Natural history study of patients with familial platelet disorder with associated myeloid malignancy.

ABSTRACT: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Public deliberation to assess patient views on biosimilar medication switching for the treatment of inflammatory bowel disease.

BACKGROUND: Biosimilars are highly similar, but not identical, versions of originator biologic medications. Switching patients to biosimilars presents an opportunity to mitigate rising drug costs and expand patient access to important biologic therapies. However, decreased patient acceptance and adherence to biosimilar medications have been reported, which can lead to loss of treatment response, adverse reactions, and inefficient resource utilization. Understanding patient perceptions of biosimilars and biosimilar switching is needed to inform patient-centered care strategies that promote efficient resource utilization. METHODS: We used democratic deliberation methods to solicit the informed and considered opinions of patients regarding biosimilar switching. Patients with inflammatory bowel disease (IBD; n = 29) from the Veterans Health Administration (VHA) participated in 5-hour deliberation sessions over two days. Following educational presentations with experts, participants engaged in facilitated small group discussions. Transcripts and facilitators' notes were used to identify key themes. Participants completed surveys pre- and post-deliberation to collect sociodemographic and clinical features as well as to assess IBD treatment knowledge and attitudes toward care and approaches to biosimilar switching. RESULTS: Five major themes emerged from the small group discussions in the context of biosimilar switching: 1) concerns about adverse consequences and unclear risk-benefit balance; (2) importance of communication and transparency; (3) desire for shared decision making and patient involvement in treatment decisions; (4) balancing cost-saving with competing priorities; and (5) advocating for individualized care and prioritization based on risk levels. These views led participants to favor approaches that prioritize switching the sickest patients last (i.e., those with poorly controlled disease) and that offer patients control and choices around biosimilar switching. Participants also expressed preferences for combining elements of different approaches to maximize fairness. CONCLUSIONS: Approaches to biosimilar switching should consider patients' desires for transparency and effective communication about biosimilar switching and engagement in their medical decision-making as part of patient-centered care. Incorporating patient preferences around biosimilar switching is critical when navigating the quality and affordability of care in resource constrained settings, both within the VHA and in other healthcare systems.

"Extremely slow and capricious": A qualitative exploration of genetic researcher priorities in selecting shared data resources.

PURPOSE: Genetic researchers' selection of a database can have scientific, regulatory, and ethical implications. It is important to understand what is driving database selection such that database stewards can be responsive to user needs while balancing the interests of communities in equitably benefiting from advances. METHODS: We conducted 23 semistructured interviews with US academic genetic researchers working with private, government, and collaboratory data stewards to explore factors that they consider when selecting a genetic database. RESULTS: Interviewees used existing databases to avoid burdens of primary data collection, which was described as expensive and time-consuming. They highlighted ease of access as the most important selection factor, integrating concepts of familiarity and efficiency. Data features, such as size and available phenotype, were also important. Demographic diversity was not originally cited by any interviewee as a pivotal factor; when probed, most stated that the option to consider diversity in database selection was limited. Database features, including integrity, harmonization, and storage were also described as key components of efficient use. CONCLUSION: There is a growing market and competition between genetic data stewards. Data need to be accessible, harmonized, and administratively supported for their existence to be translated into use and, in turn, result in scientific advancements across diverse communities.

US Residents' Preferences for Sharing of Electronic Health Record and Genetic Information: A Discrete Choice Experiment.

OBJECTIVES: The aim to this study was to assess preferences for sharing of electronic health record (EHR) and genetic information separately and to examine whether there are different preferences for sharing these 2 types of information. METHODS: Using a population-based, nationally representative survey of the United States, we conducted a discrete choice experiment in which half of the subjects (N = 790) responded to questions about sharing of genetic information and the other half (N = 751) to questions about sharing of EHR information. Conditional logistic regression models assessed relative preferences across attribute levels of where patients learn about health information sharing, whether shared data are deidentified, whether data are commercialized, how long biospecimens are kept, and what the purpose of sharing the information is. RESULTS: Individuals had strong preferences to share deidentified (vs identified) data (odds ratio [OR] 3.26, 95% confidence interval 2.68-3.96) and to be able to opt out of sharing information with commercial companies (OR 4.26, 95% confidence interval 3.42-5.30). There were no significant differences regarding how long biospecimens are kept or why the data are being shared. Individuals had a stronger preference for opting out of sharing genetic (OR 4.26) versus EHR information (OR 2.64) (P = .002). CONCLUSIONS: Hospital systems and regulatory bodies should consider patient preferences for sharing of personal medical records or genetic information. For both genetic and EHR information, patients strongly prefer their data to be deidentified and to have the choice to opt out of sharing information with commercial companies.

A qualitative investigation of resilience and well-being among medical physics residents.

PURPOSE: Medical physics residents (MPRs) will define and shape the future of physics in medicine. We sought to better understand the residency experience, as related to resilience and well-being, through the lens of current MPRs and medical physicists (MPs) working with residents. METHODS AND MATERIALS: From February-May 2019, we conducted 32, 1-h, confidential, semi-structured interviews with MPs either currently enrolled in an accredited residency (n = 16) or currently employed by a department with an accredited residency (n = 16). Interviews centered on the topics of mentorship, work/life integration, and discrimination. Qualitative analysis methods were used to derive key themes from the interview transcripts. RESULTS: With regard to the medical physics residency experience, four key themes emerged during qualitative analysis: the demanding nature of medical physics residencies, the negative impacts of residency on MPRs during training and beyond, strategies MPRs use to cope with residency stress, and the role of professional societies in addressing residency-related change. CONCLUSIONS: Residency training is a stress-inducing time in the path to becoming a board-certified MP. By uncovering several sources of this stress, we have identified opportunities to support the resiliency and well-being of MPs in training through recommendations by professional societies, programmatic changes, and interventions at the department and residency program director level for residency programs, as well as strategies that MPRs themselves can use to support well-being on their career journey.

Eliciting patient views on the allocation of limited healthcare resources: a deliberation on hepatitis C treatment in the Veterans Health Administration.

BACKGROUND: In response to the development of highly effective but expensive new medications, policymakers, payors, and health systems are considering novel and pragmatic ways to provide these medications to patients. One approach is to target these treatments to those most likely to benefit. However, to maximize the fairness of these policies, and the acceptance of their implementation, the values and beliefs of patients should be considered. The provision of treatments for chronic hepatitis C (CHC) in the resource-constrained context of the Veterans Health Administration (VHA) offered a real-world example of this situation, providing the opportunity to test the value of using Democratic Deliberation (DD) methods to solicit the informed opinions of laypeople on this complex issue. METHODS: We recruited Veterans (n = 30) from the VHA to attend a DD session. Following educational presentations from content experts, participants engaged in facilitated small group discussions to: 1) identify strategies to overcome CHC treatment barriers and 2) evaluate, vote on, and modify/improve two CHC treatment policies - "first come, first served" (FCFS) and "sickest first" (SF). We used transcripts and facilitators' notes to identify key themes from the small group discussions. Additionally, participants completed pre- and post-DD surveys. RESULTS: Most participants endorsed the SF policy over the FCFS policy, emphasizing the ethical and medical appropriateness of treating the sickest first. Concerns about SF centered on the difficulty of implementation (e.g., how is "sickest" determined?) and unfairness to other Veterans. Proposed modifications focused on: 1) the need to consider additional health factors, 2) taking behavior and lifestyle into account, 3) offering education and support, 4) improving access, and 5) facilitating better decision-making. CONCLUSIONS: DD offered a robust and useful method for addressing the allocation of the scarce resource of CHC treatment. Participants were able to develop a modified version of the SF policy and offered diverse recommendations to promote fairness and improve quality of care for Veterans. DD is an effective approach for incorporating patient preferences and gaining valuable insights for critical healthcare policy decisions in resource-limited environments.

The Role of Mitochondrial Calcium Homeostasis in Alzheimer's and Related Diseases.

Calcium signaling is essential for neuronal function, and its dysregulation has been implicated across neurodegenerative diseases, including Alzheimer's disease (AD). A close reciprocal relationship exists between calcium signaling and mitochondrial function. Growing evidence in a variety of AD models indicates that calcium dyshomeostasis drastically alters mitochondrial activity which, in turn, drives neurodegeneration. This review discusses the potential pathogenic mechanisms by which calcium impairs mitochondrial function in AD, focusing on the impact of calcium in endoplasmic reticulum (ER)-mitochondrial communication, mitochondrial transport, oxidative stress, and protein homeostasis. This review also summarizes recent data that highlight the need for exploring the mechanisms underlying calcium-mediated mitochondrial dysfunction while suggesting potential targets for modulating mitochondrial calcium levels to treat neurodegenerative diseases such as AD.

Interpretations of the Term "Actionable" when Discussing Genetic Test Results: What you Mean Is Not What I Heard.

In genomic medicine, the familiarity and inexactness of the term "actionable" can lead to multiple interpretations and mistaken beliefs about realistic treatment options. As part of a larger study focusing on public attitudes toward policies for the return of secondary genomic results, we looked at how members of the lay public interpret the term "medically actionable" in the context of genetic testing. We also surveyed a convenience sample of oncologists as part of a separate study and asked them to define the term "medically actionable." After being provided with a definition of the term, 21 out of 60 (35%) layperson respondents wrote an additional action not specified in the provided definition (12 mentioned "cure" and 9 mentioned environment or behavioral change) and 17 (28%) indicated "something can be done" with no action specified. In contrast, 52 surveyed oncologists did not mention environment, behavioral change, or cure. Based on our findings, we propose that rather than using the term "actionable" alone, providers should also say "what they mean" to reduce miscommunication and confusion that could negatively impact medical decision-making. Lastly, to guide clinicians during patient- provider discussion about genetic test results, we provide examples of phrasing to facilitate clearer communication and understanding of the term "actionable."

Biobanks and the Moral Concerns of Donors: A Democratic Deliberation.

Do members of the public believe that biobanks should accommodate the moral concerns of donors about the types of research done with their biospecimens? The answer to this question is critical to the future of genomic and precision medicine, endeavors that rely on a public willing to share their biospecimens and medical data. To explore public attitudes regarding the requirements of consent for biobank donations, we organized three democratic deliberations involving 180 participants. The deliberative sessions involved small group discussions informed by presentations given by experts in both biobank research and ethics. We found that participants had a sophisticated understanding of the ethical problems of biobank consent and the complexity of balancing donor concerns while promoting research important to the future of health care. Our research shows how deliberative methods can offer policy makers creative ideas for accommodating the moral concerns of donors in the biobank consent process.

Physician Experiences and Understanding of Genomic Sequencing in Oncology.

The amount of information produced by genomic sequencing is vast, technically complicated, and can be difficult to interpret. Appropriately tailoring genomic information for non-geneticists is an essential next step in the clinical use of genomic sequencing. To initiate development of a framework for genomic results communication, we conducted eighteen qualitative interviews with oncologists who had referred adult cancer patients to a matched tumor-normal tissue genomic sequencing study. In our qualitative analysis, we found varied levels of clinician knowledge relating to sequencing technology, the scope of the tumor genomic sequencing study, and incidental germline findings. Clinicians expressed a perceived need for more genetics education. Additionally, they had a variety of suggestions for improving results reports and possible resources to aid in results interpretation. Most clinicians felt genetic counselors were needed when incidental germline findings were identified. Our research suggests that more consistent genetics education is imperative in ensuring the proper utilization of genomic sequencing in cancer care. Clinician suggestions for results interpretation resources and results report modifications could be used to improve communication. Clinicians' perceived need to involve genetic counselors when incidental germline findings were found suggests genetic specialists could play a critical role in ensuring patients receive appropriate follow-up.

Public's Views toward Return of Secondary Results in Genomic Sequencing: It's (Almost) All about the Choice.

The therapeutic use of genomic sequencing creates novel and unresolved questions about cost, clinical efficacy, access, and the disclosure of sequencing results. The disclosure of the secondary results of sequencing poses a particularly challenging ethical problem. Experts disagree about which results should be shared and public input - especially important for the creation of disclosure policies - is complicated by the complex nature of genetics. Recognizing the value of deliberative democratic methods for soliciting informed public opinion on matters like these, we recruited participants from a clinical research site for an all-day deliberative democracy (DD) session. Participants were introduced to the clinical and ethical issues associated with genomic sequencing, after which they discussed the tradeoffs and offered their opinions about policies for the return of secondary results. Participants (n = 66; mean age = 57 (SD = 15); 70% female; 76% white) were divided into 10 small groups (5 to 8 participants each) allowing interactive deliberation on policy options for the return of three categories of secondary results: 1) medically actionable results; 2) risks for adult-onset disorders identified in children; and 3) carrier status for autosomal recessive disorders. In our qualitative analysis of the session transcripts, we found that while participants favored choice and had a preference for making information available, they also acknowledged the risks (and benefits) of learning such information. Our research reveals the nuanced reasoning used by members of the public when weighing the pros and cons of receiving genomic information, enriching our understanding of the findings of surveys of attitudes regarding access to secondary results.

Effect of Public Deliberation on Attitudes toward Return of Secondary Results in Genomic Sequencing.

The increased use of genomic sequencing in clinical diagnostics and therapeutics makes imperative the development of guidelines and policies about how to handle secondary findings. For reasons both practical and ethical, the creation of these guidelines must take into consideration the informed opinions of the lay public. As part of a larger Clinical Sequencing Exploratory Research (CSER) consortium project, we organized a deliberative democracy (DD) session that engaged 66 participants in dialogue about the benefits and risks associated with the return of secondary findings from clinical genomic sequencing. Participants were educated about the scientific and ethical aspects of the disclosure of secondary findings by experts in medical genetics and bioethics, and then engaged in facilitated discussion of policy options for the disclosure of three types of secondary findings: 1) medically actionable results; 2) adult onset disorders found in children; and 3) carrier status. Participants' opinions were collected via surveys administered one month before, immediately following, and one month after the DD session. Post DD session, participants were significantly more willing to support policies that do not allow access to secondary findings related to adult onset conditions in children (Χ 2 (2, N = 62) = 13.300, p = 0.001) or carrier status (Χ 2 (2, N = 60) = 11.375, p = 0.003). After one month, the level of support for the policy denying access to secondary findings regarding adult-onset conditions remained significantly higher than the pre-DD level, although less than immediately post-DD (Χ 2 (1, N = 60) = 2.465, p = 0.041). Our findings suggest that education and deliberation enhance public appreciation of the scientific and ethical complexities of genome sequencing.

Are patients with amyotrophic lateral sclerosis at risk of a therapeutic misconception?

OBJECTIVES: To assess whether persons with amyotrophic lateral sclerosis (ALS) are at risk of a therapeutic misconception (TM) in which they misconceive research as treatment or overestimate the likelihood of its benefit. METHODS: 72 patients with ALS recruited via academic and patient organisations were surveyed using a hypothetical first-in-human intervention study scenario. We elicited their understanding of the purpose of the study ('purpose-of-research question') and then asked how they interpreted the question. We then asked for an estimate of the likelihood that their ALS would improve by participating and asked them to explain the meaning of their estimates. RESULTS: Although 10 of 72 (14%) subjects incorrectly said that the intervention study was 'mostly intending to help [me]' in response to the purpose-of-research question, 7 of those 10 thought that the question was asking them about their own motivations for participating. Overall, only one of 72 respondents (1.4%) both understood the purpose-of-research question as intended and gave the incorrect response. Subjects' mean estimate of likelihood of benefit was 31% (SD 26). This was due to 29 of 72 of respondents providing high estimates (50%-54% likelihood), which they said were expressions of hope and need for a positive attitude; among those who said their estimates meant 'those are the facts' or 'there is a lot of uncertainty', the estimates were much lower (12.6% and 18.5%, respectively). CONCLUSIONS: In this group of patients with ALS considering a hypothetical first-in-human intervention study, apparent TM responses have alternative explanations and the risk of true TM appears low.

C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity.

Compromised lysosome function is implicated in the pathology of many neurodegenerative diseases, including Alzheimer's disease (AD). Familial Alzheimer's disease (fAD) is caused primarily by mutations in the presenilin encoding genes, but the underlying mechanism remains obscure. Loss of the conserved C. elegans presenilin orthologue SEL-12 results in increased mitochondrial calcium, which promotes neurodegeneration. Here, we find that sel-12 mutant lysosomes, independent of SEL-12 proteolytic activity, are significantly enlarged and more alkaline due to increased ER-to-mitochondrial calcium signaling and concomitant mitochondrial oxidative stress. These defects and their dependence on mitochondrial calcium are recapitulated in human fAD fibroblasts, demonstrating a conserved role for mitochondrial calcium in presenilin-mediated lysosome dysfunction. sel-12 mutants also have increased contact surface area between the ER, mitochondria, and lysosomes, suggesting sel-12 has an additional role in modulating organelle contact and communication. Overall, we demonstrate that SEL-12 maintains lysosome acidity and lysosome health by controlling ER-to-mitochondrial calcium signaling.

Genetic Researchers' Use of and Interest in Research With Diverse Ancestral Groups.

Importance: Genetic researchers must have access to databases populated with data from diverse ancestral groups to ensure research is generalizable or targeted for historically excluded communities. Objective: To determine genetic researchers' interest in doing research with diverse ancestral populations, which database stewards offer adequate samples, and additional facilitators for use of diverse ancestral data. Design, Setting, and Participants: This survey study was conducted from June to December 2022 and was part of an exploratory sequential mixed-methods project in which previous qualitative results informed survey design. Eligible participants included genetic researchers who held US academic affiliations and conducted research using human genetic databases. Exposure: Internet-administered survey to genetic research professionals. Main Outcomes and Measures: The survey assessed respondents' experience and interest in research with diverse ancestral data, perceptions of adequacy of diverse data across database stewards (ie, private, government, or consortia), and identified facilitators for encouraging use of diverse ancestral data. Descriptive statistics, χ2 tests, and z tests were used to describe respondents' perspectives and experiences. Results: A total of 294 researchers (171 men [58.5%]; 121 women [41.2%]) were included in the study, resulting in a response rate of 20.4%. Across seniority level, 109 respondents (37.1%) were senior researchers, 85 (28.9%) were mid-level researchers, 71 (24.1%) were junior researchers, and 27 (9.2%) were trainees. Significantly more respondents worked with data from European ancestral populations (261 respondents [88.8%]) compared with any other ancestral population. Respondents who had not done research with Indigenous ancestral groups (210 respondents [71.4%]) were significantly more likely to report interest in doing so than not (121 respondents [41.2%] vs 89 respondents [30.3%]; P < .001). Respondents reported discrepancies in the adequacy of ancestral populations with significantly more reporting European samples as adequate across consortium (203 respondents [90.6%]), government (200 respondents [89.7%]), and private (42 respondents [80.8%]) databases, compared with any other ancestral population. There were no significant differences in reported adequacy of ancestral populations across database stewards. A majority of respondents without access to adequate diverse samples reported that increasing the ancestral diversity of existing databases (201 respondents [68.4%]) and increasing access to databases that are already diverse (166 respondents [56.5%]) would increase the likelihood of them using a more diverse sample. Conclusions and Relevance: In this survey study of US genetic researchers, respondents reported existing databases only provide adequate ancestral samples for European populations, despite their interest in other ancestral populations. These findings suggest there are specific gaps in access to and composition of genetic databases, highlighting the urgent need to boost diversity in research samples to improve inclusivity in genetic research practices.

Using Behavioral Economics to Reduce Low-Value Care Among Older Adults: A Cluster Randomized Clinical Trial.

Importance: Use of low-value care is common among older adults. It is unclear how to best engage clinicians and older patients to decrease use of low-value services. Objective: To test whether the Committing to Choose Wisely behavioral economic intervention could engage primary care clinicians and older patients to reduce low-value care. Design, Setting, and Participants: Stepped-wedge cluster randomized clinical trial conducted at 8 primary care clinics of an academic health system and a private group practice between December 12, 2017, and September 4, 2019. Participants were primary care clinicians and older adult patients who had diabetes, insomnia, or anxiety or were eligible for prostate cancer screening. Data analysis was performed from October 2019 to November 2023. Intervention: Clinicians were invited to commit in writing to Choosing Wisely recommendations for older patients to avoid use of hypoglycemic medications to achieve tight glycemic control, sedative-hypnotic medications for insomnia or anxiety, and prostate-specific antigen tests to screen for prostate cancer. Committed clinicians had their photographs displayed on clinic posters and received weekly emails with alternatives to these low-value services. Educational handouts were mailed to applicable patients before scheduled visits and available at the point of care. Main Outcomes and Measures: Patient-months with a low-value service across conditions (primary outcome) and separately for each condition (secondary outcomes). For patients with diabetes, or insomnia or anxiety, secondary outcomes were patient-months in which targeted medications were decreased or stopped (ie, deintensified). Results: The study included 81 primary care clinicians and 8030 older adult patients (mean [SD] age, 75.1 [7.2] years; 4076 men [50.8%] and 3954 women [49.2%]). Across conditions, a low-value service was used in 7627 of the 37 116 control patient-months (20.5%) and 7416 of the 46 381 intervention patient-months (16.0%) (adjusted odds ratio, 0.79; 95% CI, 0.65-0.97). For each individual condition, there were no significant differences between the control and intervention periods in the odds of patient-months with a low-value service. The intervention increased the odds of deintensification of hypoglycemic medications for diabetes (adjusted odds ratio, 1.85; 95% CI, 1.06-3.24) but not sedative-hypnotic medications for insomnia or anxiety. Conclusions and Relevance: In this stepped-wedge cluster randomized clinical trial, the Committing to Choose Wisely behavioral economic intervention reduced low-value care across 3 common clinical situations and increased deintensification of hypoglycemic medications for diabetes. Use of scalable interventions that nudge patients and clinicians to achieve greater value while preserving autonomy in decision-making should be explored more broadly. Trial Registration: ClinicalTrials.gov Identifier: NCT03411525.

Kaposi sarcoma herpesvirus viral load in bronchoalveolar lavage as a diagnostic marker for pulmonary Kaposi sarcoma.

OBJECTIVE: Kaposi sarcoma is a vascular tumor that affects the pulmonary system. However, the diagnosis of airway lesions suggestive of pulmonary Kaposi sarcoma (pKS) is reliant on bronchoscopic visualization. We evaluated the role of Kaposi sarcoma herpesvirus (KSHV) viral load in bronchoalveolar lavage (BAL) as a diagnostic biomarker in patients with bronchoscopic evidence of pKS and evaluated inflammatory cytokine profiles in BAL and blood samples. DESIGN: In this retrospective study, we evaluated KSHV viral load and cytokine profiles within BAL and blood samples in patients who underwent bronchoscopy for suspected pKS between 2016 and 2021. METHODS: KSHV viral load and cytokine profiles were obtained from both the circulation and BAL samples collected at the time of bronchoscopy to evaluate compartment-specific characteristics. BAL was centrifuged and stored as cell pellets and KSHV viral load was measured using primers for the KSHV K6 gene regions. RESULTS: We evaluated 38 BAL samples from 32 patients (30 with HIV co-infection) of whom 23 had pKS. In patients with airway lesions suggestive of pKS, there was higher KSHV viral load (median 3188 vs. 0 copies/10 6 cell equivalent; P  = 0.0047). A BAL KSHV viral load cutoff of 526 copies/10 6 cells had a sensitivity of 72% and specificity of 89% in determining lesions consistent with pKS. Those with pKS also had higher IL-1ß and IL-8 levels in BAL. The 3-year survival rate for pKS patients was 55%. CONCLUSION: KSHV viral load in BAL shows potential for aiding in pKS diagnosis. Patients with pKS also have evidence of cytokine dysregulation in BAL.

Public's approach to surrogate consent for dementia research: cautious pragmatism.

OBJECTIVES: To describe how members of the older general public deliberate with one another in finding solutions to the dilemma of involving persons with decisional incapacity in dementia research. DESIGN, SETTING, AND PARTICIPANTS: One hundred sixty persons age 50 years and older who participated in an all-day deliberative democracy session on the ethics of surrogate consent for dementia research. The deliberative democracy day consisted of both extensive, interactive education with experts in clinical research and ethics, as well as small group deliberations. MEASUREMENTS: Audiotaped small group deliberations were transcribed and analyzed and the main thematic elements were coded. RESULTS: During deliberation, participants acknowledged the limitations of advanced research directives and discussed ways to improve their use. Although there was consensus about the necessity of surrogate consent, the participants recognized potential pitfalls and looked for ways to safeguard the process. Participants supporting surrogate consent for research emphasized societal and individual benefits, the importance of assent, and trust in surrogates and the oversight system. Other participants felt that the high risk of some research scenarios was not sufficiently offset by benefits to patients or society. CONCLUSIONS: Members of the older general public are able to make use of in-depth education and peer deliberation to provide reasoned and informed opinions on the ethical use of surrogate consent for dementia research. The public's approach to surrogate consent is one of cautious pragmatism: an overall trust in science and future surrogates with awareness of the potential pitfalls, suggesting that their trust cannot be taken for granted.

Neuropsychological correlates of capacity determinations in Alzheimer disease: implications for assessment.

OBJECTIVES: To explore the neuropsychological correlates of the capacity to consent to research and to appoint a research proxy among persons with Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTS: Interview study of 77 persons with Alzheimer disease recruited through an Alzheimer disease research center and a memory disorder clinic. MEASUREMENTS: The capacity to consent to two research scenarios (a drug randomized clinical trial and a neurosurgical clinical trial) and the capacity to appoint a research proxy were determined by five experienced consultation psychiatrists who rendered categorical judgments based on videotaped interviews of the MacArthur Competence Assessment Tool-Clinical Research and the Capacity to Appoint a Proxy Assessment. Mattis Dementia Rating Scale-Second Edition was used to assess neuropsychological functioning. RESULTS: The capacity to appoint a proxy and to consent to the drug randomized clinical trial, as determined by a majority or greater opinion of the five-psychiatrist panel, was predicted by Conceptualization and Initiation/Perseveration subscales, whereas the capacity to consent to a neurosurgical randomized clinical trial was predicted by the Memory subscale. Furthermore, the more lenient individual psychiatrists' judgments were predicted by the Conceptualization subscale, whereas the stricter psychiatrists' judgments were predicted by the Memory subscale. CONCLUSIONS: How experienced psychiatrists view the capacity of patients with Alzheimer disease for consenting to research and for appointing a proxy may be related to the patients' conceptualization and memory functioning. More explicit and standardized guidance on the role of short-term memory in capacity determinations may be useful.

Assessment of decision-making capacity: views and experiences of consultation psychiatrists.

BACKGROUND: Decision-making capacity (DMC) assessments can have profound consequences for patients. With an aging population, an increasing emphasis on shared decision-making, and a rising number of potential medical interventions, the need for such assessments will continue to grow. OBJECTIVE: To assess psychosomatic medicine clinicians' training, experiences, and views about DMC assessments. METHOD: Online survey of members of the Academy of Psychosomatic Medicine (APM). Of 780 eligible members, 288 responded to the survey (36.9% response rate). RESULTS: Approximately 1 in 6 psychiatric consultations are DMC assessments. Ninety percent of respondents reported that at least half of their capacity assessments involve patients older than 60 years. DMC assessments were seen as more challenging and time-consuming than other types of consultations; yet training in capacity evaluations was seen as suboptimal and half of respondents felt the evidence-base guiding DMC assessment is somewhat or much weaker than for other types of psychiatric consultations. In addition, the practice of capacity assessment seems to vary widely with no consistent approach among respondents. Respondents strongly endorsed multiple areas and topics for potential future research, indicating a desire for a stronger evidence-base. CONCLUSIONS: Members of the APM perceive capacity assessments as common and challenging. Yet they perceive having received subpar training with relatively weak evidence to guide their current practice. Future research should address these potential deficiencies, given the likelihood that DMC assessments will only become more common.