Archetypes of incomplete stories in chronic illness medical encounters.

OBJECTIVE: During encounters, patients and practitioners engage in conversations to address health concerns. Because these interactions are time-pressured events, it may be inevitable that any story exchanged during these encounters will be incomplete in some way, potentially jeopardizing how quality and safety of care is delivered. In this study, we explored how and why incomplete stories might arise in health interactions. METHODS: Constructivist grounded theory methodology was used to explore how patients and practitioners approach their interactions during encounters. In this two-phase study, we interviewed patients (n = 21) then practitioners (n = 12). RESULTS: We identified three distinct archetypes of incomplete storytelling - the hidden story, the interpreted story, and the tailored story. Measured information sharing, triadic encounters and pre-planned agendas influenced these storylines, respectively. CONCLUSION: Both patient and practitioner participants focused on what each considered important, appropriate, and useful for productive encounters. While incomplete stories may be a reality, educating practitioners about how incomplete stories come about from both sides of the conversation creates new opportunities to optimize interactions at medical encounters for in-depth patient practitioner storytelling.

Getting airtime: Exploring how patients shape the stories they tell health practitioners.

INTRODUCTION: Effective communication during health encounters is known to decrease patient complaints, increase patient adherence and optimise health outcomes. While the aim of patient-centred care is to find common ground, health practitioners tend to drive the encounter, often interrupting patients within the first minute of the clinical conversation. Optimal care for people with chronic illnesses requires individuals to interact with health practitioners regarding their health concerns, but given these constraints, we know little about how patients strategise conversations with their care providers. This understanding may further our efforts to educate health practitioners and trainees to learn and practice patient-centred care. METHODS: A constructivist grounded theory approach with iterative data collection and analysis was used to explore the processes patients use to present and shape their stories for interactions with health practitioners. Twenty-one patients (n = 16 female; 5 male) representing a variety of chronic illnesses participated in semi-structured interviews. Using the constant comparative method of analysis, salient themes were ascertained. RESULTS: Patients engage in extensive strategic preparations for productive health encounters. From the data, we identified four related elements comprising patients' process of planning, preparing, and strategising for health encounters: deciding to go, organising to get airtime, rehearsing a game plan, and anticipating external forces. By focusing on the extensive preparatory work patients engage in, our study expands the dimensions of how we understand illness-related work. Assembling personal health information, gathering disease information and achieving equanimity represent the dimensions of this 'health interaction work'. CONCLUSION: The work patients engage in for health encounters is noteworthy yet often invisible. And work that is unseen may also be undervalued. Acknowledging, illuminating and valuing patients' preparatory work for health encounters add to how we understand patient-centred care, and this offers new targets for us to effectively teach and deliver it.

Autoethnography as a Strategy for Engaging in Reflexivity.

Reflexivity is a key feature in qualitative research, essential for ensuring rigor. As a nurse practitioner with decades of experience with individuals who have chronic diseases, now embarking on a PhD, I am confronted with the question "how will my clinical experiences shape my research?" Since there are few guidelines to help researchers engage in reflexivity in a robust way, deeply buried aspects that may affect the research may be overlooked. The purpose of this paper is to consider the affordances of combining autoethnography (AE) with visual methods to facilitate richer reflexivity. Reflexive activities such as free writing of an autobiographical narrative, drawings of clinical vignettes, and interviews conducted by an experienced qualitative researcher were analyzed to probe and make visible perspectives that may impact knowledge production. Two key themes reflecting my values-fostering advocacy and favoring independence and autonomy were uncovered with this strategy.

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Consensus-based care recommendations for adults with myotonic dystrophy type 1.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. RECENT FINDINGS: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. SUMMARY: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

HEPES activates a MiT/TFE-dependent lysosomal-autophagic gene network in cultured cells: A call for caution.

In recent years, the lysosome has emerged as a highly dynamic, transcriptionally regulated organelle that is integral to nutrient-sensing and metabolic rewiring. This is coordinated by a lysosome-to-nucleus signaling nexus in which MTORC1 controls the subcellular distribution of the microphthalmia-transcription factor E (MiT/TFE) family of "master lysosomal regulators". Yet, despite the importance of the lysosome in cellular metabolism, the impact of traditional in vitro culture media on lysosomal dynamics and/or MiT/TFE localization has not been fully appreciated. Here, we identify HEPES, a chemical buffering agent that is broadly applied in cell culture, as a potent inducer of lysosome biogenesis. Supplementation of HEPES to cell growth media is sufficient to decouple the MiT/TFE family members-TFEB, TFE3 and MITF-from regulatory mechanisms that control their cytosolic retention. Increased MiT/TFE nuclear import in turn drives the expression of a global network of lysosomal-autophagic and innate host-immune response genes, altering lysosomal dynamics, proteolytic capacity, autophagic flux, and inflammatory signaling. In addition, siRNA-mediated MiT/TFE knockdown effectively blunted HEPES-induced lysosome biogenesis and gene expression profiles. Mechanistically, we show that MiT/TFE activation in response to HEPES requires its macropinocytic ingestion and aberrant lysosomal storage/pH, but is independent of MTORC1 signaling. Altogether, our data underscore the cautionary use of chemical buffering agents in cell culture media due to their potentially confounding effects on experimental results.

Survey of Canadian Myotonic Dystrophy Patients' Access to Computer Technology.

BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant condition affecting distal hand strength, energy, and cognition. Increasingly, patients and families are seeking information online. An online neuromuscular patient portal under development can help patients access resources and interact with each other regardless of location. It is unknown how individuals living with myotonic dystrophy interact with technology and whether barriers to access exist. We aimed to characterize technology use among participants with myotonic dystrophy and to determine whether there is interest in a patient portal. METHODS: Surveys were mailed to 156 participants with myotonic dystrophy type 1 registered with the Canadian Neuromuscular Disease Registry. RESULTS: Seventy-five participants (60% female) responded; almost half were younger than 46 years. Most (84%) used the internet; almost half of the responders (47%) used social media. The complexity and cost of technology were commonly cited reasons not to use technology. The majority of responders (76%) were interested in a myotonic dystrophy patient portal. CONCLUSIONS: Patients in a Canada-wide registry of myotonic dystrophy have access to and use technology such as computers and mobile phones. These patients expressed interest in a portal that would provide them with an opportunity to network with others with myotonic dystrophy and to access information about the disease.

Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models.

Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities. In conclusion, gpNMB acts as a marker for glucosylceramide-laden macrophages in man and mouse and gpNMB should be considered as candidate biomarker for Gaucher disease in treatment monitoring.

A Review of Azathioprine-Associated Hepatotoxicity and Myelosuppression in Myasthenia Gravis.

OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disorder in which antibodies interfere with neuromuscular transmission. Azathioprine (AZA) is an immunosuppressant frequently used for treatment of various autoimmune conditions, including MG. The literature suggests that the rates of AZA-associated hepatotoxicity and myelosuppression in MG are highly variable. Published studies have not formally analyzed their pattern, severity, timing, and/or recovery. We assessed the prevalence, pattern and timing of AZA associated toxicity in a large group of MG patients. METHODS: We identified 113 patients with MG with AZA-associated toxicity among 571 managed with this immunosuppressant. The timing of when toxicities occurred as well as pattern of laboratory abnormalities was assessed. RESULTS: The overall prevalence of hepatotoxicity and myelosuppression was 15.2% and 9.1%, respectively. The most common pattern of hepatotoxicity seen was gamma-glutamyl transpeptidase (GGT) enzyme elevation in 67.8% of patients. Of note, 21.2% of patients with myelosuppression had normocytic anemia, 17.3% had pancytopenia, and another 17.3% developed macrocytic anemia. CONCLUSIONS: AZA-associated hepatotoxicity and myelosuppression in MG are not uncommon and may be underrecognized depending on the timing, frequency, and specific tests ordered for blood work monitoring.

Hope, Coping, and Quality of Life in Adults with Myasthenia Gravis.

UNLABELLED: Myasthenia gravis significantly impacts quality of life. However, the relationship between hope, coping, and quality of life (QOL)in myasthenia patients has not been studied (Kulkantrakorn & Jarungkiatkul, 2009; Raggi et al., 2010). OBJECTIVE: The aim of this study was to explore the relationship between hope, coping, and quality of life in adults with myasthenia gravis. DATA COLLECTION: Subjects with MG (n = 100) completed six questionnaires, including a demographic profile, the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL), Herth Hope Index (HHI), Jalowiec Coping Scale (JCS), Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), and Short Form Health Survey (SF-36v2). RESULTS: Mean hope scores indicated a high level of hope. An optimistic coping style was the most common and effective coping strategy identified by subjects. Positive thinking and humour were also frequently used strategies. Participants identified quality of life as good tolerability, above general population mental well-being, and below general populationphysical well-being. Participants who identified good quality of life had low scores on the MG-QOL15 scale and high scores on the SF36v2. Hope and independence for activities of daily living were found to correlate with improved quality of life and mental well-being(p < 0.001). Age and length of illness were not significant factors. There was no mediation by well-being or quality of life in the relationship between hope and coping. Hope and coping were not important factors for well-being or quality of life. CONCLUSION: Nurses caring for adults with myasthenia gravis should use interventions that continue to support hope, quality of life, and coping throughout the unpredictable and chronic course of MG.

Hard to Swallow: A Phenomenological Exploration of the Experience of Caring for Individuals With Myotonic Dystrophy and Dysphagia.

PURPOSE: Myotonic dystrophy (DM1), a genetic, multisystemic disorder, is the most prevalent adult form of muscular dystrophy. Dysphagia is a common symptom that may be difficult to diagnose and treat and can be associated with increased morbidity and mortality. Preexisting cognitive impairment or apathy, both well described in the DM1 literature, may contribute to management challenges. Caregivers may become important for managing a family member's swallowing dysfunction. Although clinicians place great importance on swallowing difficulties, it is unknown how dysphagia impacts patients and their caregivers. Therefore, the purpose of this study was to explore the experiences of caregivers living with those with DM1and dysphagia. METHODS: An interpretive phenomenological approach was used to study the lived experience of six caregivers for individuals with DM1 and dysphagia. Audio-taped semistructured interviews were used for data collection, and data were analyzed using van Manen's steps for phenomenological analysis. FINDINGS: Despite the potential for dysphagia to cause morbidity and mortality in individuals with DM1, caregivers did not describe this as a problematic symptom. Instead, they highlighted more debilitating symptoms like fatigue or weakness and discussed the caregiving experience. Themes pertaining to participants' lived body, lived relationality, lived time, and lived space were identified. CONCLUSIONS: Healthcare providers need to balance issues of clinical concern with those that are important for individuals and their family members. Assessments of caregiver knowledge and burden at each clinic visit may be warranted.

Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors.

Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, type 2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism-glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)-is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39-compound library does not contain new GCS inhibitors; however, a potent (200 nm) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator.

Mass spectrometric quantification of glucosylsphingosine in plasma and urine of type 1 Gaucher patients using an isotope standard.

Deficiency of glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Recently, we reported marked increases of deacylated GlcCer, named glucosylsphingosine (GlcSph), in plasma of GD patients. To improve quantification, [5-9] (13)C5-GlcSph was synthesised for use as internal standard with quantitative LC-ESI-MS/MS. The method was validated using plasma of 55 GD patients and 20 controls. Intra-assay variation was 1.8% and inter-assay variation was 4.9% for GlcSph (m/z 462.3). Plasma GlcSph levels with the old and new methods closely correlate (r=0.968, slope=1.038). Next, we analysed GlcSph in 24h urine samples of 30 GD patients prior to therapy. GlcSph was detected in the patient samples (median 1.20nM, range 0.11-8.92nM), but was below the limit of quantification in normal urine. Enzyme replacement therapy led to a decrease of urinary GlcSph of GD patients, coinciding with reductions in plasma GlcSph and markers of Gaucher cells (chitotriosidase and CCL18). In analogy to globotriaosylsphingsone in urine of Fabry disease patients, additional isoforms of GlcSph differing in structure of the sphingosine moiety were identified in GD urine samples. In conclusion, GlcSph can be sensitively detected by LC-ESI-MS/MS with an internal isotope standard. Abnormalities in urinary GlcSph are a hallmark of Gaucher disease allowing biochemical confirmation of diagnosis.

A genome-wide association study of myasthenia gravis.

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

In vitro and in vivo comparative and competitive activity-based protein profiling of GH29 α-l-fucosidases.

GH29 α-l-fucosidases catalyze the hydrolysis of α-l-fucosidic linkages. Deficiency in human lysosomal α-l-fucosidase (FUCA1) leads to the recessively inherited disorder, fucosidosis. Herein we describe the development of fucopyranose-configured cyclophellitol aziridines as activity-based probes (ABPs) for selective in vitro and in vivo labeling of GH29 α-l-fucosidases from bacteria, mice and man. Crystallographic analysis on bacterial α-l-fucosidase confirms that the ABPs act by covalent modification of the active site nucleophile. Competitive activity-based protein profiling identified l-fuconojirimycin as the single GH29 α-l-fucosidase inhibitor from eight configurational isomers.

Identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase/neutral glucosylceramidase inhibitors.

This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of D-gluco and L-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (D-gluco and L-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted L-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their D-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.

Potent and selective activity-based probes for GH27 human retaining α-galactosidases.

Lysosomal degradation of glycosphingolipids is mediated by the consecutive action of several glycosidases. Malfunctioning of one of these hydrolases can lead to a lysosomal storage disorder such as Fabry disease, which is caused by a deficiency in α-galactosidase A. Herein we describe the development of potent and selective activity-based probes that target retaining α-galactosidases. The fluorescently labeled aziridine-based probes 3 and 4 inhibit the two human retaining α-galactosidases αGal A and αGal B covalently and with high affinity. Moreover, they enable the visualization of the endogenous activity of both α-galactosidases in cell extracts, thereby providing a means to study the presence and location of active enzyme levels in different cell types, such as healthy cells versus those derived from Fabry patients.

Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors.

The natural product, cyclophellitol and its aziridine analogue are potent mechanism-based retaining ß-glucosidase inhibitors. In this paper we explore the inhibitory potency of a number of cyclophellitol analogues against the three human retaining ß-glucosidases, GBA, GBA2 and GBA3. We demonstrate that N-alkyl cyclophellitol aziridine is at least equally potent in inhibiting the enzymes evaluated as its N-acyl congener, whereas the N-sulfonyl analogue is a considerably weaker inhibitor. Our results complement the literature on the inhibitory potency of cyclophellitol analogues and hold promise for the future design of more effective activity-based retaining glycosidase probes with respect to probe stability in physiological media.

Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome.

INTRODUCTION: Enzyme replacement therapy (ERT) with alpha-Galactosidase A (aGal A) may cause antibody (AB) formation against aGal A in males with Fabry disease (FD). Anti agalsidase ABs negatively influence globotriaosylceramide (Gb3) reduction. We investigated the impact of agalsidase AB on Gb3 and lysoGb3 and clinical outcome in Fabry patients on ERT. METHODS: Adult male and female patients on ERT for at least one year were included. Urinary Gb3 was measured by HPLC, plasma lysoGb3 by LC-ESI-MS/MS and AB with a neutralization assay. RESULTS: Of the 59 patients evaluable patients, 0/30 females and 17/29 males developed anti-agalsidase antibodies (AB+). Only 3/17 males had transient (low) titers (tolerized). All AB+ patients developed antibodies during the first year of treatment. Change of agalsidase preparation (or dose) did not induce antibody formation. AB+ males had significant less decline in plasma lysoGb3 compared to AB- males (p = 0.04). Urinary Gb3 levels decreased markedly in AB- but remained comparable to baseline in AB+ males (p<0.01). (Lyso)Gb3 reduction in plasma and urine on ERT was correlated with LVmass reduction in females and development white matter lesions and stroke. CONCLUSION: In male patients antibodies against aGal A remained present up to 10 years of ERT. The presence of these antibodies is associated with a less robust decrease in plasma lysoGb3 and a profound negative effect on urinary Gb3 reduction, which may reflect worse treatment outcome.