Achieving Diagnostic Excellence: Roadmaps to Develop and Use Patient-Reported Measures With an Equity Lens.

BACKGROUND: Diagnostic excellence refers to the optimal process to attain an accurate and precise explanation about a patient's condition and incorporates the perspectives of patients and their care partners. Patient-reported measures (PRMs), designed to capture patient-reported information, have potential to contribute to achieving diagnostic excellence. We aimed to craft a set of roadmaps illustrating goals and guiding the development of PRMs for diagnostic excellence ("Roadmaps"). METHODS: We used iterative inputs from environmental literature scans, expert consultations, and patient voice and employed human-centred design (HCD) and equity-focused road-mapping. The culminating activity of these approaches was an Expert Convening. RESULTS: Use of PRMs can achieve multiple goals for diagnostic excellence, including but not limited to: (1) PRMs for diagnostic continuity, (2) diagnostic PRM alerts, (3) PRM-based quality improvement, (4) PRMs for research, (5) PRMs for routine screening, (6) PRM-based diagnostic excellence population-level patterns, and (7) PRMs supporting patient storytelling. Equity is considered as a cross-cutting goal. Altogether these and future goals support operationalising a vision of patient-reported diagnostic excellence. Roadmaps were developed as a dynamic tool to illustrate PRMs in relation to specific steps with feedback loops to accomplish goals, anticipated timeframes (8-15 years), synergies to foster, and challenges to overcome. Roadmaps are practical in their following PRMs through the stages of development, endorsement, implementation and scaling, and acting upon those measures. Timeframe estimates assume immediate transitions between these stages and no acceleration through incentives and active coordination. CONCLUSION: PRMs for diagnostic excellence have potential to connect patient perspectives, equity, and achievable goals. Roadmaps offer a design approach to enable coordinating measurement activities among diverse stakeholders. Roadmaps also highlight versatility in ways patient-reported information can be collected and used, from clinical settings to public health contexts. Patient-reported diagnostic excellence cannot be established as a solely top-down endeavour, but inherently benefits from bottom-up approaches.

Development and Psychometric Analysis of a Patient-Reported Measure of Diagnostic Excellence for Emergency and Urgent Care Settings.

BACKGROUND: Emergency and urgent care settings face challenges with routinely obtaining performance feedback related to diagnostic care. Patients and their care partners provide an important perspective on the diagnostic process and outcome of care in these settings. We sought to develop and test psychometric properties of Patient-Report to IMprove Diagnostic Excellence in Emergency Department settings (PRIME-ED), a measure of patient-reported diagnostic excellence in these care settings. METHODS: We developed PRIME-ED based on literature review, expert feedback, and cognitive testing. To assess psychometric properties, we surveyed AmeriSpeak, a probability-based panel that provides sample coverage of approximately 97% of the U.S. household population, in February 2022 to adult patients, or their care partners, who had presented to an emergency department or urgent care facility within the last 30 days. Respondents rated their agreement on a 5-point Likert scale with each of 17 statements across multiple domains of patient-reported diagnostic excellence. Demographics, visit characteristics, and a subset of the Emergency Department Consumer Assessment of Healthcare Providers & Systems were also collected. We conducted psychometric testing for reliability and validity. RESULTS: Over a thousand (n = 1116) national panelists completed the PRIME-ED survey, of which 58.7% were patients and 40.9% were care partners; 49.6% received care at an emergency department and 49.9% at an urgent care facility. Responses had high internal consistency within 3 patient-reported diagnostic excellence domain groupings: diagnostic process (Cronbach's alpha 0.94), accuracy of diagnosis (0.93), and communication of diagnosis (0.94). Domain groupings were significantly correlated with concurrent Emergency Department Consumer Assessment of Healthcare Providers & Systems items. Factor analyses substantiated 3 domain groupings. CONCLUSIONS: PRIME-ED has potential as a tool for capturing patient-reported diagnostic excellence in emergency and urgent care.

FlhE functions as a chaperone to prevent formation of periplasmic flagella in Gram-negative bacteria.

The bacterial flagellum, which facilitates motility, is composed of ~20 structural proteins organized into a long extracellular filament connected to a cytoplasmic rotor-stator complex via a periplasmic rod. Flagellum assembly is regulated by multiple checkpoints that ensure an ordered gene expression pattern coupled to the assembly of the various building blocks. Here, we use epifluorescence, super-resolution, and transmission electron microscopy to show that the absence of a periplasmic protein (FlhE) prevents proper flagellar morphogenesis and results in the formation of periplasmic flagella in Salmonella enterica. The periplasmic flagella disrupt cell wall synthesis, leading to a loss of normal cell morphology resulting in cell lysis. We propose that FlhE functions as a periplasmic chaperone to control assembly of the periplasmic rod, thus preventing formation of periplasmic flagella.

Urological outcomes in adult females born with anorectal malformation or Hirschsprung disease.

INTRODUCTION: Women born with anorectal malformation (ARM) or Hirschsprung disease (HD) may have impaired urologic function resulting in sequelae in adulthood. This study assessed and compared self-reported urinary outcomes in adult females born with ARM or HD to a reference population. METHODS: This was an IRB approved, cross-sectional study of female-born patients with ARM or HD, who completed surveys between November 2021 and August 2022. Female patients between the ages of 18 and 80 years were included. Lower Urinary Tract Symptom Questionnaires were administered through REDCap and the responses were compared to a reference population using Chi-squared or Fisher's exact tests. RESULTS: Sixty-six born female patients answered the questionnaires, two of them identified as non-binary. The response rate was 76%. Median age was 31.6 years. The majority were born with cloaca (56.3%), followed by other type of ARMs (28.1%), complex malformation (9.4%), and HD (6.3%). A history of bladder reconstruction was present for 26.6%. Catheterization through a channel or native urethra was present in 18.8%. Two had ureterostomies and were excluded from the analysis. Seven had chronic kidney disease or end-stage renal disease, three with a history of kidney transplantation. Patients with cloaca had significantly higher rates of urinary incontinence, urinary tract infection, and social problems due to impaired urological functioning, when compared to an age-matched reference population (Table 3). CONCLUSION: This study emphasizes the need for a multi-disciplinary team that includes urology and nephrology following patients with ARM long term, especially within the subgroup of cloaca. LEVEL OF EVIDENCE: III.

Patient-reported outcome and experience domains for diagnostic excellence: a scoping review to inform future measure development.

PURPOSE: "Diagnostic excellence," as a relatively new construct centered on the diagnostic process and its health-related outcomes, can be refined by patient reporting and its measurement. We aimed to explore the scope of patient-reported outcome (PRO) and patient-reported experience (PRE) domains that are diagnostically relevant, regardless of the future diagnosed condition, and to review the state of measurement of these patient-reported domains. METHODS: We conducted an exploratory analysis to identify these domains by employing a scoping review supplemented with internal expert consultations, 24-member international expert convening, additional environmental scans, and the validation of the domains' diagnostic relevance via mapping these onto patient diagnostic journeys. We created a narrative bibliography of the domains illustrating them with existing measurement examples. RESULTS: We identified 41 diagnostically relevant PRO and PRE domains. We classified 10 domains as PRO, 28 as PRE, and three as mixed PRO/PRE. Among these domains, 19 were captured in existing instruments, and 20 were captured only in qualitative studies. Two domains were conceptualized during this exploratory analysis with no examples identified of capturing these domains. For 27 domains, patients and care partners report on a specific encounter; for 14 domains, reporting relates to an entire diagnostic journey over time, which presents particular measurement opportunities and challenges. CONCLUSION: The multitude of PRO and PRE domains, if measured rigorously, would allow the diagnostic excellence construct to evolve further and in a manner that is patient-centered, prospectively focused, and concentrates on effectiveness and efficiency of diagnostic care on patients' well-being.

Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells.

Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy.

Care partners and consumer health information technology: A framework to guide systems-level initiatives in support of digital health equity.

Introduction: Consumer-oriented health information technologies (CHIT) such as the patient portal have a growing role in care delivery redesign initiatives such as the Learning Health System. Care partners commonly navigate CHIT demands alongside persons with complex health and social needs, but their role is not well specified. Methods: We assemble evidence and concepts from the literature describing interpersonal communication, relational coordination theory, and systems-thinking to develop an integrative framework describing the care partner's role in applied CHIT innovations. Our framework describes pathways through which systematic engagement of the care partner affects longitudinal work processes and multi-level outcomes relevant to Learning Health Systems. Results: Our framework is grounded in relational coordination, an emerging theory for understanding the dynamics of coordinating work that emphasizes role-based relationships and communication, and the Systems Engineering Initiative for Patient Safety (SEIPS) model. Cross-cutting work systems geared toward explicit and purposeful support of the care partner role through CHIT may advance work processes by promoting frequent, timely, accurate, problem-solving communication, reinforced by shared goals, shared knowledge, and mutual respect between patients, care partners, and care team. We further contend that systematic engagement of the care partner in longitudinal work processes exerts beneficial effects on care delivery experiences and efficiencies at both individual and organizational levels. We discuss the utility of our framework through the lens of an illustrative case study involving patient portal-mediated pre-visit agenda setting. Conclusions: Our framework can be used to guide applied embedded CHIT interventions that support the care partner role and bring value to Learning Health Systems through advancing digital health equity, improving user experiences, and driving efficiencies through improved coordination within complex work systems.

VEEV TC-83 Triggers Dysregulation of the Tryptophan-Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice.

Neurodegenerative diseases are chronic conditions affecting the central nervous system (CNS). Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta in the limbic and cortical brain regions. AD is presumed to result from genetic abnormalities or environmental factors, including viral infections, which may have deleterious, long-term effects. In this study, we demonstrate that the Venezuelan equine encephalitis virus (VEEV) commonly induces neurodegeneration and long-term neurological or cognitive sequelae. Notably, the effects of VEEV infection can persistently influence gene expression in the mouse brain, suggesting a potential link between the observed neurodegenerative outcomes and long-term alterations in gene expression. Additionally, we show that alphavirus encephalitis exacerbates the neuropathological profile of AD through crosstalk between inflammatory and kynurenine pathways, generating a range of metabolites with potent effects. Using a mouse model for ß-amyloidosis, Tg2576 mice, we found that cognitive deficits and brain pathology were more severe in Tg2576 mice infected with VEEV TC-83 compared to mock-infected controls. Thus, during immune activation, the kynurenine pathway plays a more active role in the VEEV TC-83-infected cells, leading to increases in the abundance of transcripts related to the kynurenine pathway of tryptophan metabolism. This pathway generates several metabolites with potent effects on neurotransmitter systems as well as on inflammation, as observed in VEEV TC-83-infected animals.

Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model.

Alzheimer's disease is classified as a progressive disorder resulting from protein misfolding, also known as proteinopathies. Proteinopathies include synucleinopathies triggered by misfolded amyloid α-synuclein, tauopathies triggered by misfolded tau, and amyloidopathies triggered by misfolded amyloid of which Alzheimer's disease (ß-amyloid) is most prevalent. Most neurodegenerative diseases (>90%) are not due to dominantly inherited genetic causes. Instead, it is thought that the risk for disease is a complicated interaction between inherited and environmental risk factors that, with age, drive pathology that ultimately results in neurodegeneration and disease onset. Since it is increasingly appreciated that encephalitic viral infections can have profoundly detrimental neurological consequences long after the acute infection has resolved, we tested the hypothesis that viral encephalitis exacerbates the pathological profile of protein-misfolding diseases. Using a robust, reproducible, and well-characterized mouse model for ß-amyloidosis, Tg2576, we studied the contribution of alphavirus-induced encephalitis (TC-83 strain of VEEV to model alphavirus encephalitis viruses) on the progression of neurodegenerative pathology. We longitudinally evaluated neurological, neurobehavioral, and cognitive levels, followed by a post-mortem analysis of brain pathology focusing on neuroinflammation. We found more severe cognitive deficits and brain pathology in Tg2576 mice inoculated with TC-83 than in their mock controls. These data set the groundwork to investigate sporadic Alzheimer's disease and treatment interventions for this infectious disease risk factor.

Endometriosis in a Prepubertal Patient with 46,XY Difference in Sex Development: A Case Report.

INTRODUCTION: Endometriosis typically presents in postmenarchal patients with cyclic and acyclic pelvic pain. However, there are reports of endometriosis in premenarchal patients. CASE: We report a 10-year-old individual with 46,XY difference of sex development who was found to have endometriosis at the time of laparoscopic gonadectomy for gonadoblastoma. CONCLUSIONS: Although rare, endometriosis can occur in 46,XY individuals prior to puberty, highlighting the complex origin of the disease.

Barriers to Transitional Care in Spina Bifida.

The health care needs children with spina bifida evolve over their lifetime; continued, regular contact with appropraitely trained, multidisciplinary providers is crucial to a patient's health and quality of life. Substantial research has been conducted to improve the transition process starting at an early age; however, there continue to be strong barriers to successful transition. This article reviews key aspects of the care of patients with spina bifida, the impact of inadequate transition to adult care, barriers to transition, and offers a potential vision for the future.

FlhE functions as a chaperone to prevent formation of periplasmic flagella in Gram-negative bacteria.

The bacterial flagellum is an organelle utilized by many Gram-negative bacteria to facilitate motility. The flagellum is composed of a several µm long, extracellular filament that is connected to a cytoplasmic rotor-stator complex via a periplasmic rod. Composed of ∼20 structural proteins, ranging from a few subunits to several thousand building blocks, the flagellum is a paradigm of a complex macromolecular structure that utilizes a highly regulated assembly process. This process is governed by multiple checkpoints that ensure an ordered gene expression pattern coupled to the assembly of the various flagellar building blocks in order to produce a functional flagellum. Using epifluorescence, super-resolution STED and transmission electron microscopy, we discovered that in Salmonella , the absence of one periplasmic protein, FlhE, prevents proper flagellar morphogenesis and results in the formation of periplasmic flagella. The periplasmic flagella disrupt cell wall synthesis, leading to a loss of the standard cell morphology resulting in cell lysis. We propose a model where FlhE functions as a periplasmic chaperone to control assembly of the periplasmic rod to prevent formation of periplasmic flagella. Our results highlight that bacteria evolved sophisticated regulatory mechanisms to control proper flagellar assembly and minor deviations from this highly regulated process can cause dramatic physiological consequences.

Does nurse use of a standardized flowsheet to document communication with advanced providers provide a mechanism to detect pulse oximetry failures? A retrospective study of electronic health record data.

BACKGROUND: Pulse oximetry guides clinical decisions, yet does not uniformly identify hypoxemia. We hypothesized that nursing documentation of notifying providers, facilitated by a standardized flowsheet for documenting communication to providers (physicians, nurse practitioners, and physician assistants), may increase when hypoxemia is present, but undetected by the pulse oximeter, in events termed "occult hypoxemia." OBJECTIVE: To compare nurse documentation of provider notification in the 4 h preceding cases of occult hypoxemia, normal oxygenation, and evident hypoxemia confirmed by an arterial blood gas reading. METHODS: We conducted a retrospective study using electronic health record data from patients with COVID-19 at five hospitals in a healthcare system with paired SpO2 and SaO2 readings (measurements within 10 min of oxygen saturation levels in arterial blood, SaO2, and by pulse oximetry, SpO2). We applied multivariate logistic regression to assess if having any nursing documentation of provider notification in the 4 h prior to a paired reading confirming occult hypoxemia was more likely compared to a paired reading confirming normal oxygen status, adjusting for characteristics significantly associated with nursing documentation. We applied conditional logistic regression to assess if having any nursing documentation of provider notification was more likely in the 4-hour window preceding a paired reading compared to the 4-hour window 24 h earlier separately for occult hypoxemia, visible hypoxemia, and normal oxygenation. RESULTS: There were data from 1910 patients hospitalized with COVID-19 who had 44,972 paired readings and an average of 26.5 (34.5) nursing documentation of provider notification events. The mean age was 63.4 (16.2). Almost half (866/1910, 45.3 %) were White, 701 (36.7 %) were Black, and 239 (12.5 %) were Hispanic. Having any nursing documentation of provider notification was 46 % more common in the 4 h before an occult hypoxemia paired reading compared to a normal oxygen status paired reading (OR 1.46, 95 % CI: 1.28-1.67). Comparing the 4 h immediately before the reading to the 4 h one day preceding the paired reading, there was a higher likelihood of having any nursing documentation of provider notification for both evident (OR 1.45, 95 % CI 1.24-1.68) and occult paired readings (OR 1.26, 95 % CI 1.04-1.53). CONCLUSION: This study finds that nursing documentation of provider notification significantly increases prior to confirmed occult hypoxemia, which has potential in proactively identifying occult hypoxemia and other clinical issues. There is potential value to encouraging standardized documentation of nurse concern, including communication to providers, to facilitate its inclusion in clinical decision-making.

Long-term follow-up of participants in ketamine clinical trials for mood disorders.

BACKGROUND: Participants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. METHODS: Participants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. RESULTS: Of the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LIMITATIONS: Low follow-up study participation rate; varying time since discharge. CONCLUSIONS: Participants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. CLINICAL TRIALS IDENTIFIER: NCT04877977.

Structural basis of directional switching by the bacterial flagellum.

The bacterial flagellum is a macromolecular protein complex that harvests energy from uni-directional ion flow across the inner membrane to power bacterial swimming via rotation of the flagellar filament. Rotation is bi-directional, with binding of a cytoplasmic chemotactic response regulator controlling reversal, though the structural and mechanistic bases for rotational switching are not well understood. Here we present cryoelectron microscopy structures of intact Salmonella flagellar basal bodies (3.2-5.5 Å), including the cytoplasmic C-ring complexes required for power transmission, in both counter-clockwise and clockwise rotational conformations. These reveal 180° movements of both the N- and C-terminal domains of the FliG protein, which, when combined with a high-resolution cryoelectron microscopy structure of the MotA5B2 stator, show that the stator shifts from the outside to the inside of the C-ring. This enables rotational switching and reveals how uni-directional ion flow across the inner membrane is used to accomplish bi-directional rotation of the flagellum.

GABAergic/Glycinergic and Glutamatergic Neurons Mediate Distinct Neurodevelopmental Phenotypes of STXBP1 Encephalopathy.

An increasing number of pathogenic variants in presynaptic proteins involved in the synaptic vesicle cycle are being discovered in neurodevelopmental disorders. The clinical features of these synaptic vesicle cycle disorders are diverse, but the most prevalent phenotypes include intellectual disability, epilepsy, movement disorders, cerebral visual impairment, and psychiatric symptoms ( Verhage and Sørensen, 2020; Bonnycastle et al., 2021; John et al., 2021; Melland et al., 2021). Among this growing list of synaptic vesicle cycle disorders, the most frequent is STXBP1 encephalopathy caused by de novo heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1; Verhage and Sørensen, 2020; John et al., 2021). STXBP1 is an essential protein for presynaptic neurotransmitter release. Its haploinsufficiency is the main disease mechanism and impairs both excitatory and inhibitory neurotransmitter release. However, the disease pathogenesis and cellular origins of the broad spectrum of neurological phenotypes are poorly understood. Here we generate cell type-specific Stxbp1 haploinsufficient male and female mice and show that Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons causes developmental delay, epilepsy, and motor, cognitive, and psychiatric deficits, recapitulating majority of the phenotypes observed in the constitutive Stxbp1 haploinsufficient mice and STXBP1 encephalopathy. In contrast, Stxbp1 haploinsufficiency in glutamatergic neurons results in a small subset of cognitive and seizure phenotypes distinct from those caused by Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons. Thus, the contrasting roles of excitatory and inhibitory signaling reveal GABAergic/glycinergic dysfunction as a key disease mechanism of STXBP1 encephalopathy and suggest the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.

Patient portal messages to support an age-friendly health system for persons with dementia.

BACKGROUND: Patient portal secure messaging can support age-friendly dementia care, yet little is known about care partner use of the portal and how message concerns relate to age-friendly issues. METHODS: We conducted a two-part observational study. We first assessed the feasibility of automating care partner identification from patient portal messages by developing and testing a natural language processing (NLP) rule-based classification system from portal messages of 1973 unique patients 65 and older. Second, two independent reviewers manually coded a randomly selected sample of portal messages for 987 persons with dementia to identify the frequency of expressed needs from the 4M domains of an Age-Friendly Health System (medications, mentation, mobility, and what matters). RESULTS: A total of 267 (13.53%) of 1973 messages sent from older adults' portal accounts were identified through manual coding as sent by a nonpatient author. The NLP model performance to identify nonpatient authors demonstrated an AUC of 0.90. Most messages sent from the accounts of persons with dementia contained content relevant to the 4Ms (60%, 601/987), with the breakdown as follows: medications-36% (357/987), mobility-10% (101/987), mentation-16% (153/987), and what matters (aligning care with specific health goals and care preferences)-21%, 207/987. CONCLUSIONS: Patient portal messaging offers an avenue to identify care partners and meet the informational needs of persons with dementia and their care partners.