Adapting Medical Guidelines to Be Patient-centered Using a Patient-driven Process for Individuals With Sickle Cell Disease and Their Caregivers

Background: Evidence-based guidelines for sickle cell disease (SCD) health maintenance and management have been developed for primary health care providers, but not for individuals with SCD. To improve the quality of care delivered to individuals with SCD and their caregivers, the main purposes of this study were to: (1) understand the desire for patient-centered guidelines among the SCD community; and (2) adapt guideline material to be patient-centered using community-engagement strategies involving health care providers, community -based organizations, and individuals with the disease. Methods: From May–December 2016, a volunteer sample of 107 individuals with SCD and their caregivers gave feedback at community forums (n = 64) and community listening sessions (n = 43) about technology use for health information and desire for SCD-related guidelines. A team of community research partners consisting of community stakeholders, individuals living with SCD, and providers and researchers (experts) in SCD at nine institutions adapted guidelines to be patient-centered based on the following criteria: (1) understandable, (2) actionable, and (3) useful. Results: In community forums (n = 64), almost all participants (91%) wanted direct access to the content of the guidelines. Participants wanted guidelines in more than one format including paper (73%) and mobile devices (79%). Guidelines were adapted to be patient-centered. After multiple iterations of feedback, 100% of participants said the guidelines were understandable, most (88%) said they were actionable, and everyone (100%) would use these adapted guidelines to discuss their medical care with their health care providers. Conclusions: Individuals with SCD and their caregivers want access to guidelines through multiple channels, including technology. Guidelines written for health care providers can be adapted to be patient-centered using Community-engaged research involving providers and patients. These patient-centered guidelines provide a framework for patients to discuss their medical care with their health care providers

Spliceosome-mediated decay (SMD) regulates expression of nonintronic genes in budding yeast

We uncovered a novel role for the spliceosome in regulating mRNA expression levels that involves splicing coupled to RNA decay, which we refer to as spliceosome-mediated decay (SMD). Our transcriptome-wide studies identified numerous transcripts that are not known to have introns but are spliced by the spliceosome at canonical splice sites in Saccharomyces cerevisiae. Products of SMD are primarily degraded by the nuclear RNA surveillance machinery. We demonstrate that SMD can significantly down-regulate mRNA levels; splicing at canonical splice sites in the bromodomain factor 2 (BDF2) transcript reduced transcript levels roughly threefold by generating unstable products that are rapidly degraded by the nuclear surveillance machinery. Regulation of BDF2 mRNA levels by SMD requires Bdf1, a functionally redundant Bdf2 paralog that plays a role in recruiting the spliceosome to the BDF2 mRNA. Interestingly, mutating BDF2 5' splice site and branch point consensus sequences partially suppresses the bdf1Δ temperature-sensitive phenotype, suggesting that maintaining proper levels of Bdf2 via SMD is biologically important. We propose that the spliceosome can also repress protein-coding gene expression by promoting nuclear turnover of spliced RNA products and provide an insight for coordinated regulation of Bdf1 and Bdf2 levels in the cell

Correlated response to selection for litter size environmental variability in rabbits' resilience

[EN] Resilience is the ability of an animal to return soon to its initial productivity after facing diverse environmental challenges. This trait is directly related to animal welfare and it plays a key role in fluctuations of livestock productivity. A divergent selection experiment for environmental variance of litter size has been performed successfully in rabbits over ten generations. The objective of this study was to analyse resilience indicators of stress and disease in the divergent lines of this experiment. The high line showed a lower survival rate at birth than the low line (-4.1%). After correcting by litter size, the difference was -3.2%. Involuntary culling rate was higher in the high than in the low line (+12.4%). Before vaccination against viral haemorrhagic disease or myxomatosis, concentration of lymphocytes, C-reactive protein (CRP), complement C3, serum bilirubin, triglycerides and cholesterol were higher in the high line than in the low line (difference between lines +4.5%, +5.6 mu g/ml, +4.6 mg/ml, +7.9 mmol/l, +0.3 mmol/l and +0.4 mmol/l). Immunological and biochemical responses to the two vaccines were similar. After vaccination, the percentage of lymphocytes and CRP concentration were higher in the low line than in the high one (difference between lines +4.0% and +13.1 mu g/ml). The low line also showed a higher increment in bilirubin and triglycerides than the high line (+14.2 v. +8.7 mmol/l for bilirubin and +0.11 v. +0.01 mmol/l for triglycerides); these results would agree with the protective role of bilirubin and triglycerides against the larger inflammatory response found in this line. In relation to stress, the high line had higher basal concentration of cortisol than the low line (+0.2ng/ml); the difference between lines increased more than threefold after the injection of ACTH 1 to 24, the increase being greater in the high line (+0.9 ng/ml) than in the low line (+0.4 ng/ml). Selection for divergent environmental variability of litter size leads to dams with different culling rate for reproductive causes and different kits' neonatal survival. These associations suggest that the observed fitness differences are related to differences in the inflammatory response and the corticotrope response to stress, which are two important components of physiological adaptation to environmental aggressions.This study is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) with the Projects AGL2014-55921, C2-1-P and C2-2-P, and AGL2017-86083, C2-1-P and C2-2-P.Argente, M.; Garcia, M.; Zbynovska, K.; Petruska, P.; Capcarova, M.; Blasco Mateu, A. (2019). Correlated response to selection for litter size environmental variability in rabbits' resilience. Animal. 13(10):2348-2355. https://doi.org/10.1017/S1751731119000302S234823551310Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: implications for health. Nature Reviews Immunology, 5(3), 243-251. doi:10.1038/nri1571Markanday, A. (2015). Acute Phase Reactants in Infections: Evidence-Based Review and a Guide for Clinicians. Open Forum Infectious Diseases, 2(3). doi:10.1093/ofid/ofv098Rauw, W. ., Kanis, E., Noordhuizen-Stassen, E. ., & Grommers, F. . (1998). Undesirable side effects of selection for high production efficiency in farm animals: a review. Livestock Production Science, 56(1), 15-33. doi:10.1016/s0301-6226(98)00147-xPiles, M., García, M. L., Rafel, O., Ramon, J., & Baselga, M. (2006). Genetics of litter size in three maternal lines of rabbits: Repeatability versus multiple-trait models. Journal of Animal Science, 84(9), 2309-2315. doi:10.2527/jas.2005-622Guelfi, G., Zerani, M., Brecchia, G., Parillo, F., Dall’Aglio, C., Maranesi, M., & Boiti, C. (2011). Direct actions of ACTH on ovarian function of pseudopregnant rabbits. Molecular and Cellular Endocrinology, 339(1-2), 63-71. doi:10.1016/j.mce.2011.03.017García ML , Blasco A , García ME and Argente MJ 2018. Body condition and energy mobilisation in rabbits selected for litter size variability. Animal, 1–6, https://doi.org/10.1017/S1751731118002203, Published online by Cambridge University Press 28 August 2018.Furze, R. C., & Rankin, S. M. (2008). Neutrophil mobilization and clearance in the bone marrow. Immunology, 125(3), 281-288. doi:10.1111/j.1365-2567.2008.02950.xMcDade, T. W., Borja, J. B., Kuzawa, C. W., Perez, T. L. L., & Adair, L. S. (2015). C-reactive protein response to influenza vaccination as a model of mild inflammatory stimulation in the Philippines. Vaccine, 33(17), 2004-2008. doi:10.1016/j.vaccine.2015.03.019Blasco, A. (2017). Bayesian Data Analysis for Animal Scientists. doi:10.1007/978-3-319-54274-4Castellini, C., Dal Bosco, A., Arias-Álvarez, M., Lorenzo, P. L., Cardinali, R., & Rebollar, P. G. (2010). The main factors affecting the reproductive performance of rabbit does: A review. Animal Reproduction Science, 122(3-4), 174-182. doi:10.1016/j.anireprosci.2010.10.003Rosa Neto, N. S., & Carvalho, J. F. de. (2009). O uso de provas de atividade inflamatória em reumatologia. Revista Brasileira de Reumatologia, 49(4), 413-430. doi:10.1590/s0482-50042009000400008Argente, M. J., Calle, E. W., García, M. L., & Blasco, A. (2017). Correlated response in litter size components in rabbits selected for litter size variability. Journal of Animal Breeding and Genetics, 134(6), 505-511. doi:10.1111/jbg.12283Mirkena, T., Duguma, G., Haile, A., Tibbo, M., Okeyo, A. M., Wurzinger, M., & Sölkner, J. (2010). Genetics of adaptation in domestic farm animals: A review. Livestock Science, 132(1-3), 1-12. doi:10.1016/j.livsci.2010.05.003García, M. L., Blasco, A., & Argente, M. J. (2016). Embryologic changes in rabbit lines selected for litter size variability. Theriogenology, 86(5), 1247-1250. doi:10.1016/j.theriogenology.2016.04.065Feingold KR and Grunfeld C 2015. The effect of inflammation and infection on lipids and lipoproteins. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F and Vinik A. Endotext, South Dartmouth, MA, USA. Retrieved on 7 June 2018 from https://www.ncbi.nlm.nih.gov/books/NBK326741/.Minemura, M. (2014). Liver involvement in systemic infection. World Journal of Hepatology, 6(9), 632. doi:10.4254/wjh.v6.i9.632Knap, P. W. (2005). Breeding robust pigs. Australian Journal of Experimental Agriculture, 45(8), 763. doi:10.1071/ea05041Barcia, A. M., & Harris, H. W. (2005). Triglyceride-Rich Lipoproteins as Agents of Innate Immunity. Clinical Infectious Diseases, 41(Supplement_7), S498-S503. doi:10.1086/432005Webster, J. I., Tonelli, L., & Sternberg, E. M. (2002). NEUROENDOCRINEREGULATION OFIMMUNITY. Annual Review of Immunology, 20(1), 125-163. doi:10.1146/annurev.immunol.20.082401.104914Fortun-Lamothe, L. (2006). Energy balance and reproductive performance in rabbit does. Animal Reproduction Science, 93(1-2), 1-15. doi:10.1016/j.anireprosci.2005.06.009Cabezas, S., Blas, J., Marchant, T. A., & Moreno, S. (2007). Physiological stress levels predict survival probabilities in wild rabbits. Hormones and Behavior, 51(3), 313-320. doi:10.1016/j.yhbeh.2006.11.004De Nardo, D., Labzin, L. I., Kono, H., Seki, R., Schmidt, S. V., Beyer, M., … Latz, E. (2013). High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nature Immunology, 15(2), 152-160. doi:10.1038/ni.2784BURKUŠ, J., KAČMAROVÁ, M., KUBANDOVÁ, J., KOKOŠOVÁ, N., FABIANOVÁ, K., FABIAN, D., … ČIKOŠ, Š. (2015). Stress exposure during the preimplantation period affects blastocyst lineages and offspring development. Journal of Reproduction and Development, 61(4), 325-331. doi:10.1262/jrd.2015-012Posthouwer, D., Voorbij, H. A. M., Grobbee, D. E., Numans, M. E., & van der Bom, J. G. (2004). Influenza and pneumococcal vaccination as a model to assess C-reactive protein response to mild inflammation. Vaccine, 23(3), 362-365. doi:10.1016/j.vaccine.2004.05.035Ibáñez-Escriche, N., Sorensen, D., Waagepetersen, R., & Blasco, A. (2008). Selection for Environmental Variation: A Statistical Analysis and Power Calculations to Detect Response. Genetics, 180(4), 2209-2226. doi:10.1534/genetics.108.091678Colditz, I. G., & Hine, B. C. (2016). Resilience in farm animals: biology, management, breeding and implications for animal welfare. 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Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8

<p>Abstract</p> <p>Background</p> <p>Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency.</p> <p>Methods</p> <p>We identified 63 CVID patients irrespective of HLA status and 13 RESPI patients who had inherited HLA*B44. To evaluate for mutations in the gene for TACI, we PCR amplified and sequenced TACI exons 3 and 4 from these patients.</p> <p>Results</p> <p>Of the 76 patients, eleven proved heterozygous for a previously reported, silent T->G polymorphism [rs35062843] at proline 97 in exon 3. However, none of the 13 RESPI patients and only one of the 63 CVID patients inherited a TACI allele previously associated with CVID. This patient was heterozygous for the TACI A181E allele (exon 4). She did not carry *DQ2, *DR7, *DR3(17), *B8, or *B44.</p> <p>Conclusion</p> <p>These findings suggest that TACI mutations are unlikely to play a critical role in creating susceptibility to CVID among patients with previously recognized MHC class I and class II susceptibility alleles.</p> <p>Supported by NIH/USIDNET N01-AI30070, NIH R21 AI079741 and NIH M01-RR00032</p

Addressing Recruitment Challenges in the Engage-HU Trial in Young Children with Sickle Cell Disease

Background: Sickle cell disease (SCD) is a genetic disorder that causes significant medical and neurologic morbidity in children. Hydroxyurea (HU) is the primary medication used to prevent these complications. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering HU to children as young as 9 months of age with SCD (HbSS or HbSB0 thalassemia) using a shared decision-making approach. Although HU has proven efficacious it remains underutilized and caregivers report that they are not always actively involved in the decision to initiate this therapy. Reasons for limited HU uptake likely include lack of clinician knowledge and training and negative caregiver perceptions. Thus, we developed the Engage-HU trial as a novel approach to address HU utilization barriers. A critical consideration for this trial was that SCD primarily affects individuals of African and Hispanic/Latino descent. In these minority populations, intervention trials are sometimes terminated early because of recruitment difficulties related to mistrust of research, caregiver burden, and transportation issues. As such, the Engage-HU trial design included best-practice strategies for recruiting people of color in research. This study describes these strategies, the initial recruitment plan, preliminary recruitment outcomes and strategies, and our procedural adaptations. Study Design and Methods: Engage-HU is a randomized control trial (NCT03442114) to assess how clinicians can engage caregivers in a shared discussion that considers their values and preferences and includes evidence that supports HU. Engage-HU compares two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD: 1) the American Society of Hematology Pocket Guide, and 2) the HU Shared-Decision Making (H-SDM) Toolkit. The study aims to recruit 174 caregivers and evaluate the effectiveness of the dissemination methods on patient-centered outcomes (caregiver confidence in decision-making and perceptions of experiencing shared decision-making) as well as HU uptake and child health outcomes. Eligible children are aged 0 to 5 years, candidates for HU, and their caregiver has not made a decision about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a stepped-wedge design. Data will be analyzed based on the intent-to-treat principle. All participants will remain in the arm of the study to which they were randomized, regardless of whether or not they receive the assigned dissemination method. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using a linear mixed effects regression model with a robust variance estimator and maximum likelihood estimation with observations clustered within site. The Engage-HU trial includes adaptations to increase recruitment such as tailored messaging, a relational recruitment approach, streamlined data collection, and a Stakeholder Advisory Committee. However, even with these adaptations, the first 6-months of the trial yielded lower than anticipated recruitment. Rather than terminate the trial or accept low enrollment, the research team implemented a series of recruitment strategies to address barriers including helping to improve research coordinator knowledge of the study purpose and adjusting no-show and follow-up procedures (e.g., calls to families after missed appointments and reminder calls before appointments). Site clinicians and clinic staff were provided with additional training so they could give more context about Engage-HU to caregivers and the study principal investigator led monthly "all coordinator" calls to provide support by sharing updates and experiences about successful recruitment. Implementation of these strategies resulted in triple the number of enrollments over the next 7-months compared to the previous 6-months (Table 1). Our goal in sharing this information is to provide lessons learned that can be implemented in future trials with the systematically underserved SCD population. It is also anticipated that methods described here may also inform clinical approaches to better engage caregivers of young children around critical clinical conversations, such as initiating medications like HU. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; Celgene: Consultancy; Tioma Therapuetics: Consultancy; Amphivena Therapeutics: Research Funding; WUGEN: Current equity holder in private company; Cell Works: Consultancy; Incyte: Consultancy. Smith-Whitley:Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Yates:Novartis: Research Funding. Thompson:Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; BMS: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. </jats:sec

Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

10 páginas, 5 figuras, 5 tablas -- PAGS nros. 200-209OBJECTIVE Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.Obesity is closely associated with a cluster of metabolic diseases, such as dyslipidemia, hypertension, insulin resistance, type 2 diabetes, and atherosclerosis (1). Adipose tissue is well known for its essential role as an energy storage depot and for secreting adipokines that influence sites as diverse as brain, liver, muscle, β-cells, gonads, lymphoid organs, and systemic vasculature (2,3). Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for most of the proinflammatory cytokines (4). In recent years, it has become evident that alterations in the function of the innate immune system are intrinsically linked to metabolic pathways in humans (5–8). The complement system is a major component of the innate immune system, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement deficiency and abnormalities in the regulation of the complement system lead to increased susceptibility to infection and chronic inflammatory diseases (9,10,11). Factor H (fH) is a relatively abundant plasma glycoprotein that is essential to maintain complement homeostasis and to restrict the action of complement to activating surfaces. fH acts as a cofactor for factor I–mediated cleavage of C3b (the active fragment of the third component of complement C3), accelerates the dissociation of the alternative pathway C3 convertases (a bimolecular enzymatic complex formed by active fragments of C3 and factor B [fB]), and competes with fB for binding to C3b. fH regulates complement both in fluid phase and on cellular surfaces (12–16). It has been suggested that activation of the alternative pathway of the complement system could be a link between obesity and metabolic disorders (17–21). Moreover, fB and factor D (fD, adipsin) are produced by adipose tissue where they likely influence formation of the alternative pathway component C3 convertase and the production of the anaphylatoxin C3a and its carboxypeptidase B-anaphylatoxic–inactivated derivative C3adesArg (acylation-stimulating protein [ASP]). Both ASP/C3adesArg and C3a interact with the receptor C5L2 to effectively stimulate triglyceride synthesis in cultured adipocytes (22). C3 knockout (C3KO) mice are obligatorily ASP deficient and present lipid abnormalities (23). In humans, ASP levels are increased in obesity, type 2 diabetes, and in individuals at risk of arterial disease, including those with hypertension, type 2 diabetes, dyslipidemia, and coronary artery disease, whereas exercise or weight loss decreases ASP levels (24,25). These data suggest a relationship between these conditions and activation of the alternative pathway of complement. There is also a correlation between increased C3 concentration and decreased insulin action (26,27). Levels of C3 and fB were higher in subjects with insulin resistance and other features of the metabolic syndrome (28,29).Given these interactions among activation of the alternative pathway of complement, metabolic disturbances, and a chronic low-level inflammatory state, we designed experiments to study the associations among circulating fH, fB, insulin resistance, lipid parameters, and inflammatory markers. We found that circulating fH and fB are strongly associated with obesity. For that reason, we also studied whether adipose tissue could constitute a source of circulating fH and fBThis work was partially supported by research grants from the Ministerio de Educación y Ciencia (SAF2008-02073). CIBEROBN Fisiopatología de la Obesidad y Nutrición is an initiative from the Instituto de Salud Carlos III from SpainPeer reviewe