Quantitative Evaluation of Large Language Models to Streamline Radiology Report Impressions: A Multimodal Retrospective Analysis.

Background The complex medical terminology of radiology reports may cause confusion or anxiety for patients, especially given increased access to electronic health records. Large language models (LLMs) can potentially simplify radiology report readability. Purpose To compare the performance of four publicly available LLMs (ChatGPT-3.5 and ChatGPT-4, Bard [now known as Gemini], and Bing) in producing simplified radiology report impressions. Materials and Methods In this retrospective comparative analysis of the four LLMs (accessed July 23 to July 26, 2023), the Medical Information Mart for Intensive Care (MIMIC)-IV database was used to gather 750 anonymized radiology report impressions covering a range of imaging modalities (MRI, CT, US, radiography, mammography) and anatomic regions. Three distinct prompts were employed to assess the LLMs' ability to simplify report impressions. The first prompt (prompt 1) was "Simplify this radiology report." The second prompt (prompt 2) was "I am a patient. Simplify this radiology report." The last prompt (prompt 3) was "Simplify this radiology report at the 7th grade level." Each prompt was followed by the radiology report impression and was queried once. The primary outcome was simplification as assessed by readability score. Readability was assessed using the average of four established readability indexes. The nonparametric Wilcoxon signed-rank test was applied to compare reading grade levels across LLM output. Results All four LLMs simplified radiology report impressions across all prompts tested (P < .001). Within prompts, differences were found between LLMs. Providing the context of being a patient or requesting simplification at the seventh-grade level reduced the reading grade level of output for all models and prompts (except prompt 1 to prompt 2 for ChatGPT-4) (P < .001). Conclusion Although the success of each LLM varied depending on the specific prompt wording, all four models simplified radiology report impressions across all modalities and prompts tested. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Rahsepar in this issue.

Documentation of results and medication prescribing after combinatorial psychiatric pharmacogenetic testing: A case for discrete results.

PURPOSE: Combinatorial pharmacogenetic (PGx) panels intended to aid psychiatric prescribing are available to clinicians. Here, we evaluated the documentation of PGx panel results and subsequent prescribing patterns within a tertiary health care system. METHODS: We performed a query of psychiatry service note text in our electronic health record using 71 predefined PGx terms. Patients who underwent combinatorial PGx testing were identified, and documentation of test results was analyzed. Prescription data following testing were examined for the frequency of prescriptions influenced by genes on the panel along with the medical specialties involved. RESULTS: A total of 341 patients received combinatorial PGx testing, and documentation of results was found to be absent or incomplete for 198 patients (58%). The predominant method of documentation was through portable document formats uploaded to the electronic health record's "Media" section. Among patients with at least 1 year of follow-up, a large majority (194/228, 85%) received orders for medications affected by the tested genes, including 132 of 228 (58%) patients receiving at least 1 non-psychiatric medication influenced by the test results. CONCLUSION: Results from combinatorial PGx testing were poorly documented. Medications affected by these results were often prescribed after testing, highlighting the need for discrete results and clinical decision support.

Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.

PURPOSE: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants. METHODS: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. RESULTS: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors. CONCLUSION: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.

The use of Reflectance Confocal Microscopy to diagnose Malignant Melanoma and Lentigo Maligna in the United Kingdom: A Prospective Observational Trial at a Single Centre.

BACKGROUND: Previous work with Reflectance Confocal Microscopy (RCM) imaging has shown high sensitivity and specificity for Malignant Melanoma (MM), but to date there have been no studies on a UK cohort. OBJECTIVES: The study hypothesised that RCM could be used prospectively to accurately diagnose MM and lentigo maligna (LM) in a private UK secondary care, single clinician setting. The study assessed the potential for RCM to be used as a routine screening procedure. METHODS: 597 patients were recruited consecutively where MM or LM featured in the differential diagnosis after clinical examination. A sequential record was made of the clinical, dermoscopic, and RCM findings by a single dermatologist [HS] prior to biopsy. Imaging used the arm-mounted confocal microscope unless access was restricted and required the handheld probe. The likelihood of MM was scored for each modality, each diagnosis building on the last. Histology was assessed by a single blinded histopathologist [JJ]. RESULTS: 734 lesions were included in the analysis, including 86 MM and LM with a median diameter of 7.0 mm. The benign to malignant ratio was 3 to 1 (non-melanocytic malignancies included) and 8.3 to 1 for MM and LM only. The sensitivity and specificity for MM and LM was 62.8% (95% CI 51.70% to 72.98%) and 63.2% (59.27% to 66.84%) for clinical examination; 91.9% (83.95% to 96.66%) and 42.1% (38.14% to 45.88%) for dermoscopy; 94.2% (86.95% to 98.09%) and 83.2% (79.91% to 85.84%) for RCM. For RCM, PPV was 42.4% (38.13% to 46.81%) and NPV was 99.1% (97.87% to 99.60%). CONCLUSION: This study demonstrates that RCM can reliably diagnose MM and is fast enough to be integrated into UK pigmented lesion clinics by dermatologists trained in RCM. "Number needed to treat" dropped from 3.9 with clinical examination to 3.0 with dermoscopy to 1.3 with RCM.

The use of Reflectance Confocal Microscopy to diagnose Basal Cell Carcinoma in the United Kingdom: A Prospective Observational Trial at a Single Centre.

BACKGROUND: Previous work with Reflectance Confocal Microscopy (RCM) imaging has shown high sensitivity and specificity for Basal Cell Carcinoma (BCC), but to date there have been few studies on a UK cohort. OBJECTIVES: The study hypothesised that RCM could be used prospectively to accurately diagnose BCC in a private UK secondary care, single clinician setting. The study assessed the potential for RCM to be used as a routine diagnostic procedure. METHODS: 522 lesions were recruited prospectively where BCC featured in the differential diagnosis after clinical examination. 78 were subsequently excluded. Imaging used the arm-mounted confocal microscope unless access was restricted and required the handheld probe. The likelihood of BCC was scored for each modality, each diagnosis building on the last. Histology was assessed by a single blinded histopathologist [JJ]. RESULTS: 444 lesions from 326 patients were included in the analysis, including 327 BCCs. Median maximum diameter was 6 mm. The sensitivity and specificity for BCC was 69.42% (64.11% to 74.37%) and 52.99% (43.55% to 62.28%) for clinical examination alone; 91.77% (88.25% to 94.51%) and 41.03% (32.02% to 50.50%) plus dermoscopy; 98.78% (96.91% to 99.67%) and 85.47% (77.76% to 91.30%) plus RCM. For RCM PPV was 95.01% (92.14% to 97.07%) and NPV was 96.15% (90.44% to 98.94%). Area under the curve increased from 0.61 to 0.66 to 0.92 as modalities were added. CONCLUSION: This study demonstrates that RCM can, reliably and quickly, diagnose BCC, and that the addition of RCM to dermoscopy permits higher diagnostic accuracy for BCC in the UK. The specificity and sensitivity of the RCM diagnosis did not alter significantly with experience, reflecting the ease and speed of acquiring the skill. CLINICAL TRIAL REGISTRATION: NCT03509415.

Human keratin matrices promote wound healing by modulating skin cell expression of cytokines and growth factors.

A wide variety of biomaterials has been developed to assist in wound healing, including acellular animal and human-derived protein matrices. However, millions of patients worldwide still suffer from non-healing chronic wounds, demonstrating a need for further innovation in wound care. To address this need, a novel biomaterial, the human keratin matrix (HKM), was developed, characterised, and tested in vitro and in vivo. HKM was found to be degradation-resistant, and a proteomics analysis showed it to be greater than 99% human keratin proteins. PCR revealed adult human epidermal keratinocytes (HEKa) grown in contact with HKM showed increased gene expression of keratinocyte activations markers such as Epidermal Growth Factor (EGF). Additionally, a cytokine microarray demonstrated culture on HKM increased the release of cytokines involved in wound inflammatory modulation by both HEKa cells and adult human dermal fibroblasts (HDFa). Finally, in a murine chronic wound model, full-thickness wounds treated weekly with HKM were smaller through the healing process than those treated with human amniotic membrane (AM), bovine dermis (BD), or porcine decellularized small intestinal submucosa (SIS). HKM-treated wounds also closed significantly faster than AM- and SIS-treated wounds. These data suggest that HKM is an effective novel treatment for chronic wounds.

Cost-Effectiveness of CT, CTA, MRI, and Specialized MRI for Evaluation of Patients Presenting to the Emergency Department With Dizziness.

BACKGROUND. Underlying stroke is often misdiagnosed in patients presenting with dizziness. Although such patients are usually ineligible for acute stroke treatment, accurate diagnosis may still improve outcomes through selection of patients for secondary prevention measures. OBJECTIVE. The purpose of our study was to investigate the cost-effectiveness of differing neuroimaging approaches in the evaluation of patients presenting to the emergency department (ED) with dizziness who are not candidates for acute intervention. METHODS. A Markov decision-analytic model was constructed from a health care system perspective for the evaluation of a patient presenting to the ED with dizziness. Four diagnostic strategies were compared: noncontrast head CT, head and neck CTA, conventional brain MRI, and specialized brain MRI (including multiplanar high-resolution DWI). Differing long-term costs and outcomes related to stroke detection and secondary prevention measures were compared. Cost-effectiveness was calculated in terms of lifetime expenditures in 2022 U.S. dollars for each quality-adjusted life year (QALY); deterministic and probabilistic sensitivity analyses were performed. RESULTS. Specialized MRI resulted in the highest QALYs and was the most cost-effective strategy with US$13,477 greater cost and 0.48 greater QALYs compared with noncontrast head CT. Conventional MRI had the next-highest health benefit, although was dominated by extension with incremental cost of US$6757 and 0.25 QALY; CTA was also dominated by extension, with incremental cost of US$3952 for 0.13 QALY. Non-contrast CT alone had the lowest utility among the four imaging choices. In the deterministic sensitivity analyses, specialized MRI remained the most cost-effective strategy. Conventional MRI was more cost-effective than CTA across a wide range of model parameters, with incremental cost-effectiveness remaining less than US$30,000/QALY. Probabilistic sensitivity analysis yielded similar results as found in the base-case analysis, with specialized MRI being more cost-effective than conventional MRI, which in turn was more cost-effective than CTA. CONCLUSION. The use of MRI in patients presenting to the ED with dizziness improves stroke detection and selection for subsequent preventive measures. MRI-based evaluation leads to lower long-term costs and higher cumulative QALYs. CLINICAL IMPACT. MRI, incorporating specialized protocols when available, is the preferred approach for evaluation of patients presenting to the ED with dizziness, to establish a stroke diagnosis and to select patients for secondary prevention measures.

Abbreviated MRI in the evaluation of dizziness: report turnaround times and impact on length of stay compared to CT, CTA, and conventional MRI.

PURPOSE: Neuroimaging is often used in the emergency department (ED) to evaluate for posterior circulation strokes in patients with dizziness, commonly with CT/CTA due to speed and availability. Although MRI offers more sensitive evaluation, it is less commonly used, in part due to slower turnaround times. We assess the potential for abbreviated MRI to improve reporting times and impact on length of stay (LOS) compared to conventional MRI (as well as CT/CTA) in the evaluation of acute dizziness. MATERIALS AND METHODS: We performed a retrospective analysis of length of stay via LASSO regression for patients presenting to the ED with dizziness and discharged directly from the ED over 4 years (1/1/2018-12/31/2021), controlling for numerous patient-level and logistical factors. We additionally assessed turnaround time between order and final report for various imaging modalities. RESULTS: 14,204 patients were included in our analysis. Turnaround time for abbreviated MRI was significantly lower than for conventional MRI (4.40 h vs. 6.14 h, p < 0.001) with decreased impact on LOS (0.58 h vs. 2.02 h). Abbreviated MRI studies had longer turnaround time (4.40 h vs. 1.41 h, p < 0.001) and was associated with greater impact on ED LOS than non-contrast CT head (0.58 h vs. 0.00 h), however there was no significant difference in turnaround time compared to CTA head and neck (4.40 h vs. 3.86 h, p = 0.06) with similar effect on LOS (0.58 h vs. 0.53 h). Ordering both CTA and conventional MRI was associated with a greater-than-linear increase in LOS (additional 0.37 h); the same trend was not seen combining CTA and abbreviated MRI (additional 0.00 h). CONCLUSIONS: In the acute settings where MRI is available, abbreviated MRI protocols may improve turnaround times and LOS compared to conventional MRI protocols. Since recent guidelines recommend MRI over CT in the evaluation of dizziness, implementation of abbreviated MRI protocols has the potential to facilitate rapid access to preferred imaging, while minimizing impact on ED workflows.

Preclinical pharmacokinetics and tolerability of a novel meglumine-based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus.

OBJECTIVE: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy-to-use and easy-to-prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)-approved excipient meglumine. METHODS: During formulation development, we compared the solubility of TPM in bi-distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine-based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine-induced SE. RESULTS: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether-ß-cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co-administered with another ASM for SE treatment. The tolerability studies of the meglumine-based TPM solution and meglumine-based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine-induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. SIGNIFICANCE: In conclusion, the novel meglumine-based solution of TPM presented here may be well suited for clinical development.

CT With CTA Versus MRI in Patients Presenting to the Emergency Department With Dizziness: Analysis Using Propensity Score Matching.

BACKGROUND. CT with CTA is widely used to exclude stroke in patients with dizziness, although MRI has higher sensitivity. OBJECTIVE. The purpose of this article was to compare patients presenting to the emergency department (ED) with dizziness who undergo CT with CTA alone versus those who undergo MRI in terms of stroke-related management and outcomes. METHODS. This retrospective study included 1917 patients (mean age, 59.5 years; 776 men, 1141 women) presenting to the ED with dizziness from January 1, 2018, to December 31, 2021. A first propensity score matching analysis incorporated demographic characteristics, medical history, findings from the review of systems, physical examination findings, and symptoms to construct matched groups of patients discharged from the ED after undergoing head CT with head and neck CTA alone and patients who underwent brain MRI (with or without CT and CTA). Outcomes were compared. A second analysis compared matched patients discharged after CT with CTA alone and patients who underwent specialized abbreviated MRI using multiplanar high-resolution DWI for increased sensitivity for posterior circulation stroke. Sensitivity analyses were performed involving MRI examinations performed as the first or only neuroimaging examination and involving alternative matching and imputation techniques. RESULTS. In the first analysis (406 patients per group), patients who underwent MRI, compared with patients who underwent CT with CTA alone, showed greater frequency of critical neuroimaging results (10.1% vs 4.7%, p = .005), change in secondary stroke prevention medication (9.6% vs 3.2%, p = .001), and subsequent echocardiography evaluation (6.4% vs 1.0%, p < .001). In the second analysis (100 patients per group), patients who underwent specialized abbreviated MRI, compared with patients who underwent CT with CTA alone, showed greater frequency of critical neuroimaging results (10.0% vs 2.0%, p = .04), change in secondary stroke prevention medication (14.0% vs 1.0%, p = .001), and subsequent echocardiography evaluation (12.0% vs 2.0%, p = .01) and lower frequency of 90-day ED readmissions (12.0% vs 28.0%, p = .008). Sensitivity analyses showed qualitatively similar findings. CONCLUSION. A proportion of patients discharged after CT with CTA alone may have benefitted from alternative or additional evaluation by MRI (including MRI using a specialized abbreviated protocol). CLINICAL IMPACT. Use of MRI may motivate clinically impactful management changes in patients presenting with dizziness.

Artificial Intelligence to Improve Patient Understanding of Radiology Reports.

Diagnostic imaging reports are generally written with a target audience of other providers. As a result, the reports are written with medical jargon and technical detail to ensure accurate communication. With implementation of the 21st Century Cures Act, patients have greater and quicker access to their imaging reports, but these reports are still written above the comprehension level of the average patient. Consequently, many patients have requested reports to be conveyed in language accessible to them. Numerous studies have shown that improving patient understanding of their condition results in better outcomes, so driving comprehension of imaging reports is essential. Summary statements, second reports, and the inclusion of the radiologist's phone number have been proposed, but these solutions have implications for radiologist workflow. Artificial intelligence (AI) has the potential to simplify imaging reports without significant disruptions. Many AI technologies have been applied to radiology reports in the past for various clinical and research purposes, but patient focused solutions have largely been ignored. New natural language processing technologies and large language models (LLMs) have the potential to improve patient understanding of their imaging reports. However, LLMs are a nascent technology and significant research is required before LLM-driven report simplification is used in patient care.

Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.

BACKGROUND: Trastuzumab is a monoclonal antibody against HER2 (also known as ERBB2). The primary objective of the NRG Oncology/RTOG-1010 trial was to establish whether trastuzumab improves disease-free survival when combined with trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) for patients with untreated HER2-overexpressing oesophageal adenocarcinoma. METHODS: NRG Oncology/RTOG-1010 was an open label, randomised, phase 3 trial for which patients were accrued from 111 NRG-affiliated institutions in the USA. Eligible patients were adults (aged ≥18 years) with newly diagnosed pathologically confirmed oesophageal adenocarcinoma, American Joint Committee on Cancer 7th edition T1N1-2 or T2-3N0-2 stage disease, and a Zubrod performance status of 0-2. Patients were stratified by adenopathy (no vs yes [coeliac absent] vs yes [coeliac present ≤2 cm]) and randomly assigned (1:1) to receive weekly intravenous paclitaxel (50 mg/m2 intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30-60 min) for 6 weeks with radiotherapy 50·4 Gy in 28 fractions (chemoradiotherapy) followed by surgery, with or without intravenous trastuzumab (4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21-56 days after surgery). The primary endpoint, disease-free survival, was defined as the time from randomisation to death or first of locoregional disease persistence or recurrence, distant metastases, or second primary malignancy. Analyses were done by modified intention to treat. This study is registered with Clinicaltrials.gov, NCT01196390; it is now closed and in follow-up. FINDINGS: 606 patients were entered for HER2 assessment from Dec 30, 2010 to Nov 10, 2015, and 203 eligible patients who were HER2-positive were enrolled and randomly assigned to chemoradiotherapy plus trastuzumab (n=102) or chemoradiotherapy alone (n=101). Median duration of follow-up was 2·8 years (IQR 1·4-5·7). Median disease-free survival was 19·6 months (95% CI 13·5-26·2) with chemoradiotherapy plus trastuzumab compared with 14·2 months (10·5-23·0) for chemoradiotherapy alone (hazard ratio 0·99 [95% CI 0·71-1·39], log-rank p=0·97). Grade 3 treatment-related adverse events occurred in 41 (43%) of 95 patients in the chemoradiotherapy plus trastuzumab group versus 52 (54%) of 96 in the chemoradiotherapy group and grade 4 events occurred in 20 (21%) versus 21 (22%). The most common grade 3 or worse treatment-related adverse events for both groups were haematological (53 [56%] of 95 patients in the chemoradiotherapy plus trastuzumab group vs 55 [57%] of 96 patients in the chemotherapy group) or gastrointestinal disorders (28 [29%] vs 20 [21 %]). 34 (36%) of 95 patients in the chemoradiotherapy plus trastuzumab group and 27 (28%) of 96 patients in the chemoradiotherapy only group had treatment-related serious adverse events. There were eight treatment-related deaths: five (5%) of 95 patients in the chemoradiotherapy plus trastuzumab group (bronchopleural fistula, oesophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three (3%) of 96 in the chemoradiotherapy group (two multiorgan failure and one sepsis). INTERPRETATION: The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing oesophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in oesophageal cancer are warranted. FUNDING: National Cancer Institute and Genentech.

Altered closed state inactivation gating in Kv4.2 channels results in developmental and epileptic encephalopathies in human patients.

Kv4.2 subunits, encoded by KCND2, serve as the pore-forming components of voltage-gated, inactivating ISA K+ channels expressed in the brain. ISA channels inactivate without opening in response to subthreshold excitatory input, temporarily increasing neuronal excitability, the back propagation of action potentials, and Ca2+ influx into dendrites, thereby regulating mechanisms of spike timing-dependent synaptic plasticity. As previously described, a de novo variant in Kv4.2, p.Val404Met, is associated with an infant-onset developmental and epileptic encephalopathy in monozygotic twin boys. The p.Val404Met variant enhances inactivation directly from closed states, but dramatically impairs inactivation after channel opening. We now report the identification of a closely related, novel, de novo variant in Kv4.2, p.Val402Leu, in a boy with an early-onset pharmacoresistant epilepsy that evolved to an epileptic aphasia syndrome (Continuous Spike Wave during Sleep Syndrome). Like p.Val404Met, the p.Val402Leu variant increases the rate of inactivation from closed states, but significantly slows inactivation after the pore opens. Although quantitatively the p.Val402Leu mutation alters channel kinetics less dramatically than p.Val404Met, our results strongly support the conclusion that p.Val402Leu and p.Val404Met cause the clinical features seen in the affected individuals and underscore the importance of closed state inactivation in ISA channels in normal brain development and function.

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. There has been discussion concerning the extent of this obligation in the context of both research and clinical care. Although clinical recommendations have begun to emerge, guidance is lacking on the responsibilities of researchers to inform participants of reinterpreted results. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in November 2018. The workgroup included representatives from the National Society of Genetic Counselors, the Canadian College of Medical Genetics, and the Canadian Association of Genetic Counsellors. The final statement includes twelve position statements that were endorsed or supported by the following organizations: Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Human Genetics Society of Australasia, and National Society of Genetic Counselors.

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. METHODS: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice. RESULTS: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea. INTERPRETATION: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023-1035.

Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2): A novel health-related quality of life prompt for children with epilepsy.

OBJECTIVE: Pediatric epilepsy is often associated with diminished health-related quality of life (HRQOL). Our aim was to establish the validity of the Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2) questions, a novel two-item HRQOL prompt for children with epilepsy, primarily for use in clinical care. METHODS: We performed a multicenter cross-sectional study to validate the PELHS-QOL-2. Construct validity was established through bivariate comparisons with four comparator measures and known drivers of quality of life in children with epilepsy, as well as by creating an a priori multivariable model to predict the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Validity generalization was established through bivariate comparisons with demographic and clinical information. Content validity and clinical utility were established by assessing how well the PELHS-QOL-2 met eight design criteria for an HRQOL prompt established by a multistakeholder group of experts. RESULTS: The final participant sample included 154 English-speaking caregivers of children with epilepsy (mean age = 9.7 years, range = .5-18, 49% female, 70% White). The PELHS-QOL-2 correlated with the four comparator instruments (ρ = .44-.56), was significantly associated with several known drivers of quality of life in children with epilepsy (p < .05), and predicted QOLCE-55 scores in the multivariate model (adjusted R2 = .54). The PELHS-QOL-2 item was not associated with the age, sex, and ethnicity of the children nor with the setting and location of data collection, although PELHS-QOL-Medications was significantly associated with race (worse for White race). Following both quantitative and qualitative analysis, the PELHS-QOL-2 met seven of eight design criteria. SIGNIFICANCE: The PELHS-QOL-2 is a valid HRQOL prompt and is well suited for use in clinical care as a mechanism to routinely initiate conversations with caregivers about quality of life in children with epilepsy. The association of PELHS-QOL-Medications with race merits further study.

A systematic review of cost-effectiveness analyses on endovascular thrombectomy in ischemic stroke patients.

OBJECTIVE: The objective of this study was to examine the published cost-effectiveness analyses (CEAs) on endovascular thrombectomy (EVT) in acute stroke patients, with a particular focus on the practice of accounting for costs and utilities. METHODS: We conducted a systematic review of published CEAs on EVT in acute stroke patients from 1/1/2009 to 10/1/2019. Published CEAs were searched in Ovid Embase, Ovid MEDLINE, and Web of Science. Cost or comparative effectiveness analyses were excluded. Risk of bias and quality assessment was based on the Consolidated Health Economic Evaluation Reporting Standard checklist. RESULTS: Twenty-one studies were included in the final analysis, from the USA, Canada, Europe, Asia, and Australia. They all concluded EVT to be cost-effective, but with significant variations in methodology. Fifteen studies employed a long-term horizon (> 20 years), while only 11 incorporated risk of recurrent strokes. The willingness-to-pay (WTP) threshold varied from $10,000/quality-adjusted life year (QALY) to $120,000/QALY, with $50,000/QALY and $100,000/QALY being the most commonly used. Five studies undertook a societal perspective, but only one accounted for indirect costs. Seventeen studies based outcomes on 90-day modified Rankin Scale (mRS) scores, and 9 of these 17 studies grouped outcomes by mRS 0-2 and 3-5. Among these 9 studies, the range of QALY score reported for mRS 0-2 was 0.71-0.85 QALY, and that of mRS 3-5 was 0.21-0.40. CONCLUSIONS: Our study reveals significant heterogeneity in previously published thrombectomy CEAs, highlighting need for better standardization in future CEAs. KEY POINTS: • All included studies concluded thrombectomy to be cost-effective, from both long- and short-term perspectives. • Only 5 out of 22 studies undertook a societal perspective, and only 1 accounted for indirect costs. • The range of value for mRS 0-2 was 0.71-0.85 quality-adjusted life year (QALY) and 0.21-0.40 QALY for mRS 3-5.

Head and Neck CTA Utilization: Analysis of Ordering Frequency and Nonroutine Results Communication, With Focus on the 50 Most Common Emergency Department Clinical Presentations.

BACKGROUND. Utilization of head and neck CTA in the emergency department (ED) has grown disproportionately to other neuroimaging examinations. OBJECTIVE. The purpose of this article was to characterize utilization of head and neck CTA in the ED, comparing utilization and frequency of nonroutine results communication among patients' chief concerns. METHODS. All adult ED visits for a single health care system from January 2014 to December 2017 were retrospectively reviewed. Variables recorded included chief concerns, whether head and neck CTA was performed, and, if so, whether the report documented nonroutine results communication. The 50 chief concerns resulting in the highest number of head and neck CTA examinations were identified. Frequencies of head and neck CTA ordering and of nonroutine results communication were calculated. A subset of reports documenting nonroutine communication were manually reviewed. RESULTS. Head and neck CTA was ordered in 2.5% (17,903) of 708,145 ED visits in 236,476 patients (mean age, 49.8 ± 20.5 [SD] years; 110,952 men, 125,521 women, 3 unknown sex). Head and neck CTA was ordered for 833 distinct chief concerns. Nonroutine results communication was documented for 17.6% (3155/17,903) of examinations. Among the 50 chief concerns associated with the highest number of examinations, frequency of ordering head and neck CTA ranged from less than 0.5% (five concerns) to 55.2% (stroke code), and frequency of nonroutine communication ranged from 5.6% (transient ischemic attack) to 67.5% (unresponsive). Chief concerns not among the 50 most common accounted for 50.0% (8956/17,903) of examinations; these exhibited a collective frequency of nonroutine communication of 4.8% (429/8956). Manual review of 11.1% (350/3155) of reports with a nonroutine communication indicated an acute finding related to the indication in 51.1%, nonemergent but potentially explanatory finding in 14.0%, incidental finding in 28.0%, and communication of negative results in 6.9%. CONCLUSION. Head and neck CTA is ordered in 2.5% of ED visits for a wide range of chief concerns. Frequencies of ordering and of nonroutine results communication are highly variable among chief concerns. Acute indication-related findings account for half of nonroutine radiologist communications. CLINICAL IMPACT. Insight into patterns regarding head and neck CTA ordering and nonroutine results may help optimize patient selection and radiologist communications in the ED setting.

Scenarios to improve CT head utilization in the emergency department delineated by critical results reporting.

PURPOSE: Increasing use of advanced imaging in the emergency department (ED) has resulted in higher cost without better outcomes. Our goal was to evaluate the yield of CT head exams by scenario to guide efforts at improving patient selection. METHODS: We performed a retrospective study at an academic medical center over 4 years (1/1/2014-12/31/2017). The chief complaint, imaging order, and exam result text were obtained for all adult ED encounters. For the 50 most common chief complaints leading to CT head exams, the ratio of exams to total encounters and ratio of critical results to imaging studies were calculated. Significant difference in "yield" was assessed via binomial test. RESULTS: Over 708,145 adult ED encounters, 58,783 CT head exams were ordered, with an overall critical result yield of 8.0%. The three most common chief complaints had higher yield (p < 0.05): altered mental status (9.8%), fall (9.7%), and new headache (10.1%). Lower yield (p < 0.05) was found for 19 chief complaints: dizziness (6.2%), falls in patients > 65 years old (7.1%), syncope (5.3%), seizure with known epilepsy (4.8%), chest pain (3.7%), head injury (4.9%), headache re-evaluation (7.0%), alcohol intoxication (2.5%), fatigue (6.5%), headache-recurrent or in the setting of known migraines (5.2%), hypertension (4.4%), lethargy (5.8%), loss of consciousness (5.3%), migraine (3.2%), psychiatric evaluation (2.9%), near syncope (4.6%), drug problem (3.1%), symptomatically decreased blood sugar (3.2%), and suicidal (1.7%). CONCLUSION: Our study provides a priority list of low yield scenarios of CT head use for improvement of patient selection.

A pilot monitoring strategy for post-partum disease in an Australian dairy herd.

AIMS: To design a monitoring strategy that could be applied to regular veterinary visits to dairy farms to assess the prevalence and association between health conditions (uterine disease, hyperketonaemia and suboptimal body condition score) when diagnosed and treated at 1-7 days post-calving (DPC) and then re-examined at 28-35 DPC. METHODS: This study evaluated data from 187 high-yielding dairy cows (21 primiparous, 166 multiparous) on one South Australian dairy farm on two occasions; Visit A which was 1-7 DPC and Visit B which was 28-35 DPC. On each visit, the nature of vaginal discharge, concentration of beta-hydroxybutyrate (BOH) in blood and BCS were recorded and assigned a clinical score. This was converted to a categorical outcome denoting the presence or absence of an abnormal health event, namely metritis or endometritis, hyperketonaemia (BOH concentration ≥1.2 mm/L) and suboptimal body condition score (>0.5 from optimum score). Cows with uterine disease or hyperketonaemia at either visit were treated. The prevalence of abnormal health events at each visit was determined and the association between the prevalence of disease at Visit A and Visit B (following appropriate treatment at Visit A) was measured using regression analysis. RESULTS: The prevalence of abnormal vaginal discharge, hyperketonaemia and suboptimal BCS at Visits A and B were 26%, 7%, 35% and 25%,16%, 33% respectively. A higher proportion of primiparous cows (Visit A: 0.86 (95% CI = 0.70-1.00); Visit B: 0.95 (95% CI = 0.86-1.00)) were found to have suboptimal BCS at both visits compared to multiparous cows (Visit A: 0.28 (95% CI = 0.20-0.35); Visit B: 0.24 (95% CI = 0.17-0.32)). A higher prevalence of hyperketonaemia at Visit B for multiparous compared to primiparous cows (19 (95% CI = 12-25)% vs. 0 (95% CI = 0-17) respectively) was identified. An increase in clinical discharge score at Visit A increased the odds of purulent vaginal discharge at Visit B (OR = 1.77 (95% CI = 1.31-2.40)). Failing to calve at target BCS was strongly associated with cows missing target BCS at Visit B (OR = 5.77 (95% CI = 2.35-13.11)) and for every unit increase in BCS at Visit A, BCS at Visit B increased by 0.40 (95% CI = 0.26-0.53). CONCLUSIONS AND CLINICAL RELEVANCE: This study describes a pilot monitoring strategy for clinical parameters indicative of post-partum disease at 1-7 and 28-35 DPC. Determining the herd prevalence of these conditions will enable tracking of herd disease status over time.Abbreviations: BCS: Body condition score; BOH: Beta-hydroxybutyrate; DPC: Days post-calving; NEFA: Non-esterified fatty acids; SCHK: Subclinical hyperketonaemia.