Inhibition of hERG K channels by verapamil at physiological temperature: Implications for the CiPA initiative.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative reassesses using the inhibition of hERG potassium channels by drugs as the major determinant for the potential to cause drug-induced Torsades de Pointes (TdP) cardiac arrhythmias. Here we report our findings on the next phase of CiPA: Determination of hERG inhibitory properties using the standard CiPA-defined data acquisition protocol, here called the standard protocol, at physiological temperature (37 degrees Celsius). To do this, we measured inhibition of hERG1a potassium channels stably expressed in HEK293 cells by the small molecule verapamil, using manual whole-cell patch-clamp electrophysiology recordings with the standard protocol, which is characterized, in part, by a series of 10 s duration voltage steps to 0 mV, ultimately leading to a cumulative recording time of approximately 30 min. Using the standard protocol, we measured an IC50 for verapamil of 225 nM, a Hill coefficient of 1, and time constant of inhibition at 0 mV of 0.64 s. But, using the standard protocol resulted in a very low (5 %) experimental success rate per cell, which had low practicality for future experiments. To address the 5 % success rate, we generated a revised protocol characterized, in part, by a series of 3 s duration voltage steps to 0 mV, leading to a cumulative recording time of approximately 10 min. Using the revised protocol, we found an IC50 for verapamil of 252 nM, a Hill coefficient of 0.8, and time constant of inhibition at 0 mV of 0.67 s. The values measured with the revised protocol were similar to those measured using the standard protocol and, furthermore, our success rate using the revised protocol rose to 25 %, an increase of 5-fold over the standard protocol, and more in line with the success rate for biophysical studies. In summary, we captured key pharmacological data for subsequent analysis in CiPA using a revised protocol with an increased success rate and an overall enhanced feasibility and practicality. We propose that the revised protocol may be more pragmatic for generation of some hERG channel drug inhibition data for CiPA and other regulatory sciences.

Integrating causal pathway diagrams into practice facilitation to address colorectal cancer screening disparities in primary care.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer death and the second most common cancer diagnosis among the Hispanic population in the United States. However, CRC screening prevalence remains lower among Hispanic adults than among non-Hispanic white adults. To reduce CRC screening disparities, efforts to implement CRC screening evidence-based interventions in primary care organizations (PCOs) must consider their potential effect on existing screening disparities. More research is needed to understand how to leverage existing implementation science methodologies to improve health disparities. The Coaching to Improve Colorectal Cancer Screening Equity (CoachIQ) pilot study explores whether integrating two implementation science tools, Causal Pathway Diagrams and practice facilitation, is a feasible and effective way to address CRC screening disparities among Hispanic patients. METHODS: We used a quasi-experimental, mixed methods design to evaluate feasibility and assess initial signals of effectiveness of the CoachIQ approach. Three PCOs received coaching from CoachIQ practice facilitators over a 12-month period. Three non-equivalent comparison group PCOs received coaching during the same period as participants in a state quality improvement program. We conducted descriptive analyses of screening rates and coaching activities. RESULTS: The CoachIQ practice facilitators discussed equity, facilitated prioritization of QI activities, and reviewed CRC screening disparities during a higher proportion of coaching encounters than the comparison group practice facilitator. While the mean overall CRC screening rate in the comparison PCOs increased from 34 to 41%, the mean CRC screening rate for Hispanic patients did not increase from 30%. In contrast, the mean overall CRC screening rate at the CoachIQ PCOs increased from 41 to 44%, and the mean CRC screening rate for Hispanic patients increased from 35 to 39%. CONCLUSIONS: The CoachIQ program merges two implementation science methodologies, practice facilitation and causal pathway diagrams, to help PCOs focus quality improvement efforts on improving CRC screening while also reducing screening disparities. Results from this pilot study demonstrate key differences between CoachIQ facilitation and standard facilitation, and point to the potential of the CoachIQ approach to decrease disparities in CRC screening.

Top Ten Tips Palliative Care Clinicians Should Know About End-of-Life Doulas.

Palliative care has made great strides in improving the lives of people living with serious illness, with an empirical premise for increasing quality, and sometimes quantity of life. Yet in some cases, there exist gaps that impede the ability of palliative care clinicians to truly advocate, procure, and provide the comprehensive services needed for patients, family caregivers, and communities, particularly in the contexts of caring for marginalized populations and working in under-resourced practice settings. The end-of-life doula role has emerged over the last decade and the availability of trained doulas in the community has burgeoned. An end-of-life doula is a nonmedical, holistic support person who provides education, guidance, emotional, spiritual, and practical support to persons and families navigating serious and terminal illness, ideally early in the disease process, throughout the time surrounding death, and during bereavement. A pervasive Western culture of avoiding the subject of death means that we, as a society, often do not know or remember how to navigate the journey of end of life in a way that is caring, compassionate, skilled, holistic, and centered on the needs and worldview of the dying one. The ten tips provided here can guide palliative care clinicians to leverage collaboration with trusted, community-based end-of-life doulas to ensure comprehensive and people-centered palliative care.

The Impact of a Nurse-Led High-Risk Referral Protocol Implemented in a Comprehensive Breast Center.

This quality improvement project implemented a nurse-led high-risk screening referral protocol for earlier identification of women at increased risk for breast cancer. The Breast Cancer Risk Assessment Tool was used at the ma.

Monitoring emerging pathogens using negative nucleic acid test results from endemic pathogens in pig populations: Application to porcine enteric coronaviruses.

This study evaluated the use of endemic enteric coronaviruses polymerase chain reaction (PCR)-negative testing results as an alternative approach to detect the emergence of animal health threats with similar clinical diseases presentation. This retrospective study, conducted in the United States, used PCR-negative testing results from porcine samples tested at six veterinary diagnostic laboratories. As a proof of concept, the database was first searched for transmissible gastroenteritis virus (TGEV) negative submissions between January 1st, 2010, through April 29th, 2013, when the first porcine epidemic diarrhea virus (PEDV) case was diagnosed. Secondly, TGEV- and PEDV-negative submissions were used to detect the porcine delta coronavirus (PDCoV) emergence in 2014. Lastly, encountered best detection algorithms were implemented to prospectively monitor the 2023 enteric coronavirus-negative submissions. Time series (weekly TGEV-negative counts) and Seasonal Autoregressive-Integrated Moving-Average (SARIMA) were used to control for outliers, trends, and seasonality. The SARIMA's fitted and residuals were then subjected to anomaly detection algorithms (EARS, EWMA, CUSUM, Farrington) to identify alarms, defined as weeks of higher TGEV-negativity than what was predicted by models preceding the PEDV emergence. The best-performing detection algorithms had the lowest false alarms (number of alarms detected during the baseline) and highest time to detect (number of weeks between the first alarm and PEDV emergence). The best-performing detection algorithms were CUSUM, EWMA, and Farrington flexible using SARIMA fitted values, having a lower false alarm rate and identified alarms 4 to 17 weeks before PEDV and PDCoV emergences. No alarms were identified in the 2023 enteric negative testing results. The negative-based monitoring system functioned in the case of PEDV propagating epidemic and in the presence of a concurrent propagating epidemic with the PDCoV emergence. It demonstrated its applicability as an additional tool for diagnostic data monitoring of emergent pathogens having similar clinical disease as the monitored endemic pathogens.

Spillover of highly pathogenic avian influenza H5N1 virus to dairy cattle.

The highly pathogenic avian influenza (HPAI) H5N1 virus clade 2.3.4.4b has caused the death of millions of domestic birds and thousands of wild birds in the USA since January 2022 (refs. 1-4). Throughout this outbreak, spillovers to mammals have been frequently documented5-12. Here we report spillover of the HPAI H5N1 virus to dairy cattle across several states in the USA. The affected cows displayed clinical signs encompassing decreased feed intake, altered faecal consistency, respiratory distress and decreased milk production with abnormal milk. Infectious virus and viral RNA were consistently detected in milk from affected cows. Viral distribution in tissues via immunohistochemistry and in situ hybridization revealed a distinct tropism of the virus for the epithelial cells lining the alveoli of the mammary gland in cows. Whole viral genome sequences recovered from dairy cows, birds, domestic cats and a raccoon from affected farms indicated multidirectional interspecies transmissions. Epidemiological and genomic data revealed efficient cow-to-cow transmission after apparently healthy cows from an affected farm were transported to a premise in a different state. These results demonstrate the transmission of the HPAI H5N1 clade 2.3.4.4b virus at a non-traditional interface, underscoring the ability of the virus to cross species barriers.

Improving age-friendly advance care planning in primary care: Outcomes from a Pacific Northwest learning collaborative.

BACKGROUND: Advance care planning (ACP) is the process of having conversations with patients to ensure preferences are known and support patient healthcare goals. ACP and the Age-Friendly Health Systems (AFHS) Initiative's, "What Matters," are synergistic approaches to patient-centered conversations. Implementation and measurement of ACP in primary care (PC) are variables in quality and consistency. We examined whether participation in an ACP learning collaborative (LC) would improve knowledge and ability to conduct ACP discussions and increase the frequency of documented ACP in participating practices. METHODS: The WWAMI (Washington, Wyoming, Alaska, Montana, and Idaho) region Practice and Research Network (WPRN) and the Northwest Geriatrics Workforce Enhancement Center collaboratively organized a 9-month virtual LC. It consisted of 4 synchronous, 1.5-h sessions, technical support, and a panel of ACP experts. A Wilcoxon rank sum test assessed differences in knowledge from a pre-post survey. Documentation of ACP in the EHR was collected after at least one plan-do-study-act cycle. RESULTS: We enrolled 17 participants from 6 PC practices (3 hospital-affiliated; 3 Federally Qualified Health Centers) from the WPRN. Two practices did not complete all LC activities. There was a trend toward increased ACP knowledge and skills overall especially in having discussions patients and families (pre-mean 2.9 [SD = 0.7]/post-mean 4.0[SD = 1.1], p < 0.05). 4/6 practices observed an increase in EHR documentation post-collaborative (median 16.3%, IQR 1.3%-36.9%). CONCLUSIONS: The LC increased PC providers knowledge and skills of ACP and AFHS's What Matters, reported ACP EHR documentation, and contributed to practice change.

Assessment of a community pharmacist remote monitoring service in patients using continuous glucose monitors.

BACKGROUND: Diabetes is the eighth leading cause of death and has a substantial impact on the U.S. health care system. Recent changes to major insurance formularies allow for increased access to continuous glucose monitors (CGMs). Community pharmacists routinely assist and educate patients about diabetes care, including usage of CGM. OBJECTIVES: The purpose of this study was to evaluate the clinical impact of a community pharmacist remote CGM monitoring service on patients' glycemic metrics. Patient completion of comprehensive diabetes standards of care and pharmacist interventions and recommendations were assessed as secondary objectives. METHODS: This study was a prospective, feasibility study conducted at two pharmacies within 1 regional division of a large community pharmacy chain between November 2022 and June 2023. A pharmacist conducted patient enrollment visits and remotely monitored CGM glycemic metrics via cloud-based platforms per the study protocol. CGM glycemic metrics were evaluated for each patient 3 months pre- and post-study enrollment, including time above range (TAR), time in range (TIR), time below range, glucose management indicator, average glucose, CGM utilization rate, and glucose variability. Metrics were evaluated for statistical significance using the Wilcoxon signed-rank test and descriptive statistics. RESULTS: Pharmacists enrolled 36 patients in this study with 20 patients completing the full 3-month study period per protocol. There was a statistically significant improvement in three of eight glycemic metrics (very high TAR, TIR, and average glucose). Specifically, TIR had the largest improvement from 61.8% pre-enrollment to 69.9% (P < 0.006) postenrollment. All other pertinent glycemic metrics displayed improvements but were not statistically significant. CONCLUSION: The results demonstrate clinically and statistically significant improvements in several glycemic metrics for patients who participated in the community pharmacist-led remote CGM monitoring service, which may result in improved diabetes control and fewer long-term diabetes-related health complications.

Machine Learning as a Tool for Early Detection: A Focus on Late-Stage Colorectal Cancer across Socioeconomic Spectrums.

PURPOSE: To assess the efficacy of various machine learning (ML) algorithms in predicting late-stage colorectal cancer (CRC) diagnoses against the backdrop of socio-economic and regional healthcare disparities. METHODS: An innovative theoretical framework was developed to integrate individual- and census tract-level social determinants of health (SDOH) with sociodemographic factors. A comparative analysis of the ML models was conducted using key performance metrics such as AUC-ROC to evaluate their predictive accuracy. Spatio-temporal analysis was used to identify disparities in late-stage CRC diagnosis probabilities. RESULTS: Gradient boosting emerged as the superior model, with the top predictors for late-stage CRC diagnosis being anatomic site, year of diagnosis, age, proximity to superfund sites, and primary payer. Spatio-temporal clusters highlighted geographic areas with a statistically significant high probability of late-stage diagnoses, emphasizing the need for targeted healthcare interventions. CONCLUSIONS: This research underlines the potential of ML in enhancing the prognostic predictions in oncology, particularly in CRC. The gradient boosting model, with its robust performance, holds promise for deployment in healthcare systems to aid early detection and formulate localized cancer prevention strategies. The study's methodology demonstrates a significant step toward utilizing AI in public health to mitigate disparities and improve cancer care outcomes.

Integrating MOUD and Primary Care: Outcomes of a Multicenter Learning Collaborative.

BACKGROUND AND OBJECTIVES: Opioid use and overdose remain a central and worsening public health emergency in the United States and abroad. Efforts to expand treatment have struggled to match the rising incidence of opioid use disorder (OUD), and treating patients in primary care settings represents one of the most promising opportunities to meet this need. Learning collaboratives (LCs) are one evidence-based strategy to improve implementation of medication treatment for opioid use disorder (MOUD) in primary care. METHODS: We developed and studied a multidisciplinary MOUD learning collaborative involving six underserved primary care clinics. We used a mixed-methods approach to assess needs, develop curriculum, and evaluate outcomes from these clinics. RESULTS: We recruited six clinics to participate in the collaborative. Half had an established MOUD program. Approximately 80% of participants achieved their organizational quality improvement goals for the collaborative. After the collaborative, participants also reported a significant increase in their perceived competence to implement/improve a MOUD program (pre-LC competence=2.80, post-LC competence=6.33/10, P=.02). The most consistent barrier we identified was stigma around OUD and its effects on patients' ability to access services and staff/provider ability to provide services. The most frequent enablers of program success were trainee interest, organizational leadership support, and a dedicated MOUD care team. CONCLUSIONS: Organizations used clinical and systems improvement knowledge to enhance their existing programs or to take steps to create new programs. All participants identified the need for additional staff/clinician training, especially to overcome stigma around OUD. The outcomes demonstrated the crucial importance of long-term organizational support for program success.

A Review of the Literature for Individualizing Women's Care Through Breast Cancer Risk Assessment.

Breast cancer is well recognized as a leading type of cancer affecting women in the United States. Although breast cancer screening is well supported in the literature, there is a lack of clear agreement regarding which breast cancer risk calculating tools should be used to develop personalized screening regimens. In this review of 11 primary articles published from 2017 through 2022, we assess current evidence on breast cancer risk assessment in outpatient clinic and mammography settings and the pivotal role of health care providers in influencing patients' choices regarding individualized screenings. Risk assessment is strongly recommended by multiple clinical practice guidelines, yet there is inadequate evidence to endorse one risk assessment tool as best practice. Further research is needed to integrate risk assessment within the clinic workflow and screening encounters. Patient-centered communication and shared decision-making are critical components for managing each woman's perceived risk and objective risk for breast cancer.

Creating research-ready partnerships: the initial development of seven implementation laboratories to advance cancer control.

BACKGROUND: In 2019-2020, with National Cancer Institute funding, seven implementation laboratory (I-Lab) partnerships between scientists and stakeholders in 'real-world' settings working to implement evidence-based interventions were developed within the Implementation Science Centers in Cancer Control (ISC3) consortium. This paper describes and compares approaches to the initial development of seven I-Labs in order to gain an understanding of the development of research partnerships representing various implementation science designs. METHODS: In April-June 2021, members of the ISC3 Implementation Laboratories workgroup interviewed research teams involved in I-Lab development in each center. This cross-sectional study used semi-structured interviews and case-study-based methods to collect and analyze data about I-Lab designs and activities. Interview notes were analyzed to identify a set of comparable domains across sites. These domains served as the framework for seven case descriptions summarizing design decisions and partnership elements across sites. RESULTS: Domains identified from interviews as comparable across sites included engagement of community and clinical I-Lab members in research activities, data sources, engagement methods, dissemination strategies, and health equity. The I-Labs use a variety of research partnership designs to support engagement including participatory research, community-engaged research, and learning health systems of embedded research. Regarding data, I-Labs in which members use common electronic health records (EHRs) leverage these both as a data source and a digital implementation strategy. I-Labs without a shared EHR among partners also leverage other sources for research or surveillance, most commonly qualitative data, surveys, and public health data systems. All seven I-Labs use advisory boards or partnership meetings to engage with members; six use stakeholder interviews and regular communications. Most (70%) tools or methods used to engage I-Lab members such as advisory groups, coalitions, or regular communications, were pre-existing. Think tanks, which two I-Labs developed, represented novel engagement approaches. To disseminate research results, all centers developed web-based products, and most (n = 6) use publications, learning collaboratives, and community forums. Important variations emerged in approaches to health equity, ranging from partnering with members serving historically marginalized populations to the development of novel methods. CONCLUSIONS: The development of the ISC3 implementation laboratories, which represented a variety of research partnership designs, offers the opportunity to advance understanding of how researchers developed and built partnerships to effectively engage stakeholders throughout the cancer control research lifecycle. In future years, we will be able to share lessons learned for the development and sustainment of implementation laboratories.

A Retrospective Analysis of Preclinical and Clinical Pharmacokinetics from Administration of Long-Acting Aqueous Suspensions.

Administration of long-acting injectable suspensions is an increasingly common approach to increasing patient compliance and improving therapeutic efficacy through less frequent dosing. While several long-acting suspensions have recently been marketed, parameters modulating drug absorption from suspension-based formulations are not well understood. Further, methods for predicting clinical pharmacokinetic data from preclinical studies are not well established. Together, these limitations hamper compound selection, formulation design and formulation selection through heavy reliance on iterative optimization in preclinical and clinical studies. This article identifies key parameters influencing absorption from suspension-based formulations through compilation and analysis of preclinical and clinical pharmacokinetic data of seven compounds marketed as suspensions; achievable margins for predicting the clinical dose and input rate from preclinical studies as a function of the preclinical species, the clinical injection location and the intended therapeutic duration were also established.

The effect of outer-sphere anions on the spectroscopic response of metal-binding chemosensors.

Ion pair receptors typically contain two separate binding sites, for the metal and the anion respectively. Here we report a less synthetically demanding approach, whereby we prepared a family of ion pair sensors based on a rhodamine fluorescent scaffold containing a tunable cation binding motif. When exposed to ion pairs, a competition for the metal ion is established between these ligands and anions. Structural and spectroscopic evidence showed that anions bind through weaker secondary interactions in the metal's outer coordination sphere and their presence influences the optical spectroscopic properties of the coordination complex in distinctive ways. The relationship between the binding site's metal affinity and its tunable properties, and the sensors' discriminatory power for anions was explained as a function of the metal ion's binding preferences. These effects were also exploited to discriminate cations and anions concurrently through multivariate data analysis methods.

The N-linker region of hERG1a upregulates hERG1b potassium channels.

A major physiological role of hERG1 (human Ether-á-go-go-Related Gene 1) potassium channels is to repolarize cardiac action potentials. Two isoforms, hERG1a and hERG1b, associate to form the potassium current IKr in cardiomyocytes. Inherited mutations in hERG1a or hERG1b cause prolonged cardiac repolarization, long QT syndrome, and sudden death arrhythmia. hERG1a subunits assemble with and enhance the number of hERG1b subunits at the plasma membrane, but the mechanism for the increase in hERG1b by hERG1a is not well understood. Here, we report that the hERG1a N-terminal region expressed in trans with hERG1b markedly increased hERG1b currents and increased biotin-labeled hERG1b protein at the membrane surface. hERG1b channels with a deletion of the N-terminal 1b domain did not have a measurable increase in current or biotinylated protein when coexpressed with hERG1a N-terminal regions, indicating that the 1b domain was required for the increase in hERG1b. Using a biochemical pull-down interaction assay and a FRET hybridization experiment, we detected a direct interaction between the hERG1a N-terminal region and the hERG1b N-terminal region. Using engineered deletions and alanine mutagenesis, we identified a short span of amino acids at positions 216 to 220 within the hERG1a "N-linker" region that were necessary for the upregulation of hERG1b. We propose that direct structural interactions between the hERG1a N-linker region and the hERG1b 1b domain increase hERG1b at the plasma membrane. Mechanisms regulating hERG1a and hERG1b are likely critical for cardiac function, may be disrupted by long QT syndrome mutants, and serve as potential targets for therapeutics.

The evaluation of mandatory alerts on long-acting opioid prescriptions and the use of a community pharmacy naloxone protocol.

BACKGROUND: Opioid overdose deaths accounted for approximately 69.5% of the total drug overdoses in the United States in 2018. In the same year, the Centers for Disease Control and Prevention estimates that around 9 million opportunities to dispense naloxone to high-risk patients were missed. Community pharmacists are equipped to help all patients obtain naloxone to prevent opioid-related overdoses. OBJECTIVES: The purpose of this study was to determine the impact of mandatory alerts on the dispensing of naloxone by pharmacists using a physician-approved protocol. The primary objective of this study was to evaluate the change in the number of dispensed naloxone prescriptions via physician-approved protocol compared with the same time period in the previous year. The secondary objective was to evaluate the pharmacists' knowledge and confidence dispensing naloxone via physician-approved protocol. PRACTICE DESCRIPTION: A system-generated mandatory alert that prompted pharmacists to assess the need for naloxone and initiate and dispense as appropriate via a physician-approved protocol was implemented in 5 pharmacies of a large community pharmacy chain between June and July 2020. PRACTICE INNOVATION: A technology enhancement was designed that automatically created a mandatory alert in the pharmacy management system for all patients who were dispensed a long-acting opioid medication to prompt pharmacists to initiate and dispense naloxone as appropriate. EVALUATION METHODS: The impact of the mandatory alert was evaluated by assessing patients' medication fill history in the pharmacy management system to determine the change in naloxone prescriptions dispensed. RESULTS: During the intervention period, pharmacists initiated and dispensed 34 incremental naloxone prescriptions via a physician-approved protocol compared with the same time period in the previous year. CONCLUSION: The results illustrated that system-generated mandatory alerts prompting pharmacist intervention can effectively increase pharmacist utilization of a physician-approved protocol, resulting in increased naloxone prescriptions dispensed to high-risk patients.