"What Else Could It Be?" A Scoping Review of Questions for Patients to Ask Throughout the Diagnostic Process.

BACKGROUND: Diagnostic errors are a global patient safety challenge. Over 75% of diagnostic errors in ambulatory care result from breakdowns in patient-clinician communication. Encouraging patients to speak up and ask questions has been recommended as one strategy to mitigate these failures. OBJECTIVES: The goal of the scoping review was to identify, summarize, and thematically map questions patients are recommended to ask during ambulatory encounters along the diagnostic process. This is the first step in a larger study to co-design a patient-facing question prompt list for patients to use throughout the diagnostic process. METHODS: Medline and Google Scholar were searched to identify question lists in the peer-reviewed literature. Organizational websites and a search engine were searched to identify question lists in the gray literature. Articles and resources were screened for eligibility and data were abstracted. Interrater reliability (K = 0.875) was achieved. RESULTS: A total of 5509 questions from 235 resources met inclusion criteria. Most questions (n = 4243, 77.02%) were found in the gray literature. Question lists included an average of 23.44 questions. Questions were most commonly coded along the diagnostic process categories of treatment (2434 questions from 250 resources), communication of the diagnosis (1160 questions, 204 resources), and outcomes (766 questions, 172 resources). CONCLUSIONS: Despite recommendations for patients to ask questions, most question prompt lists focus on later stages of the diagnostic process such as communication of the diagnosis, treatment, and outcomes. Further research is needed to identify and prioritize diagnostic-related questions from the patient perspective and to develop simple, usable guidance on question-asking to improve patient safety across the diagnostic continuum.

Feasibility of Using Simulation to Evaluate Implementation Fidelity in an Advance Care Planning Pragmatic Trial.

Background and Objectives: Traditional methods of fidelity monitoring are not possible in pragmatic trials in real-world clinical settings. We describe our approach to monitoring and reinforcing the fidelity to ACP conversations for a hard-to-reach subpopulation by using standardized patients in a pragmatic trial. Research Design and Methods: We developed standardized patient scenarios grounded in the Respecting Choices First Steps™ Advance Care Planning curriculum to provide an opportunity to reinforce and assess ACP facilitator competency. Scenarios represented one-on-one encounters. The first case was a standardized patient with cognitive impairment and the second case involved a standardized patient with dementia and their care partner. A previously validated fidelity checklist was used to score skills and behaviors observed during simulations including encounter set-up, ACP topics, and general communication. Simulations involved voice teleconferencing to align primary modality of ACP in the pragmatic trial. Results: Six facilitators completed two standardized patient cases each. Overall fidelity scores were moderately high (78.8% ± 11.7; 63.4 - 95.6) for the case with cognitive impairment and for the case with the patient with dementia and care partner (76.2% ± 13.0; 54.4 - 91.5). Discussion and Implications: Simulation using standardized patients supported fidelity monitoring and provided coachable feedback to support facilitator competency. Our study can help inform future research and training related to advance care planning in older adults living with Alzheimer's disease and related disorders.

Using Patient Experience Surveys to Identify Potential Diagnostic Safety Breakdowns: A Mixed Methods Study.

OBJECTIVES: One in 20 outpatients in the United States experiences a diagnostic error each year, but there are no validated methods for collecting feedback from patients on diagnostic safety. We examined patient experience surveys to determine whether patients' free text comments indicated diagnostic breakdowns. Our objective was to evaluate associations between patient-perceived diagnostic breakdowns reported in free text comments and patients' responses to structured survey questions. METHODS: We conducted an exploratory mixed methods study using data from patient experience surveys collected from adult ambulatory care patients March 2020 to June 2020 in a large U.S. health system. Data analysis included content analysis of qualitative data and statistical analysis of quantitative data. RESULTS: In 2525 surveys with negative comments, 619 patients (24.5%) identified diagnostic breakdowns, including issues with accuracy (n = 282, 46%), timeliness (n = 243, 39%), or communication (n = 290, 47%); some patients (n = 181) reported breakdowns in multiple categories. Patients who gave a low average score (50 or less on a 100-point scale) on provider questions were almost seven times more likely to perceive a diagnostic breakdown than patients who scored their provider higher. Similarly, patients who gave a low average score on practice-related questions were twice as likely to perceive a diagnostic breakdown. CONCLUSIONS: Patient feedback in routinely collected patient experience surveys is a valuable and actionable information source on diagnostic breakdowns in the ambulatory setting. The more easily monitored structured survey data provide a screening method to identify encounters that may have included a patient-perceived diagnostic breakdown and therefore require further examination.

Reported impact and protective factors of the care partner role during persistent critical illness: a content analysis.

BACKGROUND: Patients with persistent critical illness experience prolonged multi-system morbidity, functional impairments, and chronic conditions. As a result, these patients have prolonged intensive care unit admissions. If discharged, they return home with long-term medical dependencies. Care partners take on a variety of physical, mental health, cognitive, and social roles to support the provision of care for these patients. There is limited evidence, however, of the impact of being a care partner for this patient population during hospitalization. METHODS: A qualitative descriptive study was conducted to explore the impact care provision on care partners for patients experiencing persistent critical illness. Patients who have or have had persistent critical illness and care partners were recruited from two inpatient units in a single community academic hospital in Toronto, Canada to participate in semi-structured interviews. Data was analyzed using a team-based inductive content analysis. RESULTS: Seven (43.8%) participants were patient survivors, and nine (56.3%) were care partners. Patients and care partners reported physical, socio-emotional, and social stress as impacts of care provision during persistent critical illness hospitalization. Care partners identified several protective strategies that they used to mitigate the impacts of care provision on them such as seeking external mental health support and boundary setting. Features of formalized and care partner programs were also identified and suggest that these programs can be protective of care partner values, mitigate feelings of helplessness and stress, and may improve relationships between the family members who are in the care partner role and the healthcare team. CONCLUSIONS: This study identified physical, socio-emotional, and social stress related impacts of care provision on care partners of patients with persistent critical illness during hospitalization. Additionally, this study identified protective factors initiated by care partners to mitigate the reported stresses of the role, as well as protective features of a care partner program. The results provide a better understanding supportive features of care partner programs that are specific to the experiences and needs of persistent critical illness and add to the growing body of evidence about how to provide equitable access to care during and post hospitalization.

Kappa opioids inhibit spinal output neurons to suppress itch.

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca2+ imaging of the dorsal horn to visualize neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal interneurons recruited by diverse itch-causing stimuli that represents a subset of neurons that express the gastrin-releasing peptide receptor (GRPR). Moreover, we find that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nuclei. We then show that the kappa opioid receptor agonist nalfurafine relieves itch by selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide a population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

Qualitative evaluation of the SHARING Choices trial of primary care advance care planning for adults with and without dementia.

BACKGROUND: Primary care can be an important setting for communication and advance care planning (ACP), including for those with dementia and their families. The study objective was to explore experiences with a pragmatic trial of a communication and ACP intervention, SHARING Choices, in primary care for older adults with and without dementia. METHODS: We conducted qualitative interviews using tailored semi-structured guides with three groups: ACP facilitators who conducted the intervention; clinicians, managers, and administrators from sites randomized to the intervention; and patients and families who met with ACP facilitators. We used thematic analysis to identify and synthesize emergent themes based on key Consolidated Framework for Implementation Research concepts and Proctor's Implementation Outcomes, triangulating the three groups' perspectives. RESULTS: We identified five key themes. For acceptability, perceptions of the intervention were mostly positive, although some components were not generally implemented. For adoption, respondents perceived that ACP facilitators mainly focused on conducting ACP, although facilitators often did not implement the ADRD and family engagement aspects with the ACP. For relational connections, ACP facilitator-practice and clinician communication and engagement were key to how the intervention was implemented. For adaptability, ACP facilitators and health systems adapted how the ACP facilitation component was implemented to local preferences and over time, given the pragmatic nature of the trial. And, for sustainability, ACP facilitators and clinicians/managers/facilitators were positive that the intervention should be continued but noted barriers to its sustainability. Patients and families generally did not recall the intervention. CONCLUSIONS: ACP facilitators and clinicians, managers, and administrators had positive perceptions of the ACP facilitator component of the intervention in this pragmatic trial with adaptation to local preferences. However, engaging those with dementia and families was more challenging in the implementation of this intervention.

Commentary: Engagement for Research and Quality Improvement - More Than Just Words.

We reflect on the paper from Hahn-Goldberg et al. (2024) who shared key learnings from a pan-Canadian quality improvement (QI) and patient engagement care transition initiative called Bridge-to-Home. In considering the approach and outcomes presented in their paper, we have generated reflections and practical suggestions on how to amplify engagement work even further: (1) patient engagement and QI are about relationships; (2) seamlessly implementing complex interventions across siloed organizations continues to be a challenge, which engagement alone cannot solve; (3) it is time for a paradigm shift; (4) QI is about human behaviour change and is inherently messy; and (5) embedding fulsome evaluation of engagement is essential.

The functional and anatomical characterization of three spinal output pathways of the anterolateral tract.

The nature of spinal output pathways that convey nociceptive information to the brain has been the subject of controversy. Here, we provide anatomical, molecular, and functional characterizations of two distinct anterolateral pathways: one, ascending in the lateral spinal cord, triggers nociceptive behaviors, and the other one, ascending in the ventral spinal cord, when inhibited, leads to sensorimotor deficits. Moreover, the lateral pathway consists of at least two subtypes. The first is a contralateral pathway that extends to the periaqueductal gray (PAG) and thalamus; the second is a bilateral pathway that projects to the bilateral parabrachial nucleus (PBN). Finally, we present evidence showing that activation of the contralateral pathway is sufficient for defensive behaviors such as running and freezing, whereas the bilateral pathway is sufficient for attending behaviors such as licking and guarding. This work offers insight into the complex organizational logic of the anterolateral system in the mouse.

Identification of a convergent spinal neuron population that encodes itch.

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca2+ imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca2+ oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord.

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

Calretinin-expressing islet cells: a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord.

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

SHARING Choices: Lessons Learned from a Primary-Care Focused Advance Care Planning Intervention.

BACKGROUND: Few advance care planning (ACP) interventions have been scaled in primary care. PROBLEM: Best practices for delivering ACP at scale in primary care do not exist and prior efforts have excluded older adults with Alzheimer's Disease and Related Dementias (ADRD). INTERVENTION: SHARING Choices (NCT#04819191) is a multicomponent cluster-randomized pragmatic trial conducted at 55 primary care practices from two care delivery systems in the Mid-Atlantic region of the U.S. We describe the process of implementing SHARING Choices within 19 practices randomized to the intervention, summarize fidelity to planned implementation, and discuss lessons learned. OUTCOMES: Embedding SHARING Choices involved engagement with organizational and clinic-level partners. Of 23,220 candidate patients, 17,931 outreach attempts by phone (77.9%) and the patient portal (22.1%) were made by ACP facilitators and 1215 conversations occurred. Most conversations (94.8%) were less than 45 minutes duration. Just 13.1% of ACP conversations included family. Patients with ADRD comprised a small proportion of patients who engaged in ACP. Implementation adaptations included transitioning to remote modalities, aligning ACP outreach with the Medicare Annual Wellness Visit, accommodating primary care practice flexibility. LESSONS LEARNED: Study findings reinforce the value of adaptable study design; co-designing workflow adaptations with practice staff; adapting implementation processes to fit the unique needs of two health systems; and modifying efforts to meet health system goals and priorities.

Patient generated research priorities to improve diagnostic safety: A systematic prioritization exercise.

BACKGROUND: Most people experience a diagnostic error at least once in their lifetime. Patients' experiences with their diagnosis could provide important insights when setting research priorities to reduce diagnostic error. OBJECTIVE: Our objective was to engage patients in research agenda setting for improving diagnosis. PATIENT INVOLVEMENT: Patients were involved in generating, discussing, prioritizing, and ranking of research questions for diagnostic error reduction. METHODS: We used the prioritization methodology based on the Child Health and Nutrition Research Initiative (CHNRI). We first solicited research questions important for diagnostic error reduction from a large group of patients. Thirty questions were initially prioritized at an in-person meeting with 8 patients who were supported by 4 researchers. The resulting list was further prioritized by patients who scored questions on five predefined criteria. We then applied previously determined weights to these prioritization criteria to adjust the final prioritization score for each question, resulting in 10 highest priority research questions. RESULTS: Forty-one patients submitted 171 research questions. After prioritization, the highest priority topics included better care coordination across the diagnostic continuum and improving care transitions, improved identification and measurement of diagnostic errors and attention for implicit bias towards patients who are vulnerable to diagnostic errors. DISCUSSION: We systematically identified the top-10 patient generated research priorities for diagnostic error reduction using transparent and objective methods. Patients prioritized different research questions than researchers and therefore complemented an agenda previously generated by researchers. PRACTICAL VALUE: Research priorities identified by patients can be used by funders and researchers to conduct future research focused on reducing diagnostic errors. FUNDING: This project was funded by the Gordon and Betty Moore Foundation.

The Delta-Opioid Receptor Bidirectionally Modulates Itch.

Opioid signaling has been shown to be critically important in the neuromodulation of sensory circuits in the superficial spinal cord. Agonists of the mu-opioid receptor (MOR) elicit itch, whereas agonists of the kappa-opioid receptor (KOR) have been shown to inhibit itch. Despite the clear roles of MOR and KOR for the modulation itch, whether the delta-opioid receptor (DOR) is involved in the regulation of itch remained unknown. Here, we show that intrathecal administration of DOR agonists suppresses chemical itch and that intrathecal application of DOR antagonists is sufficient to evoke itch. We identify that spinal enkephalin neurons co-express neuropeptide Y (NPY), a peptide previously implicated in the inhibition of itch. In the spinal cord, DOR overlapped with both the NPY receptor (NPY1R) and KOR, suggesting that DOR neurons represent a site for convergent itch information in the dorsal horn. Lastly, we found that neurons co-expressing DOR and KOR showed significant Fos induction following pruritogen-evoked itch. These results uncover a role for DOR in the modulation of itch in the superficial dorsal horn. PERSPECTIVE: This article reveals the role of the delta-opioid receptor in itch. Intrathecal administration of delta agonists suppresses itch whereas the administration of delta antagonists is sufficient to induce itch. These studies highlight the importance of delta-opioid signaling for the modulation of itch behaviors, which may represent new targets for the management of itch disorders.

Perceived Barriers and Facilitators of Implementing a Multicomponent Intervention to Improve Communication With Older Adults With and Without Dementia (SHARING Choices) in Primary Care: A Qualitative Study.

INTRODUCTION: Implementing patient- and family-centered communication strategies has proven challenging in primary care, particularly for persons with dementia. To address this, we designed SHARING Choices, a multicomponent intervention combining patient and family partnered agenda setting, electronic portal access, and supports for advance care planning (ACP). This qualitative descriptive study describes factors affecting SHARING Choices implementation within primary care. METHODS: Semi-structured interviews or focus groups with patient/family dyads (family, friends, unpaid caregivers) and primary care stakeholders (clinicians, staff, administrators) elicited perceived barriers and facilitators of SHARING Choices implementation. Field notes and interview transcripts were coded using template analysis along the Consolidated Framework for Implementation Research (CFIR) constructs. Content analysis identified themes not readily categorized within CFIR. RESULTS: About 22 dyads, including 14 with cognitive impairment, and 30 stakeholders participated in the study. Participants were receptive to the SHARING Choices components. Enablers of SHARING Choices included adaptability of the intervention, purposive engagement of family (particularly for patients with dementia), consistency with organizational priorities, and the relative advantage of SHARING Choices compared to current practices. Perceived barriers to implementation included intervention complexity, space constraints, workflow, and ACP hesitancy. The ACP facilitator was perceived as supportive in addressing individual and organizational implementation barriers including patient health and technology literacy and clinician time for ACP discussions. CONCLUSIONS: Patients, family, and primary care clinicians endorsed the objectives and individual components of SHARING Choices. Strategies to enhance adoption were to simplify materials, streamline processes, leverage existing workflows, and embed ACP facilitators within the primary care team.

Cell type-specific calcium imaging of central sensitization in mouse dorsal horn.

Allodynia is a state in which pain is elicited by innocuous stimuli. Capsaicin applied to the skin results in an allodynia that extends to a broad region beyond the application site. This sensitization is thought to be mediated by spinal networks; however, we do not have a clear picture of which spinal neurons mediate this phenomenon. To address this gap, we used two-photon calcium imaging of excitatory interneurons and spinal projection neurons in the mouse spinal dorsal horn. To distinguish among neuronal subtypes, we developed CICADA, a cell profiling approach to identify cell types during calcium imaging. We then identified capsaicin-responsive and capsaicin-sensitized neuronal populations. Capsaicin-sensitized neurons showed emergent responses to innocuous input and increased receptive field sizes consistent with psychophysical reports. Finally, we identified spinal output neurons that showed enhanced responses from innocuous input. These experiments provide a population-level view of central sensitization and a framework with which to model somatosensory integration in the dorsal horn.

Altered Intrinsic Properties and Inhibitory Connectivity in Aged Parvalbumin-Expressing Dorsal Horn Neurons.

The incidence of pain symptoms such as allodynia are known to increase with age. Parvalbumin expressing interneurons (PVINs) within the dorsal horn (DH) of the spinal cord play an important role in allodynia whereby their inhibitory connections prevent innocuous touch information from exciting nociceptive pathways. Here we ask whether the functional properties of PVINs are altered by aging, comparing their functional properties in adult (3-7 month) and aged mice (23-28 month). Patch clamp recordings were made from PVINs in laminae IIi-III of parasagittal spinal cord slices. The intrinsic excitability of PVINs changed with age. Specifically, AP discharge shifted from initial bursting to tonic firing, and firing duration during current injection increased. The nature of excitatory synaptic input to PVINs also changed with age with larger but less frequent spontaneous excitatory currents occurring in aged mice, however, the net effect of these differences produced a similar level of overall excitatory drive. Inhibitory drive was also remarkably similar in adult and aged PVINs. Photostimulation of ChR2 expressing PVINs was used to study inhibitory connections between PVINs and unidentified DH neurons and other PVINs. Based on latency and jitter, monosynaptic PVIN to unidentified-cell and PVIN-PVIN connections were compared in adult and aged mice, showing that PVIN to unidentified-cell connection strength increased with age. Fitting single or double exponentials to the decay phase of IPSCs showed there was also a shift from mixed (glycinergic and GABAergic) to GABAergic inhibitory transmission in aged animals. Overall, our data suggest the properties of PVIN neurons in aged animals enhance their output in spinal circuits in a manner that would blunt allodynia and help maintain normal sensory experience during aging.

SHARING Choices: Design and rationale for a pragmatic trial of an advance care planning intervention for older adults with and without dementia in primary care.

BACKGROUND: Advance care planning (ACP) and involving family are particularly important in dementia, and primary care is a key setting. The purpose of this trial is to examine the impact and implementation of SHARING Choices, an intervention to improve communication for older adults with and without dementia through proactively supporting ACP and family engagement in primary care. METHODS: We cluster-randomized 55 diverse primary care practices across two health systems to the intervention or usual care. SHARING Choices is a multicomponent intervention that aims to improve communication through patient and family engagement in ACP, agenda setting, and shared access to the patient portal for all patients over 65 years of age. The primary outcomes include documentation of an advance directive or medical orders for life-sustaining treatment in the electronic health record (EHR) at 12 months for all patients and receipt of potentially burdensome care within 6 months of death for the subgroup of patients with serious illness. We plan a priori sub-analysis for patients with dementia. Data sources include the health system EHRs and the Maryland health information exchange. We use a mixed-methods approach to evaluate uptake, fidelity and adaptation of the intervention and implementation facilitators and barriers. CONCLUSIONS: This cluster-randomized pragmatic trial examines ACP with a focus on the key population of those with dementia, implementation in diverse settings and innovative approaches to trial design and outcome abstraction. Mixed-methods approaches enable understanding of intervention delivery and facilitators and barriers to implementation in rapidly changing health care systems. CLINICALTRIALS: gov Identifier: NCT04819191.

Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit.

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved. We now expose a cellular circuit that inhibits nocioception and itch in mice. Through a combination of molecular, tracing and behavioural approaches, we found that rostral ventromedial medulla neurons containing the kappa-opioid receptor inhibit itch and nocioception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that rostral ventromedial medulla kappa-opioid receptor neurons inhibit nocioception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal grey that modulates nociception within the rostral ventromedial medulla. These discoveries highlight a distinct population of rostral ventromedial medulla neurons capable of broadly and robustly inhibiting itch and nocioception.