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Several agencies interested in serving Cambodian immigrants established a substance abuse treatment demonstration project which included culturally specific elements such as co-therapy done by a bilingual, bicultural Cambodian worker and a mainstream American social worker; formation of an advisory committee with Cambodian members; home visiting and family involvement; emphasis on traditional cultural values as motivators; integration of Buddhist philosophy; and use of acupuncture for detoxification. In spite of careful planning and several program accomplishments, the program initially received few client referrals. A fact-finding process revealed several barriers, including stigmatization of substance abuse and few Cambodian providers with substance abuse training. Case vignettes and organizational and clinical recommendations are provided for community leaders and advisory groups working with other low-incidence refugee and immigrant populations. [ABSTRACT FROM AUTHOR]

( Headache 2005;45:951-959) [ABSTRACT FROM AUTHOR]

Phosphodiesterase type 5 (PDE 5) inhibitors are widely used in the treatment of erectile dysfunction. However, the results on the cerebral vasculature are unknown. Several cases of intraparenchymal hemorrhage in the setting of PDE 5 inhibitor use have been reported. The effect of these agents on the risk of arteriovenous malformation (AVM) hemorrhage is speculative. This report illustrates a possible association between tadalafil (Cialis, Lilly ICOS, Indianapolis, IN), a new long-acting PDE 5 inhibitor, and AVM hemorrhage during coitus. A 59-year-old male suffered a coital intraparenchymal hemorrhage after premedication with tadalafil. Angiography and magnetic resonance imaging demonstrated an underlying right temporoparital AVM. The AVM was excised, and the patient made an uneventful recovery. AVMs are felt to be dynamic lesions that evolve in response to changes in blood flow. Repeated use of PDE 5 inhibitors could induce changes in an AVM that would make it more likely to hemorrhage, particularly in the setting of additional stress from coitus and elevated blood pressure. The potential for risk of devastating neurovascular complications related to PDE 5 inhibitors should be monitored. Copyright © 2005 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Background: Low nephron number has a direct impact on the development of hypertension and chronic kidney disease later in life. While intrauterine growth restriction caused by maternal low protein diet (LPD) is thought to be a significant cause of reduced nephron endowment in impoverished communities, its influence on the cellular and molecular processes which drive nephron formation are poorly understood., Methods: We conducted a comprehensive characterization of the impact of LPD on kidney development using tomographic and confocal imaging to quantify changes in branching morphogenesis and the cellular and morphological features of nephrogenic niches across development. These analyses were paired with single-cell RNA sequencing to dissect the transcriptional changes that LPD imposes during renal development to affect nephron number., Results: Single cell analysis at E14.5 and P0 revealed differences in the expression of genes and pathways involved in metabolism, cell cycle, epigenetic regulators and reciprocal inductive signals in most cell types analyzed, yielding imbalances and shifts in cellular energy production and cellular trajectories. In the nephron progenitor cells, LPD impeded cellular commitment and differentiation towards pre-tubular and renal vesicle structures. Confocal microscopy revealed a reduction in the number of pre-tubular aggregates and proliferation in nephron progenitor cells. We also found changes in branching morphogenesis, with a reduction in cell proliferation in the ureteric tips as well as reduced tip and tip parent lengths by optical projection tomography which causes patterning defects., Conclusions: This unique profiling demonstrates how a fetal programming defect leads to low nephron endowment which is intricately linked to changes in both branching morphogenesis and the commitment of nephron progenitor cells. The commitment of progenitor cells is pivotal for nephron formation and is significantly influenced by nutritional factors, with a low protein diet driving alterations in this program which directly results in a reduced nephron endowment., Significance Statement: While a mother's diet can negatively impact the number of nephrons in the kidneys of her offspring, the root cellular and molecular drivers of these deficits have not been rigorously explored. In this study we use advanced imaging and gene expression analysis in mouse models to define how a maternal low protein diet, analogous to that of impoverished communities, results in reduced nephron endowment. We find that low protein diet has pleiotropic effects on metabolism and the normal developmental programs of gene expression. These profoundly impact the process of branching morphogenesis necessary to establish niches for nephron generation and change cell behaviors which regulate how and when nephron progenitor cells commit to differentiation.

Background: Relatives of probands diagnosed with familial hypercholesterolemia (FH) should undergo cascade testing for FH., Objectives: The purpose of this study was to evaluate probands' choices of innovative strategies to communicate their FH result with relatives and facilitate cascade testing uptake., Methods: Probands with an FH genetic result from the MyCode Community Health Initiative could choose to share their FH result with adult blood relatives via the Family and Healthcare Professional Packet (packet), family sharing and cascade chatbots (chatbot), and/or FH Outreach and Support Program (direct contact). Cascade testing uptake was measured as reported completion of genetic or cholesterol testing. Generalized estimating equations models were used to identify factors associated with testing., Results: One hundred seventy five probands received an FH result, median age was 58.9 (IQR: 44.9-69.3), and 58.9% were female. Probands shared information about 1,915 adult and 163 minor relatives (11.9 relatives per proband). Seventy percent of probands (121/175) selected at least one strategy for at least one adult relative. An average of 1.2 strategies was selected per adult relative. Cascade testing was completed for 26.6% (144/541) of adults with at least one strategy selected, 2.4% (33/1,374) of adults without a strategy selected, and 25.2% (41/163) of minor relatives. Factors associated with increased cascade testing uptake were selection of at least one strategy (6.32 higher odds), specifically, selection of direct contact (16.78 higher odds)., Conclusions: Strategies implemented improved FH cascade testing uptake compared to previous estimates and in families where no strategy was selected. Overall uptake remains insufficient, which can be attributed to probands reluctance to select a strategy for many relatives., Competing Interests: Dr Jones is a consultant for Novartis. Dr McGowan is on the advisory board for Novartis. Dr Gidding is a consultant for Esperion. Dr Sturm is an employee and stockholder in 23andMe; and on the advisory board for Nest Genomics. Research reported in this publication was supported by the 10.13039/100000050National Heart, Lung, And Blood Institute of the 10.13039/100000002National Institutes of Health under Award Number R01HL148246. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The IMPACT-FH study implemented strategies (packet, chatbot, direct contact) to promote family member cascade testing for familial hypercholesterolemia (FH). We evaluated the impact of genetic counseling (GC) on medical outcomes, strategy selection, and cascade testing. Probands (i.e., patients with FH) were recommended to complete GC and select sharing strategies. Comparisons were performed for both medical outcomes and strategy selection between probands with or without GC. GEE models for Poisson regression were used to examine the relationship between proband GC completion and first-degree relative (FDR) cascade testing. Overall, 46.3% (81/175) of probands completed GC. Probands with GC had a median LDL-C reduction of -13.0 mg/dL (-61.0, 4.0) versus -1.0 mg/dL (-16.0, 17.0) in probands without GC ( p = 0.0054). Probands with and without GC selected sharing strategies for 65.3% and 40.3% of FDRs, respectively ( p < 0.0001). Similarly, 27.1% of FDRs of probands with GC completed cascade testing, while 12.0% of FDRs of probands without GC completed testing ( p = 0.0043). Direct contact was selected for 47 relatives in total and completed for 39, leading to the detection of 18 relatives with FH. Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for the subset who participated.

Background: Cascade testing can be highly effective in identifying individuals with familial hypercholesterolemia (FH) and help prevent atherosclerotic cardiovascular disease. The IMPACT-FH cascade testing program offered multiple optimized implementation strategies to improve FH cascade testing uptake., Objective: Guided by the Conceptual Model of Implementation Research, this study assessed the IMPACT-FH cascade testing program's implementation outcomes., Methods: Implementation outcomes were assessed qualitatively and quantitatively. Interviews were conducted with 33 IMPACT-FH program participants including 15 probands, 12 relatives, and 6 healthcare professionals (HCPs). Transcripts were analyzed using thematic analysis to investigate implementation outcomes. Descriptive statistics were analyzed for scaled implementation outcome measures asked after interviews., Results: Participants described adopting strategies offered in the IMPACT-FH program because they presented an opportunity to pursue low-cost FH cascade testing. Participants identified barriers to feasibility including: the complexity of disclosing an FH result and offering strategies on, inherent limitations of probands choosing strategies, confusion over testing costs, limitations sharing with relatives' clinicians, discomfort with chatbot technology, and concerns about the workload for HCPs. Participants evaluated the program positively regarding its appropriateness (Mean (M) = 4.70, Standard Deviation (SD) = 0.41), acceptability (M = 4.79, SD = 0.40), and feasibility (M = 4.24, SD = 0.53)., Conclusion: The IMPACT-FH cascade testing program and its strategies were evaluated as valuable to adopt and highly appropriate, acceptable, and feasible by participants. Participants identified areas to enhance the program that could improve FH cascade testing uptake., (Copyright © 2024. Published by Elsevier Inc.)

Background: Reflecting clinical trial data showing improved outcomes with lower LDL-C levels, guidelines across the globe are increasingly recommending a goal of LDL-C <55 mg/dL in persons with atherosclerotic cardiovascular disease (ASCVD). What proportion of patients with ASCVD are already meeting those goals in the US remains understudied., Methods: Using electronic health record data from 8 large US health systems, we evaluated lipid-lowering therapy (LLT), LDL-C levels, and factors associated with an LDL-C <55 mg/dL in persons with ASCVD treated between 1/1/2021-12/31/2021. Multivariable modeling was used to evaluate factors associated with achievement of an LDL-C <55 mg/dL., Results: Among 167,899 eligible patients, 22.6% (38,016) had an LDL-C <55 mg/dL. While 76.1% of individuals overall were on a statin, only 38.2% were on a high-intensity statin, 5.9% were on ezetimibe, and 1.7% were on a PCSK9i monoclonal antibody (mAb). Factors associated with lower likelihood of achieving an LDL-C <55 mg/dL included: younger age (odds ratio [OR] 0.91 per 10y), female sex (OR 0.69), Black race (OR 0.76), and noncoronary artery disease forms of ASCVD including peripheral artery disease (OR 0.72) and cerebrovascular disease (OR 0.85), while high-intensity statin use was associated with increased odds of LDL-C <55 mg/dL (OR 1.55). Combination therapy (statin+ezetimibe or statin+PCSK9i mAb) was rare (4.4% and 0.5%, respectively) and was associated with higher odds of an LDL-C <55 mg/dL (OR 1.39 and 3.13, respectively)., Conclusion: Less than a quarter of US patients with ASCVD in community practice are already achieving an LDL-C <55 mg/dL. Marked increases in utilization of both high intensity statins and combination therapy with non-statin therapy will be needed to achieve LDL-C levels <55 mg/dL at the population level in secondary prevention., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones., Methods: Four authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy., Results: Detection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target)., Management: A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target)., Conclusions: We demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice., Competing Interests: Declaration of competing interest LKJ: research grants from Amarin and reports consulting fees from Novartis. SSG: reports consulting fees from Esperion. PL: Dr. Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk and Genentech. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. RDS: received honoraria related to consulting, research and/or speaker activities from: Abbott, Ache, Amgen, Esperion, Kowa, Libbs, Eli-Lilly, Novartis, Novo-Nordisk, PTC Therapeutics, and Sanofi/Regeneron, outside the submitted work. GFW: research grants and honoraria for lectures and advisory boards from Amgen, Arrowhead, Esperion, Silence Therapeutics, Novartis, and NovoNordisk. MNS: No competing interest declared., (Copyright © 2024. Published by Elsevier Inc.)

Large language models (LLMs) are advanced artificial intelligence (AI) systems that excel in recognizing and generating human-like language, possibly serving as valuable tools for neurology-related information tasks. Although LLMs have shown remarkable potential in various areas, their performance in the dynamic environment of daily clinical practice remains uncertain. This article outlines multiple limitations and challenges of using LLMs in clinical settings that need to be addressed, including limited clinical reasoning, variable reliability and accuracy, reproducibility bias, self-serving bias, sponsorship bias, and potential for exacerbating health care disparities. These challenges are further compounded by practical business considerations and infrastructure requirements, including associated costs. To overcome these hurdles and harness the potential of LLMs effectively, this article includes considerations for health care organizations, researchers, and neurologists contemplating the use of LLMs in clinical practice. It is essential for health care organizations to cultivate a culture that welcomes AI solutions and aligns them seamlessly with health care operations. Clear objectives and business plans should guide the selection of AI solutions, ensuring they meet organizational needs and budget considerations. Engaging both clinical and nonclinical stakeholders can help secure necessary resources, foster trust, and ensure the long-term sustainability of AI implementations. Testing, validation, training, and ongoing monitoring are pivotal for successful integration. For neurologists, safeguarding patient data privacy is paramount. Seeking guidance from institutional information technology resources for informed, compliant decisions, and remaining vigilant against biases in LLM outputs are essential practices in responsible and unbiased utilization of AI tools. In research, obtaining institutional review board approval is crucial when dealing with patient data, even if deidentified, to ensure ethical use. Compliance with established guidelines like SPIRIT-AI, MI-CLAIM, and CONSORT-AI is necessary to maintain consistency and mitigate biases in AI research. In summary, the integration of LLMs into clinical neurology offers immense promise while presenting formidable challenges. Awareness of these considerations is vital for harnessing the potential of AI in neurologic care effectively and enhancing patient care quality and safety. The article serves as a guide for health care organizations, researchers, and neurologists navigating this transformative landscape.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading cause of kidney failure and is associated with substantial morbidity and mortality. Interstitial inflammation is attributed to the action of infiltrating macrophages and is a feature thought to aggravate disease progression. Here, we investigated the therapeutic potential of the anti-inflammatory IL37b cytokine as a treatment for ADPKD using genetic mouse models, demonstrating that transgenic expression of human IL37b reduced collecting duct cyst burden in both early and adult-onset ADPKD rodent models. Moreover, injection of recombinant human IL37b could also reduce cyst burden in early onset ADPKD mice, an observation not associated with increased macrophage number at early stages of cyst formation. Interestingly, transgenic IL37b expression also did not alter macrophage numbers in advanced disease. Whole kidney RNA-seq highlighted an IL37b-mediated upregulation of the interferon signaling pathway and single-cell RNA-seq established that these changes originate at least partly from kidney resident macrophages. We further found that blocking type I interferon signaling in mice expressing IL37b resulted in increased cyst number, confirming this as an important pathway by which IL37b exerts its beneficial effects. Thus, our studies show that IL37b promotes interferon signaling in kidney resident macrophages which suppresses cyst initiation, identifying this protein as a potential therapy for ADPKD., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: We designed the Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia (CARE-FH) clinical trial to improve FH screening in primary care and facilitate guideline-based care., Objective: The goal was to incorporate perspectives from end-users (healthcare system leaders, primary care clinicians, cardiologists, genetic counselors, nurses, and clinic staff) and improve translation of screening guidance into practice., Methods: We partnered with end-users to sequentially define the current state of FH screening, assess acceptability, feasibility, and appropriateness of implementing an FH screening program, and select clinically actionable strategies at the patient-, clinician-, and system-level to be deployed as a package in the CARE-FH clinical trial. Methods informed by implementation science and human centered design included: contextual inquiries, surveys, and deliberative engagement sessions., Results: Screening for FH occurred rarely in primary care, and then only after a cardiovascular event or sometimes due to a family history of high cholesterol or early heart attack. Surveys suggested FH screening in primary care was acceptable, appropriate, and feasible. Reported and observed barriers to screening include insufficient time at patient encounters to screen, cost and convenience of testing for patients, and knowledge regarding causes of dyslipidemia. Facilitators included clear guidance on screening criteria and new therapies to treat FH. These results led to the development of multilevel strategies that were presented to end-users, modified, and then pilot tested in one primary care clinic., Conclusions: A refined implementation strategy package for FH screening was created with a goal of improving FH awareness, identification, and initiation of guideline-based care., Clinical Trial Registration: https://clinicaltrials.gov/study/NCT05284513?id=NCT05284513&rank=1 Unique Identifier: NCT05284513., Competing Interests: Declaration of competing interest Laney K. Jones is a consultant for Novartis. Samuel S. Gidding is a consultant for Esperion., (Copyright © 2024. Published by Elsevier Inc.)

Familial hypercholesterolaemia (FH), a common monogenic disorder, is a preventable cause of premature coronary artery disease and death. Up to 35 million people worldwide have FH, but most remain undetected and undertreated. Several clinical guidelines have addressed the gaps in care of FH, but little focus has been given to implementation science and practice. The International Atherosclerosis Society (IAS) has developed an evidence-informed guidance for the detection and management of patients with FH, supplemented with implementation strategies to optimize contextual models of care. The guidance is partitioned into detection, management and implementation sections. Detection deals with screening, diagnosis, genetic testing and counselling. Management includes risk stratification, treatment of adults and children with heterozygous and homozygous FH, management of FH during pregnancy, and use of lipoprotein apheresis. Specific and general implementation strategies, guided by processes specified by the Expert Recommendations for Implementing Change taxonomy, are provided. Core generic implementation strategies are given for improving care. Nation-specific cholesterol awareness campaigns should be utilized to promote better detection of FH. Integrated models of care should be underpinned by health policy and adapted to meet local, regional and national needs. Clinical centres of excellence are important for taking referrals from the community. General practitioners should work seamlessly with multidisciplinary teams. All health-care providers must receive training in essential skills for caring for patients and families with FH. Management should be supported by shared decision-making and service improvement driven by patient-reported outcomes. Improvements in services require sharing of existing resources that can support care. Advocacy should be utilized to ensure sustainable funding. Digital health technologies and clinical quality registries have special value. Finally, academic-service partnerships need to be developed to identify gaps in care and set priorities for research. This new IAS guidance on FH complements the recent World Heart Federation Cholesterol Roadmap., Competing Interests: G.F.W. has received honoraria related to consulting, research and/or speaker activities from Amgen, Arrowhead, AstraZeneca, CRISPR Therapeutics, Esperion, Novartis and Sanofi. L.K.J. is a consultant for Novartis. M.N.S. has received personal fees from Amgen. J.P. has received grants from the National Health and Medical Research Council (NHMRC, Australia), the Medical Research Future Fund (MRRF, Australia), the Department of Health of Western Australia and the Royal Perth Hospital Research Foundation. S.S.G. is a consultant for Esperion and on a scientific advisory panel for Silence Therapeutics. P.L. has received research funding from Novartis; is on the Board of Directors of XBiotech; has a financial interest in Soley Therapeutics, TenSixteen Bio and XBiotech; is an unpaid consultant to, or involved in clinical trials for, Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer and Sanofi-Regeneron; is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Moderna, Novartis, PlaqueTec, Soley Thereapeutics, TenSixteen Bio and XBiotech. R.D.S. has received honoraria related to consulting, research and/or speaker activities from Abbott, Ache, Amgen, AstraZeneca, EMS, Esperion, GETZ Pharma, Kowa, Libbs, Novartis, Novo-Nordisk, Merck, MSD, Pfizer, PTC Therapeutics and Sanofi/Regeneron., (Copyright: © 2024 The Author(s).)

Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA's role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT., (© 2024. The Author(s).)

A web-based clinical simulation program, known as FIRST 2 ACT (Feedback Incorporating Review and Simulation Techniques to Act on Clinical Trends), was designed to increase the efficacy of clinicians' actions in the recognition and immediate response to a patient's deterioration. This study, which was nested in a larger mixed method project, used ten focus groups ( n = 65) of graduate, enrolled, registered nurses, associate nurse unit managers, and general managers/educators/coordinators from four different institutions to investigate whether nurses felt their practice was influenced by participating in either a face-to-face or web-based simulation educational programme about patient deterioration. The results indicate that individuals who were less "tech-savvy" appreciated the flexibility of web-based learning, which increased their confidence. Face-to-face students appreciated self-reflection through performance evaluation. While face-to-face simulations were unable to completely duplicate symptoms, they showed nurses' adaptability. Both interventions enhanced clinical practice by improving documentation and replies while also boosting confidence and competence. Web learners initially experienced tech-related anxiety, which gradually subsided, demonstrating healthcare professionals' resilience to new learning approaches. Overall, the study highlighted the advantages and challenges of web-based and face-to-face education in clinical practice, emphasising the importance of adaptability and reflective learning for healthcare professionals. Further exploration of specific topics is required to improve practice, encourage knowledge sharing among colleagues, and improve early detection of patient deterioration.

This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide., (© 2023. Springer Nature Limited.)

The integration of natural language processing (NLP) tools into neurology workflows has the potential to significantly enhance clinical care. However, it is important to address the limitations and risks associated with integrating this new technology. Recent advances in transformer-based NLP algorithms (e.g., GPT, BERT) could augment neurology clinical care by summarizing patient health information, suggesting care options, and assisting research involving large datasets. However, these NLP platforms have potential risks including fabricated facts and data security and substantial barriers for implementation. Although these risks and barriers need to be considered, the benefits for providers, patients, and communities are substantial. With these systems achieving greater functionality and the pace of medical need increasing, integrating these tools into clinical care may prove not only beneficial but necessary. Further investigation is needed to design implementation strategies, mitigate risks, and overcome barriers., (© 2023 American Academy of Neurology.)

With recent data demonstrating that lecanemab treatment can slow cognitive and functional decline in early symptomatic Alzheimer disease (AD), it is widely anticipated that this drug and potentially other monoclonal antibody infusions targeting β-amyloid protein will imminently be realistic options for some patients with AD. Given that these new antiamyloid monoclonal antibodies (mAbs) are associated with nontrivial risks and burdens of treatment that are radically different from current mainstays of AD management, effectively and equitably translating their use to real-world clinical care will require systematic and practice-specific modifications to existing workflows and infrastructure. In this Emerging Issues in Neurology article, we provide practical guidance for a wide audience of neurology clinicians on logistic adaptations and decision making around emerging antiamyloid mAbs. Specifically, we briefly summarize the rationale and available evidence supporting antiamyloid mAb use in AD to facilitate appropriate communication with patients and care partners on potential benefits. We also discuss pragmatic approaches to optimizing patient selection and treatment monitoring, with a particular focus on the value of incorporating shared decision making and multidisciplinary collaboration. In addition, we review some of the recognized limitations of current knowledge and highlight areas of future evolution to guide the development of sustainable and flexible models for treatment and follow-up. As the field enters a new era with disease-modifying treatment options for AD, it will be critical for neurology practices to prepare and continually innovate to ensure optimal outcomes for patients., (© 2023 American Academy of Neurology.)

Background and Objectives: The 2023 Match cycle was the third virtual interview season for adult neurology residency programs. This recruitment cycle differed from years prior because an in-person second-look event was offered by some programs to complement the virtual interview day. We sought feedback from those who interviewed for adult neurology residency positions at Mayo Clinic in Arizona, Florida, and Minnesota to gain applicants' perspectives on such events and identify best practices to improve the interview experience for future applicants., Methods: Virtual interviews were conducted for adult neurology residency positions at Mayo Clinic in Arizona, Florida, and Minnesota for the 2023 Match. Each site hosted optional, in-person, no-stakes second-look events after program rank lists were finalized. After Match Day, interviewees at all 3 sites were invited to complete an anonymous electronic survey using Qualtrics software to gather feedback on the in-person events., Results: Of the 240 interviewees for adult neurology residency positions at Mayo Clinic, 52 candidates participated in the in-person second-look event on the Arizona, Florida, or Minnesota campus in 2023. One-third of applicants (80/240) completed the anonymous survey, and of them, 34% (27/80) of respondents had attended a Mayo Clinic second-look event. The desire to step foot on campus, meet the residents in person, and visit the geographic area were the most important reasons driving attendance. Those who did not participate cited financial burden, lack of time, and insufficient notice to make travel plans as the most common factors influencing their decision not to attend. Nearly half of attendees who responded to the survey (10/21, 48%) changed their rank order list after the in-person event. Most of them who participated in a Mayo Clinic second-look event (19/21, 91%) would encourage future applicants to partake., Discussion: While there are many advantages to virtual residency interviews, most applicants who participated in second-look events found that having an opportunity to visit the program in person was valuable when determining their rank list. Offering an optional, no-stakes, in-person visit allows interviewees to make more informed rank lists. Second-look events have the potential to complement the virtual interview day and may ultimately lead to greater satisfaction for matched applicants., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NE for full disclosures., (© 2023 American Academy of Neurology.)

Background: Severe hypercholesterolemia, defined as LDL (low-density lipoprotein) cholesterol (LDL-C) measurement ≥190 mg/dL, is associated with increased risk for coronary artery disease (CAD). Causes of severe hypercholesterolemia include monogenic familial hypercholesterolemia, polygenic hypercholesterolemia, elevated lipoprotein(a) [Lp(a)] hypercholesteremia, polygenic hypercholesterolemia with elevated Lp(a) (two-hit), or nongenetic hypercholesterolemia. The added value of using a genetics approach to stratifying risk of incident CAD among those with severe hypercholesterolemia versus using LDL-C levels alone for risk stratification is not known., Methods: To determine whether risk stratification by genetic cause provided better 10-year incident CAD risk stratification than LDL-C level, a retrospective cohort study comparing incident CAD risk among severe hypercholesterolemia subtypes (genetic and nongenetic causes) was performed among 130 091 UK Biobank participants. Analyses were limited to unrelated, White British or Irish participants with available exome sequencing data. Participants with cardiovascular disease at baseline were excluded from analyses of incident CAD., Results: Of 130 091 individuals, 68 416 (52.6%) were women, and the mean (SD) age was 56.7 (8.0) years. Of the cohort, 9.0% met severe hypercholesterolemia criteria. Participants with LDL-C between 210 and 229 mg/dL and LDL-C ≥230 mg/dL showed modest increases in incident CAD risk relative to those with LDL-C between 190 and 209 mg/dL (210-229 mg/dL: hazard ratio [HR], 1.3 [95% CI, 1.1-1.7]; ≥230 mg/dL: HR, 1.3 [95% CI, 1.0-1.7]). In contrast, when risk was stratified by genetic subtype, monogenic familial hypercholesterolemia, elevated Lp(a), and two-hit hypercholesterolemia subtypes had increased rates of incident CAD relative to the nongenetic hypercholesterolemia subtype (monogenic familial hypercholesterolemia: HR, 2.3 [95% CI, 1.4-4.0]; elevated Lp(a): HR, 1.5 [95% CI, 1.2-2.0]; two-hit: HR, 1.9 [95% CI, 1.4-2.6]), while polygenic hypercholesterolemia did not., Conclusions: Genetics-based subtyping for monogenic familial hypercholesterolemia and Lp(a) in those with severe hypercholesterolemia provided better stratification of 10-year incident CAD risk than LDL-C-based stratification., Competing Interests: Disclosures S.S. Gidding is a consultant at Esperion. L.K. Jones is a consultant at Novartis. E.J. Sijbrands received a research grant from Amgen. The other authors report no conflicts.

Background: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States. Case-based learning using electronic delivery of the modules can educate clinicians and improve translation of evidence-based guidelines into practice for high-risk ASCVD patients., Objective: To develop and optimize module design, content, and usability of e-learning modules to teach clinicians evidence-based management in accordance with multi-society guidelines for high-risk ASCVD patients that will be implemented and evaluated in U.S. health systems in the TEACH-ASCVD study., Methods: Seven e-learning modules were created by a committee of lipid experts. Focus groups were conducted with lipid experts to elicit feedback on case content followed by interviews with a target audience of clinicians to assess usability of the online module platform. Responses from both groups were evaluated, and appropriate changes were made to improve the e-learning modules. Design of the TEACH-ASCVD study is presented., Results: Feedback regarding case content by lipid experts included providing more detailed patient histories, clarifying various diagnostic criteria, and emphasizing clinical best practices based on evidence-based guidelines. The target audience clinician group reported an agreeable experience with the e-learning modules but noted a discordance between the evidence-based guidelines and clinical decision-making in their own practices. Participants felt the modules would help educate clinicians in managing high-risk ASCVD patients., Conclusion: Clinicians must be informed of best practices as the field of lipidology continues to evolve. E-learning modules provide a concise, valuable, and accessible mechanism for educating clinicians regarding changes in the field to deliver the best patient care., (Copyright © 2023 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To review recent international and domestic definitions, considerations, and treatment algorithms for statin intolerance, and specifically, statin-associated muscle symptoms (SAMS)., Recent Findings: Multiple organizations around the world have produced guidance documents to aid clinicians on managing statin intolerance. A common theme resides among all the guidance documents that most patients can tolerate statins. For those patients who cannot, healthcare teams need to evaluate, rechallenge, educate, and ensure adequate reduction of atherogenic lipoproteins. Statin therapy remains the cornerstone of lipid-lowering therapies to reduce atherosclerotic cardiovascular disease (ASCVD) and reduce mortality and morbidity. The common theme throughout all these guidance documents is the importance of statin therapy to reduce ASCVD and continual adherence to treatment. Because adverse events occur and inhibit patients from achieving adequate lowering of their atherogenic lipoproteins, trial and rechallenge of statin therapy, as well as addition of non-statin therapies, especially in high-risk patients, is also undisputed. The main differences stem from laboratory monitoring and the classification of the severity of the adverse effect. Future research should focus on consistently diagnosing SAMS so that these patients can be easily identified in the electronic health records., (© 2023. The Author(s).)

Competing Interests: The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NE for full disclosures.

Background Data mining of electronic health records to identify patients suspected of familial hypercholesterolemia (FH) has been limited by absence of both phenotypic and genomic data in the same cohort. Methods and Results Using the Geisinger MyCode Community Health Initiative cohort (n=130 257), we ran 2 screening algorithms (Mayo Clinic [Mayo] and flag, identify, network, deliver [FIND] FH) to determine FH genetic and phenotypic diagnostic yields. With 29 243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in electronic health records), 52 034 excluded by FIND FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59 729 participants was created. Genetic diagnosis was based on presence of a pathogenic or likely pathogenic variant in FH genes. Charts from 180 variant-negative participants (60 controls, 120 identified by FIND FH and Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score ≥5 defined probable phenotypic FH. Mayo flagged 10 415 subjects; 194 (1.9%) had a pathogenic or likely pathogenic FH variant. FIND FH flagged 573; 34 (5.9%) had a pathogenic or likely pathogenic variant, giving a net yield from both of 197 out of 280 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of electronic health record data on physical findings or family history. Phenotypic FH by chart review was present by Mayo and/or FIND FH in 13 out of 120 versus 2 out of 60 not flagged by either ( P <0.09). Conclusions Applying 2 recognized FH screening algorithms to the Geisinger MyCode Community Health Initiative identified 70% of those with a pathogenic or likely pathogenic FH variant. Phenotypic diagnosis was rarely achievable due to missing data.

Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within human cardiac organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein we optimize our protocol to generate vascular populations in addition to epicardial, fibroblast, and cardiomyocyte cells that self-organize into in-vivo-like structures in hCOs. We identify mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes that ultimately contribute to cardiac organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression of mature sarcomeric proteins and contractility, and (2) paracrine platelet-derived growth factor receptor β (PDGFRβ) signaling from vascular cells upregulates matrix deposition to augment hCO contractile force. Finally, we demonstrate that vascular cells determine the magnitude of diastolic dysfunction caused by inflammatory factors and identify a paracrine role of endothelin driving dysfunction. Together this study highlights the importance and role of vascular cells in organoid models., Competing Interests: Declaration of interests R.J.M., J.E.H., G.A.Q.-R., and E.R.P. are listed as co-inventors on pending patents that relate to cardiac organoid maturation and cardiac regeneration therapeutics. E.R.P. and J.E.H. are listed as co-inventors on pending patents that relate to endothelial cells in 3D cardiac products. J.E.H. is a co-inventor on licensed patents relating to engineered heart muscle. R.J.M., E.R.P., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The role of teledermatology for skin lesion assessment has been a recent development, particularly, since the COVID-19 pandemic has impacted the ability to assess patients in person. The growing number of studies relating to this area reflects the evolving interest., Objective: This literature review aims to analyze the available research on store-and-forward teledermatology for skin lesion assessment., Methods: MEDLINE was searched for papers from January 2010 to November 2021. Papers were searched for assessment of time management, effectiveness, and image quality., Results: The reported effectiveness of store-and-forward teledermatology for skin lesion assessment produces heterogeneous results likely due to significant procedure variations. Most studies show high accuracy and diagnostic concordance of teledermatology compared to in-person dermatologist assessment and histopathology. This is improved through the use of teledermoscopy. Most literature shows that teledermatology reduces time to advice and definitive treatment compared to outpatient clinic assessment., Conclusions: Overall, teledermatology offers a comparable standard of effectiveness to in-person assessment. It can save significant time in expediting advice and management. Image quality and inclusion of dermoscopy have a considerable bearing on the overall effectiveness., (©Leah Kirsten Jones, Amanda Oakley. Originally published in JMIR Dermatology (http://derma.jmir.org), 17.05.2023.)

There is a growing number of forcibly displaced persons (FDPs) worldwide. With more than 100 million people forcibly displaced today, there is an urgent mandate to understand the neurologic care needs of this population and how neurologists and other health care workers can most effectively provide that care. In this Emerging Issues in Neurology article, we attempt to (1) define the scope of the problem of providing neurologic care to FDPs, (2) highlight commonly encountered clinical challenges related to neurologic care of FDPs, and (3) provide useful clinical information for neurologists and other clinicians who deliver care to FDPs with neurologic needs. We address the terminology of forcible displacement and how terms may differ across a person's migration journey. Common challenges encountered by FDPs with neurologic needs across settings include loss of support systems, loss of personal health information, language barriers and differing expression of symptoms, differing belief systems, epidemiologic patterns of disease unfamiliar to the clinician, and patients' fear and perceived risks of engaging with health systems. Practical approaches are shared for clinicians who encounter an FDP with a neurologic presentation. Finally, the article discusses many unmet neurologic needs of FDPs, which require significant investment. These include addressing lapses in neurologic care during displacement and understanding the effects of forcible displacement on people with chronic neurologic conditions. Future research and educational resources should focus on improving epidemiologic intelligence for neurologic conditions across geographies, developing curricula for optimizing the neurologic care of FDPs, and evaluating the most appropriate and effective uses of health technologies in humanitarian settings., (© 2023 American Academy of Neurology.)

Background: The cost-effectiveness of screening the U.S. population for Centers for Disease Control and Prevention (CDC) Tier 1 genomic conditions is unknown., Objective: To estimate the cost-effectiveness of simultaneous genomic screening for Lynch syndrome (LS), hereditary breast and ovarian cancer syndrome (HBOC), and familial hypercholesterolemia (FH)., Design: Decision analytic Markov model., Data Sources: Published literature., Target Population: Separate age-based cohorts (ages 20 to 60 years at time of screening) of racially and ethnically representative U.S. adults., Time Horizon: Lifetime., Perspective: U.S. health care payer., Intervention: Population genomic screening using clinical sequencing with a restricted panel of high-evidence genes, cascade testing of first-degree relatives, and recommended preventive interventions for identified probands., Outcome Measures: Incident breast, ovarian, and colorectal cancer cases; incident cardiovascular events; quality-adjusted survival; and costs., Results of Base-Case Analysis: Screening 100 000 unselected 30-year-olds resulted in 101 (95% uncertainty interval [UI], 77 to 127) fewer overall cancer cases and 15 (95% UI, 4 to 28) fewer cardiovascular events and an increase of 495 quality-adjusted life-years (QALYs) (95% UI, 401 to 757) at an incremental cost of $33.9 million (95% UI, $27.0 million to $41.1 million). The incremental cost-effectiveness ratio was $68 600 per QALY gained (95% UI, $41 800 to $88 900)., Results of Sensitivity Analysis: Screening 30-, 40-, and 50-year-old cohorts was cost-effective in 99%, 88%, and 19% of probabilistic simulations, respectively, at a $100 000-per-QALY threshold. The test costs at which screening 30-, 40-, and 50-year-olds reached the $100 000-per-QALY threshold were $413, $290, and $166, respectively. Variant prevalence and adherence to preventive interventions were also highly influential parameters., Limitations: Population averages for model inputs, which were derived predominantly from European populations, vary across ancestries and health care environments., Conclusion: Population genomic screening with a restricted panel of high-evidence genes associated with 3 CDC Tier 1 conditions is likely to be cost-effective in U.S. adults younger than 40 years if the testing cost is relatively low and probands have access to preventive interventions., Primary Funding Source: National Human Genome Research Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-0846.

Introduction: Familial hypercholesterolemia (FH) is a common inherited cholesterol disorder that, without early intervention, leads to premature cardiovascular disease. Multilevel strategies that target all components of FH care including identification, cascade testing, and management are needed to address gaps that exist in FH care. We utilized intervention mapping, a systematic implementation science approach, to identify and match strategies to existing barriers and develop programs to improve FH care., Methods: Data were collected utilizing two methods: a scoping review of published literature, related to any component of FH care, and a parallel mixed method study using interviews and surveys. The scientific literature was searched using key words including "barriers" or "facilitators" and "familial hypercholesterolemia" from inception to December 1, 2021. The parallel mixed method study recruited individuals and families with FH to participate in either dyadic interviews ( N  = 11 dyads/22 individuals) or online surveys ( N  = 98 respondents). Data generated from the scoping review, dyadic interviews, and online surveys were used in the 6-step intervention mapping process. Steps 1-3 included a needs assessment, development of program outcomes and creation of evidence-based implementation strategies. Steps 4-6 included program development, implementation, and evaluation of implementation strategies., Results: In steps 1-3, a needs assessment found barriers to FH care included underdiagnosis of the condition which led to suboptimal management due to a myriad of determinants including knowledge gaps, negative attitudes, and risk misperceptions by individuals with FH and clinicians. Literature review highlighted barriers to FH care at the health system level, notably the relative lack of genetic testing resources and infrastructure needed to support FH diagnosis and treatment. Examples of strategies to overcome identified barriers included development of multidisciplinary care teams and educational programs. In steps 4-6, an NHLBI-funded study, the Collaborative Approach to Reach Everyone with FH (CARE-FH), deployed strategies that focused on improving identification of FH in primary care settings. The CARE-FH study is used as an example to describe program development, implementation, and evaluation techniques of implementation strategies., Conclusion: The development and deployment of evidence-based implementation strategies that address barriers to FH care are important next steps to improve identification, cascade testing, and management., Competing Interests: LJ is a consultant for Novartis Corporation. SG is a consultant for Esperion. AG has received research funding from Amgen, Sanofi, Novartis, Arrowhead, IONIS, Regeneron, New Amsterdam, Esperion, and Pfizer and is a consultant for IONIS, New Amsterdam, and Regeneron. AS is an employee and has stockholder in 23andMe and an Advisor to Nest Genomics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Jones, Calvo, Campbell-Salome, Walters, Brangan, Rodriguez, Ahmed, Morgan, Gidding, Williams, Brownson, Seaton, Goldberg, Mcgowan, Rahm and Sturm.)