Discrepancies between self- and proxy-rated quality of life in people living with dementia.

INTRODUCTION: The aim of this study was to analyze discrepancies between self- and proxy-rated health-related quality of life (HRQoL), measured with the EuroQol 5 Dimension 5 Level survey (EQ-5D-5L), in people living with dementia (PlwD) and their caregivers on an individual response level. METHODS: EQ-5D-5L, sociodemographic and clinical data were obtained from baseline data of n = 174 dyads of a cluster-randomized, controlled intervention trial. Self- and proxy-rated EQ-5D-5L health profiles were evaluated in terms of response distribution and agreement (weighted Kappa), and discrepancies in individual dimension level were analyzed using the Paretian Classification of Health Change (PCHC) as well as the presence and degree of inconsistencies between ratings. RESULTS: PlwD had a mean age of 80.1, nearly the half were female and 82.3% were mildly to moderately cognitively impaired. PlwD reported a higher utility index than caregiver proxies (mean 0.75 vs. 0.68, 83% of PlwD > 0.5). According to the PCHC and inconsistency approach, 95% of PlwD rated their health differently compared to proxies; 66% with divergent responses in at least three EQ-5D-5L dimensions. Nine dyads (5%) showed identical ratings. Discrepancies of one higher or lower EQ-5D-5L response represented the most frequent discrepancy (35.4%). Caregivers were two times more likely to report "moderate problems," representing the middle of the 5-point Likert scale. Usual activities had the lowest agreement between ratings (weighted kappa = 0.23). In PlwD reporting no or some problems in EQ-5D-5L-dimensions, proxies were more likely to report more problems and vice versa, especially in the more observable dimension usual activities and less likely in the less observable domains pain/discomfort and anxiety/depression. DISCUSSION: The central tendency bias observed in proxy-ratings could be associated with assessment uncertainties, resulting in an underestimation (overestimation) in PlwD reporting better (worse) health. This diverging trend extends the knowledge from previous studies and underlines the need for more methodological research in this area. Highlights: People living with dementia (PlwD) rate their health differently than proxies.Proxy-ratings over- or underestimate PlwD health when self-ratings are low or high.Proxies indicate a possible central tendency bias.Further research is needed to understand influencing factors.

Health Fluctuations in Dementia and its Impact on the Assessment of Health-Related Quality of Life Using the EQ-5D-5L.

OBJECTIVES: To quantify health fluctuations, identify affected health-related quality of life (HRQoL) dimensions, and evaluate if fluctuations affect the HRQoL instruments recall period adherence in people living with dementia (PlwD). METHODS: Caregivers of PlwD completed a daily diary for 14 days, documenting if PlwD's health was better or worse than the day before and the affected HRQoL dimensions. Health fluctuation was categorized into low (0-4 fluctuations in 14 days), moderate (5-8), and high (9-14). Also, caregivers and PlwD completed the EQ-5D-5L (proxy- and self-reported) on days 1, 7, and 14. Subsequently, caregivers were interviewed to determine whether recurrent fluctuations were considered in the EQ-5D-5L assessment of today's health (recall period adherence). RESULTS: Fluctuations were reported for 96% of PlwD, on average, for 7 of the 14 days. Dimensions most frequently triggering fluctuations included memory, mobility, concentration, sleep, pain, and usual activities. Fluctuations were associated with higher EQ-5D-5L health-states variation and nonadherence to the EQ-5D-5L recall period "today." PlwD with moderate to high fluctuation had the highest EQ-5D-5L utility change between day 1 and 14 (0.157 and 0.134) and recall period nonadherence (31% and 26%) compared with PlwD with low fluctuation (0.010; 17%). Recall period nonadherence was higher in PlwD with improved compared with those with deteriorated health in the diary (37% vs 9%). CONCLUSIONS: Health fluctuations frequently occur in dementia and strongly affect HRQoL assessments. Further research is needed to evaluate if more extended recall periods and multiple, consecutive assessments could capture health fluctuations more appropriately in dementia.

Factors Influencing Health-Related Quality of Life of Patients with Spinocerebellar Ataxia.

BACKGROUND: Little is known about the progression of health-related quality of life (HRQoL) and predicting factors in spinocerebellar ataxia (SCA). Such knowledge is crucial to identify modifiable factors promoting everyday life with SCA and attenuating HRQoL decline. OBJECTIVES: This study is to assess HRQoL progression and identify factors affecting SCA patients' HRQoL. METHODS: Longitudinal data (three-year follow-up) of 310 SCA patients of the European SCA3/Machado-Joseph-Disease Initiative (ESMI) (2016-2022) and 525 SCA patients (SCA1, SCA2, SCA3 or SCA6) of the EUROSCA natural history study cohort (2006-2015) were assessed. Both large cohort studies share standardized assessments of clinical measures, SARA, INAS, PHQ-9, and HRQoL (EQ-5D-3L). The association between HRQoL and clinical measures was assessed by Spearman Correlation (rs). Multivariable panel regression models were performed to evaluate the impact of patients' socio-demographics, age of onset, SCA type and body mass index (BMI), and clinical measures on HRQoL progression. RESULTS: HRQoL significantly decreased over one (- 0.014, p = 0.095), two (- 0.028, p = 0.003), and three years (- 0.032, p = 0.002). Ataxia severity and mental health strongly correlated with HRQoL (rsSARA = - 0.589; rsPHQ-9 = - 0.507). HRQoL more intensively declined in male (ß = - 0.024, p = 0.038) patients with an earlier age of onset (ß = 0.002, p = 0.058). Higher progression of ataxia severity (ß = - 0.010, p ≤ 0.001), mental health problems (ß = - 0.012, p < 0.001), and higher BMI (ß = - 0.003, p = 0.029) caused more severe decline of patients' HRQoL over time. DISCUSSION: In absence of curative treatments, stronger focus on mental health and weight influence could help clinical evaluation and accompany treatment improving SCA patients' HRQoL, especially in male patients with early disease onset.

Health-Related Quality of Life in Patients with Spinocerebellar Ataxia: a Validation Study of the EQ-5D-3L.

Although health-related quality of life (HRQoL) has developed into a crucial outcome parameter in clinical research, evidence of the EQ-5D-3L validation performance is lacking in patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The objective of this study is to assess the acceptability, validity, reliability, and responsiveness of the EQ-5D-3L. For n = 842 predominantly European SCA patients of two longitudinal cohort studies, the EQ-5D-3L, PHQ-9 (Patient Health Questionnaire), and ataxia-specific clinical assessments (SARA: Scale for Assessment and Rating of Ataxia; ADL: activities of daily living as part of Friedreich's Ataxia Rating Scale; INAS: Inventory of Non-Ataxia Signs) were assessed at baseline and multiple annual follow-ups. The EQ-5D-3L was evaluated regarding acceptability, distribution properties, convergent and known-groups validity, test-retest reliability, and effect size measures to analyze health changes. The non-item response was low (EQ-5D-3L index: 0.8%; EQ-VAS: 3.4%). Ceiling effects occurred in 9.9% (EQ-5D-3L) and 3.0% (EQ-VAS) with a mean EQ-5D-3L index of 0.65 ± 0.21. In total, convergent validity showed moderate to strong Spearman's rho (rs > 0.3) coefficients comparing EQ-5D-3L and EQ-VAS with PHQ-9, SARA, ADL, and INAS. EQ-5D-3L could discriminate between groups of age, SARA, ADL, and INAS. Intra-class correlation coefficients (EQ-5D-3LICC: 0.95/EQ-VASICC: 0.88) and Kappa statistics (range 0.44 to 0.93 for EQ-5D-3L items) indicated tolerable reliability. EQ-5D-3L shows small (effect size < 0.3) to moderate (effect size 0.3-0.59) health changes regarding ataxia severity. The analysis confirms an acceptable, reliable, valid, and responsive recommended EQ-5D-3L in SCA patients, measuring the HRQoL adequately, besides well-established clinical instruments.

Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app.

INTRODUCTION: Friedreich ataxia (FA) is the most common hereditary ataxia in Europe, characterised by progressively worsening movement and speech impairments with a typical onset before the age of 25 years. The symptoms affect the patients' health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app). METHODS AND ANALYSIS: The PROFA Study is a prospective observational study. Patients with FA (n=200) will be recruited at six European study centres (Germany, France and Austria). We will interview patients at baseline in the study centre and subsequently assess the patients' health at home via mobile health app. Patients will self-report ataxia severity, HRQoL, speech and hearing disabilities, coping strategies and well-being, health services usage, adverse health events and productivity losses due to informal care on a daily to monthly basis on the app for 6 months. Our study aims to (1) validate measurements of HRQoL and psychosocial health, (2) assess the usability of the mobile health app, and (3) use descriptive and multivariate statistics to analyse patient-reported and economic outcomes and the interaction effects between these outcomes. Insights into the app's usability could be used for future studies using momentary data assessments to measure outcomes of patients with FA. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of the University Medicine of Greifswald, (BB096/22a, 26 October 2022) and from all local ethics committees of the participating study sites. Findings of the study will be published in peer-reviewed journals, presented at relevant international/national congresses and disseminated to German and French Patient Advocacy Organizations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05943002); Pre-results.

Fluctuations of health states in dementia diseases and their impact on the assessment of health today using the EQ-5D-5L: Protocol of a mixed-methods study.

Introduction: The EQ-5D is a widely used health-related quality of life (HRQoL) instrument. The recall period "today" may miss out on recurrent health fluctuations often observed in people with dementia (PlwD). Thus, this study aims to assess the frequency of health fluctuations, affected HRQoL dimensions and the impact of the health fluctuations on the assessment of health today using the EQ-5D-5L. Methods and analysis: This mixed-methods study will base on n=50 patient and caregiver dyads and four main study phases: (1) Baseline assessment of patients' socio-demographic and clinical characteristics; (2) caregivers self-completion of a daily diary for 14 days, documenting patient's today's health compared to yesterday, the affected HRQoL dimensions, and events that could have caused the fluctuations; (3) administration of the EQ-5D-5L as self- and proxy-rating at baseline, day seven and day 14; (4) interviewing caregivers on patient's health fluctuation, the consideration of past fluctuations in the assessment of health today using the EQ-5D-5L, and the appropriateness of recall periods to capture health fluctuations on day 14. Qualitative semi-structured interview data will be analyzed thematically. Quantitative analyses will be used to describe the frequency and intensity of health fluctuations, affected dimensions, and the association between health fluctuation and its consideration in the assessment of health today. Discussion: This study aims to reveal insights into the health fluctuation in dementia, the affected dimensions, and underlying health events, as well as whether individuals adhere to the recall period of health today using the EQ-5D-5L. This study will also provide information about more appropriate recall periods that could better capture health fluctuations. Trial registration: This study is registered in the German Clinical Trials Register (DRKS00027956).

Do They Align? Congruence Between Patient Preferences of People Living with Cognitive Impairments and Physicians' Judgements for Person-Centered Care: An Analytic Hierarchy Process Study.

BACKGROUND: Person-centered care (PCC) requires knowledge about patient preferences. Among people living with cognitive impairments (PlwCI), evidence on quantitative, choice-based preferences, which allow to quantify, weigh, and rank care elements, is limited. Furthermore, data on the congruence of patient preferences with physicians' judgements for PCC are missing. Such information is expected to support the implementation of PCC; state-of-the-art medical care aligned with patients' preferences. OBJECTIVE: To elicit patient preferences and physicians' judgements for PCC and their congruence. METHODS: Data from the mixed-methods PreDemCare study, including a cross-sectional, paper-and-pencil, interviewer-assisted analytic hierarchy process (AHP) survey conducted with n = 50 community-dwelling PlwCI and n = 25 physicians. Individual AHP weights (preferences/judgements) were calculated with the principal eigenvector method and aggregated per group by aggregation of individual priorities mode. Individual consistency ratios (CRs) were calculated and aggregated per group. Group differences in preferences/judgements were investigated descriptively by means and standard deviations (SDs) of AHP weights, resulting ranks, and boxplots. Additionally, differences between groups were investigated with independent paired t-test/Mann Whitney U-test. Sensitivity of AHP results was tested by inclusion/exclusion of inconsistent respondents, with an accepted threshold at CR≤0.3 for patients, and CR≤0.2 for physicians, due to better cognitive fitness of the latter group. RESULTS: Patient preferences and physicians' judgements did not differ significantly, except for the criterion Memory Exercises (AHP weights (mean (SD)): 0.135 (0.066) versus 0.099 (0.068), p = 0.01). We did not see rank-reversals of criteria after exclusion of inconsistent participants. Mean CR for patients at the criteria level was 0.261, and 0.181 for physicians. CONCLUSION: Physicians' judgements in our setting aligned well with patients' preferences. Our findings may be used to guide the implementation of preference-based PCC.

A school-based educational on-site vaccination intervention for adolescents in an urban area in Germany: feasibility and psychometric properties of instruments in a pilot study.

BACKGROUND: Vaccination rates for measles, mumps, and rubella (MMR) and diphtheria, tetanus, pertussis, and polio (Tdap-IPV) are not optimal among German adolescents. Education in combination with easy access to vaccination may be a promising approach to improve vaccination rates. The present paper describes a pilot study of a planned cluster randomized controlled trial (cRCT) in which we aim to improve MMR and Tdap-IPV vaccination rates together with knowledge and self-efficacy in a school setting. METHODS: The study covered 863 students from 41 classes of four schools. The optimization and feasibility of access to schools, recruitment strategies, intervention, and assessment procedures were examined. The course and content of the educational unit were evaluated with a mixed-methods approach. A pre-post measurement design was tested for the vaccination rate in all schools. Additionally, at two schools, improvement in vaccination-related knowledge and perceived self-efficacy were measured by questionnaire pre-educational unit (n=287) and post-educational unit (n=293). The remaining two schools provided only postintervention data. Finally, we evaluated the psychometric properties (i.e., reliability, retest reliability, and change rates) of the questionnaire, applying Cronbach's alpha, factor analyses, generalized estimating equations and linear mixed models. RESULTS: The findings of the pilot study indicated good feasibility. Of the total sample, 437 students (50.9%) brought their vaccination cards to school, 68 students received Tdap-IPV vaccinations, and 11 received MMR vaccinations. Out of six knowledge questions, on average, the students had M=2.84 (95% CI [2.69, 3.10]) correct answers before and M=4.45 (95% CI [4.26, 4.64]) after the class. Ranging from 1 to 4, the self-efficacy scale changed by 0.3 points (p <.001); Cronbach's alpha was 0.67 and 0.76 pre- and post-educational unit, respectively, and a one-factor solution was found. Content analysis of the five semistructured group interviews (n=12, 58.3% female) showed that all students found the length of the intervention to be appropriate. The teaching methods, including interactive and social media components, were perceived as very good. CONCLUSIONS: A school-based educational and on-site vaccination intervention appears to be feasible in terms of procedures and the adequacy of the instruments for the adolescent target group. TRIAL REGISTRATION: ISRCTN, ISRCTN18026662 . Pilot study for main trial registered 8 December 2017.

Polaronic Contributions to Friction in a Manganite Thin Film.

Despite the huge importance of friction in regulating movement in all natural and technological processes, the mechanisms underlying dissipation at a sliding contact are still a matter of debate. Attempts to explain the dependence of measured frictional losses at nanoscale contacts on the electronic degrees of freedom of the surrounding materials have so far been controversial. Here, it is proposed that friction can be explained by considering the damping of stick-slip pulses in a sliding contact. Based on friction force microscopy studies of La(1- x )Sr x MnO3 films at the ferromagnetic-metallic to a paramagnetic-polaronic conductor phase transition, it is confirmed that the sliding contact generates thermally-activated slip pulses in the nanoscale contact, and argued that these are damped by direct coupling into the phonon bath. Electron-phonon coupling leads to the formation of Jahn-Teller polarons and to a clear increase in friction in the high-temperature phase. There is neither evidence for direct electronic drag on the atomic force microscope tip nor any indication of contributions from electrostatic forces. This intuitive scenario, that friction is governed by the damping of surface vibrational excitations, provides a basis for reconciling controversies in literature studies as well as suggesting possible tactics for controlling friction.

Tickbite-associated chronic pruritic lesions in an Afro-descendant population in the Cauca Department, Colombia. I. Clinical features and impact on health.

BACKGROUND: During a health survey in a remote area in southwest Colombia, it became apparent that a high percentage of the population suffered from chronic pruritus in association with high numbers of ticks and tickbites. OBJECTIVE: To determine the clinical features and severity of tickbite-associated pruritus. METHOD: At twotime points - 8 weeks apart to account for seasonal effects - a cross-sectional study was conducted encompassing physical examination of the population, histological analysis of skin biopsies, and determining serum for antibodies against spotted fever (SFG) rickettsiae and typhus group (TG) rickettsiae. Ticks were identified using morphological criteria, and infection by rickettsiae was determined by PCR. RESULTS: About 94.5% of the population (95% CI 92-97%) showed clinical signs of a pruritic arthropod reaction and of chronic pruritus with lichenoid papules and hyper- and hypopigmented nodules on otherwise noninflamed skin. Pruritus markedly impaired the quality of life in terms of sleeping disturbances. No signs for other diseases were observed. Chronic pruritus appeared to be because of repeated tickbites and scratching, but not because of other dermatological or medical conditions. Antibodies against SFG and TG-rickettsiae were detected at 79.0% (95% CI 73-86) and 3.6% (95% CI 0.7-6), respectively. Ticks were identified as Amblyomma cajennense. CONCLUSION: Remarkably high exposure to tick bites caused an unusually high rate of acute and chronic pruritus and markedly impaired quality of life of the investigated rural community. This underlines the necessity of public health measures and surveillance of rickettsial disease.

Shark Attack: high affinity binding proteins derived from shark vNAR domains by stepwise in vitro affinity maturation.

A novel method for stepwise in vitro affinity maturation of antigen-specific shark vNAR domains is described that exclusively relies on semi-synthetic repertoires derived from non-immunized sharks. Target-specific molecules were selected from a CDR3-randomized bamboo shark (Chiloscyllium plagiosum) vNAR library using yeast surface display as platform technology. Various antigen-binding vNAR domains were easily isolated by screening against several therapeutically relevant antigens, including the epithelial cell adhesion molecule (EpCAM), the Ephrin type-A receptor 2 (EphA2), and the human serine protease HTRA1. Affinity maturation was demonstrated for EpCAM and HTRA1 by diversifying CDR1 of target-enriched populations which allowed for the rapid selection of nanomolar binders. EpCAM-specific vNAR molecules were produced as soluble proteins and more extensively characterized via thermal shift assays and biolayer interferometry. Essentially, we demonstrate that high-affinity binders can be generated in vitro without largely compromising the desirable high thermostability of the vNAR scaffold.

Varifocal MOEMS fiber scanner for confocal endomicroscopy.

Based on an advanced silicon optical bench technology with integrated MOEMS (Micro-Opto-Electro-Mechanical-System) components, a piezo-driven fiber scanner for confocal microscopy has been developed. This highly-miniaturized technology allows integration into an endoscope with a total outer probe diameter of 2.5 mm. The system features a hydraulically-driven varifocal lens providing axial confocal scanning without any translational movement of components. The demonstrated resolutions are 1.7 µm laterally and 19 µm axially.

Combinatorial optimization of cystine-knot peptides towards high-affinity inhibitors of human matriptase-1.

Cystine-knot miniproteins define a class of bioactive molecules with several thousand natural members. Their eponymous motif comprises a rigid structured core formed by six disulfide-connected cysteine residues, which accounts for its exceptional stability towards thermic or proteolytic degradation. Since they display a remarkable sequence tolerance within their disulfide-connected loops, these molecules are considered promising frameworks for peptide-based pharmaceuticals. Natural open-chain cystine-knot trypsin inhibitors of the MCoTI (Momordica cochinchinensis trypsin inhibitor) and SOTI (Spinacia oleracea trypsin inhibitor) families served as starting points for the generation of inhibitors of matriptase-1, a type II transmembrane serine protease with possible clinical relevance in cancer and arthritic therapy. Yeast surface-displayed libraries of miniproteins were used to select unique and potent matriptase-1 inhibitors. To this end, a knowledge-based library design was applied that makes use of detailed information on binding and folding behavior of cystine-knot peptides. Five inhibitor variants, four of the MCoTI family and one of the SOTI family, were identified, chemically synthesized and oxidatively folded towards the bioactive conformation. Enzyme assays revealed inhibition constants in the low nanomolar range for all candidates. One subnanomolar binder (Ki = 0.83 nM) with an inverted selectivity towards trypsin and matriptase-1 was identified.

Highly compact imaging using Bessel beams generated by ultraminiaturized multi-micro-axicon systems.

Employing Bessel beams in imaging takes advantage of their self-reconstructing properties to achieve small focal points while maintaining a large depth of focus. Bessel beams are efficiently generated using axicons, and their utility in scanning imaging systems, such as optical coherence tomography (OCT), has been demonstrated. As these systems are miniaturized to allow, for example, endoscopic implementations, micro-axicons are required to assure the maintenance of a large depth of focus. We demonstrate here the design, fabrication, and application of molded micro-axicons for use in silicon-based micro-optical benches. It is shown that arrangements of multiple convex and concave axicons may be implemented to optimize the depth of focus in a miniaturized OCT system, using a telescopic optical arrangement of considerably shorter optical system length than that achievable with classical micro-optics.