Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.

Evaluating the impact of in silico predictors on clinical variant classification.

PURPOSE: According to the American College of Medical Genetics and Genomics/Association of Medical Pathology (ACMG/AMP) guidelines, in silico evidence is applied at the supporting strength level for pathogenic (PP3) and benign (BP4) evidence. Although PP3 is commonly used, less is known about the effect of these criteria on variant classification outcomes. METHODS: A total of 727 missense variants curated by Clinical Genome Resource expert groups were analyzed to determine how often PP3 and BP4 were applied and their impact on variant classification. The ACMG/AMP categorical system of variant classification was compared with a quantitative point-based system. The pathogenicity likelihood ratios of REVEL, VEST, FATHMM, and MPC were calibrated using a gold standard set of 237 pathogenic and benign variants (classified independent of the PP3/BP4 criteria). RESULTS: The PP3 and BP4 criteria were applied by Variant Curation Expert Panels to 55% of missense variants. Application of those criteria changed the classification of 15% of missense variants for which either criterion was applied. The point-based system resolved borderline classifications. REVEL and VEST performed best at a strength level consistent with moderate evidence. CONCLUSION: We show that in silico criteria are commonly applied and often affect the final variant classifications. When appropriate thresholds for in silico predictors are established, our results show that PP3 and BP4 can be used at a moderate strength.

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: "Definitive," "Strong," "Moderate," "Limited," "No Reported Evidence," or "Conflicting Evidence." Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.

ClinGen Allele Registry links information about genetic variants.

Effective exchange of information about genetic variants is currently hampered by the lack of readily available globally unique variant identifiers that would enable aggregation of information from different sources. The ClinGen Allele Registry addresses this problem by providing (1) globally unique "canonical" variant identifiers (CAids) on demand, either individually or in large batches; (2) access to variant-identifying information in a searchable Registry; (3) links to allele-related records in many commonly used databases; and (4) services for adding links to information about registered variants in external sources. A core element of the Registry is a canonicalization service, implemented using in-memory sequence alignment-based index, which groups variant identifiers denoting the same nucleotide variant and assigns unique and dereferenceable CAids. More than 650 million distinct variants are currently registered, including those from gnomAD, ExAC, dbSNP, and ClinVar, including a small number of variants registered by Registry users. The Registry is accessible both via a web interface and programmatically via well-documented Hypertext Transfer Protocol (HTTP) Representational State Transfer Application Programming Interface (REST-APIs). For programmatic interoperability, the Registry content is accessible in the JavaScript Object Notation for Linked Data (JSON-LD) format. We present several use cases and demonstrate how the linked information may provide raw material for reasoning about variant's pathogenicity.

Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene.

The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes.

Three-dimensional atrial wall thickness maps to inform catheter ablation procedures for atrial fibrillation.

AIMS: Transmural lesion formation is critical to success in atrial fibrillation ablation and is dependent on left atrial wall thickness (LAWT). Pre- and peri-procedural planning may benefit from LAWT measurements. METHODS AND RESULTS: To calculate the LAWT, the Laplace equation was solved over a finite element mesh of the left atrium derived from the segmented computed tomographic angiography (CTA) dataset. Local LAWT was then calculated from the length of field lines derived from the Laplace solution that spanned the wall from the endocardium or epicardium. The method was validated on an atrium phantom and retrospectively applied to 10 patients who underwent routine coronary CTA for standard clinical indications at our institute. The Laplace wall thickness algorithm was validated on the left atrium phantom. Wall thickness measurements had errors of <0.2 mm for thicknesses of 0.5-5.0 mm that are attributed to image resolution and segmentation artefacts. Left atrial wall thickness measurements were performed on 10 patients. Successful comprehensive LAWT maps were generated in all patients from the coronary CTA images. Mean LAWT measurements ranged from 0.6 to 1.0 mm and showed significant inter and intra patient variability. CONCLUSIONS: Left atrial wall thickness can be measured robustly and efficiently across the whole left atrium using a solution of the Laplace equation over a finite element mesh of the left atrium. Further studies are indicated to determine whether the integration of LAWT maps into pre-existing 3D anatomical mapping systems may provide important anatomical information for guiding radiofrequency ablation.

Quantitative magnetic resonance imaging analysis of the relationship between contact force and left atrial scar formation after catheter ablation of atrial fibrillation.

BACKGROUND: Catheter contact force (CF) is an important determinant of radiofrequency (RF) lesion quality during pulmonary vein isolation (PVI). Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) allows good visualization of ablation lesions. OBJECTIVE: This study describes a new technique to examine the relationship between CF during RF delivery and LGE signal intensity (SI) following PVI. METHODS: Six patients underwent PVI for paroxysmal AF using a CF-sensing catheter and following preprocedural MRI. During ablation, CF-time integral (FTI) and position was documented for each RF application. All patients underwent repeat LGE MRI 3 months later. The LGE SIs were projected onto a MRI-derived 3-dimensional left atrial (LA) shell and a CF map was generated on the same shell. The entire LA surface was divided into 5 mm(2) segments. Force and LGE maps were fused and compared for each 5 mm(2) zone. An effective lesion was defined when MRI-defined scar occupied >90% of a 5 mm(2) analysis zone. RESULTS: Acute PVI was achieved in 100%. Two hundred sixty-eight RF lesions were tagged on the LA shells and given a lesion-specific FTI. Increasing FTI correlated with increased LGE SI, which was greater when the FTI was > 1,200 gs. Below an FTI of 1,200 gs, an increment in the FTI resulted in only a small increment in scar, whereas above 1,200 gs an increment in the FTI resulted in a large change of scar. CONCLUSION: There is a correlation between FTI and LGE SI in MRI following AF ablation. Real-time FTI maps are feasible and may prevent inadequate lesion formation.

Enhancing Aotearoa, New Zealand's Free Healthline Service through Image Upload Technology.

Background: Healthline is one of the 39 free telehealth services that Whakarongorau Aotearoa/New Zealand Telehealth Services provides to New Zealanders. In early 2021, an image upload system for viewing service user-uploaded images was implemented into the Healthline service. Aims: The aim of this research was to understand the utilisation of Healthline's image upload system by clinicians and service users in New Zealand. Methods: This is a retrospective observational study analysing Healthline image upload data over a two-year period: March 2021 through to December 2022. A total of 40,045 images were analysed, including demographics of the service users who uploaded an image: ethnicity, age group, and area of residence. The outcome or recommendation of the Healthline call was also assessed based on whether an image was included. Results: Images uploaded accounted for 6.0% of total Healthline calls (n = 671,564). This research found that more service users were advised to go to an Emergency Department if they did not upload an image compared to service users who used the tool (13.5% vs. 7.7%), whereas a higher proportion of service users were given a lower acuity outcome if they included an image, including visiting an Urgent Care (24.0% vs. 16.9%) and GP (36.7% vs. 24.3%). Conclusion: Service users who did not upload an image had a higher proportion of Emergency Department outcomes than service users who did use the tool. This image upload tool has shown the potential to decrease stress on Emergency Departments around Aotearoa, New Zealand, through increased lower acuity outcomes.

Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Accessing clinical-grade genomic classification data through the ClinGen Data Platform.

The Clinical Genome Resource (ClinGen) serves as an authoritative resource on the clinical relevance of genes and variants. In order to support our curation activities and to disseminate our findings to the community, we have developed a Data Platform of informatics resources backed by standardized data models. In this workshop we demonstrate our publicly available resources including curation interfaces, (Variant Curation Interface, CIViC), supporting infrastructure (Allele Registry, Genegraph), and data models (SEPIO, GA4GH VRS, VA).

Analysis of skin condition emergency department outcomes via the free Healthline service from Whakarongorau Aotearoa.

The aim of this research is to gain a deeper understanding of the ethnic and socio-demographic differences in the utilisation of the national 24/7 Healthline service in relation to skin condition calls and their outcomes. Healthline is one of the 39 free telehealth services that Whakarongorau Aotearoa | New Zealand Telehealth Services provides to New Zealanders. This is a retrospective observational study analysing Healthline data over a 4-year period: January 2019 through to December 2022. A total of 61,876 skin condition calls were analysed including demographics of service users: age group, ethnicity, area of residence and call outcome. Higher acuity skin condition calls resulting in an outcome of a recommendation for emergency department (ED) care accounted for 5.3% (n=3,294) of calls. This research found that Maori were over-represented in this ED recommendation data over four years (942 ED outcomes; 28.6%), and Pasifika were under-represented (203 ED outcomes; 5.9%). Wairarapa and West Coast were found to have the highest number of ED outcomes per capita. Our results support the theory that severe skin conditions positively correlate with smaller district populations and increased deprivation in access to services. This study highlights the potential that telehealth services have to help reduce the inequity of access to care.

Whakarongorau abdominal pain review.

AIMS: The purpose of this study was to compare the frequency and profile of abdominal pain calls to Healthline with that from other national healthcare providers; to evaluate the outcomes for this symptom against international telehealth providers; and to explore any inter-clinician variation in the response to abdominal pain that could be part of a quality improvement cycle. METHODS: Data routinely collected about abdominal pain calls to Healthline from 2017 to 2019 were extracted, analysed; and compared to the literature, hospital, and ambulance data and international telehealth providers. A specialist group was convened to review the profile of Healthline callers and outcome data. Variation in outcome changes and acuity grouping was evaluated at an individual level. RESULTS: Approximately 50,000 abdominal pain calls to Healthline over three years were analysed, with three-quarters from women, mostly of childbearing age. The majority call afterhours, with NZ European and, to a lesser extent, Maori, and callers from smaller geographical areas are over-represented. One quarter of patients had a hospital outcome (including 4% receiving an ambulance), which was found to be less acute than comparable health systems. Whakarongorau's Clinical Governance Committee and the Specialist Group both supported the relative distribution of outcomes given by Healthline for abdominal pain. There was found to be variation in the outcomes given to abdominal pain callers at an individual clinician level. This was both in their changes to the disposition given by the Odyssey decision support tool and in their overall outcome distribution. CONCLUSION: Healthline should be considered a key part of New Zealand's healthcare system, as illustrated by the volume of calls that it receives and the fact that presentation types are similar to general practice and emergency departments. Given that abdominal pain is a difficult symptom to accurately address without in-person examination and investigation, the findings support Healthline's outcomes as appropriate with hospitalisation rates lower than comparable healthcare systems. Whakarongorau's (the organisation which runs Healthline) ability to identify individual clinician behaviours gives it a unique opportunity to improve care through decreasing variation.

An Investigation of the Knowledge Overlap between Pharmacogenomics and Disease Genetics.

Precision medicine faces many challenges, including the gap of knowledge between disease genetics and pharmacogenomics (PGx). Disease genetics interprets the pathogenicity of genetic variants for diagnostic purposes, while PGx investigates the genetic influences on drug responses. Ideally, the quality of health care would be improved from the point of disease diagnosis to drug prescribing if PGx is integrated with disease genetics in clinical care. However, PGx genes or variants are usually not reported as a secondary finding even if they are included in a clinical genetic test for diagnostic purposes. This happens even though the detection of PGx variants can provide valuable drug prescribing recommendations. One underlying reason is the lack of systematic classification of the knowledge overlap between PGx and disease genetics. Here, we address this issue by analyzing gene and genetic variant annotations from multiple expert-curated knowledge databases, including PharmGKB, CPIC, ClinGen and ClinVar. We further classified genes based on the strength of evidence supporting a gene's pathogenic role or PGx effect as well as the level of clinical actionability of a gene. Twenty-six genes were found to have pathogenic variation associated with germline diseases as well as strong evidence for a PGx association. These genes were classified into four sub-categories based on the distinct connection between the gene's pathogenic role and PGx effect. Moreover, we have also found thirteen RYR1 genetic variants that were annotated as pathogenic and at the same time whose PGx effect was supported by a preponderance of evidence and given drug prescribing recommendations. Overall, we identified a nontrivial number of gene and genetic variant overlaps between disease genetics and PGx, which laid out a foundation for combining PGx and disease genetics to improve clinical care from disease diagnoses to drug prescribing and adherence.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.

A novel series of IKKß inhibitors part II: description of a potent and pharmacologically active series of analogs.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

A novel series of IKKß inhibitors part I: Initial SAR studies of a HTS hit.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

Whakarongorau Aotearoa: insight into the delivery of New Zealand's national telehealth services.

Whakarongorau Aotearoa/New Zealand Telehealth Services, formerly known as Homecare Medical, is New Zealand's largest digital healthcare service. It originated as a house call doctor service about 20 years ago and now delivers free 24/7 telehealth services to the New Zealand public 365 days a year. Whakarongorau Aotearoa changed its name in April 2021 to reflect the growing kaupapa and was gifted this whakatauki: He reo marohirohi ka taringa rongohia-A brave voice deserves a listening ear. This viewpoint sets out to address a number of public and professional misconceptions about Whakarongorau Aotearoa and provide a more detailed description of the depth, breadth and complexity of the organisation, how it is structured, the range of services available to the public and its clinical governance, leadership and oversight.

Quality of life and healthcare utilisation improvements after atrial fibrillation ablation.

OBJECTIVE: Pulmonary vein isolation (PVI) guided by a standardised CLOSE (contiguous optimised lesions) protocol has been shown to increase clinical success after catheter ablation for paroxysmal atrial fibrillation (PAF). This study analysed healthcare utilisation and quality of life (QOL) outcomes from a large multicentre prospective study, measured association between QOL and atrial fibrillation (AF) burden and identified factors associated with lack of QOL improvement. METHODS: CLOSE-guided ablation was performed in 329 consecutive patients (age 61.4 years, 60.8% male) with drug-refractory PAF in 17 European centres. QOL was measured at baseline and 12 months post-ablation via Atrial Fibrillation Effect on QualiTy of Life Survey (AFEQT) and EuroQoL EQ-5D-5L questionnaires. All-cause and cardiovascular hospitalisations and cardioversions over 12 months pre-ablation and post-ablation were recorded. Rhythm monitoring included weekly and symptom-driven trans-telephonic monitoring, plus ECG and Holter monitoring at 3, 6 and 12 months. AF burden was defined as the percentage of postblanking tracings with an atrial tachyarrhythmia ≥30 s. Continuous measures across multiple time points were analysed using paired t-tests, and associations between various continuous measures were analysed using independent sample t-tests. Each statistical test used two-sided p values with a significance level of 0.05. RESULTS: Both QOL instruments showed significant 12-month improvements across all domains: AFEQT score increased 25.1-37.5 points and 33.3%-50.8% fewer patients reporting any problem across EuroQoL EQ-5D-5L domains. Overall, AFEQT improvement was highly associated with AF burden (p=0.009 for <10% vs ≥10% burden, p<0.001 for <20% vs ≥20% burden). Cardiovascular hospitalisations were significantly decreased after ablation (42%, p=0.001). Patients without substantial improvement in AFEQT (55/301, 18.2%) had higher AFEQT and CHA2DS2-VASc scores at baseline, and higher AF burden following PVI. CONCLUSIONS: QOL improved and healthcare utilisation decreased significantly after ablation with a standardised CLOSE protocol. QOL improvement was significantly associated with impairment at baseline and AF burden after ablation. TRIAL REGISTRATION NUMBER: NCT03062046.