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Background: Oncological patients have high information needs that are often unmet. Patient versions of oncological clinical practice guidelines (PVG) translate clinical practice guidelines into laypersons' language and might help to address patients' information needs. Currently, 30 oncological PVG have been published in Germany and more are being developed. Following a large multi-phase project on oncological PVGs in Germany, recommendations to improve use and dissemination of PVG were adopted in a multi-stakeholder workshop., Methods: Organisations representing users of PVGs (patients, medical personnel, and multipliers), creators, initiators/funding organisations of PVGs, and organisations with methodological expertise in the development of clinical practice guidelines or in patient health information were invited to participate. The workshop included a World Café for discussion of pre-selected recommendations and structured consensus procedure for of all recommendations. Recommendations with agreement of > 75% were approved, and in case of ≤ 75% agreement, recommendations were rejected., Results: The workshop took place on 24th April 2023 in Cologne, Germany. Overall, 23 people from 24 organisations participated in the discussion. Of 35 suggested recommendations 28 recommendations reached consensus and were approved. The recommendations referred to the topics dissemination (N = 13), design and format (N = 7), (digital) links (N = 5), digitalisation (N = 4), up-to-dateness (N = 3), and use of the PVG in collaboration between healthcare providers and patients (N = 3)., Conclusion: The practical recommendations consider various perspectives and can help to improve use and dissemination of oncological PVG in Germany. The inclusion of different stakeholders could facilitate the transfer of the results into practice., (© 2024. The Author(s).)

Background: People with cancer have high information needs; however, they are often inadequately met. Patient versions of clinical practice guidelines (PVGs), a special form of evidence-based information, translate patient-relevant recommendations from clinical practice guidelines into lay language. To date, little is known about the experience of PVGs from healthcare providers' perspective in healthcare. This study aims to investigate the use, applicability, and dissemination of PVGs in oncology from the healthcare providers' perspective in Germany., Methods: Twenty semi-structured telephone interviews were conducted with oncological healthcare providers in Germany between October and December 2021. Interviews were recorded and transcribed verbatim. Mayring's qualitative content analysis with MAXQDA software was utilised to analyse the data., Results: A total of 20 healthcare providers (14 female, 6 male), mainly working as psychotherapists/psycho-oncologists and physicians, participated. Most participants (75%) were aware of the existence of PVGs. The content was predominantly perceived as comprehensible and relevant, whereas opinions on the design and format were mixed. The perceived lack of up-to-date information limited participants' trust in the content. Most felt that PVGs positively impact healthcare owing to the fact that they improve patients' knowledge about their disease. Additionally, PVGs served as a guide and helped healthcare providers structure physician-patient talks. Healthcare provider's unawareness of the existence of PVGs was cited as an obstructive factor to its dissemination to patients., Conclusion: Limited knowledge of the existence of PVGs among healthcare providers, coupled with alternative patient information, hinders the use and dissemination of PVGs in healthcare. However, the applicability of PVGs seemed to be acceptable owing to their content and good comprehensibility, especially with respect to physician-patient communication., (© 2024. The Author(s).)

Background: Several guideline organizations produce patient versions of clinical practice guidelines (PVGs) which translate recommendations into simple language. A former study of our working group revealed that few guideline organizations publish their methods used to develop PVGs. Clear definitions of PVGs do not prevail and their purposes often remain unclear. We aimed to explore experts' perspectives on developing, disseminating and implementing PVGs to discuss and incorporate these experiences when consenting on methodological guidance and further improving PVGs., Methods: We conducted 17 semi-structured telephone interviews with international experts working with PVGs from September 2021 through January 2022. We conducted the interviews in English or German, they were recorded and transcribed verbatim. We utilized Mayring's qualitative content analysis with MAXQDA software to analyze the data., Results: In two interviews two participants were interviewed at the same time. This resulted in a total of 19 participants from 16 different organizations and eight different countries participated. Most were female (16/19) and their experience in working with PVGs ranged from 1 to 20 years. All follow methodological standards when developing PVGs, but the extent of these standards and their public accessibility differs. Aims and target groups of PVGs vary between organizations. Facilitators for developing PVGs are working with a multidisciplinary team, financial resources, consultation processes and a high-quality underlying CPG. Facilitators for disseminating and implementing PVGs are using various strategies. Barriers, on the other hand, are the lack of these factors. All participants mentioned patient involvement as a key aspect in PVG development., Conclusion: The steps in the PVG development process are largely similar across the countries. Focus is placed on the involvement of patients in the development process, although the extent of participation varies. The experts collectively attribute great importance to PVGs overall, but in order to constantly adapt to medical progress and changing conditions, the focus in the future may be more on formats like living guidelines. Although there are different views on the mandatory development of PVGs, there is a consistent call for more transparency regarding the methodology used for PVGs., (© 2024. The Author(s).)

Objectives: We aimed to gain an overview of the methods and approaches used to develop, disseminate, and implement patient versions of clinical practice guidelines (PVGs)., Methods: We searched PubMed and MEDLINE through Ovid for articles reporting on the development, dissemination, or implementation of PVGs until March 2022. We searched the homepages of guideline organizations, screened the reference lists of the included documents, and asked experts to complement the publications. We narratively synthesized the findings., Results: Of 3,941 publications screened, 27 were included in the study. The identified method reports focused on patient involvement and peer-review processes. The other included publications highlighted the relevance of broad dissemination strategies and emphasized the importance of patient involvement and improving the readability of PVGs by using lay terms and shorter sentences., Conclusion: The terminology used for PVGs varies widely. The extent to which the methods were described was heterogeneous. Organizations developing PVGs should make their methods publicly available and use uniform labeling for PVGs in English to improve their use and recognition, not only for other PVG producers but also for patients and the public. A consensus regarding a minimum reporting standard for developing PVGs internationally and developing guiding principles is desirable., Competing Interests: Declaration of competing interest The authors (N.M., I.H., J.B., J.H., S.W., N.K., S.B., G.C., S.F., N.S., and D.W.) declare that they have no competing interests. M.B. is involved in the development of PVGs in oncology in Germany. S.Bl. and M.N. are representatives of the Association of the Scientific Medical Societies in Germany (AWMF), which receives constant financial support from the German Cancer Aid to support the German Guideline Program in Oncology (GGPO) and are involved in the methodological counseling of oncology and other CPGs. M.F. is a representative of a publisher of PVGs in oncology in Germany and is involved in the methodological counseling of CPGs and PVGs in oncology. T.L. is a representative for the publisher of PVGs in oncology in Germany. C.S. was involved in the development of PVGs in oncology in Germany until 2019 and is responsible for the development of patient versions in the National Disease Management Guidelines Program and their methodological refinement., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Natural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes that play an important role in the first line of defense against malignant or virus-infected cells. A better understanding of the transcriptional regulation of human NK cell differentiation is crucial to improve the efficacy of NK cell-mediated immunotherapy for cancer treatment. Here, we studied the role of the transcription factor interferon regulatory factor (IRF) 2 in human NK cell differentiation by stable knockdown or overexpression in cord blood hematopoietic stem cells and investigated its effect on development and function of the NK cell progeny. IRF2 overexpression had limited effects in these processes, indicating that endogenous IRF2 expression levels are sufficient. However, IRF2 knockdown greatly reduced the cell numbers of all early differentiation stages, resulting in decimated NK cell numbers. This was not caused by increased apoptosis, but by decreased proliferation. Expression of IRF2 is also required for functional maturation of NK cells, as the remaining NK cells after silencing of IRF2 had a less mature phenotype and showed decreased cytotoxic potential, as well as a greatly reduced cytokine secretion. Thus, IRF2 plays an important role during development and functional maturation of human NK cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Persyn, Wahlen, Kiekens, Van Loocke, Siwe, Van Ammel, De Vos, Van Nieuwerburgh, Matthys, Taghon, Vandekerckhove, Van Vlierberghe and Leclercq.)

Type 3 innate lymphoid cells (ILC3s) are characterized by RORγt expression and they produce IL-22 upon activation. ILC3s play a role in maintenance of barrier integrity in the intestine. Under inflammatory conditions, the ILC composition of the mucosal tissues is altered due to a high degree of plasticity. It has been extensively demonstrated that both murine and human ILC3s convert into ILC1s to mediate appropriate immune responses. However, plasticity between human ILC3s and NK cells is less well documented. As T-BET and EOMES are key transcription factors in NK cell differentiation, we investigated whether ectopic T-BET or EOMES expression converts human ILC3s into NK cells. ILC3s with ectopic T-BET and EOMES expression downregulate RORγt expression, while T-BET-overexpressing ILC3s additionally upregulate EOMES expression. High E ctopic T-BET expression in ILC3s results in transdifferentiation towards CD94 + NK cells, whereas ectopic EOMES overexpression results in dedifferentiation of ILC3s into CD94-CD117 -/low cells but is ineffective in NK cell generation. Dedifferentiating ILC3s from both T-BET and EOMES overexpression cultures upregulate NK cell receptors, perforin and granzyme B. Finally, IL-22 secretion is completely blocked in transdifferentiating ILC3s with both T-BET and EOMES ectopic expression, whereas only T-BET overexpression increases IFN-γ secretion and cytotoxicity. Altogether, these findings demonstrate that human ILC3s can convert into functional NK cells, wherein T-BET, and not EOMES, is the main driver., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kiekens, Wahlen, Persyn, De Vos, Taghon, Vandekerckhove and Leclercq.)

The ability of natural killer (NK) cells to kill tumor cells without prior sensitization makes them a rising player in immunotherapy. Increased understanding of the development and functioning of NK cells will improve their clinical utilization. As opposed to murine NK cell development, human NK cell development is still less understood. Here, we studied the role of thioredoxin-interacting protein (TXNIP) in human NK cell differentiation by stable TXNIP knockdown or overexpression in cord blood hematopoietic stem cells, followed by in vitro NK cell differentiation. TXNIP overexpression only had marginal effects, indicating that endogenous TXNIP levels are sufficient in this process. TXNIP knockdown, however, reduced proliferation of early differentiation stages and greatly decreased NK cell numbers. Transcriptome analysis and experimental confirmation showed that reduced protein synthesis upon TXNIP knockdown likely caused this low proliferation. Contrary to its profound effects on the early differentiation stages, TXNIP knockdown led to limited alterations in NK cell phenotype, and it had no effect on NK cell cytotoxicity or cytokine production. Thus, TXNIP promotes human NK cell differentiation by affecting protein synthesis and proliferation of early NK cell differentiation stages, but it is redundant for functional NK cell maturation.

Natural killer (NK) cells are innate lymphocytes that eliminate virus-infected and cancer cells by cytotoxicity and cytokine secretion. In addition to circulating NK cells, distinct tissue-resident NK subsets have been identified in various organs. Although transcription factors regulating NK cell development and function have been extensively studied in mice, the role of RUNX2 in these processes has not been investigated, neither in mice nor in human. Here, by manipulating RUNX2 expression with either knockdown or overexpression in human haematopoietic stem cell-based NK cell differentiation cultures, combined with transcriptomic and ChIP-sequencing analyses, we established that RUNX2 drives the generation of NK cells, possibly through induction of IL-2Rβ expression in NK progenitor cells. Importantly, RUNX2 promotes tissue residency in human NK cells. Our findings have the potential to improve existing NK cell-based cancer therapies and can impact research fields beyond NK cell biology, since tissue-resident subsets have also been described in other lymphocyte subpopulations., Competing Interests: SW, FM, WV, ST, LK, EP, EV, ZD, SD, PM, FV, TT, BV, PV, GL No competing interests declared, (© 2022, Wahlen et al.)

To enhance mental health care for youth in a midwestern residential treatment facility, Wolverine Human Services partnered with the Beck Institute (an intermediary) and an implementation research team to implement cognitive-behavioral therapy (CBT). CBT has strong evidence supporting effectiveness for treating youth internalizing and externalizing problems, but it is a complex psychosocial intervention that demands a thoughtful implementation approach. This study outlines the implementation phase (2.5 years) of a 5-year collaborative effort. The implementation phase focused on (a) adapting CBT to fit the complex youth needs and the roles of the multidisciplinary team members resulting in a new comprehensive and coordinated care model, and (b) the strategies utilized to support its competent integration by all team members. Six blended implementation strategies were deployed in this phase: forging implementation teams, installing progress monitoring, adapting CBT, training, providing supervision and consultation, and training the trainers. A components-based approach to CBT yielded six core skills: active listening, problem solving, mood monitoring and intervention mapping, activity scheduling, distress tolerance, and cognitive restructuring. By the end of this phase, all staff had robust exposure to and experience with the adapted form of CBT. The work of our academic-community partnership has both research and clinical implications, with respect to integrating an adapted version of CBT for residential environments (CBT-RE)., Competing Interests: Authors have no conflicts of interests.

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies., Competing Interests: An international patent application WO2020070070 was filed by Ghent University (Ghent, Belgium) on 30/09/2019, with title ‘Accelerated human hematopoietic stem cell differentiation towards mature natural killer cells with enhanced antibody-dependent cytotoxic activity’, with LK and GL as inventors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kiekens, Van Loocke, Taveirne, Wahlen, Persyn, Van Ammel, De Vos, Matthys, Van Nieuwerburgh, Taghon, Van Vlierberghe, Vandekerckhove and Leclercq.)

Staphylococcus aureus virulence has been associated with the production of phenol-soluble modulins (PSMs). These PSMs have distinct virulence functions and are known to activate, attract and lyse neutrophils. These PSM-associated biological functions are inhibited by lipoproteins in vitro. We set out to address whether lipoproteins neutralize staphylococcal PSM-associated virulence in experimental animal models. Serum from both LCAT an ABCA1 knockout mice strains which are characterised by near absence of high-density lipoprotein (HDL) levels, was shown to fail to protect against PSM-induced neutrophil activation and lysis in vitro. Importantly, PSM-induced peritonitis in LCAT -/- mice resulted in increased lysis of resident peritoneal macrophages and enhanced neutrophil recruitment into the peritoneal cavity. Notably, LCAT -/- mice were more likely to succumb to staphylococcal bloodstream infections in a PSM-dependent manner. Plasma from homozygous carriers of ABCA1 variants characterized by very low HDL-cholesterol levels, was found to be less protective against PSM-mediated biological functions compared to healthy humans. Therefore, we conclude that lipoproteins present in blood can protect against staphylococcal PSMs, the key virulence factor of community-associated methicillin resistant S. aureus., (© 2021. The Author(s).)

Natural killer (NK) cells are important in the immune defense against tumor cells and pathogens, and they regulate other immune cells by cytokine secretion. Although murine NK cell biology has been extensively studied, knowledge about transcriptional circuitries controlling human NK cell development and maturation is limited. By generating ETS1-deficient human embryonic stem cells and by expressing the dominant-negative ETS1 p27 isoform in cord blood hematopoietic progenitor cells, we show that the transcription factor ETS1 is critically required for human NK cell differentiation. Genome-wide transcriptome analysis determined by RNA-sequencing combined with chromatin immunoprecipitation-sequencing analysis reveals that human ETS1 directly induces expression of key transcription factors that control NK cell differentiation (ie, E4BP4, TXNIP, TBET, GATA3, HOBIT, BLIMP1). In addition, ETS1 regulates expression of genes involved in apoptosis and NK cell activation. Our study provides important molecular insights into the role of ETS1 as an important regulator of human NK cell development and terminal differentiation., (© 2020 by The American Society of Hematology.)

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20 -/- cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20 -/- cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis., (© 2019 Vetters et al.)

Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR(-) and NCR(+) ILC3 subsets in the small intestine of mice raised on a vitamin A-deficient diet. Additionally, the percentages of IL-22-producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR(-) ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A-deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid-related orphan receptor γt-Cre × RARα-DN mice had reduced numbers of NCR(-) and NCR(+) ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid-related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Some studies suggest that immunochemical fecal occult blood tests (FOBTs) and HemoQuant are more efficient at detecting fecal occult blood than the commonly employed Hemoccult II (guaiac) test. We undertook this study to determine whether an immunochemical test either alone or in combination with a guaiac test gives efficiency superior to the Hemoccult II test in predicting significant gastrointestinal tract disease., Design: Criterion standard, prospective, blinded., Setting: Referral population of ambulatory patients at an institutional and a private hospital., Patients: Eight-one patients referred to a gastroenterologist and in whom colonoscopy was indicated., Interventions: While on a restricted diet, patients made preparations for FOBTs from three consecutive bowel movements. Patients then underwent colonoscopy. Polyps larger than 1 cm in size, carcinoma of the colon, peptic ulcers, gastric erosions, and angiodysplasia were considered to be likely causes of occult gastrointestinal tract bleeding., Main Outcome Measures: Using colonoscopy results as the reference standard, sensitivity, specificity, and positive and negative predictive values for each of eight tests or pair of tests were compared with those of Hemoccult II., Results: Of 81 patients, 10 had significant lower gastrointestinal tract lesions and six had significant upper gastrointestinal tract lesions. Hemoccult SENSA, Heme-Select, and FECA-EIA were shown to be more sensitive than Hemoccult II but slightly less specific. Paired tests showed less efficiency than Hemoccult II alone., Conclusions: We did not find an ideal test or pair of tests; however, Hemoccult SENSA exhibited higher sensitivity than Hemoccult II and many other tests. The sensitivity, specificity, and positive predictive values of many of the FOBTs were believed to be low. We recommend that physicians consider FOBTs only as adjuncts to history and physical examination findings in deciding how to proceed in diagnosing gastrointestinal tract disease.

Advanced cervix cancer has a local failure rate of 40-45% when treated with a combination of external beam irradiation and intracavitary implants, and approximately 60-65% when treated by external beam irradiation alone. Because of the absorption characteristics of protons, there is the potential for improved dose distributions and delivery of greater total doses to cervical neoplasms. Using computer-modelled examples, this theoretical advantage has been tested and the results have been extrapolated to show a therapeutic advantage in local control and morbidity. The first example shows the use of protons and intracavitary implants in advanced cervix tumors. Larger tumor doses are possible with protons than with photons, while the dose-volume to normal structures is decreased. In the second example, external proton beam treatment alone also reveals significantly higher tumor doses and lower normal tissue doses, compared to photon irradiation. With new proton therapy facilities being designed and built in the United States and overseas, protocols are being designed to evaluate the therapeutic potential of proton therapy in locally advanced cervix cancer.