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Abstract Background Quality of care (QoC) is a highly important topic in inflammatory bowel disease (IBD). We recently elaborated a decalogue of QoC indicators (IQCARO-QoC) developed by IBD patients. The aim of the present study was to assess the factors associated with patients’ evaluation of QoC in Spain using the IQCARO-QoC Decalogue recently developed by IBD patients. Methods A survey including patients’ socio-demographic and clinical characteristics, and the IQCARO-QoC Decalogue, was completed by IBD patients. We described patients’ assessment of QoC across Spanish patients. A univariable and multivariable analysis was performed to explore the associations between patients’ characteristics and QoC. Results Questionnaires from 788 participant patients were analysed. Participants’ mean age was 43.4 years, 63% were females and 58% had Crohn’s disease. The mean QoC score was 8.1 (± 2.4 SD) points out of a maximum of 10. Items with the lowest score were related to the provision of information and the implication of the medical team throughout the entire patient care. Factors associated with better QoC scores included: being employed better disease control, fewer numbers of unscheduled visits, and being followed by a gastroenterologist specialized in IBD. Conclusions Spanish patients’ reported QoC seems to be globally good although there is room for improvement, especially in providing adequate information to patients. Care provided by specialized IBD gastroenterologists seems to be related with higher QoC scores.

Microalgae are photosynthetic organisms with cosmopolitan distribution (i.e., marine, freshwater and terrestrial habitats) and possess a great diversity of species [1] and consequently an immense variation in biochemical compositions [2]. To date genomic information is available mainly from the model green microalga Chlamydomonas reinhardtii [3]. Here we provide the dataset of a de novo assembly and functional annotation of the transcriptomes of three native oleaginous microalgae from the Peruvian Amazon. Native oleaginous microalgae species Ankistrodesmus sp., Chlorella sp., and Scenedesmus sp. were cultured in triplicate using Chu-10 medium with or without a source of nitrate (NaNO3). Total RNA was purified, the cDNA libraries were constructed and sequenced as paired-end reads on an Illumina HiSeq™2500 platform. Transcriptomes were de novo assembled using Trinity v2.9.1. A total of 48,554 transcripts (range from 250 to 7966 bp; N50 = 1047) for Ankistrodesmus sp., 108,126 transcripts (range from 250 to 8160 bp; N50 = 1090) for Chlorella sp., and 77,689 transcripts (range from 250 to 8481 bp; N50 = 1281) for Scenedesmus sp. were de novo assembled. Completeness of the assembled transcriptomes were evaluated with the Benchmarking Universal Single-Copy Orthologs (BUSCO) software v2/v3. Functional annotation of the assembled transcriptomes was conducted with TransDecoder v3.0.1 and the web-based platforms Kyoto Encyclopedia of Genes and Genomes (KEGG) Automatic Annotation Server (KAAS) and FunctionAnnotator. The raw reads were deposited into NCBI and are accessible via BioProject accession number PRJNA628966 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA628966) and Sequence Read Archive (SRA) with accession numbers: SRX8295665 (https://www.ncbi.nlm.nih.gov/sra/SRX8295665), SRX8295666 (https://www.ncbi.nlm.nih.gov/sra/SRX8295666), SRX8295667 (https://www.ncbi.nlm.nih.gov/sra/SRX8295667), SRX8295668 (https://www.ncbi.nlm.nih.gov/sra/SRX8295668), SRX8295669 (https://www.ncbi.nlm.nih.gov/sra/SRX8295669), and SRX8295670 (https://www.ncbi.nlm.nih.gov/sra/SRX8295670). Additionally, transcriptome shotgun assembly sequences and functional annotations are available via Discover Mendeley Data (https://data.mendeley.com/datasets/47wdjmw9xr/1).

Introduction: Arousal disorders (AD) are sleep disorders that primarily involve behaviour typical of being awake (e.g. talking, walking, handling objects, yelling or crying). They present during partial arousal typically during slow wave sleep (SWS). By definition it has been suggested that parasomnias do not cause changes in sleep architecture or insomnia symptoms or daytime drowsiness. Method: A comparative and retrospective study was conducted to study the sleep architecture of a group of paediatric patients with clinical and polysomnographic diagnosis of arousal disorders (ADG), paired by age and gender with a group of healthy children (HCG). The research was conducted at the Sleep Disorders Clinic of the Faculty of Medicine of the Universidad Nacional Autónoma de Mexico. The Student's t test for independent samples was used to compare sleep architecture and a value of p

Abstract: The synthesis of strontium aluminates of the SrAl2O4 and Sr3Al2O6 type using SrCO3–Al2O3 blends was investigated. Blends 3:1 molar ratio of Al2O3 and mechanically activated SrCO3 were prepared and conformed into pellets by uniaxial compression at 100MPa. In an experimental stage, thermogravimetric analysis was used to investigate the isothermal decomposition of mechanically activated SrCO3 powders in the blend, in the range of temperatures from 900 to 1100°C. Then, samples were sintered at 1450°C for several periods of time (4–36h), and the products obtained were analyzed by X-ray diffraction and scanning electron microscopy. The results obtained showed that the formation of Sr3Al2O6 starts after 4h of heat treatment, and it is completed at 36h. Moreover, other phase such as SrAl2O4 formed in small amounts in the samples sintered for 12h. Kinetic measurements showed that the conversion of SrCO3 into Sr3Al2O6 follow two different reaction mechanisms, with different controlling steps. The first mechanism relates to the order of reaction model for the Sr3Al2O6 phase formation, whereas the second mechanism relates to the nucleation and growth of these phase particles. The activation energy measured for both processes was 88.59kJ and 54.06kJ, respectively. [Copyright &y& Elsevier]

The COVID-19 pandemic has led to a change in healthcare models. The aim of this study was to evaluate patient acceptance of telehealth as an alternative to physical consultations, and to identify factors predicting higher satisfaction. This was an observational, cross-sectional, multi-center, international study. All consecutive patients for whom telehealth was used in consultations between April and July 2020 were considered for inclusion. The validated Telehealth Usability Questionnaire (TUQ) was used as a model to measure patient acceptance. Overall, 747 patients were observed, of whom 721 agreed to participate (96·5%). The TUQ showed that 86·9% of patients agreed that telehealth was useful; 85·2% supported the interface quality and 81·4% endorsed the interaction quality. Patients aged > 60 y were less likely to agree with the use of telehealth (p < 0·05). A web-based prediction tool was generated to calculate global satisfaction and to identify patients more likely to feel comfortable with telehealth. Telehealth is feasible and allows consultations that are satisfactory for patients. Technological advancements could ease safe implementation of telehealth into everyday practice. Adequate patient selection can be useful to ensure that the ideal strategy is used for each individual during and after the pandemic., (© 2024. Italian Society of Surgery (SIC).)

Background: As the therapeutic landscape for inflammatory bowel disease (IBD) continues to expand, a need exists to understand how patients perceive and value different attributes associated with their disease as well as with current and emerging treatments. These insights can inform the development and regulation of effective interventions for IBD, benefiting various stakeholders including healthcare professionals, drug developers, regulators, Health Technology Assessment bodies, payers, and ultimately patients suffering from IBD. In response to this, the present patient preference study was developed with the aim to (1) determine the relative preference weights for IBD treatment and disease related attributes, and (2) explain how preferences may differ across patients with different characteristics (preference heterogeneity)., Methods: The patient preference study (PPS) was developed through an 8-step process, with each step being informed by an advisory board. This process included: (1) stated preference method selection, (2) attribute and level development (including a scoping literature review, focus group discussions, and advisory board meetings), (3) choice task construction, (4) sample size estimation, (5) survey implementation, (6) piloting, (7) translation, and (8) pre-testing. The resulting discrete choice experiment (DCE) survey comprises 14 attributes with between two and five varying levels. Participants will answer 15 DCE questions with a partial profile design, where each of the choice questions encompasses two hypothetical treatment profiles showing four attributes. Additionally, questions about patients' socio-demographic and clinical characteristics, as well as contextual factors are implemented. The survey is available in 15 different languages and aims to minimally recruit 700 patients globally., Discussion: This protocol gives valuable insights toward preference researchers and decision-makers on how PPS design can be transparently reported, demonstrating solutions to remaining gaps in preference research. Results of the PPS will provide evidence regarding the disease and treatment related characteristics that are most important for IBD patients, and how these may differ across patients with different characteristics. These findings will yield valuable insights applicable to preference research, drug development, regulatory approval, and reimbursement processes, enabling decision making across the medicinal product life cycle that is aligned with the true needs of IBD patients., Competing Interests: SV has received research support from AbbVie, J&J, Pfizer, Takeda, and Galapagos; and speakers' and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, and Zealand Pharma. MF has received research support from AbbVie, Biogen, EG, Janssen, Pfizer, Takeda, and Viatris; consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, MSD, Pfizer, Takeda, and ThermoFisher; and speakers' fees from AbbVie, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, MSD, Pfizer, Takeda, Truvion Healthcare, and Viatris. JS has received research support from Galapagos and Viatris; consultancy fees from Pfizer, Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia; and speaker's fees from Pfizer, Abbvie, Ferring, Falk, Takeda, Janssen, Fresenius, and Galapagos. BV has received research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares, and Takeda; consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, BenevolentAI, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Santa Ana Bio, Sosei Heptares, Takeda, Tillots Pharma, and Viatris; and speaker's fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion, and Viatris. LA, MD, MS-S, and RS were employed by EFCCA and has received funding support from Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Ferring, Galapagos, Celltrion, Janssen, Lilly, Novartis/Sandoz, Pfizer, Arena, and Roche. IH has received research support from Bristol Myers Squibb and unrestricted research grants from other organizations. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Schoefs, Vermeire, Ferrante, Sabino, Verstockt, Avedano, De Rocchis, Sajak-Szczerba, Saldaña, Straetemans, Vandebroek, Janssens and Huys.)

Spinal opioids have mixed efficacy and their adverse effects force treatment cessation of postoperative pain. Consequently, there is an ongoing search for new therapeutic strategies. Here, we evaluated the analgesic efficacy of intrathecal UCM707, an anandamide reuptake inhibitor, and morphine combination. Firstly, we assessed the effects of morphine (1, 5 and 10 μg), UCM707 (75 μg) and its combination in the hot plate. Then, morphine + UCM707 at sub-effective doses was evaluated in a rat post-incisional pain model. In addition, μ-, CB1r-, CB2r- and TRPV1-antagonists were pre-administered before the combination. Activation of μ-opioid and CB1r, and Cnr1, Cnr2, Oprm1 and TRPV 1 expressions were evaluated in the lumbar sacra and periaqueductal grey by [35 S]-GTPγS binding autoradiography and qPCR studies. In the hot plate, morphine (1 μg) and UCM707 (75 μg) induced a more robust analgesic effect than each drug alone. Morphine plus UCM707 did not modify μ-opioid nor CB1 receptor function in the PAG or LS. Cnr1 and TRPV1 expression increased in the lumbar sacra (LS). Morphine plus UCM707 significantly reduced post-incisional pain at 1 and 4 days after surgery. Cnr1, Cnr2 and TRPV1 expressions increased in the LS. Blockade of μ-opioid receptor reduced combination effects on days 1 and 4. CB1r- and CB2r-antagonism reduced morphine + UCM707 effects on days 1 and 4, respectively. CB1r and TRPV1-antagonism improved their antinociceptive effects on day 4. These results revealed a synergistic/additive analgesic effect of UCM707 and morphine combination controlling postincisional pain. CB1r, CB2r and TRPV1 contribute differently as central sensitization occurs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.

Background: Heterogeneity in demographic and outcomes data with corresponding measurement instruments [MIs] creates barriers to data pooling and analysis. Several core outcome sets have been developed in inflammatory bowel disease [IBD] to homogenize outcomes data. A parallel Minimum Data Set [MDS] for baseline characteristics is lacking. We conducted a systematic review to develop the first MDS., Methods: A systematic review was made of observational studies from three databases [2000-2021]. Titles and abstracts were screened, full-text articles were reviewed, and data were extracted by two reviewers. Baseline data were grouped into ten domains: demographics, clinical features, disease behaviour/complications, biomarkers, endoscopy, histology, radiology, healthcare utilization and patient-reported data. Frequency of baseline data and MIs within respective domains are reported., Results: From 315 included studies [600 552 subjects], most originated from Europe [196; 62%] and North America [59; 19%], and were published between 2011 and 2021 [251; 80%]. The most frequent domains were demographics [311; 98.7%] and clinical [289; 91.7%]; 224 [71.1%] studies reported on the triad of sex [306; 97.1%], age [289; 91.7%], and disease phenotype [231; 73.3%]. Few included baseline data for radiology [19; 6%], healthcare utilization [19; 6%], and histology [17; 5.4%]. Ethnicity [19; 6%], race [17; 5.4%], and alcohol/drug consumption [6; 1.9%] were the least reported demographics. From 25 MIs for clinical disease activity, the Harvey-Bradshaw Index [n = 53] and Mayo score [n = 37] were most frequently used., Conclusions: Substantial variability exists in baseline population data reporting. These findings will inform a future consensus for MDS in IBD to enhance data harmonization and credibility of real-world evidence., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT., Methods: In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT., Findings: We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months)., Interpretation: Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT., Funding: amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds., Competing Interests: Declaration of interests AB reports grants from Gilead Sciences and participating on the advisory board of ViiV Healthcare. AW reports funding for this manuscript from the American Foundation for AIDS Research (amfAR) and Aidsfunds; grants from Gilead and NOW; consulting fees from ViiV Healthcare/GSK, MSD, and Gilead Sciences; participating on the board of the Dutch Federation of Medical Microbiology, the board of the European Society for Translational Antiviral Research, chair on the IAS-USA mutations work group, the Committee of ZonMW (Dutch research organization) Research, and the Committee of the Dutch Federation for Long Covid; and received funding from Ark. AS-C reports funding for this manuscript from amfAR; grants from ANRS, the National Institutes of Health (NIH), Institute Pasteur, and MSDAVENIR; honoraria from MSD, ViiV Healthcare, and Gilead Sciences; and is chair of the Scientific and Medical Committee of Sidaction. B-EOJ reports consulting fees from Gilead Sciences, ViiV Healthcare, and Merck Sharp & Dohme; honoraria from Gilead Sciences and ViiV Healthcare; travel expenses for attending meetings from Gilead; and is scientific secretary for the German AIDS Society. BR reports honoraria from Gilead Sciences, Janssen, and ViiV Healthcare; payment for advice from ViiV Healthcare; and travel expenses for attending meetings and travel from ViiV Healthcare and Gilead Sciences. GH reports travel expenses for attending the meeting and travel for the HIV Persistence Workshop 2022. JB reports receiving honoraria from AbbVie, Pfizer, and Gilead Sciences; and travel expenses for attending meetings from AbbVie, Pfizer, and Gilead Sciences. JK reports grants from Novartis and Miltenyi Biotech; royalties from GADETA and Miltenyi Biotech; a patent with GADETA; and holds stock interest in GADETA. JM-P reports funding for this manuscript from amfAR. JSZW reports funding for this manuscript from The German Center for Infection Research, EU H2020 Research and Innovation Programme, HW & J Hector Foundation, the German Research Foundation, The Hamburg Investment and Development Bank, and amfAR; and honoraria from Nobite, GSK, and Gilead Sciences. JTS reports funding for this manuscript from the NIH and National Institute of Allergy and Infectious Diseases. LB report grants from Abbvie and Gilead Sciences; consulting fees from Abbvie and Gilead Sciences; and honoraria from AbbVie and Gilead Sciences. LV reports receiving grants from ViiV Healthcare and Gilead Sciences; and consulting fees from ViiV Healthcare and Gilead Sciences. MJG and GA declare being an employee of Ragon Institute of Mass General, MIT, and Harvard during the study; and an employee of Moderna afterwards. MNi reports receiving consulting fees from Gilead Sciences; and honoraria for lectures from ViiV Healthcare. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Oats are known for their nutritional value and also for their beneficial properties on human health, such as the reduction of cholesterol levels and risk of coronary heart disease; they are an important export product for Chile. During the last decade (2010-2022) over 90% of the oat cultivated area in Chile has been covered with Avena sativa L. cv. Supernova INIA. This lack of genetic diversity in a context of climate change could limit the long-term possibility of growing oats in Chile. The present study is a phenotypic and genetic analysis of 132 oat cultivars and pure lines of diverse origin that can be considered as potential breeding material. The germplasm was evaluated for 28 traits and analyzed with 14 SSR markers. The effects of genotypes on phenotype were significant over all traits ( P ≤ 0.05). Most traits exhibited moderate to high broad-sense heritability with exceptions such as yield (H 2 = 0.27) and hulls staining (H 2 = 0.32). Significant undesirable correlations between traits were generally of small biological importance, which is auspicious for achieving breeding objectives. Some of the heritability data and correlations provided here have not been previously reported. The overall phenotypic diversity was high (H' = 0.68 ± 0.18). The germplasm was grouped into three phenotypic clusters, differing in their qualities for breeding. Twenty-six genotypes outperforming Supernova INIA were identified for breeding of conventional food-oats. The genetic diversity of the germplasm was moderate on average (He = 0.58 ± 0.03), varying between 0.32 (AM22) and 0.77 (AME178). Two genetic subpopulations supported by the Structure algorithm exhibited a genetic distance of 0.24, showing low divergence of the germplasm. The diversity and phenotypic values found in this collection of oat genotypes are promising with respect to obtaining genetic gain in the short term in breeding programs. However, the similar genetic diversity, higher phenotypic diversity, and better phenotypic performance of the germplasm created in Chile compared to foreign germplasm suggest that germplasm harboring new genetic diversity will be key to favor yield and quality in new oat cultivars in the long term., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Mathias-Ramwell, Pavez, Meneses, Fernández, Valdés, Lobos, Silva, Saldaña and Hinrichsen.)

Introduction: The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B-ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin (IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B-ALL., Patients and Methods: This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología)., Results: Thirty-four patients with a median age of 43 years (range, 19-73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression-free survival and overall survival (OS) were 4.7 (95%CI, 2.4-7.0 months), 3.5 (95%CI, 1.0-5.0 months) and 4 months (95%CI, 1.9-6.1 months) respectively, with better OS for patients with relapsed B-ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p = .01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months [95%CI, 3.2-11.2] vs. 3 months [95% CI, 1.8-4.2] respectively) (p = .054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3-4 SOS during alloHSCT after IO treatment., Conclusions: Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tuberculosis remains a challenge in both rural and urban areas. Although a majority of countries display a higher burden in urban areas compared with rural areas, Panama continues to report the highest mortality rate in Central America. Urban areas, such as Panama City, report a high tuberculosis burden, whereas Panama's western region, including the provinces of Chiriquí, Bocas del Toro (both semiurban) and Ngäbe-Bugle (rural), show a lower burden. We aimed to identify highly transmitted Mycobacterium tuberculosis strains within rural and semiurban settings of Panama's western region during a 3-year period (2017, 2019, 2021). We randomly selected 87 M. tuberculosis isolates from a biobank from Panama's western region and analyzed them using allele-specific oligonucleotide polymerase chain reaction and 24-mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR). Our results show only 11.7% (10/85) of M. tuberculosis strains identified as prevalent A-Beijing, B-Haarlem, or C-LAM Strains. We found a low prevalence of A, B, and C M. tuberculosis strains in both rural and semirural settings compared with isolates collected from the Eastern Colon Province. MIRU-VNTR genotyping revealed a high degree of diversity with no clusters with single loci variation of ≥ 2 loci. These results support the notion that tuberculosis prevalence in the rural and semiurban western region of Panama are not due to previously described highly transmitted strains but is influenced instead by other health determinants, including poor health system access and a lack of systematic transmission chain monitoring. For remote rural and semiurban settings, we recommend allocating resources to reinforce efforts to prevent tuberculosis spread.

Background and Aims: As more therapeutic options with their own characteristics become available for inflammatory bowel disease [IBD], drug development and individual treatment decision-making needs to be tailored towards patients' preferences and needs. This study aimed to understand patient preferences among IBD patients, and their most important treatment outcomes and unmet needs., Methods: This qualitative study consisted of [1] a scoping literature review, [2] two focus group discussions [FGDs] with IBD patients [n = 11] using the nominal group technique, and [3] two expert panel discussions., Results: IBD patients discussed a multitude of unmet needs regarding their symptoms, side-effects, and psychological and social issues for which they would welcome improved outcomes. In particular, IBD patients elaborated on the uncertainties and fears they experienced regarding the possible need for surgery or an ostomy, the effectiveness and onset of action of their medication, and the medication's long-term effects. Furthermore, participants extensively discussed the mental impact of IBD and their need for more psychological guidance, support, and improved information and communication with healthcare workers regarding their disease and emotional wellbeing. The following five characteristics were identified during the attribute grading as most important: prevent surgery, long-term clinical remission, improved quality of life [QoL], occurrence of urgency and improved labour rate., Conclusions: This study suggests that IBD drug development and treatment decision-making are needed to improve IBD symptoms and adverse events that significantly impact IBD patients' QoL. Furthermore, this study underlines patients' need for a shared decision-making process in which their desired treatment outcomes and uncertainties are explicitly discussed and considered., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: The utility of real-world data is dependent on the quality and homogeneity of reporting. We aimed to develop a core outcome set for real-world studies in adult patients with inflammatory bowel disease [IBD]., Methods: Candidate outcomes and outcome measures were identified and categorised in a systematic review. An international panel including patients, dietitians, epidemiologists, gastroenterologists, nurses, pathologists, radiologists, and surgeons participated in a modified Delphi consensus process. A consensus meeting was held to ratify the final core outcome set., Results: A total of 26 panellists from 13 countries participated in the consensus process. A total of 271 items [130 outcomes, 141 outcome measures] in nine study domains were included in the first-round survey. Panellists agreed that real-world studies on disease activity should report clinical, endoscopic, and biomarker disease activity. A disease-specific clinical index [Harvey-Bradshaw Index, Partial Mayo Score, Simple Clinical Colitis Activity Index] should be used, rather than physician global assessment. In ulcerative colitis [UC], either the UC Endoscopic Index of Severity or the Mayo Endoscopic Score can be used, but there was no consensus on an endoscopic index for Crohn's disease, nor was there consensus on the use of the presence of ulcers. There was consensus on using faecal calprotectin and C-reactive protein. There was no consensus on the use of histology in real-world studies., Conclusions: A core outcome set for real-world studies in IBD has been developed based on international multidisciplinary consensus. Its adoption will facilitate synthesis in the generation of real-world evidence., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Describe the measurements of systolic, diastolic and mean blood pressure in healthy term and late preterm newborns to establish normal values., Methods: Cross-sectional study carried out in the nursery of the Hospital Español, located in Mexico City. A sample of 551 healthy newborns were included in the study. Blood pressure (BP) measurements were taken within the first 48 hours of life with the oscillometric method. After the evaluation of normality, a descriptive analysis of the population and calculation of percentiles (25, 50 and 75) specific for each week of gestation was performed. All analyzes were performed in STATA v14.2., Results: Male newborns had a mean SBP value of 64.6 mmHg at week 35 of gestation, this value increased to 69.8 mmHg at week 40; the systolic blood pressure (SBP) value was 42.6 mmHg at week 35 of gestation, which decreased to 40.8 mmHg at week 40. The mean SBP values in female newborns were 65.5 mmHg at week 35, increasing to 73.5 mmHg at week 40; the diastolic blood pressure (DBP) value at week 35 of gestation was 38 mmHg, increasing to 41.3 mmHg at week 40., Conclusions: The BP values in healthy newborns are modified by the gestational age and sex of the patients. These results can serve as a reference for other physicians located in countries or cities with a similar altitude than the one in Mexico City., (Copyright: © 2023 Permanyer.)

Background: Heterogeneity exists in reported outcomes and outcome measurement instruments [OMI] from observational studies. A core outcome set [COS] for observational and real-world evidence [RWE] in inflammatory bowel disease [IBD] will facilitate pooling large datasets. This systematic review describes and classifies clinical and patient-reported outcomes, for COS development., Methods: The systematic review of MEDLINE, EMBASE, and CINAHL databases identified observational studies published between 2000 and 2021 using the population exposure outcome [PEO] framework. Studies meeting eligibility criteria were included. After titles and abstracts screening, full-text articles were extracted by two independent reviewers. Primary and secondary outcomes with corresponding OMI were extracted and categorised in accordance with OMERACT Filter 2.1 framework. The frequency of outcomes and OMIs are described., Results: From 5854 studies, 315 were included: 129 [41%] Crohn's disease [CD], 60 [19%] ulcerative colitis [UC], and 126 [40%] inflammatory bowel disease [IBD] studies with 600 552 participants. Totals of 1632 outcomes and 1929 OMI were extracted mainly from medical therapy [181; 72%], surgical [34; 11%], and endoscopic [6; 2%] studies. Clinical and medical therapy-related safety were frequent outcome domains recorded in 194 and 100 studies. Medical therapy-related adverse events [n = 74] and need for surgery [n = 71] were the commonest outcomes. The most frequently reported OMI were patient or event numbers [n = 914], Harvey-Bradshaw Index [n = 45], and Montreal classification [n = 42]., Conclusions: There is substantial variability in outcomes reporting and OMI types. Categorised outcomes and OMI from this review will inform a Delphi consensus on a COS for future RWE in IBD. Data collection standardisation may enhance the quality of RWE applied to decision-making., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Analgesics are widely used, but evidence regarding whether their use increases the risk of inflammatory bowel disease (IBD) flares or complications is unclear. Therefore, self-medication with analgesics in IBD is usually not recommended. The aim of this study was to explore the prevalence of self-medication with analgesics in a cohort of ulcerative colitis (UC) patients and to identify reasons and factors associated with self-medication., Methods: This cross-sectional study included consecutive unselected adult patients with UC. Participants were asked to complete an anonymous web-based survey with multiple-choice questions and closed responses. No clinical data were collected., Results: A total of 546 patients (61.2% women, mean age 39.9 years) completed the survey. The prevalence of self-medication with analgesics was 49.8% (272/546). Paracetamol (45.2%) and metamizole (21.2%) were the most frequently used drugs; frequencies of self-medication were <5% for other analgesics (nonsteroidal anti-inflammatory drugs, opioids). The most frequent reasons for self-medication were the need for quick symptom relief and that it had been agreed with/prescribed by the treating physician. Multivariable analysis identified female sex (odds ratio [OR]=1.9), sick leave (OR=2.2), treatment with intravenous drugs (OR=2.9), and emergency room visit (OR=2.3) as variables associated with self-medication, whilst follow-up by a nurse was associated with less self-medication (OR=0.6)., Conclusion: The frequency of self-medication with analgesics in UC patients is high and appears to be associated with variables suggesting worse disease control. Closer follow-up, including a specialized nurse, could decrease self-medication. Strategies to improve disease control, including close monitoring of symptoms such as pain, are needed., (Copyright © 2021 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Quality of care (QoC) is a highly important topic in inflammatory bowel disease (IBD). We recently elaborated a decalogue of QoC indicators (IQCARO-QoC) developed by IBD patients. The aim of the present study was to assess the factors associated with patients' evaluation of QoC in Spain using the IQCARO-QoC Decalogue recently developed by IBD patients., Methods: A survey including patients' socio-demographic and clinical characteristics, and the IQCARO-QoC Decalogue, was completed by IBD patients. We described patients' assessment of QoC across Spanish patients. A univariable and multivariable analysis was performed to explore the associations between patients' characteristics and QoC., Results: Questionnaires from 788 participant patients were analysed. Participants' mean age was 43.4 years, 63% were females and 58% had Crohn's disease. The mean QoC score was 8.1 (± 2.4 SD) points out of a maximum of 10. Items with the lowest score were related to the provision of information and the implication of the medical team throughout the entire patient care. Factors associated with better QoC scores included: being employed better disease control, fewer numbers of unscheduled visits, and being followed by a gastroenterologist specialized in IBD., Conclusions: Spanish patients' reported QoC seems to be globally good although there is room for improvement, especially in providing adequate information to patients. Care provided by specialized IBD gastroenterologists seems to be related with higher QoC scores., (© 2021. The Author(s).)

Background: Measuring quality of care (QoC) from a patient's perspective is becoming increasingly important in inflammatory bowel disease., Objective: The objective of this study was to determine whether patients' evaluations of QoC correlate with better inflammatory bowel disease outcomes., Methods: A survey including patients' characteristics, a decalogue of QoC indicators, and self-reported disease outcomes was completed by Spanish patients with inflammatory bowel disease. A QoC index (QoCI) was constructed with the sum of the "yes" answers in the decalogue. We evaluated the correlation of QoCI with outcomes. A sub-analysis comparing patients with high QoCI vs those with low QoCI was performed (QoCI = 10 or ≤ 7)., Results: Seven hundred and eighty-eight questionnaires were analyzed. Mean age of participants was 43.4 years (63% women). Mean QoCI was 8.1 (± 2.4). The QoCI correlated significantly with activity of the disease, number of flares, emergency/unscheduled visits, and disease control. Patients scoring in the first QoCI quartile reported a decreased rate of moderate/severe disease (34.8% vs 55.3%, p < 0.001), fewer numbers of flares (p < 0.001), and fewer emergency/unscheduled visits (p < 0.001) compared with those in the lower QoCI quartile. The high QoC group also reported better disease control., Conclusions: Patient-evaluated QoC correlates with better outcomes. Evaluation of QoC by patients may be useful to detect inadequate care and improve inflammatory bowel disease outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique oncogenic event involving the constitutively active tyrosine-kinase (TK) BCR/ABL1 . TK inhibitors (TKI) changed its prognosis and natural history. Unfortunately, ABL1 remains unaffected by TKIs. Leukemic stem cells (LSCs) remain, and resistant mutations arise during treatment. To address this problem, we have designed a therapeutic CRISPR-Cas9 deletion system targeting BCR/ABL1 . The system was efficiently electroporated to cell lines, LSCs from a CML murine model, and LSCs from CML patients at diagnosis, generating a specific ABL1 null mutation at high efficiency and allowing the edited leukemic cells to be detected and tracked. The CRISPR-Cas9 deletion system triggered cell proliferation arrest and apoptosis in murine and human CML cell lines. Patient and murine-derived xenografts with CRISPR-edited LSCs in NOD SCID gamma niches revealed that normal multipotency and repopulation ability of CRISPR edited LSCs were fully restored. Normal hematopoiesis was restored, avoiding myeloid bias. To the best of our knowledge, we show for the first time how a CRISPR-Cas9 deletion system efficiently interrupts BCR/ABL1 oncogene in primary LSCs to bestow a therapeutic benefit. This study is a proof of concept for genome editing in all those diseases, like CML, sustained by a single oncogenic event, opening up new therapeutic opportunities.

The potential role of active CMV infection in promoting acute Graft-versus-Host Disease (aGvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. We further addressed this issue conducting a retrospective, observational, multicenter study of 632 patients subjected to allogeneic peripheral blood HSCT at 20 Spanish centers. Monitoring of CMV DNA load in plasma or whole blood was performed by real-time PCR assays. Cumulative incidence of CMV DNAemia was 48.9% (95% CI, 45%-52.9%), of any grade aGvHD, 45.6; 95% (CI, 41.3%-50.1%), and of grade II-IV aGvHD, 30.7 (95% CI, 24.9%-36.4%). Overall, development of CMV DNAemia at any level resulted in an increased risk of subsequent all grade (HR, 1.38; 95% CI, 1.08 - 1.76; P = .009) or grade II-IV (HR, 1.58; 95% CI, 1.22 - 2.06; P = .001) aGvHD. The increased risk of aGvHD linked to prior occurrence of CMV DNAemia was similar to the above when only clinically significant episodes were considered for the analyses (HR for all grade aGvHD, 1.48; 95% CI, 1.13 - 1.91; P = .041, and HR for grade II-IV aGvHD, 1.53; 95% CI. 1.13-1.81; P = .04). The CMV DNA doubling time in blood was comparable overall in episodes of CMV DNAemia whether followed by aGvHD or not. Whether CMV replication is a surrogate risk marker of aGvHD or it is causally involved is an important question to be addressed in future experimental research., (© 2021 Wiley Periodicals LLC.)

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

There is limited information on the impact of CMV DNAemia episodes developing prior to engraftment (pre-CMV DNAemia) on clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This issue was addressed in the current retrospective multicenter study including 878 patients. All participant centers used preemptive antiviral therapy strategies for prevention of CMV disease. CMV DNA load in blood was monitored by real-time PCR assays. A total of 144 patients (cumulative incidence 16.5%, 95% CI, 14%-19%) had an episode of pre-CMV DNAemia at a median of 10 days after allo-HSCT. Patients who developed pre-CMV DNAemia had a significantly higher (P = < 0.001) probability of recurrent episodes (50%) than those who experienced post-CMV DNAemia (32.9%); Nevertheless, the incidence of CMV disease was comparable (P = 0.52). Cumulative incidences of overall mortality (OM) and non-relapse mortality (NRM) at 1-year after allo-HSCT were 32% (95% CI, 29-35%) and 23% (95% CI 20-26%), respectively. The risk of OM and NRM in adjusted models appeared comparable in patients developing a single episode of CMV DNAemia, regardless of whether it occurred before or after engraftment, in patients with pre- and post-engraftment CMV DNAemia episodes or in those without CMV DNAemia.

Background: Few studies have examined self-medication with corticosteroids among patients with ulcerative colitis (UC)., Aims: To assess the frequency of self-medication with oral corticosteroids in UC patients, and associated factors and reasons., Methods: An anonymous, voluntary, web-based survey was administered to adults with UC recruited via a Spanish patient association (ACCU) and hospital gastroenterology departments. Information was provided by patients; no clinical data were collected. Descriptive statistics and comparisons of frequencies are displayed., Results: Among 546 respondents (mean age 39.9 years, median duration of UC since diagnosis 7 years,) 36 (6.6%) reported self-medication with oral corticosteroids during the past year (once: 23 patients; 2-3 times: 10 patients; >3 times: 3 patients). Self-medication was more common among patients managed in general gastroenterology vs. inflammatory bowel disease clinics [23 (9.0%) vs. 11 (2.9%), P = 0.019], patients with no regular follow-up [4 (22.2%) vs. 32 (6.1%), P = 0.026] and patients with more flares (P < 0.001). Patients who stored steroids from previous flares (17.9% vs. 6.0%, P < 0.001) or who lived with a partner taking steroids (9.3% vs. 1.1%, P = 0.038) were more likely to self-medicate than other patients. Common reasons for self-medicating included the need for quick symptom relief (55.6%), fear of worsening (47.2%) and difficulty in getting an appointment (25.0%). Only seven patients (19.4%) informed their physician when they started self-medicating and only four (11.1%) declared they would not start corticosteroids again., Conclusion: Self-medication with oral corticosteroids is not a common practice among patients with UC in Spain, but several areas of improvement exist., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The net impact of cytomegalovirus (CMV) DNAemia on overall mortality (OM) and nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. This was a retrospective, multicenter, noninterventional study finally including 749 patients. CMV DNA monitoring was conducted by real-time polymerase chain reaction (PCR) assays. Clinical outcomes of interest were OM and NRM through day 365 after allo-HSCT. The cumulative incidence of CMV DNAemia in this cohort was 52.6%. A total of 306 out of 382 patients with CMV DNAemia received preemptive antiviral therapy (PET). PET use for CMV DNAemia, but not the occurrence of CMV DNAemia, taken as a qualitative variable, was associated with increased OM and NRM in univariate but not in adjusted models. A subcohort analysis including patients monitored by the COBAS Ampliprep/COBAS Taqman CMV Test showed that OM and NRM were comparable in patients in whom either low or high plasma CMV DNA threshold (<500 vs ≥500 IU/mL) was used for PET initiation. In conclusion, CMV DNAemia was not associated with increased OM and NRM in allo-HSCT recipients. The potential impact of PET use on mortality was not proven but merits further research., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Aims: Our objective was to define, describe and organize (on the basis of consensus) the patient's preferences in the management of ulcerative colitis (UC), in order to further incorporate them in daily practice and improve patients satisfaction, adherence to the treatment and quality of care., Methods: Qualitative study. A narrative literature review in Medline using Mesh and free-text terms was conducted to identify articles on UC patient preferences as well as clinical scenarios that may influence the preferences. The results were presented and discussed in a multidisciplinary nominal group meeting composed of six gastroenterologists, one primary care physician, one nurse practitioner and one expert patient. Key clinical scenarios and patient preferences were then defined, generating a series of points to consider and recommendations. The level of agreement with the final selection of preferences was established following a Delphi process., Results: The narrative review retrieved 69 articles of qualitative design and moderate quality. The following key clinical scenarios were identified: diagnosis, follow-up, surgery, and special situations/patients profiles such as adolescents or women. Patient preferences were classified into information, treatment (pharmacological and non-pharmacological), follow-up, relations with health professionals, relations with the health system and administration. Finally, 11 recommendations on patient preferences for UC in relation to its management reached the level of agreement established., Conclusion: The consensual description of patient's preferences contribute to identify different areas for improvement in healthcare practice.

Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined., Patients and Methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020., Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2-3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p < 0.0001); ECOG 3-4 (OR, 2.56, 95% CI 1.4-4.7, p = 0.003); neutropenia (< 0.5 × 10 9 /L) (OR 2.8, 95% CI 1.3-6.1, p = 0.01); and a C-reactive protein (CRP) > 20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p < 0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p = 0.02) whereas the use of hidroxycloroquine did not show significant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P = 0.1)., Conclusions: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of inflammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19., Competing Interests: Competing interestsThe author(s) declare that they have no conflict of interests., (© The Author(s) 2020.)

Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, inflammatory bowel diseases (IBD). Each class and type of medication available for the treatment of IBD has distinct characteristics and long-term effects that a patient may consider. We present the results of qualitative research that aimed to develop a descriptive framework that outlines the most relevant disease and/or treatment attributes for IBD treatment decisions and focuses on the patient perspective., Methods: This research employed a three-step approach: a literature review to identify a broad list of attributes, a focus group meeting including patients and clinicians to assess the relevance of the attributes, and two rounds of voting to name and define each attribute. The literature review was used to develop the initial list of attributes. Although the same attributes were defined for both UC and CD, the relative importance of each attribute to UC or CD was considered. The list of attributes was discussed and evaluated in the focus group meeting, which included eight patient representatives and nine gastroenterologists. Using feedback elicited from the focus group meeting, the research team developed a draft of the descriptive framework that grouped the attributes into domain subsets. All members of the focus group participated in two subsequent rounds of structured, online voting, which was used to refine the wording to name and define each attribute. Additionally, participants ranked all the attributes included in the descriptive framework to suggest which attributes were less relevant and could be omitted., Results: Among 574 publications retrieved from the databases and registries, we identified 32 eligible publications, and an initial list of attributes was developed. This list was refined during the focus group meeting, resulting in a draft descriptive framework of attributes within subsets of domains. The final descriptive framework was developed based on structured rounds of online voting to further refine attribute names and definitions. In the final descriptive framework, a total of ten attributes were identified: abdominal pain, other disease-related pain, bowel urgency, fatigue, risk of cancer and serious infections within the next 10 years, risk of mild to moderate complications, aesthetic complications related to treatment, emotional status, sexual life, and social life and relationships. These attributes were distributed across three domains: efficacy, complications and risk, and health-related quality of life., Conclusions: Through the identification of the ten most relevant attributes that influence patient decision making for IBD treatments, we developed a descriptive framework that should be considered by physicians when discussing IBD treatment options with their patients. The results of our qualitative research may also be helpful for the development of future IBD clinical studies and quantitative research.

Purpose: Information regarding patients' needs, fears and experiences/perceptions in the perioperative setting is limited. Through two focus groups, we explored the needs, fears and experiences of patients who had recently undergone, or were scheduled for, surgery under general anaesthesia, with regard to the entire perioperative process., Materials and Methods: Adults were invited to participate in a focus group if they had (a) undergone abdominal or gynaecological surgery with general anaesthesia in the past 4 months (focus group 1) or (b) been indicated for abdominal or gynaecological surgery and were waiting for the assigned surgery date (focus group 2). Discussions were audio recorded and, through thematic analysis, patients' needs and experiences/perceptions regarding perioperative surgical stages were obtained/coded. Analysis of code co-occurrence was performed using a codes matrix., Results: Focus groups consisted of 13 females, 1 male (50% aged >45 years). The immediate postoperative period generated the highest number of co-occurrences, followed by the indication of surgery. The most frequent code was the need for information, especially at the indication of surgery, the pre-anaesthesia clinic and in the postoperative period. Fears were described particularly at the indication of surgery, the waiting period, the surgical room, anaesthesia induction and the postoperative period, particularly after hospital discharge; pain was cited most commonly in the postoperative period. Stress/anxiety and emotional impact were also cited in the postoperative period including home arrival., Conclusion: Information collected in these patients' focus groups should inform future research and healthcare planning. Patients demand receiving more comprehensive and understandable information and more involvement in several steps; this could reduce fears and stress/anxiety described across the perioperative process. Importantly, findings also extend to the postoperative period and home arrival., Competing Interests: José M de Pedro and Luis Cea-Calvo are full-time employees of Merck Sharp & Dohme Spain. Milena Gobbo reports personal fees from MSD, during the conduct of the study; personal fees from Sanofi, Pfizer, Abbvie, Sandoz, outside the submitted work. Roberto Saldaña reports grants from MSD, during the conduct of the study; grants from MSD, Abbvie, Janssen, Pfizer, Roche, Dr. Falk, Ferring, and Takeda, outside the submitted work. María I García-Vega reports personal fees from MSD, during the conduct of the study. The rest of the authors report no other conflicts of interest in this work., (© 2020 Gobbo et al.)

Background: Quality improvement is a major topic in inflammatory bowel disease (IBD) care, and measuring quality of care (QoC) is necessary for QoC improvement. Most QoC projects or consensus statements are designed from the health care professional point of view. Having QoC indicators designed for and fully evaluable by patients may provide a key tool for external evaluation of QoC improvement measures. The aim of the IQCARO project was to identify indicators to measure QoC from the IBD patient's point of view., Methods: An extensive review of the literature to identify indicators of QoC was performed; first the identified indicators were reviewed by a steering committee including patients, nurses, IBD specialists, and methodologists. Then 2 focus groups of IBD patients analyzed the QoC indicators to determine whether they could be understood and evaluated by patients. The final QoC indicators were selected by a group of IBD patients using a Delphi consensus methodology., Results: An initial list of 54 QoC indicators was selected by the steering committee. The QoC indicators were evaluated by 16 patients who participated in 2 focus groups. They identified 21 indicators that fulfilled the understandability and evaluability requirements. The 10 most relevant QoC indicators were selected by 26 patients with IBD using a Delphi consensus. The selected items covered important aspects of QoC, including professionalism, patients' autonomy, information, accessibility, and continuity of care., Conclusions: The present Delphi consensus identified QoC indicators that are useful for developing and measuring improvement strategies in the management of IBD., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The function of the CCCTC-binding factor (CTCF) in the organization of the genome has become an important area of investigation, but the mechanisms by which CTCF dynamically contributes to genome organization are not clear. We previously discovered that CTCF binds to large numbers of endogenous RNAs, promoting its self-association. In this regard, we now report two independent features that disrupt CTCF association with chromatin: inhibition of transcription and disruption of CTCF-RNA interactions through mutations of 2 of its 11 zinc fingers that are not required for CTCF binding to its cognate DNA site: zinc finger 1 (ZF1) or zinc finger 10 (ZF10). These mutations alter gene expression profiles as CTCF mutants lose their ability to form chromatin loops and thus the ability to insulate chromatin domains and to mediate CTCF long-range genomic interactions. Our results point to the importance of CTCF-mediated RNA interactions as a structural component of genome organization., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBR i ) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBR i impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBR i mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBR i -independent and RBR i -dependent loops. We speculate that evidence for RBR i -dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBR i -interacting partners., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Chromatin domains and their associated structures must be faithfully inherited through cellular division to maintain cellular identity. However, accessing the localized strategies preserving chromatin domain inheritance, specifically the transfer of parental, pre-existing nucleosomes with their associated post-translational modifications (PTMs) during DNA replication, is challenging in living cells. We devised an inducible, proximity-dependent labeling system to irreversibly mark replication-dependent H3.1 and H3.2 histone-containing nucleosomes at desired loci in mouse embryonic stem cells so that their fate after DNA replication could be followed. Strikingly, repressed chromatin domains are preserved through local re-deposition of parental nucleosomes. In contrast, nucleosomes decorating active chromatin domains do not exhibit such preservation. Notably, altering cell fate leads to an adjustment of the positional inheritance of parental nucleosomes that reflects the corresponding changes in chromatin structure. These findings point to important mechanisms that contribute to parental nucleosome segregation to preserve cellular identity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity., (© 2019 Lee et al.; Published by Cold Spring Harbor Laboratory Press.)

CRISPR/Cas9 allows the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null result in all cases, but instead generate a similar, functionally active protein. This effect could limit the therapeutic efficiency of gene therapy strategies based on abrogating oncogene expression, and therefore needs to be considered carefully. If there is an acceptable degree of efficiency of CRISPR/Cas9 delivery to cells, the key step for success lies in the effectiveness of a specific sgRNA at knocking out the oncogene, when only one sgRNA can be used. This study shows that the null effect could be increased with an sgRNA targeting the splice donor site (SDS) of the chosen exon. Following this strategy, the generation of null alleles would be facilitated in two independent ways: the probability of producing a frameshift mutation and the probability of interrupting the canonical mechanism of pre-mRNA splicing. In these contexts, we propose to improve the loss-of-function yield driving the CRISPR system at the SDS of critical exons., Competing Interests: The authors have declared that no competing interests exist.

To assess inflammatory bowel disease (IBD) patients' experience of chronic illness care and the relationship with demographic and healthcare-related characteristics.This cross-sectional survey used the Instrument to Evaluate the EXperience of PAtients with Chronic diseases (IEXPAC) questionnaire to identify parameters associated with a better healthcare experience for IBD patients. IEXPAC questionnaire responses are grouped into 3 factors - productive interactions, new relational model, and patient self-management, scoring from 0 (worst) to 10 (best experience). Scores were analyzed by bivariate comparisons and multiple linear regression models.Surveys were returned by 341 of 575 patients (59.3%, mean age 46.8 (12.9) years, 48.2% women). Mean (SD) IEXPAC score was 5.9 (2.0); scores were higher for the productive interactions (7.7) and patient self-management factors (6.7) and much lower for the new relational model factor (2.2). Follow-up by a nurse, being seen by the same physician, and being treated with a lower number of medicines were associated with higher (better) overall patient experience score, and higher productive interactions and self-management factor scores. A higher productive interactions score was also associated with patients receiving medication subcutaneously or intravenously. Higher new relational model scores were associated with follow-up by a nurse, affiliation to a patients' association, receiving help from others for healthcare, a lower number of medicines and a higher educational level.In patients with IBD, a better overall patient experience was associated with follow-up by a nurse, being seen by the same physician, and being treated with a lower number of medicines.

Objectives: Patient involvement in drug evaluation decision making is increasing. The aim of the current study was to develop a multi-criteria decision analysis (MCDA) framework that would enable the inclusion of the patient perspective in the selection of appropriate criteria for MCDAs being used in the value assessments of oncologic drugs., Methods: A literature review was conducted to identify and define criteria used in drug assessments from patient perspectives. The Evidence and Value: Impact on Decision Making methodology was used to develop a MCDA framework. Identified criteria were discussed by a sample of oncology patient association representatives who decided which criteria were important from patient perspectives. Selected criteria were rated by importance. The preliminary MCDA framework was tested through the assessment of a hypothetical oncology treatment. A discussion was carried out to agree on a final pilot MCDA framework., Results: Twenty-two criteria were extracted from the literature review. After criteria discussion, sixteen criteria remained. The most important criteria were comparative patient reported outcomes (PRO), comparative efficacy and disease severity. After the discussion generated by the scoring of the hypothetical oncology treatment, the final pilot MCDA framework included seven quantitative criteria ("disease severity", "unmet needs", "comparative efficacy / effectiveness", "comparative safety / tolerability", "comparative PROs", "contribution of oncological innovation") and one contextual criterion ("population priorities and access")., Conclusions: The present study developed a pilot reflective MCDA framework that could increase patient's capability to participate in the decision-making process by providing systematic drug assessments from the patient perspective.

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs). However, we also show that a PRC2-associated protein, AEBP2, can stimulate the activity of both complexes through a mechanism independent of and additive to allosteric activation. These results have strong implications regarding the cellular requirements for and the accompanying adjustments in PRC2 activity, given the differential expression of EZH1 and EZH2 upon cellular differentiation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: We describe the results of a prospective multicenter phase I/II trial evaluating the impact of the use of vitamin D (VitD) from day -5 to +100 on the outcome of patients undergoing allogeneic transplantation (EudraCT: 2010-023279-25; ClinicalTrials.gov: NCT02600988)., Experimental Design: A total of 150 patients were included in three consecutive cohorts of 50 patients each group: control group (CG, not receive VitD); low-dose group (LdD, received 1,000 IU VitD daily); and high-dose group (HdD, 5,000 IU VitD daily). We measured levels of VitD, cytokines, and immune subpopulations after transplantation., Results: No significant differences were observed in terms of cumulative incidence of overall and grades 2-4 acute GVHD in terms of relapse, nonrelapse mortality, and overall survival. However, a significantly lower cumulative incidence of both overall and moderate plus severe chronic GVHD (cGVHD) at 1 year was observed in LdD (37.5% and 19.5%, respectively) and HdD (42.4% and 27%, respectively) as compared with CG (67.5% and 44.7%, respectively; P < 0.05). In multivariable analysis, treatment with VitD significantly decreased the risk of both overall (for LdD: HR = 0.31, P = 0.002; for HdD: HR = 0.36, P = 0.006) and moderate plus severe cGVHD (for LdD: HR = 0.22, P = 0.001; for HdD: HR = 0.33, P = 0.01). VitD modified the immune response, decreasing the number of B cells and naïve CD8 T cells, with a lower expression of CD40L., Conclusions: This is the first prospective trial that analyzes the effect of VitD postransplant. We observed a significantly lower incidence of cGVHD among patients receiving VitD. Interestingly, VitD modified the immune response after allo-SCT. Clin Cancer Res; 22(23); 5673-81. ©2016 AACR., (©2016 American Association for Cancer Research.)