher likelihood of meeting the PA guidelines among respondents who were insufficiently active at baseline (OR = 1.34, 95%CI = 1.001-1.80). No significant intervention effects were found for self-reported smoking status. Of the participants, 81% actually visited the website., Conclusions: The Internet-delivered, computer-tailored lifestyle intervention was effective in reducing self-reported saturated fat intake and in increasing self-reported PA among participants who completed the study.

Aims: To examine the effects of the 'Healthy School and Drugs' project, a Dutch school-based drug prevention project that was developed in the late 1980s and disseminated during the 1990s. This programme is currently being used by 64-73% of Dutch secondary schools and it is estimated that at least 350000 high school students receive this intervention each year., Design, Setting and Participants: A quasi-experimental study in which students of nine experimental (N = 1156) schools were compared with students of three control schools (N = 774). The groups were compared before the intervention, 1 year later, 2 years later and 3 years later., Measurements: Self-report measures of tobacco, alcohol and marijuana use, attitudes towards substance use, knowledge about substances and self-efficacy., Findings: Some effects on the use of tobacco, alcohol and cannabis were found. Two years after the intervention, significant effects could still be shown on alcohol use. Effects of the intervention were also found on knowledge, but there was no clear evidence for any effects on attitude towards substance use and on self-efficacy., Conclusions: This study shows the Healthy School and Drugs project as implemented in Holland may have some effect on drug use in the children exposed to it.

The Dutch Asthma Centre Davos in Switzerland is a clinic where patients with chronic nonspecific lung disease (CNSLD) are given multidisciplinary treatment. In a prospective study in the clinic, data on quality of life (functional, psychological and social characteristics) and medical consumption (use of oral corticosteroids and use of health services) were collected in a group of 147 patients with CNSLD. 18 patients were lost due to non-medical reasons. Quality of life and the use of oral corticosteroids were registered on admission, at discharge and 4 weeks, 6 and 12 months after discharge. Data on use of health services were gathered over the period between one year before admission and one year after discharge from the asthma centre. The results of this study show a decrease in the use of oral corticosteroids, in the number of visits to the family physician and outpatient department and the number and duration of hospital admissions. Favourable changes occurred in psychological functioning, (including anxiety and depression) and positive changes were observed in the degree of limitation the patients experienced in their activities of daily living. No convincing changes were found in social functioning, including social support. It can be concluded, on the basis of these results, that a stay in the Dutch Asthma Centre Davos has favourable effects on medical consumption and on some aspects of quality of life.

The most important aim of diabetes education is to alter the self-care behaviour of patients with diabetes. In order to change their behaviour its determinants must be known. The pretest of a multicentre evaluation study with 558 participating insulin treated patients with diabetes was analysed to test the usefulness of the attitude-behaviour theory of Fishbein & Ajzen in explaining and possibly changing diabetes related active self-care behaviour. The theory of Fishbein & Ajzen is based on the assumption that human behaviour is reasoned behaviour. The theory views a person's intention as the immediate determinant of action. Determinants of intention are attitude and social norm. The results showed that the attitude was the most important determinant of active self-care, while a sufficient level of knowledge and a low orientation on the powerful others health locus of control scale were prerequisites for a positive attitude. The influence of the social environment was detrimental; although people tried to motivate patients to active self-care, they could not provide any real help in performing this desired behaviour. According to the results of this study, diabetes education should first aim at improving the level of knowledge and the health locus of control of the patients and second, at a positive attitude to active self-care. It is necessary to educate the social environment to create a more supportive atmosphere for the patient with diabetes.