The development of fatigue after treatment for pediatric brain tumors does not differ between tumor locations.

BACKGROUND: Children and adolescents treated for a brain tumor suffer from more fatigue than survivors of other types of childhood cancer. As tumor location might be predictive of fatigue, our aim was to investigate the longitudinal development of fatigue in children with brain tumors and risk factors for fatigue separately for different tumor locations. METHODS: Fatigue was assessed 1235 times for 425 participants. Self-report versions of PedsQL Multidimensional Fatigue Scale were used to repeatedly assess fatigue from the end of treatment up to 8 years later. Mixed models were used to analyze fatigue over time and determinants separately for infratentorial (N = 205), supratentorial hemispheric (N = 91), and supratentorial midline tumors (N = 129). RESULTS: Cognitive fatigue worsened with time, while sleep-rest and general fatigue first decreased and then increased. There was no difference in fatigue between the tumor locations, but the risk factors differed when stratified by location. Radiotherapy was associated with more fatigue for infratentorial tumors, and centralization of care was associated with less fatigue for the supratentorial midline tumors. For supratentorial hemispheric tumors, female sex was associated with more fatigue. Higher parental education was associated with less fatigue regardless of tumor location. CONCLUSIONS: The development of fatigue seems to be more related to sociodemographic and treatment variables than to tumor location. Healthcare providers need to be aware that fatigue may develop in the years following end of treatment, and that patients with a low/middle educational family background might be more vulnerable and in need of targeted support.

Neuroinflammation is associated with Alzheimer's disease co-pathology in dementia with Lewy bodies.

BACKGROUND: Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology. METHODS: The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis. RESULTS: Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases. CONCLUSIONS: In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

Determining Hemodynamically Significant Coronary Artery Disease: Patient-Specific Cutoffs in Quantitative Myocardial Blood Flow Using [15O]H2O PET Imaging.

Currently, cutoffs of quantitative [15O]H2O PET to detect fractional flow reserve (FFR)-defined coronary artery disease (CAD) were derived from a single cohort that included patients without prior CAD. However, prior CAD, sex, and age can influence myocardial blood flow (MBF). Therefore, the present study determined the influence of prior CAD, sex, and age on optimal cutoffs of hyperemic MBF (hMBF) and coronary flow reserve (CFR) and evaluated whether cutoff optimization enhanced diagnostic performance of quantitative [15O]H2O PET against an FFR reference standard. Methods: Patients with chronic coronary symptoms underwent [15O]H2O PET and invasive coronary angiography with FFR. Optimal cutoffs for patients with and without prior CAD and subpopulations based on sex and age were determined. Results: This multicenter study included 560 patients. Optimal cutoffs were similar for patients with (n = 186) and without prior CAD (hMBF, 2.3 vs. 2.3 mL·min-1·g-1; CFR, 2.7 vs. 2.6). Females (n = 190) had higher hMBF cutoffs than males (2.8 vs. 2.3 mL·min-1·g-1), whereas CFRs were comparable (2.6 vs. 2.7). However, female sex-specific hMBF cutoff implementation decreased diagnostic accuracy as compared with the cutoff of 2.3 mL·min-1·g-1 (72% vs. 82%, P < 0.001). Patients aged more than 70 y (n = 79) had lower hMBF (1.7 mL·min-1·g-1) and CFR (2.3) cutoffs than did patients aged 50 y or less, 51-60 y, and 61-70 y (hMBF, 2.3-2.4 mL·min-1·g-1; CFR, 2.7). Age-specific cutoffs in patients aged more than 70 y yielded comparable accuracy to the previously established cutoffs (hMBF, 72% vs. 76%, P = 0.664; CFR, 80% vs. 75%, P = 0.289). Conclusion: Patients with and without prior CAD had similar [15O]H2O PET cutoffs for detecting FFR-defined significant CAD. Stratifying patients according to sex and age led to different optimal cutoffs; however, these values did not translate into an increased overall accuracy as compared with previously established thresholds for MBF.

Impact of sex on myocardial perfusion following percutaneous coronary intervention of chronic total coronary occlusions.

OBJECTIVES: We sought to investigate the impact of sex on myocardial perfusion changes following chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) as measured by [15O]H2O positron-emission tomography (PET) perfusion imaging. BACKGROUND: CTO PCI has been associated with an increase in myocardial perfusion, yet females are less likely to undergo revascularization. As such, data on the impact of sex on myocardial perfusion following CTO PCI is scarce. METHODS: A total of 212 patients were prospectively enrolled and underwent CTO PCI combined with [15O]H2O PET perfusion imaging prior to and 3 months after PCI. Hyperemic myocardial blood flow (hMBF, mL·min-1·g-1) and coronary flow reserve (CFR) allocated to the CTO territory were quantitatively assessed. RESULTS: This study comprised 34 (16 %) females and 178 (84 %) males. HMBF at baseline did not differ between sexes. Females showed a higher increase in hMBF than males (Δ1.34 ± 0.67 vs. Δ1.06 ± 0.74, p = 0.044), whereas post-PCI hMBF was comparable (2.59 ± 0.85 in females vs. 2.28 ± 0.84 in males, p = 0.052). Female sex was independently associated with a higher increase in hMBF after correction for clinical covariates. CFR increase after revascularization was similar in females and males (Δ1.47 ± 0.99 vs. Δ1.30 ± 1.14, p = 0.711). CONCLUSIONS: The present study demonstrates a greater recovery of stress perfusion in females compared to males as measured by serial [15O]H2O PET imaging. In addition, a comparable increase in CFR was found in females and males. These results emphasize the benefit of performing CTO PCI in both sexes. CLINICAL PERSPECTIVE: What is new? What are the clinical implications?

Social Activity and Cognitive Decline in Older Residents of Long-Term Care Facilities: A Cohort Study.

Background: Cognitive decline is a major reason for dependence and resource use in long-term care. Objective: We explored whether social activities may prevent cognitive decline of older residents of long-term care facilities. Methods: In a routine care cohort, 3,603 residents of long-term care facilities were assessed on average 4.4 times using the interRAI-Long-Term-Care-Facilities instrument which includes frequency of participation in social activities of long standing interest over the last 30 days and the Cognitive Performance Scale. Linear mixed models repeated measures analyses were performed corrected for age, sex, physical activity, Activities of Daily Living, mood, and health indicators. Results: Social activity was associated with cognitive preservation over time. This association was stronger in those with no or mild cognitive impairment at baseline, relative to those with moderate to severe impairment. Participation in specific social activities such as conversing and helping others showed a similar positive association. The relation between social activity and cognitive impairment appeared to be bi-directional. Conclusions: The protective effects of social activity offer a window of opportunity to preserve cognitive functioning in long-term care residents.

The effects of individual music therapy in nursing home residents with dementia to improve general well-being: study protocol of a randomized controlled trial.

BACKGROUND: Dementia is often associated with Neuropsychiatric Symptoms (NPS) such as agitation, depression, hallucinations, anxiety, that can cause distress for the resident with dementia in long-term care settings and can impose emotional burden on the environment. NPS are often treated with psychotropic drugs, which, however, frequently cause side effects. Alternatively, non-pharmacological interventions can improve well-being and maintain an optimal quality of life (QoL) of those living with dementia. Other QoL related outcomes, such as pain, discomfort and sleep disruption are relevant outcomes in music trials as well. Music therapy is a non-pharmacological intervention that can reduce NPS and improve well-being, and its associated symptoms in dementia. METHODS: The research will be conducted at eight nursing home facilities of a health care organization in the Netherlands. A sample size of 30 in each group (experimental and control group) is required, totalling 60 residents increased to 80 when considering expected drop out to follow up. The participants in the intervention group receive 30 min of individual music therapy (MT) in their own room by a music therapist twice a week for 12 weeks. The participants in the control group will receive 30 min of individual attention in their own room by a volunteer twice a week for 12 weeks. Assessments will be done at baseline, 6 weeks and 12 weeks. An independent observer, blinded for the intervention or control condition, will assess directly observed well-being (primary outcome) and pain (secondary outcome) before and after the sessions. Nurses will assess other secondary outcomes unblinded, i.e., perceived quality of life and NPS, both assessed with validated scales. The sleep duration will be indirectly assessed by a wrist device called MotionWatch. Information about psychotropic drug use will be derived from electronic medical chart review. DISCUSSION: The main purpose of this study is to assess the effects of individual music therapy on directly observed well-being controlled for individual attention in nursing home residents with dementia with NPS. The outcomes refer to both short-term and long-term effects consistent with therapeutic goals of care for a longer term. We hope to overcome limitations of previous study designs such as not blinded designs and music facilitators that were not only music therapists but also occupational therapists and nurses. This study should lead to more focused recommendations for practice and further research into non-pharmacological interventions in dementia such as music therapy. TRIAL REGISTRATION: The trial is registered at the International Clinical Trials Registry Platform (ICTRP) search portal in the Netherlands Trial Registration number NL7708, registration date 04-05-2019.

Two-year course of walking adaptability in persons living with late effects of polio.

OBJECTIVE: To evaluate the 2-year course of walking adaptability in persons with late effects of polio. DESIGN: Prospective cohort study. PATIENTS: A total of 48 persons with late effects of polio (69% female, mean age 63.1 years) with a fall history and/or fear of falling. METHODS: Walking adaptability (i.e. variable target-stepping and reactive obstacle-avoidance) was assessed on an interactive treadmill at baseline, 1 year and 2 years. Further, leg-muscle strength and balance were assessed at baseline. The course of walking adaptability was analysed with linear mixed models. Based on median values, subgroups were defined for low vs high baseline walking-adaptability and for clinical characteristics. Tme by subgroup interactions were analysed. RESULTS: Variable target-stepping and reactive obstacle-avoidance did not change (p > 0.285). Reactive obstacle-avoidance improved for persons with a high balance score at baseline (p = 0.037), but not for those with lower scores (p = 0.531). No other time by subgroup interactions were found (p > 0.126). CONCLUSION: Walking adaptability did not change in persons with late effects of polio over 2 years, and walking adaptability course did not differ between subgroups stratified for walking adaptability determinants, except for balance. Since falls are a major problem among persons with late effects of polio, future studies should investigate whether walking adaptability declines over a longer time and which persons are most at risk.

The influence of health literacy, anxiety and education on shared decision making and decisional conflict in older adults, and the mediating role of patient participation: A video observational study.

OBJECTIVE: To explore the relationship between personal characteristics of older adults with multiple chronic conditions (MCCs) and perceived shared decision making (SDM) resp. decisional conflict. METHODS: In a video-observational study (N = 213) data were collected on personal characteristics. The main outcomes were perceived level of SDM and decisional conflict. The mediating variable was participation in the SDM process. A twostep mixed effect multilinear regression and a mediation analysis were performed to analyze the data. RESULTS: The mean age of the patients was 77.3 years and 56.3% were female. Health literacy (ß.01, p < .001) was significantly associated with participation in the SDM process. Education (ß = -2.43, p = .05) and anxiety (ß = -.26, p = .058) had a marginally significant direct effect on the patients' perceived level of SDM. Education (ß = 12.12, p = .002), health literacy (ß = -.70, p = .005) and anxiety (ß = 1.19, p = .004) had a significant direct effect on decisional conflict. The effect of health literacy on decisional conflict was mediated by participation in SDM. CONCLUSION: Health literacy, anxiety and education are associated with decisional conflict. Participation in SDM during consultations plays a mediating role in the relationship between health literacy and decisional conflict. PRACTICE IMPLICATIONS: Tailoring SDM communication to health literacy levels is important for high quality SDM.

Is the association between social jetlag and BMI mediated by lifestyle? A cross-sectional survey study in the Dutch general population.

OBJECTIVE: Social jetlag is a discordance between the social and biological rhythm and is associated with higher HbA1c, higher BMI, and higher odds of obesity. The pathways that could explain these associations are still debated. This study aims to assess the mediating role of several lifestyle factors in the cross-sectional association between social jetlag and BMI. METHODS: We used cross-sectional data from 1784 adults from urban areas in the Netherlands, collected in 2019. Social jetlag (difference in midpoint of sleep between week and weekend nights) was categorized as low(<1 h), moderate(1-2h), and high(>2 h). BMI(kg/m2) was calculated from self-reported height and weight. The association between social jetlag and BMI was assessed using linear regression, adjusted for sex, age, education, and sleep duration and stratified for the effect modifier stress (high vs. low). Mediation analysis was performed for self-reported smoking, physical activity, alcohol consumption, and adherence to a healthy diet. RESULTS: High social jetlag was associated with higher BMI (0.69 kg/m2,95%CI 0.05;1.33). This association was stronger in people with high stress (0.93 kg/m2,95%CI 0.09;1.76). Social jetlag was also associated with higher odds of smoking, lower physical activity, higher alcohol consumption, and lower healthy diet adherence. In people with high stress, these factors mediated 10-15% of the association between social jetlag and BMI. CONCLUSIONS: Social jetlag is associated with higher BMI and this association is stronger in people with high stress. In people with high stress, healthy diet adherence mediated 12% of this association. Other pathways involved in this association should be further investigated.

The associations between sleep quality, mood, pain and appetite in community dwelling older adults: a daily experience study.

OBJECTIVES: To investigate the daily life experiences of sleep, mood, and pain in relation to appetite in community-dwelling older adults aged 75 years and older, stratified by sex. DESIGN: Existing data from a daily experience study embedded in the Longitudinal Aging Study Amsterdam (LASA) among the oldest-old (≥75 years). SETTING: LASA is an ongoing cohort study of a nationally representative sample of older adults aged ≥55 years from three culturally distinct regions in the Netherlands. PARTICIPANTS: 434 community-dwelling older adults aged ≥75 years. MEASUREMENTS: Participants filled-out a one-week diary on daily experience of pain, mood, last night sleep (10-point Likert scale), and appetite (5-point Likert scale) on five measurement occasions between 2016 and 2021. (Hybrid) linear mixed models were used to investigate overall, within-subject and between-subject association between mood, sleep, and pain (independent variables) and appetite (dependent variable), while correcting between-subject associations for season, age, educational level, partner status, body mass index, alcohol consumption, physical activity level, smoking status, chronic diseases and use of nervous system medication, stratified by sex. RESULTS: Averaged over all days, males reported a poor appetite on 12% of the days and females on 19% of the days. Statistically significant between-subject associations with a poorer appetite were found for lower mood (unstandardized b = 0.084 [95% CI 0.043-0.126] (males), (b = 0.126 [95% CI 0.082-0.170] (females)), poorer sleep (b = 0.045 [95% CI 0.007-0.083] (males), (b = 0.51 [95% CI 0.017-0.085] (females)) and more severe pain in males only (b = 0.026 [95% CI 0.002-0.051]). Except for pain, within-subject associations were somewhat weaker: mood: b = 0.038 [95% CI 0.016-0.060] (males), (b = 0.082 [95% CI 0.061-0.104] (females)); sleep: b = 0.029 [95% CI 0.008-0.050] (males), (b = 0.15 [95% CI 0.005-0.025] (females)); and pain (b = 0.032 [95% CI 0.004-0.059] (males)). CONCLUSIONS: This study found that poor sleep, low mood (more strongly in females) and more severe pain (males only) are associated with poor appetite in older adults on a daily level both within and between persons. Sex differences in factors related to poor appetite should be considered in future research.

Long-term effectiveness of a lifestyle intervention for rheumatoid arthritis and osteoarthritis: 1-year follow-up of the 'Plants for Joints' randomised clinical trial.

OBJECTIVES: In two randomised controlled trials, the Plants for Joints (PFJ) multidisciplinary lifestyle intervention reduced signs and symptoms of rheumatoid arthritis (RA), or metabolic syndrome-associated hip or knee osteoarthritis (MSOA) compared with usual care. The current study investigated long-term outcomes. METHODS: After completion of two 16-week trials in people with (1) RA or (2) MSOA, control groups switched to the active PFJ intervention. At the end of the intervention, all participants were followed up in a 1-year observational extension study. Primary outcomes were 28-joint Disease Activity Score (DAS28) (RA) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (MSOA). Secondary outcomes included body composition, metabolic outcomes, medication changes and intervention adherence. An intention-to-treat analysis with a linear mixed model was used to analyse within-group changes. RESULTS: 65 (84%) of 77 RA participants and 49 (77%) of 64 MSOA participants completed the extension study. The effects of the PFJ intervention were replicated in the original control groups and sustained within the RA group a year after intervention completion (mean DAS28 -0.9 points; p<0.001), while in the MSOA group mean WOMAC increased towards but remained well under the starting value (-7.8 points, p<0.001). Improvements in C-reactive protein, waist circumference (RA and MSOA); low-density lipoprotein cholesterol (RA); and weight, haemoglobin A1c, blood pressure (MSOA) were also sustained. Participants had a net decrease of medication, and intervention adherence was largely sustained. CONCLUSIONS: A year after the PFJ lifestyle intervention, improvements of disease activity and metabolic outcomes within RA and MSOA groups were largely sustained and related to sustained adherence, with a net decrease of medication. TRIAL REGISTRATION NUMBERS: NL7800, NL7801.

The immunological landscape of peripheral blood in glioblastoma patients and immunological consequences of age and dexamethasone treatment.

Background: Glioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied. Age and dexamethasone administration in glioblastoma patients have been hypothesized to limit the effectiveness of immunotherapy, but their effects remain unclear. We compared peripheral blood immune composition in patients with different types of brain tumor to determine the influence of age, dexamethasone treatment, and tumor volume. Methods: High-dimensional mass cytometry was used to characterise peripheral blood mononuclear cells of 169 patients with glioblastoma, lower grade astrocytoma, metastases and meningioma. We used blood from medically-refractory epilepsy patients and healthy controls as control groups. Immune phenotyping was performed using FlowSOM and t-SNE analysis in R followed by supervised annotation of the resulting clusters. We conducted multiple linear regression analysis between intracranial pathology and cell type abundance, corrected for clinical variables. We tested correlations between cell type abundance and survival with Cox-regression analyses. Results: Glioblastoma patients had significantly fewer naive CD4+ T cells, but higher percentages of mature NK cells than controls. Decreases of naive CD8+ T cells and alternative monocytes and an increase of memory B cells in glioblastoma patients were influenced by age and dexamethasone treatment, and only memory B cells by tumor volume. Progression free survival was associated with percentages of CD4+ regulatory T cells and double negative T cells. Conclusion: High-dimensional mass cytometry of peripheral blood in patients with different types of intracranial tumor provides insight into the relation between intracranial pathology and peripheral immune status. Wide immunosuppression associated with age and pre-operative dexamethasone treatment provide further evidence for their deleterious effects on treatment with immunotherapy.

Hemodynamic Insights into Combined Fractional Flow Reserve and Instantaneous Wave-Free Ratio Assessment Through Quantitative [15O]H2O PET Myocardial Perfusion Imaging.

In patients evaluated for obstructive coronary artery disease (CAD), guidelines recommend using either fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) to guide coronary revascularization decision-making. The hemodynamic significance of lesions with discordant FFR and iFR measurements is debated. This study compared [15O]H2O PET-derived absolute myocardial perfusion between vessels with concordant and discordant FFR and iFR measurements. Methods: We included 197 patients suspected of obstructive CAD who had undergone [15O]H2O PET perfusion imaging and combined FFR/iFR interrogation in 468 vessels. Resting myocardial blood flow (MBF), hyperemic MBF, and coronary flow reserve (CFR) were compared among 4 groups: FFR low/iFR low (n = 79), FFR high/iFR low (n = 22), FFR low/iFR high (n = 22), and FFR high/iFR high (n = 345). Predefined [15O]H2O PET thresholds for ischemia were 2.3 mL·min-1·g-1 or less for hyperemic MBF and 2.5 or less for CFR. Results: Hyperemic MBF was lower in the concordant low (2.09 ± 0.67 mL·min-1·g-1), FFR high/iFR low (2.41 ± 0.80 mL·min-1·g-1), and FFR low/iFR high (2.40 ± 0.69 mL·min-1·g-1) groups compared with the concordant high group (2.91 ± 0.84 mL·min-1·g-1) (P < 0.001, P = 0.004, and P < 0.001, respectively). A lower CFR was observed in the concordant low (2.37 ± 0.76) and FFR high/iFR low (2.64 ± 0.84) groups compared with the concordant high group (3.35 ± 1.07, P < 0.01 for both). However, for vessels with either low FFR or low iFR, quantitative hyperemic MBF and CFR values exceeded the ischemic threshold in 38% and 49%, respectively. In addition, resting MBF exhibited a negative correlation with iFR (P < 0.001) and was associated with FFR low/iFR high discordance compared with concordant low FFR/low iFR measurements, independent of clinical and angiographic characteristics, as well as hyperemic MBF (odds ratio [OR], 0.41; 95% CI, 0.26-0.65; P < 0.001). Conclusion: We found reduced myocardial perfusion in vessels with concordant low and discordant FFR/iFR measurements. However, FFR/iFR combinations often inaccurately classified vessels as either ischemic or nonischemic when compared with hyperemic MBF and CFR. Furthermore, a lower resting MBF was associated with a higher iFR and the occurrence of FFR low/iFR high discordance. Our study showed that although combined FFR/iFR assessment can be useful to estimate the hemodynamic significance of coronary lesions, these pressure-derived indices provide a limited approximation of [15O]H2O PET-derived quantitative myocardial perfusion as the physiologic standard of CAD severity.

Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

Effects of a 1 year aerobic and strength training on cognitive functioning after transient ischemic attack or minor stroke: A randomized controlled trial.

OBJECTIVES: Patients who have recently suffered a transient ischemic attack (TIA) or minor ischemic stroke are at increased risk of cognitive impairment. In the present study, we aimed to investigate the effect of a 1-year exercise intervention on cognitive functioning up to 2 years post intervention. MATERIAL AND METHODS: We conducted a single-blind randomized controlled trial to investigate the effect of an exercise intervention on cognitive functioning, compared with usual care, for up to 2 years. Patients with a TIA or minor stroke were randomly allocated to an intervention group receiving the 1-year exercise intervention (n = 60) or to usual care (n = 59). Outcome measures were assessed at baseline and after 1 and 2 years. We measured cognition with neuropsychological tests on three domains: (1) executive functioning, (2) attention-psychomotor speed, and (3) memory. Linear mixed models were used for longitudinal data to determine the effect of the exercise intervention on cognitive functioning. Statistical analyses were performed using IBM SPSS software 24.0. RESULTS: We found that over the two years study period -and corrected for age, sex, and educational level- the intervention group on average improved significantly more in executive functioning than the control group (ß = 0.13; 95 % CI [0.02 to 0.25]; p = 0.03). No significant intervention effects were found on either memory or attention-psychomotor speed. CONCLUSIONS: Our data show that a 1-year exercise intervention significantly improved executive functioning over time, compared to usual care. We recommend that health care professionals consider broadening standard secondary stroke prevention treatment in patients with TIA/minor stroke by adding exercise and physical activity.

Methotrexate Safety and Efficacy in Combination Therapies in Patients With Early Rheumatoid Arthritis: A Post Hoc Analysis of a Randomized Controlled Trial.

OBJECTIVE: We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). METHODS: This post hoc analysis included 812 treatment-naïve patients with early RA who were randomized (1:1:1:1) in the NORD-STAR trial to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment. RESULTS: Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.20-1.84) but not with certolizumab-pegol (HR 0.99, 95% CI 0.79-1.23) or with abatacept (HR 0.93, 95% CI 0.75-1.16). With ACT as the reference, the methotrexate dose was significantly lower when used in combination with tocilizumab (ß -4.65, 95% CI -5.83 to -3.46; P < 0.001) or abatacept (ß -1.15, 95% CI -2.27 to -0.03; P = 0.04), and it was numerically lower in combination with certolizumab-pegol (ß -1.07, 95% CI -2.21 to 0.07; P = 0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations. CONCLUSION: Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/wk, and these were more frequent in combination with tocilizumab versus ACT. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks.

A Longitudinal Study in Worrisome Sexual Behavior Following Sexual Abuse in Infancy or Early Childhood: The Amsterdam Sexual Abuse Case.

Worrisome sexual behavior (WSB) is often described as an outcome specific to child sexual abuse (CSA). Therefore, it is highly relevant to study WSB in relation to sexual abuse, especially in very young children, as it is hard to recognize sexual abuse in children who have limited verbal capacities of disclosing. Over time, literature describing WSB following CSA has gradually broadened. However, a gap remains regarding the long-term development of WSB in children who were sexually abused during infancy or very early childhood. To our knowledge, our study is the first to examine developmentally-related sexual behavior versus sexual abuse-specific behavior longitudinally in children who were sexually abused at a very young age. In total, we examined the sexual behavior, as reported by parents of 45 children who experienced early-age sexual abuse for a period of more than five years. Overall, we found that WSB is likely to be a CSA-specific and potentially long-term outcome for children who were sexually abused at a very young age. Despite the decrease in sexual abuse-specific behavior over time, the level of this behavior was still significantly high 8 years after the sexual abuse. This finding supports long-term monitoring and assessment and intervention for WSB over time. Despite these findings, it is important to note that WSB does not serve as proof of sexual abuse in children; likewise, when a child does not present with WSB, it does not indicate the absence of a substantiated history of sexual abuse.

Implant supported overdentures in Sjögren's disease patients: a multicentre prospective cohort study.

OBJECTIVES: To prospectively investigate patient-reported outcomes and clinical performance of implant supported overdentures in edentulous Sjögren's disease (SjD) patients compared to subjects without SjD. METHODS: 51 implants were placed in 12 patients with SjD and 50 implants in 12 non-SjD patients to support overdentures. Clinical performance, marginal bone-level changes, patient satisfaction and oral health related quality of life (OHRQoL) were assessed at 1 (T1), 6 (T6), 12 (T12) and 18 (T18) months after placement of the overdenture. Patient satisfaction, ability to chew and OHRQoL were assessed with validated questionnaires. Marginal bone-level changes were measured on standardised dental radiographs. Clinical parameters included implant and overdenture survival, plaque, bleeding and gingival indices, and probing depth. RESULTS: OHRQoL in patients with SjD improved significantly after placement of implant supported overdentures at all measuring moments compared to baseline (p<0.05). Nevertheless, ability to chew tough and hard food was significantly better for non-SjD patients at all timepoints after placement of an implant supported overdenture (p<0.05). Implant survival at T18 was 100% in the patients with SjD and 98% in the non-SS group. Mean marginal bone loss at T18 did not differ between patients with SjD and non-SS patients, 1.12±0.74 mm and 1.43±1.66 mm, respectively (p=0.58). Clinical performance was good with no differences between the groups for all outcome measures (p>0.05). CONCLUSIONS: Implant-supported overdentures have a positive effect on OHRQoL and dental implants can be successfully applied in edentulous patients with SjD with nearly similar outcomes as in non-SjD subjects.

Study protocol for a nationwide implementation of internet-based vestibular rehabilitation for patients with chronic vestibular symptoms (I-RECOVER).

BACKGROUND: Vestibular rehabilitation is a safe and effective exercise-based treatment for patients with chronic vestibular symptoms. However, it is underused in general practice. Internet-based vestibular rehabilitation (Vertigo Training), which has proven to be effective as well, was developed to increase uptake. We now aim to improve the quality of care for patients with vestibular symptoms by carrying out a nationwide implementation of Vertigo Training. We will evaluate the effect of this implementation on primary care. METHODS: Our implementation study consists of three successive phases: 1) We will perform a retrospective observational cohort study and a qualitative interview study to evaluate the current management of patients with vestibular symptoms in primary care, in particular anti-vertigo drug prescriptions, and identify areas for improvement. We will use the results of this phase to tailor our implementation strategy to the needs of general practitioners (GPs) and patients. 2) This phase entails the implementation of Vertigo Training using a multicomponent implementation strategy, containing: guideline adaptations; marketing strategy; pharmacotherapeutic audit and feedback meetings; education; clinical decision support; and local champions. 3) In this phase, we will evaluate the effect of the implementation in three ways. a. Interrupted time series. We will use routine primary care data from adult patients with vestibular symptoms to compare the number of GP consultations for vestibular symptoms, referrals for vestibular rehabilitation, prescriptions for anti-vertigo drugs, and referrals to physiotherapy and secondary care before and after implementation. b. Prospective observational cohort study. We will extract data from Vertigo Training to investigate the usage and the characteristics of participants. We will also determine whether these characteristics are associated with successful treatment. c. Qualitative interview study. We will conduct interviews with GPs to explore their experiences with the implementation. DISCUSSION: This is one of the first studies to evaluate the effect of a nationwide implementation of an innovative treatment on Dutch primary care. Implementation strategies have been researched before, but it remains unclear which ones are the most effective and under what conditions. We therefore expect to gain relevant insights for future projects that aim to implement innovations in primary care.

Longitudinal resting-state EEG in amyloid-positive patients along the Alzheimer's disease continuum: considerations for clinical trials.

BACKGROUND: To enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer's disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD. METHODS: Resting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration. RESULTS: Whole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures' rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power. CONCLUSIONS: Resting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.