Health‐relatedquality of life of children born to childhood cancer survivors in Germany

Objective: Rising childhood cancer survival rates have increased the importance of health-related quality of life (HRQL) assessment. While survivors show comparable HRQL to peers, concerns that cancer treatment could impact the health of prospective children were reported. No previous publications address HRQL of childhood cancer survivor offspring. Methods: We assessed survivor offspring HRQL using the parental KINDL questionnaire. Matched-pair analysis was conducted with data from the general population (KiGGS study) using age, gender and education (1:1, n = 1206 cases). Multivariate analyses were conducted to detect the influence of parental diagnose and treatment on offspring HRQL. Results: Overall, within KINDL dimensions, survivors reported comparable to higher HRQL for their children than the general population. Survivor parents reported significantly (p < 0.001) higher psychological (86.7% vs. 83.0%, Cohen's d = 0.3) and self-esteem (79.1% vs. 73.3%, Cohen's d = 0.5) well-being scores for younger children (3–6-year-olds). As time since diagnosis increased, parents reported higher well-being scores. Accordingly, recently diagnosed survivors reported significantly lower psychological well-being scores (p = 0.28; OR = 0.457; 95% CI = 0.228–0.918) for their children. With increasing age, average HRQL scores decreased in both cohorts; yet, this drop was less pronounced for survivor offspring. The biggest difference between age groups (7–10- vs. 14–17-year-olds) was found for school-specific well-being (6.2-point drop in survivor offspring vs. 18.2-point drop in KiGGS offspring). Conclusion: Comparable to higher parentally assessed HRQL was reported for survivor offspring compared to peers. These findings are reassuring and consistent with self-reported HRQL in childhood cancer survivors. Type of parental cancer diagnosis and treatment showed no negative impact on offspring HRQL.Peer Reviewe

Health‐related quality of life of children born to childhood cancer survivors in Germany

Objective: Rising childhood cancer survival rates have increased the importance of health-related quality of life (HRQL) assessment. While survivors show comparable HRQL to peers, concerns that cancer treatment could impact the health of prospective children were reported. No previous publications address HRQL of childhood cancer survivor offspring. Methods: We assessed survivor offspring HRQL using the parental KINDL questionnaire. Matched-pair analysis was conducted with data from the general population (KiGGS study) using age, gender and education (1:1, n = 1206 cases). Multivariate analyses were conducted to detect the influence of parental diagnose and treatment on offspring HRQL. Results: Overall, within KINDL dimensions, survivors reported comparable to higher HRQL for their children than the general population. Survivor parents reported significantly (p < 0.001) higher psychological (86.7% vs. 83.0%, Cohen's d = 0.3) and self-esteem (79.1% vs. 73.3%, Cohen's d = 0.5) well-being scores for younger children (3-6-year-olds). As time since diagnosis increased, parents reported higher well-being scores. Accordingly, recently diagnosed survivors reported significantly lower psychological well-being scores (p = 0.28; OR = 0.457; 95% CI = 0.228-0.918) for their children. With increasing age, average HRQL scores decreased in both cohorts; yet, this drop was less pronounced for survivor offspring. The biggest difference between age groups (7-10- vs. 14-17-year-olds) was found for school-specific well-being (6.2-point drop in survivor offspring vs. 18.2-point drop in KiGGS offspring). Conclusion: Comparable to higher parentally assessed HRQL was reported for survivor offspring compared to peers. These findings are reassuring and consistent with self-reported HRQL in childhood cancer survivors. Type of parental cancer diagnosis and treatment showed no negative impact on offspring HRQL

Perfusion in hand arthritis on dynamic contrast-enhanced computed tomography: a randomized prospective study using MRI as a standard of reference

Objective: To evaluate the performance of dynamic contrast-enhanced CT (DCE-CT) in detecting and quantitatively assessing perfusion parameters in patients with arthritis of the hand compared with dynamic contrast-enhanced MRI (DCE-MRI) as a standard of reference. Materials and methods: In this IRB-approved randomized prospective single-centre study, 36 consecutive patients with suspected rheumatoid arthritis underwent DCE-CT (320-row, tube voltage 80 kVp, tube current 8.25 mAs) and DCE-MRI (1.5 T) of the hand. Perfusion maps were calculated separately for mean transit time (MTT), time to peak (TTP), relative blood volume (rBV), and relative blood flow (rBF) using four different decomposition techniques. Region of interest (ROI) analysis was performed in metacarpophalangeal joints II–V and in the wrist. Pairs of perfusion parameters in DCE-CT and DCE-MRI were compared using a two-tailed t test for paired samples and interpreted for effect size (Cohen’s d). According to the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) scoring results, differentiation of synovitis-positive and synovitis-negative joints with both modalities was assessed with the independent t test. Results: The two modalities yielded similar perfusion parameters. Identified differences had small effects (d 0.01–0.4). DCE-CT additionally differentiates inflamed and noninflamed joints based on rBF and rBV but tends to underestimate these parameters in severe inflammation. The total dose-length product (DLP) was 48 mGy*cm with an estimated effective dose of 0.038 mSv. Conclusion: DCE-CT is a promising imaging technique in arthritis. In patients with a contraindication to MRI or when MRI is not available, DCE-CT is a suitable alternative to detect and assess arthritis

Burden of disease in myasthenia gravis: taking the patient’s perspective

Background: Myasthenia gravis (MG) leads to exertion-dependent muscle weakness, but also psychological and social well-being are limited. We aim to describe the burden of disease in MG including sociodemographic, economical, psychosocial as well as clinical aspects, to compare health-related quality of life (HRQoL) of patients with MG to the general population (genP) and to explore risk factors for a lower HRQoL. Methods: This case-control study was conducted with MG patients of the German Myasthenia Association. A questionnaire-based survey included sociodemographic and clinical data as well as standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was compared to genP in a matched-pairs analysis. Participants of the German Health Interview and Examination Survey for Adults (DEGS1) served as control group. Results: In our study, 1660 MG patients participated and were compared to 2556 controls from the genP. Patients with MG showed lower levels of physical functioning (SF-36 mean 56.0, SD 30.3) compared to the genP (mean 81.8, SD 22.1, adjusted difference: 25, 95% CI 22-29) and lower mental health sub-score (SF-36 mean 67.3, SD 19.8, vs. 74.1, SD 16.7, adjusted difference: 5, 95% CI 2-8). Female gender, higher age, low income, partnership status, lower activities of daily life, symptoms of depression, anxiety and fatigue and self-perceived low social support were associated with a lower HRQoL in MG patients. Discussion: HRQoL is lower in patients with MG compared to genP. The burden of MG on patients includes economic and social aspects as well as their emotional well-being. New therapies must achieve improvements for patients in these areas

Two-Channel Kondo Physics from Tunnelling Impurities with Triangular Symmetry

Tunnelling impurities in metals have been known for some time to have the potential for exhibiting Kondo-like physics. However previous models based on an impurity hopping between two equivalent positions have run into trouble due to the existence of relevant operators that drive the system away from the non-Fermi-liquid Kondo fixed point. In the case of an impurity hopping among positions with higher symmetry, such as triangular symmetry, it is shown here that the non-Fermi-liquid behavior at low temperatures can be generic. Using various bosonization techniques, the fixed point is shown to be {\em stable}. However, unlike the conventional two-channel Kondo (2CK) model, it has {\em four} leading irrelevant operators, implying that while the form of the singular temperature dependence of physical quantities is similar to the 2CK model, there will not be simple universal amplitude ratios. The phase diagram of this system is analyzed and a critical manifold is found to separate the non-Fermi-liquid from a conventional Fermi liquid fixed point. Generalization to higher symmetries, such as cubic, and the possibility of physical realizations with dynamic Jahn-Teller impurities is discussed.Comment: 20 pages, 4 figures, RevTex format, submitted to Phys. Rev.

Health outcomes in offspring born to survivors of childhood cancers following assisted reproductive technologies

Purpose: An increasing number of childhood cancer survivors are using assisted reproductive technologies (ART) to overcome treatment-related fertility impairment. We report perinatal and health outcomes of offspring born to survivors following ART. Methods: The FeCt Multicenter Offspring Study surveyed the health of offspring of childhood cancer survivors. Health outcomes in offspring born to survivors following ART (n = 57, 4.6%) or after spontaneous conception (n = 1182) were assessed in the German cohort (n = 1239) using bivariate analysis. Findings were put into the context of the general German population by health outcome assessment in 1:1 matched-pair analysis (n = 2478). Results: Nearly twice the survivors used ART compared with numbers reported for the German general population (4.6% vs. 2.6%). Successful pregnancies were achieved after a median of two cycles, mainly using non-cryopreserved oocytes/sperm. Multiple sibling births (p < 0.001, 28.1% vs. 3.0%) and low birth weight (p = 0.008; OR = 2.659, 95% CI = 1.258-5.621) occurred significantly more often in offspring born to survivors who utilized ART than spontaneously conceived children, whereas similar percentages were born preterm or too small for their gestational age. ART did not increase the prevalence of childhood cancer or congenital malformations in offspring born to survivors. Conclusion: ART use by childhood cancer survivors was successful with both fresh and cryopreserved oocytes/sperm, and did not influence perinatal health or health outcomes when known confounders were taken into account. Implications for cancer survivors: Oncofertility is an important component of patient care. Our study implicates that the utilization of ART by adult survivors of childhood cancer does not put offspring at additional risk for adverse perinatal or health outcomes

Guidance on the integrated assessment of complex health technologies: the INTEGRATE-HTA model

Challenges in assessments of health technologies In recent years there have been major advances in the development of health technology assessment (HTA). However, HTA still has certain limitations when assessing technologies which are complex, i.e. consist of several interacting components, target different groups or organizational levels, have multiple and variable outcomes, and/or permit a certain degree of flexibility or tailoring (Craig et al., 2008), fi are context-dependent - current HTA usually focusses on the technology, not on the system within which it is used, fi perform differently depending on the way they are implemented, fi have different effects on different individuals. Furthermore, HTA usually assesses and appraises aspects side-by-side, while decision-making needs an integrated perspective on the value of a technology. In the EU-funded INTEGRATE-HTA project, we developed concepts and methods to deal with these challenges, which are described in six guidances. Because of the interactions, an integrated assessment needs to start from the beginning of the assessment. This guidance provides a systematic five-step-process for an integrated assessment of complex technologies (the INTEGRATE-HTA Model). Purpose and scope of the guidance The aim of the INTEGRATE-HTA project is to provide concepts and methods that enable a patient-centred, comprehensive, and integrated assessment of complex health technologies. The purpose of this guidance is to structure the overall HTA-process. The INTEGRATE-HTA Model outlines an integrated scoping process, a coordinated application of assessment methods for different aspects and an integrated and structured decision-making process. It is intended for HTA agencies, HTA researchers and those engaged in the evaluation of complex health technologies. As it links the assessment to the decision-making process, it also addresses HTA commissioners and other stakeholders using or planning HTAs. While all technologies are arguably complex, some are more complex than others. Applying this guidance might lead to a more thorough and therefore more time-consuming process. Depending on the degree of complexity, one might choose to follow the whole process as described in this guidance, or only focus on certain steps. The guidance provides an operational definition to assess the complexity of technologies which can be used to identify specific aspects that will need more attention than others. What the guidance does not provide is a post-hoc solution for assessments that have already been completed. | 6 Development of the guidance The INTEGRATE-HTA Model presented in this guidance was developed based on a systematic literature search on approaches for integration, on the experiences of traditional HTAs, as well as on the other methodological guidances developed in the INTEGRATE-HTA project. It was tested in a case study on palliative care and iteratively revised during the practical application. The guidance was again revised after internal and external peer-review. Application of this guidance For a comprehensive integrated assessment of a complex technology, we developed a five-step process, the INTEGRATE-HTA model. In Step 1, the HTA objective and the technology are defined with the support from a panel of stakeholders. An initial logic model is developed in Step 2. The initial logic model provides a structured overview of the technology, the context, implementation issues, and relevant patient groups. It then frames the assessment of the effectiveness, as well as economic, ethical, legal, and socio-cultural aspects in Step 3. In Step 4, a graphical overview of the assessment results, structured by the logic model, is provided. Step 5 is a structured decision-making process informed by the HTA (and is thus not formally part of the HTA, but follows it). fi Step 1: In step 1, the technology under assessment and the objective of the HTA are defined. Especially for complex technologies, such as palliative care, the definition of the technology alone is a challenge that must not be underestimated. It is recommended to do this based on a tentative literature review and with the support of stakeholder advisory panels (SAPs) which should comprise clinical experts, academics, patients, possibly their relatives and/or other caretakers, and the public. The setting of an objective considering all relevant aspects of complexity and structured by assessment criteria is important. The assessment criteria will usually reflect values of the stakeholders as well as the input from the theoretical, methodological and empirical literature. fi Step 2: In step 2, an initial logic model is developed (see Guidance on the use of logic models in health technology assessments of complex interventions). The model provides a structured overview on participants, interventions, comparators, and outcomes. Parallel to this, groups of patients that are distinguished by different preferences and treatment moderators (see Guidance for the assessment of treatment moderation and patients’ preferences) are identified. Specific context and implementation issues are also identified as part of the initial logic model (see Guidance for the Assessment of Context and Implementation in Health Technology Assessments (HTA) and Systematic Reviews of Complex Interventions). The product of this step is the logic model as a graphical representation of all aspects and their interactions that are relevant for the assessment of the complex technology. fi Step 3: In step 3, the logic model serves as a conceptual framework that guides the evidence assessment. Depending on the specific aspect (e.g. effectiveness, economic, ethical, socio-cultural, or legal aspects) different methods are available for the assessment (see Guidance for assessing effectiveness, economic aspects, ethical aspects, socio-cultural aspects and legal aspects in complex technologies). The outputs of step 3 are evidence reports and standardized evidence summaries for each assessment aspect (e.g. report on economics, report on ethical aspects, etc.). fi Step 4: In step 4, the assessment results of step 3 are structured using the logic model developed in step 2. Whereas the initial logic model in step 2 specifies what evidence is relevant, the extended logic model to assist decision-making in step 4 visualizes the assessment results as well as the interaction with respect to the HTA objectives. It also allows for the consideration of different scenarios depending on the variation in context, implementation and patient characteristics. 7 | fi Step 5: Step 5 involves a structured decision-making process and is not an integral part of the HTA in the narrow sense. Decision-making can be supported by applying quantitative e.g. MCDA- (Multi-criteria decision analysis) or qualitative decision support tools. Flexibility in the application of these tools by the decision committee is crucial, taking different decision settings and evidence needs into consideration. Conclusions In current HTA, different aspects are usually assessed and presented independent of each other. Context, implementation issues and patient characteristics are rarely considered. The INTEGRATE-HTA Model enables a coordinated assessment of all these aspects and addresses their interdependencies. The perspective of stakeholders such as patients and professionals with their values and preferences is integrated in the INTEGRATE-HTA Model to obtain HTA results that are meaningful for all relevant stakeholders. Finally, health policy makers obtain an integrated perspective of the assessment results to achieve fair and legitimate conclusions at the end of the HTA process. The application of the model will usually require more time and resources than traditional HTA. An initial assessment of the degree and the character of complexity of a technology might be helpful to decide whether or not the whole process or only specific elements will be applied

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline : Decline A Randomized Clinical Trial

IMPORTANCE Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, AND PARTICIPANTS This 12-month randomized, double-masked, placebocontrolled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. INTERVENTIONS One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (O.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. MAIN OUTCOMES AND MEASURES Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. RESULTS A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.Peer reviewe

Fertility education for adolescent cancer patients: Gaps in current clinical practice in Europe

Objective: As adolescent cancer patients may suffer from infertility following treatment, fertility counselling is essential. Our aim was to explore the current situation in four European countries in terms of (I) education about the risk for infertility, (II) counselling on fertility preservation, (III) patients' knowledge on fertility, (IV) sufficiency of information and (V) uptake of cryopreservation. Methods: In total, 113 patients (13–20 years) at 11 study centres completed a self-report questionnaire three and six months after cancer diagnosis. Multivariate logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI). Results: As many as 80.2% of participants reported having received education about the risk for infertility prior to treatment, 73.2% recalled counselling on fertility preservation. Only 52.3% stated they felt sufficiently informed to make a decision. Inability to recall counselling on fertility preservation (OR = 0.03, CI: 0.00–0.47) and female gender (OR = 0.11, CI: 0.03–0.48) was associated with lower use of cryopreservation, whereas older age was associated with higher use. Conclusion: Fertility counselling was available to a relatively high proportion of patients, and it did influence the utilisation of cryopreservation. However, many patients did not feel sufficiently informed. Further improvement is needed to enable adolescent cancer patients to make an informed decision on fertility preservation