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Alizé A Rogge,1 Isabel Baur,2 Gabriele Blettner,3 Ulrike Holtkamp,4 Markus Horneber,5 Patrick Jahn,6 Stefanie Joos,7 Silva Keberle,8 Anita Kettelgerdes,9 David Klemperer,10 Alfred Längler,11 Petra Voiß,12,13 Joachim Weis,14 Claudia M Witt1,15,16 1Institute for Social Medicine, Epidemiology, and Health Economics, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany; 2Legal Institute, Competence Center Medicine - Ethics - Law Helvetiae, University of Zurich, Zurich, Switzerland; 3Deutsche Krebshilfe, INFONETZ KREBS, Bonn, Germany; 4German Leukemia & Lymphoma Patients‘ Association, Bonn, Germany; 5Department of Internal Medicine, Division of Oncology and Hematology, Paracelsus Medical University, Klinikum Nuremberg, Nuremberg, Germany; 6Department for Nursing Science, Institute for Health Science, Medical Faculty, Eberhard Karls University Tübingen, Tübingen, Germany; 7Institute for General Practice and Interprofessional Health Care, University Clinic Tübingen, Tübingen 72076, Germany; 8Eskamed AG, Basel, Switzerland; 9TK – Techniker Krankenkasse, Hamburg, Germany; 10Faculty of Social and Health Sciences, Ostbayerische Technische Hochschule Regensburg, Regensburg., Germany; 11Gemeinschaftskrankenhaus Herdecke, Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany; 12Department of Internal and Integrative Medicine, Evang. Kliniken Essen-Mitte, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany; 13Gynaecological Clinic, Städtisches Klinikum Karlsruhe gGmbH, Karlsruhe, Germany; 14Department of Self-Help Research, Comprehensive Cancer Center University Clinic Freiburg, Freiburg i.Br., Germany; 15Institute for Complementary and Integrative Medicine, University of Zurich and University Hospital Zurich, Zurich, Switzerland; 16Center for Integrative Medicine, University of Maryland School of Medicine Baltimore, Baltimore, MarylandCorrespondence: Claudia M WittInstitute for Complementary and Integrative Medicine, University Hospital Zurich and University Zurich, Sonneggstrasse 6, Zurich 8091, SwitzerlandEmail claudia.witt@uzh.chPurpose: Even in cases of positive evidence for complementary medicine (CM) therapies, it is still difficult for cancer patients to identify reputable providers. The aim of this study was to develop and evaluate a criteria list to provide guidance to cancer patients seeking a reputable CM provider.Methods: The design combined a literature review, an expert consensus procedure (n=15) and an assessment from three stakeholder perspectives (patients (n=18), CM providers (n=26) and oncology physicians (n=20)).Results: A total of 30 existing CM criteria were extracted from the literature, and 12 more were added by the experts. The main challenge was to define criteria that could easily be applied by the patients. A final comprehensive list of 8 criteria guiding cancer patients to find a reputable CM provider was developed.Conclusion: Health professionals and cancer information services might find the criteria list helpful when aiming to strengthen patients’ awareness of quality-related factors associated with CM providers. The criteria developed might be helpful when standards are established for quality assurance in CM in oncology.Keywords: neoplasms, complementary medicine, patient-centered care, standards, healthcare quality assurance

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Background: With prevalence estimates between 50% and 90% of people with cancer, cancer-related fatigue is one of the most common morbidities related to cancer and its treatment. Exercise is beneficial for the treatment of cancer-related fatigue. However, the efficacy of different types of exercise (i.e. cardiovascular training and resistance training) have not yet been investigated systematically and compared directly in a meta-analysis., Objectives: To compare the benefits and harms of cardiovascular training versus resistance training for treatment or prevention of cancer-related fatigue in people with cancer., Search Methods: We searched CENTRAL, MEDLINE, Embase, and five other databases in January 2023. We searched ClinicalTrials.gov and the International Clinical Trials Registry Platform for ongoing trials. We integrated results from update searches of previously published Cochrane reviews. In total, our searches included trials from inception to October 2023., Selection Criteria: We included randomised controlled trials investigating cardiovascular training compared with resistance training, with exercise as the main component. We included studies on adults with cancer (aged 18 years and older), with or without a diagnosis of cancer-related fatigue, for any type of cancer and any type of cancer treatment, with the intervention starting before, during, or after treatment. We included trials evaluating at least one of our primary outcomes (cancer-related fatigue or quality of life). We excluded combined cardiovascular and resistance interventions, yoga, and mindfulness-based interventions. Our primary outcomes were cancer-related fatigue and quality of life. Our secondary outcomes were adverse events, anxiety, and depression., Data Collection and Analysis: We used standard Cochrane methodology. For analyses, we pooled results within the same period of outcome assessment (i.e. short term (up to and including 12 weeks' follow-up), medium term (more than 12 weeks' to less than six months' follow-up), and long term (six months' follow-up or longer)). We assessed risk of bias using the Cochrane RoB 1 tool, and certainty of the evidence using GRADE., Main Results: We included six studies with 447 participants with prostate, breast, or lung cancer who received radiotherapy or chemotherapy, had surgery, or a combination of these. All studies had a high risk of bias due to lack of blinding. Three studies had an additional high risk of bias domain; one study for attrition bias, and two studies for selection bias. Interventions in the cardiovascular training groups included training on a cycle ergometer, treadmill, an elliptical trainer, or indoor bike. Interventions in the resistance training group included a varying number of exercises using bodyweight, weights, or resistance bands. Interventions varied in frequency, intensity, and duration. None of the included studies reported including participants with a confirmed cancer-related fatigue diagnosis. The interventions in four studies started during cancer treatment and in two studies after cancer treatment. Before treatment No studies reported interventions starting before cancer treatment. During treatment The evidence was very uncertain about the effect of cardiovascular training compared with resistance training for short-term cancer-related fatigue (mean difference (MD) -0.29, 95% confidence interval (CI) -2.52 to 1.84; 4 studies, 311 participants; Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) scale where higher values indicate better outcome; very low-certainty evidence) and long-term cancer-related fatigue (MD 1.30, 95% CI -2.17 to 4.77; 1 study, 141 participants; FACIT-Fatigue scale; very low-certainty evidence). The evidence was very uncertain about the effect of cardiovascular training compared with resistance training for short-term quality of life (MD 1.47, 95% CI -1.47 to 4.42; 4 studies, 319 participants; Functional Assessment of Cancer Therapy - General scale where higher values indicate better outcome; very low-certainty evidence) and for long-term quality of life (MD 3.40, 95% CI -4.85 to 11.65; 1 study, 141 participants; Functional Assessment of Cancer Therapy - Anemia scale where higher values indicate better outcome; very low-certainty evidence). The evidence is very uncertain about the effect of cardiovascular training compared with resistance training on the occurrence of adverse events at any follow-up (risk ratio (RR) 2.00, 95% CI 0.19 to 21.18; 2 studies, 128 participants; very low-certainty evidence). No studies reported medium-term cancer-related fatigue or quality of life. After treatment The evidence was very uncertain about the effect of cardiovascular training compared with resistance training for short-term cancer-related fatigue (MD 1.47, 95% CI -0.09 to 3.03; 1 study, 95 participants; Multidimensional Fatigue Inventory-20 General Fatigue subscale where higher values indicate worse outcome; very low-certainty evidence). Resistance training may improve short-term quality of life compared to cardiovascular training, but the evidence is very uncertain (MD -10.96, 95% CI -17.77 to -4.15; 1 study, 95 participants; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 Global Health subscale where higher values indicate better outcome; very low-certainty evidence). No studies reported outcomes at medium-term or long-term follow-up., Authors' Conclusions: The evidence is very uncertain about the effects of cardiovascular training compared with resistance training on treatment of cancer-related fatigue in people with cancer. Larger, well-conducted studies including people with different cancer types receiving different treatments are needed to increase the certainty in the evidence and to better understand who may benefit most from cardiovascular or resistance training. Moreover, studies comparing the effects of cardiovascular and resistance training initiated before as well as after cancer treatment are needed to understand the prophylactic and rehabilitative effects of these exercise types on cancer-related fatigue., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: Patient involvement (PI) in systematic reviews (SRs) can help to improve the quality of SRs and enhance the credibility of the research process. At the same time, PI in SRs poses challenges such as the need for extra time. While several organizations and working groups from English-speaking countries provide recommendations for PI in SRs, there is a lack of current insights from stakeholders in Germany, including researchers and patients. Eliciting their perspectives is indicated, as PI in SRs in Germany might differ due to language barriers and organizational dissimilarities. For sharing and discussing stakeholders' experiences in Germany, a workshop was facilitated. This paper summarizes the results of the workshop to elucidate stakeholders' perspectives on key aspects of PI in SRs in Germany., Methods: A World Café was conducted at the 2023 conference of the Network for Evidence-based Medicine. Participants at all levels of experience could take part without prior registration. The data obtained was summarized narratively in an iterative process, and a framework of the topics discussed was developed., Results: 22 participants, predominantly researchers, took part. Participants formulated several general conditions for PI in SRs such as time and transparency. The majority of the tasks described referred to the application phase and the initial phase of a SR. The development of training and information materials in plain German language was deemed essential. The application phase of an externally funded SR and patient recruitment were considered as particularly challenging., Discussion: Several of the formulated aspects such as time and transparency are consistent with earlier work. The project start of a SR, however, has so far not been explicitly described in the literature as being of particular importance. This phase might be even more crucial to SR projects in Germany since researchers are expected to develop information materials for patients. Both the application phase and patient recruitment could be considered particularly challenging due to a lower degree of organisation of PI in Germany., Conclusion: World Café participants described many aspects referring to the project start of a SR. This underlines that PI in SRs needs to be described as a process. A process model intertwining the phases of a SR with the respective phases of PI, ideally including best practices for each phase, could be of great value. With respect to the specific context in Germany, a greater degree of organization of PI, i.e. coordinated by an institution, could help to manage challenges such as patient recruitment., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Sickle cell disease (SCD) is a group of hemoglobinopathies with a common point mutation causing the production of sickle cell hemoglobin (HbS). In high-throughput newborn screening (NBS) for SCD, a two-step procedure is suitable, in which qPCR first pre-selects relevant samples that are differentiated by a second method., Methods: Three NBS centers using qPCR-based primary screening for SCD performed a laboratory comparison. Methods using tandem MS or HPLC were used for differentiation., Results: In a benchmarking test, 450 dried blood samples were analyzed. Samples containing HbS were detected as reliably by qPCR as by methods established for hemoglobinopathy testing. In a two-step screening approach, the 2 nd -tier-analyses have to distinguish the carrier status from pathological variants. In nine months of regular screening, a total of 353,219 samples were analyzed using two-stage NBS procedures. The 1 st -tier screening by qPCR reduced the number of samples for subsequent differentiation by>99.5%. Cases with carrier status or other variants were identified as inconspicuous while 78 cases with SCD were revealed. The derived incidence of 1:4,773, is in good agreement with previously published incidences., Conclusion: In high-throughput NBS for SCD, qPCR is suitable to focus 2 nd -tier analyses on samples containing HbS, while being unaffected by factors such as prematurity or transfusions. The substantial reduction of samples numbers positively impacts resource conservation, sustainability, and cost-effectiveness. No false negative cases came to attention., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: The development process for clinical guidelines is influenced by factors that are relevant to the validity of a guideline but often are not captured sufficiently in the final guideline documents. PANELVIEW is an English-language tool that can be used to explore the guideline development process from the perspective of guideline group members. Our aim was to translate the PANELVIEW tool into German, taking into account national contexts and linguistic differences., Methods: The PANELVIEW tool was initially translated by a core team, then refined and approved by a group of experts in a consensus-based Delphi process. The experts were selected on the basis of their experience in guideline development covering different fields (clinical, methodological, organisational, health professional, patient perspective) and geographical regions (Germany, Austria, Switzerland). A representative of the original PANELVIEW team was also involved. The Delphi steps included an online survey, an online consensus conference and final approval by circulating the results via email. Individual items were seen as generally agreed upon if the level of agreement in the respective steps was 75 % or more., Results: The expert group consisted of 12 persons. Of these, 11 (92 %) participated in the online survey and 10 (83 %) in the subsequent consensus conference. After the first Delphi step, sufficient agreement was achieved for 19 of 34 items (56 %). The remaining 15 items were discussed in the consensus conference and finally obtained 100 % agreement. The discussion focused on clarifying and adapting terms whose meaning was ambiguous or inadequate in the German context, which led to a deviation from the original wording in some instances., Discussion: The PANELVIEW tool was translated into German by means of a Delphi process. PANELVIEW complements existing instruments for assessing the methodological quality of guidelines by capturing the perspective of the guideline group. This will enable guideline developers and organisations to identify problems in the drafting process and avoid them in future projects. User testing and validation of the German-language PANELVIEW tool are planned for the future., Conclusion: The German-language translation of PANELVIEW will enable guideline developers in German-speaking countries to continuously evaluate and, where necessary, improve the process and methods of guideline development., (Copyright © 2022. Published by Elsevier GmbH.)

Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: 17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns., Design: GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography-tandem mass spectrometry method (LC-MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody., Results: There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC-MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited., Conclusions: Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.

Background: Blood samples for neonatal screening for inborn errors of metabolism are collected and shipped on standardized filter paper cards. Occasionally these samples are contaminated with EDTA, which is often used for anticoagulation. EDTA may interfere with newborn screening tests based on lanthanide fluorescence and thus lead to false-negative or false-positive results., Methods: We used tandem mass spectrometry (MS/MS) to detect EDTA in dried blood spots by use of an extra experiment that was integrated into the standard MS/MS neonatal screening and did not require an additional sample spot, nor extra time or work. We analyzed the influence of different blood sampling procedures on lanthanide fluorescence tests for thyroid-stimulating hormone (TSH) and 17-hydroxyprogesterone (17-OHP)., Results: EDTA was increased in 138 of 190 000 newborn screening samples, 27 of which caused false- positive results in the immunoassay for 17-OHP. No false-negative TSH results were found. False-positive results in the 17-OHP test occurred when EDTA concentrations were >2.0 g/L; the TSH test, however, produced false negatives only when EDTA concentrations were >3.0 g/L. Using EDTA-containing devices the procedure of blood collection significantly influenced the concentration of the anticoagulant., Conclusion: Addition of EDTA quantification into standard MS/MS tests is a simple and useful method to avoid false-positive or false-negative neonatal screening results in lanthanide fluorescence-based tests.

Background: False-positive and false-negative results occur in current newborn-screening programs for hepatorenal tyrosinemia, which measure tyrosine concentrations in blood spots, sometimes in combination with other metabolites, including succinylacetone. We present our experience with a newly described method for succinylacetone quantification in routine newborn screening., Methods: Succinylacetone was extracted from blood spots that had already been extracted with absolute methanol for acylcarnitine and amino acid analysis. The solvent was acetonitrile-water (80:20 by volume) containing formic acid, hydrazine hydrate, and 100 nmol/L 5,7-dioxooctanoic acid as internal standard. Analysis was performed by tandem mass spectrometry in a separate run., Results: Of 61,344 samples, 99.6% had succinylacetone concentrations < or =5 micromol/L. With a cutoff of 10 micromol/L, no false-positive results were obtained. In 2 patients, the succinylacetone concentrations in the dried blood spots from the 36th and 56th hours of life were 152 and 271 micromol/L, respectively, and the tyrosine concentrations were 54 and 129 micromol/L. Hepatorenal tyrosinemia was subsequently confirmed in both patients. Retrospective analysis of the neonatal screening samples of 2 additional known patients revealed increased succinylacetone concentrations of 46 and 169 micromol/L, respectively., Conclusions: Tandem mass spectrometric quantification directly from residual blood spots is a useful method for the early detection of hepatorenal tyrosinemia in newborn-screening programs.

In this study we have sequenced peptides eluted from a truncated recombinant HLA-A*6602 molecule, and compared their features with data reported for peptides presented in the A*6601 molecule. A striking change in the amino-acid binding preferences was observed at peptide position P1, which interacts with pocket A of the HLA peptide-binding region. For A*6601, aspartic acid and glutamic acid, both of which possess polar acidic side-chains, have been described as auxiliary anchors. This is in marked contrast to A*6602, where we observed serine, which has a neutral polar side-chain, as auxiliary anchor at P1. Accordingly, this shift in the physico-chemical properties of the auxiliary anchor may be best explained by the HLA amino-acid polymorphism at position 163, where arginine (hydrophilic, alkaline) in A*6601 has been replaced by glutamic acid in A*6602. This amino-acid exchange results in a shift towards higher acidity in pocket A, apparently resulting in the loss of preference for acidic auxiliary anchors, and leading to the preference for the neutral amino acid serine. The change of the auxiliary anchor residue at P1 is likely to alter the spectrum of peptides presented by A*6602 compared with A*6601, which may result in allogenicity in the case of a mismatch in allogeneic stem cell transplantation.

A degranulation inhibiting protein could be isolated from human plasma ultrafiltrate by a three-step purification method including ion-exchange chromatography, gelfiltration and affinity-chromatography. The protein was identified as complement factor D by means of sequence analysis. Its degranulation inhibiting activity was determined with regard to its effect on the FNLPNTL-induced lactoferrin secretion of human polymorphonuclear leukocytes. Complement factor D caused a dose-dependent decrease of the FNLPNTL-stimulated lactoferrin degranulation down to 34% of stimulated controls.