Predictors of Societal Costs of Older Care-Dependent Adults Living in the Community in 11 European Countries

BACKGROUND: The objective was to identify predictors of societal costs covering formal and informal care utilization by older home care clients in 11 European countries. METHODS : Societal costs of 1907 older clients receiving home care for 12 months from the Aged in Home care (AdHoc) study were estimated using the InterRAI Minimum Data Set for Home Care's (MDS-HC) resource use items. Predictors (medical, functional, and psychosocial domains) of societal costs were identified by performing univariate and multivariate generalized linear model analyses. RESULTS : Mean societal costs per participant were (sic)36 442, ranging from (sic)14 865 in Denmark to (sic)78 836 in the United Kingdom. In the final multivariate model, country, being married, activities of daily living (ADL) dependency, cognitive impairment, limitations of going out, oral conditions, number of medications, arthritis, and cerebro vascular accident (CVA) were significantly associated with societal costs. CONCLUSIONS: Of the predictors, ADL dependency and limitations of going out may be modifiable. Developing interventions targeted at improving these conditions may create opportunities to curtail societal costs.Peer reviewe

Dosimetric verification of murine proton irradiations and in vitro analysis of DNA damage repair modulators and FLASH irradiations

With almost 900.000 new patients per year suffering from head and neck squamous cell carcinomas (HNSCC), who after radiotherapy treatments experience severe side effects, the focus is drawn to proton therapy. Proton therapy results to less side effects since healthy tissues surrounding the tumour receive less radiation dose. This results from the proton’s specific depth-dose profile with its Bragg peak.To further reduce the effect on surrounding tissues, major improvements should be made in understanding the biologic response to proton therapy which will eventually lead to enlarging the therapeutic window. Here in vitro analysis with DNA damage repair inhibition or increasing proton dose rates can be performed to assess which DNA repair pathways repair radiation induced DNA damage and to assess the effect of proton dose rates on biological tissues. This will be investigated in vitro, while in vivo experiments are necessary as well. However, currently most mice are irradiated with protons in the plateau of the Bragg curve instead of the Bragg peak. Therefore, a dosimetric pipeline should be designed to allow for accurate placement of mouse tumours in the proton’s Bragg peak.In this thesis, the osteosarcoma- and HNSCC-derived U2OS and FaDu cell lines were incubated with non-homologous end-joining or homologous recombination inhibitors during x-ray and proton irradiations. We have shown a radiosensitising effect of the non-homologous end joining inhibitor AZD7648 on FaDu cells during x-ray irradiation, but an effect during proton irradiation could not be proved nor neglected. The homologous recombination inhibitor B02 could not effectively inhibit homologous recombination and was shown to not affect clonogenic survival of FaDu during X-ray irradiations. The observed radiosensitising effect of the non-homologous recombination inhibitor AZD7648 can be exploited in patient selection based on already existing DNA damage repair deficiencies in the tumour. Furthermore, combination therapies could be used of photon irradiations with AZD7648 targeted to the tumour to artificially enlarge the therapeutic window.Besides this, the HNSCC-derived FaDu cells were irradiated with varying dose rates to assess induction of a FLASH effect. This FLASH effect is usually observed after irradiations of >40 Gy/s resulting in a reduction of normal tissue complications while tumour control is maintained. In our analysis, small differences in low dose rates did not have any impact. The experimental set up for proton FLASH irradiations of cells was prepared and though we performed the first set of experiments no definite conclusion could be drawn due to the level of biological variation we observed.Of course, differential effects between tumours and tissues like the FLASH effect should be investigated in vivo. Therefore, a set-up should be created to irradiate the mural tumour with Bragg peak protons. To reach this, two micro-CT scanners were calibrated to link Hounsfield units to stopping power ratios. The proton range in mice was determined and a 3D-printed mouse-like phantom was irradiated. In this thesis, determined stopping powers of all CIRS phantom inserts except for lung tissues were accurate with a maximum deviation of 2% or 6.5% after calibration with QuantumGx or VECTor micro-CT scanners. Larger deviations were observed for CIRS lung inserts or Gammex inserts. The irradiated gafchromic films inserted in the murinemorphic phantom showed dose distributions visualising the mouse’s anatomy, yet the dose was too low due to irradiation in the distal edge of the Bragg peak. The latter was confirmed with Monte Carlo simulations. This dosimetric set-up to place mice tumours in the proton Bragg peak should thus be slightly improved and can then be of great value for in vivo experiments of proton therapy. This enables execution of many new experiments with DNA damage repair inhibition and FLASH irradiations, potentially leading to an increase of the therapeutic window in proton therapy and less side effects for HNSCC-patients.Biomedical Engineering | Nanobiolog

Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30–38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy

Linking the genotypes and phenotypes of cancer cells in heterogenous populations via real-time optical tagging and image analysis

Linking single-cell genomic or transcriptomic profiles to functional cellular characteristics, in particular time-varying phenotypic changes, could help unravel molecular mechanisms driving the growth of tumour-cell subpopulations. Here we show that a custom-built optical microscope with an ultrawide field of view, fast automated image analysis and a dye activatable by visible light enables the screening and selective photolabelling of cells of interest in large heterogeneous cell populations on the basis of specific functional cellular dynamics, such as fast migration, morphological variation, small-molecule uptake or cell division. Combining such functional single-cell selection with single-cell RNA sequencing allowed us to (1) functionally annotate the transcriptomic profiles of fast-migrating and spindle-shaped MCF10A cells, of fast-migrating MDA-MB-231 cells and of patient-derived head-and-neck squamous carcinoma cells, and (2) identify critical genes and pathways driving aggressive migration and mesenchymal-like morphology in these cells. Functional single-cell selection upstream of single-cell sequencing does not depend on molecular biomarkers, allows for the enrichment of sparse subpopulations of cells, and can facilitate the identification and understanding of the molecular mechanisms underlying functional phenotypes

Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis

Background Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals. Methods The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses. Results Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity. Conclusions Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab

Use Patterns of Leave-on Personal Care Products among Swiss-German Children, Adolescents, and Adults

In order to model exposure to ingredients contained in personal care products (PCPs) and assess their potential risks to human health, access to reliable PCP use data, including co-use patterns, is essential. A postal questionnaire survey was conducted to determine the use patterns of eight leave-on PCP categories among the German-speaking population of Switzerland (N = 1,196; ages 0–97 years), providing for the first time in Europe PCP use data for children <12 years of age. The majority of respondents (99%) reported having used at least one of the investigated PCP categories in the past year. Co-use of two or more PCP categories at the same time was common and more complex amongst adults. Regular use of face cream and body lotion was very high in the youngest group of children aged 0–4 years (more than 79% respondents) who may be more vulnerable to certain adverse effects of some PCP ingredients. A comparison with previously collected information on PCP use patterns in Germany and the Netherlands indicates differences in PCP use patterns among European consumers and suggests that surrogate PCP use data from other countries must be used with caution. This work extends the existing knowledge of PCP use patterns and will be useful for new exposure assessments for ingredients contained in PCPs used by the young consumers

The role of appraisal and coping style in relation with societal participation in fatigued patients with multiple sclerosis: a cross-sectional multiple mediator analysis

To determine the relationship between appraisal and societal participation in fatigued patients with Multiple Sclerosis (MS), and whether this relation is mediated by coping styles. 265 severely-fatigued MS patients. Appraisal, a latent construct, was created from the General Self-Efficacy Scale and the helplessness and acceptance subscales of the Illness Cognition Questionnaire. Coping styles were assessed using the Coping Inventory Stressful Situations (CISS21) and societal participation was assessed using the Impact on Participation and Autonomy. A multiple mediator model was developed and tested by structural equation modeling on cross-sectional data. We corrected for confounding by disease-related factors. Mediation was determined using a product-of-coefficients approach. A significant relationship existed between appraisal and participation (β = 0.21, 95 % CI 0.04–0.39). The pathways via coping styles were not significant. In patients with severe MS-related fatigue, appraisal and societal participation show a positive relationship that is not mediated by coping styles

Real-Time Assessment of Fatigue in Patients With Multiple Sclerosis: How Does It Relate to Commonly Used Self-Report Fatigue Questionnaires?

OBJECTIVES: (1) To assess real-time patterns of fatigue; (2) to assess the association between a real-time fatigue score and 3 commonly used questionnaires (Checklist Individual Strength [CIS] fatigue subscale, Modified Fatigue Impact Scale (MFIS), and Fatigue Severity Scale [FSS]); and (3) to establish factors that confound the association between the real-time fatigue score and the conventional fatigue questionnaires in patients with multiple sclerosis (MS). DESIGN: Cross-sectional study. SETTING: MS-specialized outpatient facility. PARTICIPANTS: Ambulant patients with MS (N=165) experiencing severe self-reported fatigue. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A real-time fatigue score was assessed by sending participants 4 text messages on a particular day (How fatigued do you feel at this moment?; score range, 0-10). Latent class growth mixed modeling was used to determine diurnal patterns of fatigue. Regression analyses were used to assess the association between the mean real-time fatigue score and the CIS fatigue subscale, MFIS, and FSS. Significant associations were tested for candidate confounders (eg, disease severity, work status, sleepiness). RESULTS: Four significantly different fatigue profiles were identified by the real-time fatigue score, namely a stable high (n=79), increasing (n=57), stable low (n=16), and decreasing (n=13). The conventional questionnaires correlated poorly (r<.300) with the real-time fatigue score. The Epworth Sleepiness Scale significantly reduced the regression coefficient between the real-time fatigue score and conventional questionnaires, ranging from 15.4% to 35%. CONCLUSIONS: Perceived fatigue showed 4 different diurnal patterns in patients with MS. Severity of sleepiness is an important confounder to take into account in the assessment of fatigue

The role of appraisal and coping style in relation with societal participation in fatigued patients with multiple sclerosis : a cross-sectional multiple mediator analysis

To determine the relationship between appraisal and societal participation in fatigued patients with Multiple Sclerosis (MS), and whether this relation is mediated by coping styles. 265 severely-fatigued MS patients. Appraisal, a latent construct, was created from the General Self-Efficacy Scale and the helplessness and acceptance subscales of the Illness Cognition Questionnaire. Coping styles were assessed using the Coping Inventory Stressful Situations (CISS21) and societal participation was assessed using the Impact on Participation and Autonomy. A multiple mediator model was developed and tested by structural equation modeling on cross-sectional data. We corrected for confounding by disease-related factors. Mediation was determined using a product-of-coefficients approach. A significant relationship existed between appraisal and participation (β = 0.21, 95 % CI 0.04–0.39). The pathways via coping styles were not significant. In patients with severe MS-related fatigue, appraisal and societal participation show a positive relationship that is not mediated by coping styles

The role of appraisal and coping style in relation with societal participation in fatigued patients with multiple sclerosis : a cross-sectional multiple mediator analysis

To determine the relationship between appraisal and societal participation in fatigued patients with Multiple Sclerosis (MS), and whether this relation is mediated by coping styles. 265 severely-fatigued MS patients. Appraisal, a latent construct, was created from the General Self-Efficacy Scale and the helplessness and acceptance subscales of the Illness Cognition Questionnaire. Coping styles were assessed using the Coping Inventory Stressful Situations (CISS21) and societal participation was assessed using the Impact on Participation and Autonomy. A multiple mediator model was developed and tested by structural equation modeling on cross-sectional data. We corrected for confounding by disease-related factors. Mediation was determined using a product-of-coefficients approach. A significant relationship existed between appraisal and participation (β = 0.21, 95 % CI 0.04–0.39). The pathways via coping styles were not significant. In patients with severe MS-related fatigue, appraisal and societal participation show a positive relationship that is not mediated by coping styles