Transdifferentiation is uncoupled from progenitor pool expansion during hair cell regeneration in the zebrafish inner ear.

Death of mechanosensory hair cells in the inner ear is a common cause of auditory and vestibular impairment in mammals, which have a limited ability to regrow these cells after damage. In contrast, non-mammalian vertebrates including zebrafish can robustly regenerate hair cells following severe organ damage. The zebrafish inner ear provides an understudied model system for understanding hair cell regeneration in organs that are highly conserved with their mammalian counterparts. Here we quantitatively examine hair cell addition during growth and regeneration of the larval zebrafish inner ear. We used a genetically encoded ablation method to induce hair cell death and observed gradual regeneration with correct spatial patterning over two weeks following ablation. Supporting cells, which surround and are a source of new hair cells, divide in response to hair cell ablation, expanding the possible progenitor pool. In parallel, nascent hair cells arise from direct transdifferentiation of progenitor pool cells uncoupled from progenitor division. These findings reveal a previously unrecognized mechanism of hair cell regeneration with implications for how hair cells may be encouraged to regenerate in the mammalian ear.

Associations Between Organizational Communication and Patients' Experience of Prolonged Emotional Impact Following Medical Errors.

BACKGROUND: The emotional impact of medical errors on patients may be long-lasting. Factors associated with prolonged emotional impacts are poorly understood. METHODS: The authors conducted a subanalysis of a 2017 survey (response rate 36.8% [2,536/6,891]) of US adults to assess emotional impact of medical error. Patients reporting a medical error were included if the error occurred ≥ 1 year prior. Duration of emotional impact was categorized into no/short-term impact (impact lasting < 1 month), prolonged impact (> 1 month), and especially prolonged impact (> 1 year). Based on their reported experience with communication about the error, patients' experience was categorized as consistent with national disclosure guidelines, contrary to guidelines, mixed, or neither. Multinomial regression was used to examine associations between patient factors, event characteristics, and organizational communication with prolonged emotional impact (> 1 month, > 1 year). RESULTS: Of all survey respondents, 17.8% (451/2,536) reported an error occurring ≥ 1 year prior. Of these, 51.2% (231/451) reported prolonged/especially prolonged emotional impact (30.8% prolonged, 20.4% especially prolonged). Factors associated with prolonged emotional impact included female gender (adjusted odds ratio 2.1 [95% confidence interval 1.5-2.9]); low socioeconomic status (SES; 1.7 [1.1-2.7]); physical impact (7.3 [4.3-12.3]); no organizational disclosure and no patient/family error reporting (1.5 [1.03-2.3]); communication contrary to guidelines (4.0 [2.1-7.5]); and mixed communication (2.2 [1.3-3.7]). The same factors were significantly associated with especially prolonged emotional impact (female, 1.7 [1.2-2.5]; low SES, 2.2 [1.3-3.6]; physical impact, 6.8 [3.8-12.5]; no disclosure/reporting, 1.9 [1.2-3.2]; communication contrary to guidelines, 4.6 [2.2-9.4]; mixed communication, 2.1 [1.1-3.9]). CONCLUSION: Prolonged emotional impact affected more than half of Americans self-reporting a medical error. Organizational failure to communicate according to disclosure guidelines after patient-perceived errors may exacerbate harm, particularly for patients at risk of health care disparities.

Topographical and cell type-specific connectivity of rostral and caudal forelimb corticospinal neuron populations.

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, with notable exceptions that suggest that these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive highly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.

What's going well: a qualitative analysis of positive patient and family feedback in the context of the diagnostic process.

OBJECTIVES: Accurate and timely diagnosis relies on close collaboration between patients/families and clinicians. Just as patients have unique insights into diagnostic breakdowns, positive patient feedback may also generate broader perspectives on what constitutes a "good" diagnostic process (DxP). METHODS: We evaluated patient/family feedback on "what's going well" as part of an online pre-visit survey designed to engage patients/families in the DxP. Patients/families living with chronic conditions with visits in three urban pediatric subspecialty clinics (site 1) and one rural adult primary care clinic (site 2) were invited to complete the survey between December 2020 and March 2022. We adapted the Healthcare Complaints Analysis Tool (HCAT) to conduct a qualitative analysis on a subset of patient/family responses with ≥20 words. RESULTS: In total, 7,075 surveys were completed before 18,129 visits (39 %) at site 1, and 460 surveys were completed prior to 706 (65 %) visits at site 2. Of all participants, 1,578 volunteered positive feedback, ranging from 1-79 words. Qualitative analysis of 272 comments with ≥20 words described: Relationships (60 %), Clinical Care (36 %), and Environment (4 %). Compared to primary care, subspecialty comments showed the same overall rankings. Within Relationships, patients/families most commonly noted: thorough and competent attention (46 %), clear communication and listening (41 %) and emotional support and human connection (39 %). Within Clinical Care, patients highlighted: timeliness (31 %), effective clinical management (30 %), and coordination of care (25 %). CONCLUSIONS: Patients/families valued relationships with clinicians above all else in the DxP, emphasizing the importance of supporting clinicians to nurture effective relationships and relationship-centered care in the DxP.

Partnering with Patients and Families to Improve Diagnostic Safety through the OurDX Tool: Effects of Race, Ethnicity, and Language Preference.

BACKGROUND: Patients and families at risk for health disparities may also be at higher risk for diagnostic errors but less likely to report them. OBJECTIVES: This study aimed to explore differences in race, ethnicity, and language preference associated with patient and family contributions and concerns using an electronic previsit tool designed to engage patients and families in the diagnostic process (DxP). METHODS: Cross-sectional study of 5,731 patients and families presenting to three subspecialty clinics at an urban pediatric hospital May to December 2021 who completed a previsit tool, codeveloped and tested with patients and families. Prior to each visit, patients/families were invited to share visit priorities, recent histories, and potential diagnostic concerns. We used logistic regression to determine factors associated with patient-reported diagnostic concerns. We conducted chart review on a random subset of visits to review concerns and determine whether patient/family contributions were included in the visit note. RESULTS: Participants provided a similar mean number of contributions regardless of patient race, ethnicity, or language preference. Compared with patients self-identifying as White, those self-identifying as Black (odds ratio [OR]: 1.70; 95% confidence interval [CI]: [1.18, 2.43]) or "other" race (OR: 1.48; 95% CI: [1.08, 2.03]) were more likely to report a diagnostic concern. Participants who preferred a language other than English were more likely to report a diagnostic concern than English-preferring patients (OR: 2.53; 95% CI: [1.78, 3.59]. There were no significant differences in physician-verified diagnostic concerns or in integration of patient contributions into the note based on race, ethnicity, or language preference. CONCLUSION: Participants self-identifying as Black or "other" race, or those who prefer a language other than English were 1.5 to 2.5 times more likely than their counterparts to report potential diagnostic concerns when proactively asked to provide this information prior to a visit. Actively engaging patients and families in the DxP may uncover opportunities to reduce the risk of diagnostic errors and potential safety disparities.

Patient and family contributions to improve the diagnostic process through the OurDX electronic health record tool: a mixed method analysis.

BACKGROUND: Accurate and timely diagnosis relies on sharing perspectives among team members and avoiding information asymmetries. Patients/Families hold unique diagnostic process (DxP) information, including knowledge of diagnostic safety blindspots-information that patients/families know, but may be invisible to clinicians. To improve information sharing, we co-developed with patients/families an online tool called 'Our Diagnosis (OurDX)'. We aimed to characterise patient/family contributions in OurDX and how they differed between individuals with and without diagnostic concerns. METHOD: We implemented OurDX in two academic organisations serving patients/families living with chronic conditions in three subspecialty clinics and one primary care clinic. Prior to each visit, patients/families were invited to contribute visit priorities, recent histories and potential diagnostic concerns. Responses were available in the electronic health record and could be incorporated by clinicians into visit notes. We randomly sampled OurDX reports with and without diagnostic concerns for chart review and used inductive and deductive qualitative analysis to assess patient/family contributions. RESULTS: 7075 (39%) OurDX reports were submitted at 18 129 paediatric subspecialty clinic visits and 460 (65%) reports were submitted among 706 eligible adult primary care visits. Qualitative analysis of OurDX reports in the chart review sample (n=450) revealed that participants contributed DxP information across 10 categories, most commonly: clinical symptoms/medical history (82%), tests/referrals (54%) and diagnosis/next steps (51%). Participants with diagnostic concerns were more likely to contribute information on DxP risks including access barriers, recent visits for the same problem, problems with tests/referrals or care coordination and communication breakdowns, some of which may represent diagnostic blindspots. CONCLUSION: Partnering with patients and families living with chronic conditions through OurDX may help clinicians gain a broader perspective of the DxP, including unique information to coproduce diagnostic safety.

Partnering with patients and families living with chronic conditions to coproduce diagnostic safety through OurDX: a previsit online engagement tool.

OBJECTIVE: Patients and families are key partners in diagnosis, but methods to routinely engage them in diagnostic safety are lacking. Policy mandating patient access to electronic health information presents new opportunities. We tested a new online tool ("OurDX") that was codesigned with patients and families, to determine the types and frequencies of potential safety issues identified by patients/families with chronic health conditions and whether their contributions were integrated into the visit note. METHODS: Patients/families at 2 US healthcare sites were invited to contribute, through an online previsit survey: (1) visit priorities, (2) recent medical history/symptoms, and (3) potential diagnostic concerns. Two physicians reviewed patient-reported diagnostic concerns to verify and categorize diagnostic safety opportunities (DSOs). We conducted a chart review to determine whether patient contributions were integrated into the note. We used descriptive statistics to report implementation outcomes, verification of DSOs, and chart review findings. RESULTS: Participants completed OurDX reports in 7075 of 18 129 (39%) eligible pediatric subspecialty visits (site 1), and 460 of 706 (65%) eligible adult primary care visits (site 2). Among patients reporting diagnostic concerns, 63% were verified as probable DSOs. In total, probable DSOs were identified by 7.5% of pediatric and adult patients/families with underlying health conditions, respectively. The most common types of DSOs were patients/families not feeling heard; problems/delays with tests or referrals; and problems/delays with explanation or next steps. In chart review, most clinician notes included all or some patient/family priorities and patient-reported histories. CONCLUSIONS: OurDX can help engage patients and families living with chronic health conditions in diagnosis. Participating patients/families identified DSOs and most of their OurDX contributions were included in the visit note.

Diagnostic error experiences of patients and families with limited English-language health literacy or disadvantaged socioeconomic position in a cross-sectional US population-based survey.

BACKGROUND: Language barrier, reduced self-advocacy, lower health literacy or biased care may hinder the diagnostic process. Data on how patients/families with limited English-language health literacy (LEHL) or disadvantaged socioeconomic position (dSEP) experience diagnostic errors are sparse. METHOD: We compared patient-reported diagnostic errors, contributing factors and impacts between respondents with LEHL or dSEP and their counterparts in the 2017 Institute for Healthcare Improvement US population-based survey, using contingency analysis and multivariable logistic regression models for the analyses. RESULTS: 596 respondents reported a diagnostic error; among these, 381 reported LEHL or dSEP. After adjusting for sex, race/ethnicity and physical health, individuals with LEHL/dSEP were more likely than their counterparts to report unique contributing factors: "(No) qualified translator or healthcare provider that spoke (the patient's) language" (OR and 95% CI 4.4 (1.3 to 14.9)); "not understanding the follow-up plan" (1.9 (1.1 to 3.1)); "too many providers… but no clear leader" (1.8 (1.2 to 2.7)); "not able to keep follow-up appointments" (1.9 (1.1 to 3.2)); "not being able to pay for necessary medical care" (2.5 (1.4 to 4.4)) and "out-of-date or incorrect medical records" (2.6 (1.4 to 4.8)). Participants with LEHL/dSEP were more likely to report long-term emotional, financial and relational impacts, compared with their counterparts. Subgroup analysis (LEHL-only and dSEP-only participants) showed similar results. CONCLUSIONS: Individuals with LEHL or dSEP identified unique and actionable contributing factors to diagnostic errors. Interpreter access should be viewed as a diagnostic safety imperative, social determinants affecting care access/affordability should be routinely addressed as part of the diagnostic process and patients/families should be encouraged to access and update their medical records. The frequent and disproportionate long-term impacts from self-reported diagnostic error among LEHL/dSEP patients/families raises urgency for greater prevention and supportive efforts.

Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.

BACKGROUND: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. METHODS: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RESULTS: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. CONCLUSION: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Patient Identification of Diagnostic Safety Blindspots and Participation in "Good Catches" Through Shared Visit Notes.

Policy Points Patients and families can identify clinically relevant errors, including "blindspots"-safety hazards that are difficult for clinicians or organizations to see. Health information transparency, including patient access to electronic visit notes, now federally mandated in the US and the subject of policy debate worldwide, creates a new opportunity to engage patients in diagnostic safety. However, not all patients access notes. Patient identification of blindspots in their notes underscores the need to systematically and equitably engage willing patients in safety, promote patient "good catches," and establish routine systems for patient feedback to help avoid preventable diagnostic errors and delays. CONTEXT: Policy shifts toward health information transparency provide a new opportunity for patients to contribute to diagnostic safety. We investigated whether sharing clinical notes with patients can support identification of "diagnostic safety blindspots"-potentially consequential breakdowns in the diagnostic process that may be difficult for clinical staff to observe. METHOD: We used mixed methods to analyze patient-reported ambulatory documentation errors among 22,889 patients at three US health care centers who read ≥ 1 visit note(s). We identified blindspots by tailoring a previously established taxonomy. We used multiple regression analysis to identify factors associated with blindspot identification. FINDINGS: 774 patients reported a total of 962 blindspots in 4 categories: (1) diagnostic misalignments (n = 421, 43.8%), including inaccurate symptoms or histories and failures or delay in diagnosis; (2) errors of omission (38.1%) including missed main concerns or next steps, and failure to listen to patients; (3) problems occurring outside visits (14.3%) such as tests, referrals, or appointment access; and (4) multiple low-level problems (3.7%) cascading into diagnostic breakdowns. Many patients acted on the blindspots they identified, resulting in "good catches" that may prevent potential negative consequences. Older, female, sicker, unemployed or disabled patients, or those who work in health care were more likely to identify a blindspot. Individuals reporting less formal education; those self-identifying as Black, Asian, other, or multiple races; and participants who deferred decision-making to providers were less likely to report a blindspot. CONCLUSION: Patients who read notes have unique insight about potential errors in their medical records that could impact diagnostic reasoning but may not be known to clinicians-underscoring a critical role for patients in diagnostic safety and organizational learning. From a policy standpoint, organizations should encourage patient review of visit notes, build systems to track patient-reported blindspots, and promote equity in note access and blindspot reporting.

Escalating the conflict? Intersex genetic correlations influence adaptation to environmental change in facultatively migratory populations.

Males and females are often subject to different and even opposing selection pressures. When a given trait has a shared genetic basis between the sexes, sexual conflict (antagonism) can arise. This can result in significant individual-level fitness consequences that might also affect population performance, whilst anthropogenic environmental change can further exacerbate maladaptation in one or both sexes driven by sexual antagonism. Here, we develop a genetically explicit eco-evolutionary model using an agent-based framework to explore how a population of a facultatively migratory fish species (brown trout Salmo trutta) adapts to environmental change across a range of intersex genetic correlations for migration propensity, which influence the magnitude of sexual conflict. Our modelled focal trait represents a condition threshold governing whether individuals adopt a resident or anadromous (sea migration) tactic. Anadromy affords potential size-mediated reproductive advantages to both males and females due to improved feeding opportunities at sea, but these can be undermined by high background marine mortality and survival/growth costs imposed by marine parasites (sea lice). We show that migration tactic frequency for a given set of environmental conditions is strongly influenced by the intersex genetic correlation, such that one sex can be dragged off its optimum more than the other. When this occurred in females in our model, population productivity was substantially reduced, but eco-evolutionary outcomes were altered by allowing for sneaking behaviour in males. We discuss real-world implications of our work given that anadromous salmonids are regularly challenged by sea lice infestations, which might act synergistically with other stressors such as climate change or fishing that impact marine performance, driving populations towards residency and potentially reduced resilience.

Monocarboxylate Transporter 1 (MCT1) Mediates Succinate Export in the Retina.

Purpose: Succinate is exported by the retina and imported by eyecup tissue. The transporters mediating this process have not yet been identified. Recent studies showed that monocarboxylate transporter 1 (MCT1) can transport succinate across plasma membranes in cardiac and skeletal muscle. Retina and retinal pigment epithelium (RPE) both express multiple MCT isoforms including MCT1. We tested the hypothesis that MCTs facilitate retinal succinate export and RPE succinate import. Methods: We assessed retinal succinate export and eyecup succinate import in short-term ex vivo culture using gas chromatography-mass spectrometry. We tested the dependence of succinate export and import on pH, proton ionophores, conventional MCT substrates, and the MCT inhibitors AZD3965, AR-C155858, and diclofenac. Results: Succinate exits retinal tissue through MCT1 but does not enter the RPE through MCT1 or any other MCT. Intracellular succinate levels are a contributing factor that determines if an MCT1-expressing tissue will export succinate. Conclusions: MCT1 facilitates export of succinate from retinas. An unidentified, non-MCT transporter facilitates import of succinate into RPE.