Background Clinical care guidelines are typically developed by clinicians and researchers. Including patient and caregiver voices in guideline development may help create guidelines that are more useful for patients and consequently improve their guideline adherence. Although there is substantial research on the factors that affect providers’ adherence to guidelines, there is less research on the factors that affect patients’ compliance with guideline recommendations, especially among those with rare disorders. The purpose of this study is to explore factors that are likely to affect patient/caregiver adherence to endocrine and bone health recommendations for Duchenne Muscular Dystrophy (DMD). To do so, we used qualitative data collected as part of the study designed to develop, implement, and evaluate a new online, modified-Delphi approach to engaging patients with rare diseases and their caregivers in guideline development, using care guidelines for DMD as a case study. Methods We thematically analyzed qualitative data collected from 95 adults with DMD and their caregivers who participated in at least one round of our online modified-Delphi panel process. Participants rated and commented on the patient-centeredness of 19 recommendations about vertical growth, weight management, bone health, and delayed puberty included in the 2018 DMD care considerations. Patient-centeredness was operationalized as the importance and acceptability of care recommendations. Results Thematic analyses revealed six factors that affect guideline adherence from the patient/caregiver perspective: content and format of recommendations, patient and provider characteristics, and social and financial factors. Conclusions This study used a novel approach to exploring patient and caregiver perspectives on factors that may affect guideline adherence. The six factors identified by DMD patients and caregivers are similar to the factors affecting provider adherence and are not limited to DMD. Understanding consistency between provider- and patient/caregiver-identified barriers to following guideline recommendations can lead to developing more successful interventions for increasing guideline adherence. Electronic supplementary material The online version of this article (10.1186/s13023-019-1173-7) contains supplementary material, which is available to authorized users.

SummaryJunctate is a 33 kDa integral protein of sarco(endo)plasmic reticulum membranes that forms a macromolecular complex with inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] receptors and TRPC3 channels. TIRF microscopy shows that junctate enhances the number of fluorescent puncta on the plasma membrane. The size and distribution of these puncta are not affected by the addition of agonists that mobilize Ca 2+ from Ins(1,4,5)P 3 -sensitive stores. Puncta are associated with a significantly larger number of peripheral junctions between endoplasmic reticulum and plasma membrane, which are further enhanced upon stable co-expression of junctate and TRPC3. The gap between the membranes of peripheral junctions is bridged by regularly spaced electron-dense structures of 10 nm. Ins(1,4,5)P 3 inhibits the interaction of the cytoplasmic N-terminus of junctate with the ligand-binding domain of the Ins(1,4,5)P 3 receptor. Furthermore, Ca 2+ influx evoked by activation of Ins(1,4,5)P 3 receptors is increased where puncta are located. We conclude that stable peripheral junctions between the plasma membrane and endoplasmic reticulum are the anatomical sites of agonist-activated Ca 2+ entry.

BackgroundA human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine‐rich Ca2+‐binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. However, the precise mechanisms affecting SR function and leading to arrhythmias remain elusive.Methods and ResultsWe generated transgenic mice with cardiac‐specific expression of human Ala96 HRC or Ser96 HRC in the null background to assess function in absence of endogenous protein. Ala96 HRC decreased (25% to 30%) cardiomyocyte contractility and Ca2+ kinetics compared with Ser96 HRC in the absence of any structural or histological abnormalities. Furthermore, the frequency of Ca2+ waves was significantly higher (10‐fold), although SR Ca2+ load was reduced (by 27%) in Ala96 HRC cells. The underlying mechanisms involved diminished interaction of Ala96 HRC with triadin, affecting ryanodine receptor (RyR) stability. Indeed, the open probability of RyR, assessed by use of ryanodine binding, was significantly increased. Accordingly, stress conditions (5 Hz plus isoproterenol) induced aftercontractions (65% in Ala96 versus 12% in Ser96) and delayed afterdepolarizations (70% in Ala96 versus 20% in Ser96). The increased SR Ca2+ leak was accompanied by hyperphosphorylation (1.6‐fold) of RyR at Ser2814 by calmodulin‐dependent protein kinase II. Accordingly, inclusion of the calmodulin‐dependent protein kinase II inhibitor KN93 prevented Ser2814 phosphorylation and partially reversed the increases in Ca2+ spark frequency and wave production. Parallel in vivo studies revealed ventricular ectopy on short‐term isoproterenol challenge and increased (4‐fold) propensity to arrhythmias, including nonsustained ventricular tachycardia, after myocardial infarction in Ala96 HRC mice.ConclusionsThese findings suggest that aberrant SR Ca2+ release and increased susceptibility to delayed afterdepolarizations underlie triggered arrhythmic activity in human Ala96 HRC carriers.

Purpose. To determine the patient-centeredness of endocrine and bone health Duchenne muscular dystrophy (DMD) care considerations using the RAND/PPMD Patient-Centeredness Method (RPM), which is a novel, online, modified-Delphi approach to engaging patients and caregivers in clinical guideline development. Methods. We solicited input on the patient-centeredness of care considerations from 28 individuals with DMD and 94 caregivers, randomly assigned to 1 of 2 mixed panels. During a 3-round online modified-Delphi process, participants rated the importance and acceptability of 19 DMD care considerations (round 1), reviewed and discussed the initial results (round 2), and revised their original ratings (round 3). Patient-centeredness was operationalized as importance and acceptability of recommendations. We considered a care consideration to be patient-centered if both panels deemed it important and acceptable. Results. Ninety-five panelists (78%) participated in this study. Of these, 88 (93%) participated in round 1, 74 (78%) in round 2, and 56 (59%) in round 3. Panelists deemed 12 care considerations to be patient-centered: 3 weight management, 3 bone health, 4 vertical growth, and 2 puberty recommendations. Seven care considerations did not meet patient-centeredness criteria. Common reasons were lack of evidence specific to DMD and concerns about insurance coverage, access to treatment, and patient safety. Conclusions. Using the RPM, Duchenne families considered most care considerations to be patient-centered. Besides being clinically appropriate, these considerations are likely to be consistent with the preferences, needs, and values of Duchenne families. While all relevant care considerations should be discussed during patient-provider encounters, those that did not meet patient-centeredness criteria in particular should be carefully considered as part of joint decision making between Duchenne families and their providers. Study Registration: HSRProj 20163126.