Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma.

ABSTRACT: Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from patients with SCD. Here, we used induced pluripotent stem cells (iPSCs), derived from patients with SCD, differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Furthermore, we find that plasma taken from patients with SCD during acute pain associated with a vaso-occlusive event increases the calcium responses to the nociceptive stimulus capsaicin in SCD iSNs compared with those treated with paired plasma from patients with SCD at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of plasma from patients with SCD, which sensitizes SCD iSNs to subthreshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology.

Preliminary construct validity of patient-reported outcomes to assess chronic pain in adults with sickle cell disease.

Chronic pain affects 30% to 40% of individuals with sickle cell disease (SCD) and impairs patient functioning. Clinically meaningful, practical, and valid assessment tools for investigation, evaluation, and management of chronic pain are limited, representing a barrier for advancing SCD care. We sought to determine whether patient-reported outcomes (PROs) show preliminary construct validity in identifying individuals with SCD who were a priori defined as suggestive of having chronic pain based on previously published criteria. All individuals completed the Patient-Reported Outcomes Measurement Information System (PROMIS) domains: pain interference, pain behavior, pain quality (nociceptive, neuropathic), fatigue, sleep disturbance, depression, and anxiety; the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) domains: pain impact and emotional impact; and the painDETECT questionnaire. Thirty-three adults living with SCD were enrolled, and 42.4% had chronic pain. Pain-related PROs scores distinctly differentiated individuals with chronic pain from those without. Individuals with chronic pain had significantly worse pain-related PROs scores: PROMIS pain interference (64.2 vs 54.3), PROMIS pain behavior (63.2 vs 50), and ASCQ-Me pain impact (42.9 vs 53.2). According to published PROMIS clinical cut scores for the pain-related domains, individuals with chronic pain were categorized as having moderate impairment, whereas those without chronic pain had mild or no impairment. Individuals with chronic pain had PRO pain features consistent with neuropathic pain and worse scores in fatigue, depression, sleep disturbance, and emotional impact. Pain-related PROs show preliminary construct validity in differentiating individuals with and without chronic SCD pain and could be used as valuable tools for research and clinical monitoring of chronic pain.

Neuropathic pain is associated with poor health-related quality of life in adolescents with sickle cell disease: A preliminary report.

BACKGROUND: Neuropathic pain is associated with poor health-related quality of life (HRQL) in pain conditions other than sickle cell disease (SCD); this relationship in SCD is unknown. We investigated this relationship and hypothesized neuropathic pain is associated with poor HRQL in adolescents with SCD. METHODS: We conducted a cross-sectional study of patients with SCD ages 13-18 years during baseline health. Primary outcome was HRQL, assessed by the PedsQL SCD Module (child self-report, parent proxy report). PedsQL is scored from 0 to 100, with higher scores indicating better HRQL. Neuropathic pain was assessed using the painDETECT questionnaire (scored 0-38); higher scores indicated greater likelihood of neuropathic pain. All completed both PedsQL SCD Module and painDETECT questionnaire. Descriptive statistics were used and associations between painDETECT and PedsQL Total Score, Pain Impact, Pain and Hurt, and Pain Management and Control Scores were determined via Pearson correlation. Significance was P < .05. RESULTS: Twelve patients were enrolled. Median (interquartile range [IQR]) age was 15 (14-16.5) years, 75% were female, and 83% were on hydroxyurea. Higher painDETECT scores were significantly associated with lower PedsQL SCD Module child self-report Pain and Hurt Scores (r = -0.68, P = .01). Higher painDETECT scores were also significantly associated with lower PedsQL parent proxy-report Total Scores (r = -0.64, P = .03) and Pain and Hurt Scores (r = -0.67, P = .02). CONCLUSIONS: These data suggest that adolescents with SCD and neuropathic pain have poor HRQL even in their baseline state of health. Prospective, larger studies are needed to confirm this preliminary finding and explore a multimodal approach for pain assessment in SCD.

Utilizing the Electronic Health Record to Improve Advance Care Planning: A Systematic Review.

PURPOSE: Advance care planning may ensure care that is concordant with patient wishes. However, advance care plans are frequently absent when needed due to failure to engage patients in planning, inability to access prior documentation, or poor documentation quality. Interventions utilizing tools within the electronic health record (EHR) may address these barriers at the point of care. We aimed to identify EHR interventions previously utilized to improve advance care plans. METHODS: We systematically searched 7 databases for observational and experimental studies of EHR interventions associated with advance care plans. We abstracted information on the study populations, EHR and non-EHR components of the interventions, and the efficacy for advance care plan-related outcomes. RESULTS: We identified 16 articles that contained an EHR intervention to improve advance care plans. Study populations, study designs, and EHR components of the interventions were heterogeneous. Documentation templates were the most common EHR tool reported (n = 8), followed by automated prompts (n = 7) and electronic order sets (n = 5). The most common reported outcomes were documentation of an advance care planning conversation in the EHR (n = 7) and the placement of code status orders (n = 7). All studies reporting efficacy (n = 9) demonstrated an improvement in 1 or more advance care planning outcomes. CONCLUSIONS: The use of EHR interventions may improve advance care plan completion and availability at the point of care. Further work should seek to develop and evaluate standardized EHR tools for advance care planning.

Patient Advocacy Organizations, Industry Funding, and Conflicts of Interest.

Importance: Patient advocacy organizations (PAOs) are influential health care stakeholders that provide direct counseling and education for patients, engage in policy advocacy, and shape research agendas. Many PAOs report having financial relationships with for-profit industry, yet little is known about the nature of these relationships. Objective: To describe the nature of industry funding and partnerships between PAOs and for-profit companies in the United States. Design, Setting, and Participants: A survey was conducted from September 1, 2013, to June 30, 2014, of a nationally representative random sample of 439 PAO leaders, representing 5.6% of 7865 PAOs identified in the United States. Survey questions addressed the nature of their activities, their financial relationships with industry, and the perceived effectiveness of their conflict of interest policies. Main Outcomes and Measures: Amount and sources of revenue as well as organizational experiences with and policies regarding financial conflict of interest. Results: Of the 439 surveys mailed to PAO leaders, 289 (65.8%) were returned with at least 80% of the questions answered. The PAOs varied widely in terms of size, funding, activities, and disease focus. The median total revenue among responding organizations was $299 140 (interquartile range, $70 000-$1 200 000). A total of 165 of 245 PAOs (67.3%) reported receiving industry funding, with 19 of 160 PAOs (11.9%) receiving more than half of their funding from industry. Among the subset of PAOs that received industry funding, the median amount was $50 000 (interquartile range, $15 000-$200 000); the median proportion of industry support derived from the pharmaceutical, device, and/or biotechnology sectors was 45% (interquartile range, 0%-100%). A total of 220 of 269 respondents (81.8%) indicated that conflicts of interest are very or moderately relevant to PAOs, and 94 of 171 (55.0%) believed that their organizations' conflict of interest policies were very good. A total of 22 of 285 PAO leaders (7.7%) perceived pressure to conform their positions to the interests of corporate donors. Conclusions and Relevance: Patient advocacy organizations engage in wide-ranging health activities. Although most PAOs receive modest funding from industry, a minority receive substantial industry support, raising added concerns about independence. Many respondents report a need to improve their conflict of interest policies to help maintain public trust.

'Someone should oversee it': patient perspectives on the ethical issues arising with the regulation of probiotics.

BACKGROUND: Although many probiotic products are currently available in yogurt or pill form in the United States (US), there is uncertainty surrounding the structure of regulation of these products. As more therapeutic probiotics are developed, changes to existing regulatory process in the United States may be required to meet the needs of patients and users in the population. OBJECTIVE: This study examined how patients with chronic gastrointestinal (GI) diseases view the regulation of probiotics. DESIGN: We conducted a multi-site qualitative study consisting of focus groups of patients with chronic gastrointestinal diseases at three tertiary hospitals: at [institutions removed for blinded review]. RESULTS: We conducted 22 focus groups with 136 patients with major gastrointestinal (GI) diseases between March and August 2009. Participants were not familiar with the existing regulation of probiotic products but wanted assurances of accurate labelling of strain as well as safety. Participants raised concerns that regulation of probiotics might be accompanied by greater costs, reduced access and increased involvement of pharmaceutical companies. Although participants voiced significant doubt of government regulators, they felt that products containing genetically modified probiotic strains should have oversight comparable to that of pharmaceutical drugs. DISCUSSION AND CONCLUSION: If GI patient perspectives are indicative of public perceptions of therapeutic probiotics in the United States, consumers may expect more rigorous regulation in the future while simultaneously wanting low costs, easy access and low involvement of pharmaceutical companies. Manufacturers, translational scientists, clinicians and regulators should be sensitive to consumer attitudes when designing, testing and regulating new therapeutic probiotics.

Genetics patients' perspectives on clinical genomic testing.

AIMS: Advances in next-generation sequencing technologies make it possible to envisage multiple contexts in which genomic tools might be used to enhance patient care. We describe how genetics patients and their caregivers view the promises and perils of clinical genomic testing. PATIENTS & METHODS: Fifty-one interviews with patients and parents of pediatric patients seeking genetic evaluation at an academic medical center. RESULTS: Themes from interviews include participants' enthusiasm for clinical genomic testing for diagnostic purposes, medical benefits and concerns about emotional and psychosocial burdens resulting from clinical genomic testing. CONCLUSION: By clarifying these patients' and caregivers' views of clinical genomic testing, the findings we report can help to anticipate other patients' reactions to new forms of personalized medicine enabled by genomic technologies.

Ethical Discourse about the Modification of Food for Therapeutic Purposes: How Patients with Gastrointestinal Diseases View the Good, the Bad, and the Healthy.

BACKGROUND: Researchers have the potential to utilize genetic modification (GM) technologies to create a hybrid of "food" and "medicine" that may challenge traditional understandings of what is "natural". Moral and ethical concerns are likely to arise in any discussion of these therapeutic foods and will affect the integration of products into clinical care and daily life. This study examined how patients with chronic gastrointestinal (GI) diseases view probiotics as future bioengineered therapeutic foods. METHODS: A multi-site qualitative study consisting of focus groups with chronic GI diseases was conducted at Cleveland Clinic, Mayo Clinic, and Johns Hopkins University RESULTS: We conducted twenty-two focus groups with 136 patients with major GI diseases between March and August 2009. GI patients associated the term "natural" with concepts of diminished risk and morally "good"; conversely, patients associated the term "unnatural" with things that are "risky," "foreign", and morally "bad". Readily available unmodified probiotics were more commonly described as "natural" while genetically modified probiotics were more commonly labeled as "unnatural" and "risky". However, patients acknowledged that not all natural products are safe, nor are unnatural products always harmful. CONCLUSIONS: If GI patient perspectives are indicative of public perceptions of therapeutic foods, our findings suggest that the potential benefits and risks of clinical and public health initiatives employing therapeutic foods will be understood in moralistic terms. Bioethicists and others should be sensitive to the implicit normative appeals that are often embedded in the language of what is "natural" and "unnatural".

How patients view probiotics: findings from a multicenter study of patients with inflammatory bowel disease and irritable bowel syndrome.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) have access to a growing number of probiotic products marketed to improve digestive health. It is unclear how patients make decisions about probiotics and what role they expect their gastroenterologists to play as they consider using probiotics. Understanding patients' knowledge, attitudes and expectations of probiotics may help gastroenterologists engage patients in collaborative discussions about probiotics. STUDY: Focus groups were conducted with patients with IBD and IBS at the Cleveland Clinic, Mayo Clinic, and Johns Hopkins University. Inductive analytic methods were used to identify common themes and draw interpretations from focus group narratives. RESULTS: One hundred thirty-six patients participated in 22 focus groups between March and August 2009. Patients viewed probiotics as an appealing alternative to pharmaceutical drugs and understood probiotics as a more "natural," low-risk therapeutic option. Many patients were hesitant to use them without consulting their gastroenterologists. Patients would weigh the risks and benefits of probiotics, their disease severity and satisfaction with current treatments when considering probiotic use. CONCLUSIONS: Patients are interested in probiotics but have many unanswered questions about their use. Our findings suggest that patients with IBD and IBS will look to gastroenterologists and other clinicians as trustworthy advisors regarding the utility of probiotics as an alternative or supplement to pharmaceutical drugs. Gastroenterologists and other clinicians who care for patients with these diseases should be prepared to discuss the potential benefits and risks of probiotics and assist patients in making informed decisions about their use.

Initiation of health behavior discussions during primary care outpatient visits.

OBJECTIVE: Despite the importance of health promotion, rates of health behavior advice remain low and little is known about how advice is integrated into routine primary care. This study examines how health behavior topics of diet, physical activity and smoking are initiated during outpatient visits. METHODS: Audio recording of 187 adults visit to five purposefully selected physicians. An iterative analysis involved listening to and discussing cases to identify emergent patterns of initiation of health behavior talk and advice that followed. RESULTS: Physicians initiated 65% of discussions and used two overarching strategies (1) Structured: a routine to ask about health behavior and (2) Opportunistic: use of a trigger to make a transition to talk about health behavior. Opportunistic strategies identified a greater proportion of patients at risk (50% vs. 34%) and led to a greater rate of advice (100% vs. 75%). Patients initiated one-third of health behavior discussions and were more likely to receive advice if they explicitly indicated readiness to change. CONCLUSIONS: Opportunistic strategies show promise for a higher yield of identifying patients at risk and leading to advice. PRACTICE IMPLICATIONS: Encouraging patients to be explicit about their readiness to change is likely to increase physician advice and assistance.