Peter M. van de Ven

Prevalence of attention-deficit hyperactivity disorder in older adults in The Netherlands.

BACKGROUND Little is known about the prevalence of attention-deficit hyperactivity disorder (ADHD) among older adults. AIMS To estimate the prevalence of the syndromatic and symptomatic DSM-IV ADHD diagnosis in older adults in The Netherlands. METHOD Data were used from the Longitudinal Aging Study Amsterdam (LASA). At baseline, 1494 participants were screened with an ADHD questionnaire and in 231 respondents a structured diagnostic interview was administered. The weighted prevalence of ADHD was calculated. RESULTS The estimated prevalence rate of syndromatic ADHD in older adults was 2.8%; for symptomatic ADHD the rate was 4.2%. Younger elderly adults (60-70 years) reported significantly more ADHD symptoms than older elderly adults (71-94 years). CONCLUSIONS This is the first epidemiological study on ADHD in older persons. With a prevalence of 2.8% the study demonstrates that ADHD does not fade or disappear in adulthood and that it is a topic very much worthy of further study.

Does a family meetings intervention prevent depression and anxiety in family caregivers of dementia patients? A randomized trial

Background Family caregivers of dementia patients are at increased risk of developing depression or anxiety. A multi-component program designed to mobilize support of family networks demonstrated effectiveness in decreasing depressive symptoms in caregivers. However, the impact of an intervention consisting solely of family meetings on depression and anxiety has not yet been evaluated. This study examines the preventive effects of family meetings for primary caregivers of community-dwelling dementia patients. Methods A randomized multicenter trial was conducted among 192 primary caregivers of community dwelling dementia patients. Caregivers did not meet the diagnostic criteria for depressive or anxiety disorder at baseline. Participants were randomized to the family meetings intervention (n = 96) or usual care (n = 96) condition. The intervention consisted of two individual sessions and four family meetings which occurred once every 2 to 3 months for a year. Outcome measures after 12 months were the incidence of a clinical depressive or anxiety disorder and change in depressive and anxiety symptoms (primary outcomes), caregiver burden and quality of life (secondary outcomes). Intention-to-treat as well as per protocol analyses were performed. Results A substantial number of caregivers (72/192) developed a depressive or anxiety disorder within 12 months. The intervention was not superior to usual care either in reducing the risk of disorder onset (adjusted IRR 0.98; 95% CI 0.69 to 1.38) or in reducing depressive (randomization-by-time interaction coefficient = −1.40; 95% CI −3.91 to 1.10) or anxiety symptoms (randomization-by-time interaction coefficient = −0.55; 95% CI −1.59 to 0.49). The intervention did not reduce caregiver burden or their health related quality of life. Conclusion This study did not demonstrate preventive effects of family meetings on the mental health of family caregivers. Further research should determine whether this intervention might be more beneficial if provided in a more concentrated dose, when applied for therapeutic purposes or targeted towards subgroups of caregivers. Trial Registration Controlled-Trials.com ISRCTN90163486

Outcome after burns: an observational study on burn scar maturation and predictors for severe scarring.

Long‐term outcome of burn scars as well as the relation with clinically relevant parameters has not been studied quantitatively. Therefore, we conducted a detailed analysis on the clinical changes of burn scars in a longitudinal setup. In addition, we focused on the differences in scar quality in relation to the depth, etiology of the burn wound and age of the patient. Burn scars of 474 patients were subjected to a scar assessment protocol 3, 6, and 12 months postburn. Three different age groups were defined (≤5, 5–18, and ≥18 years). The observer part of the Patient and Observer Scar Assessment Scale revealed a significant (p < 0.001) improvement in scar quality at 12 months compared with the 3‐ and 6‐month data. Predictors for severe scarring are depth of the wound (p < 0.001) and total body surface area burned (p < 0.001). Etiology (p = 0.753) and age (p > 0.230) have no significant influence on scar quality when corrected for sex, total body surface area burned, time, and age or etiology, respectively.

Guideline on the requirements of external quality assessment programs in molecular pathology

Molecular pathology is an integral part of daily diagnostic pathology and used for classification of tumors, for prediction of prognosis and response to therapy, and to support treatment decisions. For these reasons, analyses in molecular pathology must be highly reliable and hence external quality assessment (EQA) programs are called for. Several EQA programs exist to which laboratories can subscribe, but they vary in scope, number of subscribers, and execution. The guideline presented in this paper has been developed with the purpose to harmonize EQA in molecular pathology. It presents recommendations on how an EQA program should be organized, provides criteria for a reference laboratory, proposes requirements for EQA test samples, and defines the number of samples needed for an EQA program. Furthermore, a system for scoring of the results is proposed as well as measures to be taken for poorly performing laboratories. Proposals are made regarding the content requirements of an EQA report and how its results should be communicated. Finally, the need for an EQA database and a participant manual are elaborated. It is the intention of this guideline to improve EQA for molecular pathology in order to provide more reliable molecular analyses as well as optimal information regarding patient selection for treatment.

Topical silicone gel versus placebo in promoting the maturation of burn scars: a randomized controlled trial

Background: Silicone sheets are widely used in the treatment of hypertrophic scars, although application around joints may cause limited adherence and reduced movement. To approach these problems, a topical silicone gel was developed that can be applied easily in a thin layer, and that is nonrestrictive and less apparent. The objective of this study was to investigate the effectiveness of topical silicone gel in promoting the maturation of burn scars. Methods: Forty-six scars on 23 patients were included in a randomized, placebo-controlled, within-subject comparative, double-blinded, clinical trial and followed for 1 year. The mean age of the scars at inclusion was 4 months. Effectiveness on scar quality was evaluated using the Patient and Observer Scar Assessment Scale and the DermaSpectrometer. Significance was tested using repeated measures analyses and Wilcoxon paired-sample signed rank tests. Results: Over all visits, the benefit on surface roughness was statistically significant (p = 0.012). At individual time points, the surface of the topical silicone gel–treated scars showed significantly less roughness (p = 0.014) at 3 months after start of the treatment, and the topical silicone gel–treated scars were significantly less itchy (p = 0.018 and p = 0.013, respectively) at 3 and 6 months. Conclusion: Topical silicone gel significantly improves the surface roughness of burn scars, and patients experience significantly less itching in the first half year after application.

Dynamic and Static Overloading Induce Early Degenerative Processes in Caprine Lumbar Intervertebral Discs

Mechanical overloading of the spine is associated with low back pain and intervertebral disc (IVD) degeneration. How excessive loading elicits degenerative changes in the IVD is poorly understood. Comprehensive knowledge of the interaction between mechanical loading, cell responses and changes in the extracellular matrix of the disc is needed in order to successfully intervene in this process. The purpose of the current study was to investigate whether dynamic and static overloading affect caprine lumbar discs differently and what mechanisms lead to mechanically induced IVD degeneration. Lumbar caprine IVDs (n = 175) were cultured 7, 14 and 21 days under simulated-physiological loading (control), high dynamic or high static loading. Axial deformation and stiffness were continuously measured. Cell viability, cell density, and gene expression were assessed in the nucleus, inner- and outer annulus. The extracellular matrix (ECM) was analyzed for water, glycosaminoglycan and collagen content. IVD height loss and changes in axial deformation were gradual with dynamic and acute with static overloading. Dynamic overloading caused cell death in all IVD regions, whereas static overloading mostly affected the outer annulus. IVDs expression of catabolic and inflammation-related genes was up-regulated directly, whereas loss of water and glycosaminoglycan were significant only after 21 days. Static and dynamic overloading both induced pathological changes to caprine lumbar IVDs within 21 days. The mechanism by which they inflict biomechanical, cellular, and extracellular changes to the nucleus and annulus differed. The described cascades provide leads for the development of new pharmacological and rehabilitative therapies to halt the progression of DDD.

Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines

BackgroundDespite encouraging results with the proteasome inhibitor bortezomib in the treatment of hematologic malignancies, emergence of resistance can limit its efficacy, hence calling for novel strategies to overcome bortezomib-resistance. We previously showed that bortezomib-resistant human leukemia cell lines expressed significantly lower levels of immunoproteasome at the expense of constitutive proteasomes, which harbored point mutations in exon 2 of the PSMB5 gene encoding the β5 subunit. Here we investigated whether up-regulation of immunoproteasomes by exposure to interferon-γ restores sensitivity to bortezomib in myeloma and leukemia cell lines with acquired resistance to bortezomib.MethodsRPMI-8226 myeloma, THP1 monocytic/macrophage and CCRF-CEM (T) parental cells and sub lines with acquired resistance to bortezomib were exposed to Interferon-γ for 24-48 h where after the effects on proteasome subunit expression and activity were measured, next to sensitivity measurements to proteasome inhibitors bortezomib, carfilzomib, and the immunoproteasome selective inhibitor ONX 0914. At last, siRNA knockdown experiments of β5i and β1i were performed to identify the contribution of these subunits to sensitivity to proteasome inhibition. Statistical significance of the differences were determined using the Mann-Whitney U test.ResultsInterferon-γ exposure markedly increased immunoproteasome subunit mRNA to a significantly higher level in bortezomib-resistant cells (up to 30-fold, 10-fold, and 6-fold, in β1i, β5i, and β2i, respectively) than in parental cells. These increases were paralleled by elevated immunoproteasome protein levels and catalytic activity, as well as HLA class-I. Moreover, interferon-γ exposure reinforced sensitization of bortezomib-resistant tumor cells to bortezomib and carfilzomib, but most prominently to ONX 0914, as confirmed by cell growth inhibition studies, proteasome inhibitor-induced apoptosis, activation of PARP cleavage and accumulation of polyubiquitinated proteins. This sensitization was abrogated by siRNA silencing of β5i but not by β1i silencing, prior to pulse exposure to interferon-γ.ConclusionDownregulation of β5i subunit expression is a major determinant in acquisition of bortezomib-resistance and enhancement of its proteasomal assembly after induction by interferon-γ facilitates restoration of sensitivity in bortezomib-resistant leukemia cells towards bortezomib and next generation (immuno) proteasome inhibitors.

The predictive value of low heart rate and heart rate variability during stress for reoffending in delinquent male adolescents

Low autonomic (re)activity is a consistent correlate of antisocial behavior in juveniles. However, longitudinal research relating autonomic measures to persistent antisocial behavior has remained scarce. Therefore, in the present study we examined the predictive value of heart rate (HR) and heart rate variability (HRV, often studied as respiratory sinus arrhythmia) for reoffending in delinquent male adolescents. At initial assessment, HR and HRV were measured at rest and in response to a public speaking task. Registered reoffending was assessed after 5-year follow-up. Attenuated HR response and stronger HRV response to stress predicted higher reoffending rates. Results provide evidence that HR/HRV reactivity are neurobiological markers for persistent juvenile antisocial behavior. Although effect sizes were small to moderate, our findings underscore the consistency of the relationship between autonomic markers and antisocial behavior.

Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve

Importance At present, the choice of noninvasive testing for a diagnosis of significant coronary artery disease (CAD) is ambiguous, but nuclear myocardial perfusion imaging with single-photon emission tomography (SPECT) or positron emission tomography (PET) and coronary computed tomography angiography (CCTA) is predominantly used for this purpose. However, to date, prospective head-to-head studies are lacking regarding the diagnostic accuracy of these imaging modalities. Furthermore, the combination of anatomical and functional assessments configuring a hybrid approach may yield improved accuracy. Objectives To establish the diagnostic accuracy of CCTA, SPECT, and PET and explore the incremental value of hybrid imaging compared with fractional flow reserve. Design, Setting, and Participants A prospective clinical study involving 208 patients with suspected CAD who underwent CCTA, technetium 99m/tetrofosmin–labeled SPECT, and [15O]H2O PET with examination of all coronary arteries by fractional flow reserve was performed from January 23, 2012, to October 25, 2014. Scans were interpreted by core laboratories on an intention-to-diagnose basis. Hybrid images were generated in case of abnormal noninvasive anatomical or functional test results. Main Outcomes and Measures Hemodynamically significant stenosis in at least 1 coronary artery as indicated by a fractional flow reserve of 0.80 or less and relative diagnostic accuracy of SPECT, PET, and CCTA in detecting hemodynamically significant CAD. Results Of the 208 patients in the study (76 women and 132 men; mean [SD] age, 58 [9] years), 92 (44.2%) had significant CAD (fractional flow reserve ⩽0.80). Sensitivity was 90% (95% CI, 82%-95%) for CCTA, 57% (95% CI, 46%-67%) for SPECT, and 87% (95% CI, 78%-93%) for PET, whereas specificity was 60% (95% CI, 51%-69%) for CCTA, 94% (95% CI, 88%-98%) for SPECT, and 84% (95% CI, 75%-89%) for PET. Single-photon emission tomography was found to be noninferior to PET in terms of specificity (P < .001) but not in terms of sensitivity (P > .99) using the predefined absolute margin of 10%. Diagnostic accuracy was highest for PET (85%; 95% CI, 80%-90%) compared with that of CCTA (74%; 95% CI, 67%-79%; P = .003) and SPECT (77%; 95% CI, 71%-83%; P = .02). Diagnostic accuracy was not enhanced by either hybrid SPECT and CCTA (76%; 95% CI, 70%-82%; P = .75) or by PET and CCTA (84%; 95% CI, 79%-89%; P = .82), but resulted in an increase in specificity (P = .004) at the cost of a decrease in sensitivity (P = .001). Conclusions and Relevance This controlled clinical head-to-head comparative study revealed PET to exhibit the highest accuracy for diagnosis of myocardial ischemia. Furthermore, a combined anatomical and functional assessment does not add incremental diagnostic value but guides clinical decision-making in an unsalutary fashion.

Adherence and patients experiences with the use of oral anticancer agents

Abstract A rapidly growing number of oral anticancer agents has become available in oncology and hematology. Though these introductions have several benefits, medication adherence is an issue of concern. Little is known about the factors influencing adherence to treatment with oral anticancer agents in daily practice. Material and methods. In this observational, multicenter study including 216 patients, carried out between October 2010 and March 2012, the use of oral anticancer drugs was assessed by means of a telephonic pill count, a questionnaire and a review of the patients medical file and pharmacy medication records. Parameters collected were patients’ demographics, treatment characteristics, beliefs and attitude towards disease and medicines, self-reported adherence, side effects, quality of life and satisfaction about information. Patients off treatment filled out a questionnaire about the reasons for discontinuation. Optimal adherence was defined as ≥ 95%–≤ 105%. Results. The mean adherence rate (AR) (n = 177) was 99.1% with 20.3% of patients having a sub-optimal AR (< 95%, > 105%) consisting both of under- and over-adherence. Multivariate analyses showed that being on a cyclic dosing regimen (rather than a continuous regimen), not living alone and being highly educated increased the chances of optimal adherence (ORs = 4.88, 4.59 and 2.53, respectively). In addition, optimal adherence was found to be less common in patients reporting treatment control (OR = 0.77). One third of 79 patients off treatment reported their experienced side effects as one of the reasons for discontinuation. Discussion. Although most patients are fully adherent to oral anticancer agents, there is a substantial number tending to non-adherence. Patients living alone and those on a continuous dosing regimen are most likely to adhere sub-optimally. Interventions to improve adherence should specifically address these patients and be tailored to the needs of the individual patient.