Population screening shows risk of inherited cancer and familial hypercholesterolemia in Oregon.

The Healthy Oregon Project (HOP) is a statewide effort that aims to build a large research repository and influence the health of Oregonians through providing no-cost genetic screening to participants for a next-generation sequencing 32-gene panel comprising genes related to inherited cancers and familial hypercholesterolemia. This type of unbiased population screening can detect at-risk individuals who may otherwise be missed by conventional medical approaches. However, challenges exist for this type of high-throughput testing in an academic setting, including developing a low-cost high-efficiency test and scaling up the clinical laboratory for processing large numbers of samples. Modifications to our academic clinical laboratory including efficient test design, robotics, and a streamlined analysis approach increased our ability to test more than 1,000 samples per month for HOP using only one dedicated HOP laboratory technologist. Additionally, enrollment using a HIPAA-compliant smartphone app and sample collection using mouthwash increased efficiency and reduced cost. Here, we present our experience three years into HOP and discuss the lessons learned, including our successes, challenges, opportunities, and future directions, as well as the genetic screening results for the first 13,670 participants tested. Overall, we have identified 730 pathogenic/likely pathogenic variants in 710 participants in 24 of the 32 genes on the panel. The carrier rate for pathogenic/likely pathogenic variants in the inherited cancer genes on the panel for an unselected population was 5.0% and for familial hypercholesterolemia was 0.3%. Our laboratory experience described here may provide a useful model for population screening projects in other states.

Parent Interventions Improve Behavior After Pediatric Traumatic Brain Injury: A Systematic Review and Meta-analysis.

OBJECTIVE: To examine child behavior change scores from randomized controlled trials (RCTs) of parent interventions for pediatric traumatic brain injury (TBI). METHODS: MEDLINE, EMBASE, PsycINFO, and CINAHL were searched to identify studies that examined parent interventions for pediatric TBI. Inclusion criteria included (i) a parent intervention for children with TBI; (ii) an RCT study design; (iii) statistical data for child behavior outcome(s); and (iv) studies that were published in English. RESULTS: Seven studies met inclusion criteria. All interventions reported improved child behavior after pediatric TBI; however, child and parent factors contributed to behavior change scores in some interventions. Factors found to contribute to the level of benefit included age of child, baseline behavior levels, sociodemographics (eg, parent income, parent education), and parent mental health. CONCLUSION: Improved child behavior outcomes resulting from parent interventions for pediatric TBI are well supported by the evidence in the peer-reviewed literature. Clinicians are encouraged to consider child and parent factors as they relate to child behavior outcomes.

Exploring oculomotor functions in a pilot study with healthy controls: Insights from eye-tracking and fMRI.

Eye-tracking techniques have gained widespread application in various fields including research on the visual system, neurosciences, psychology, and human-computer interaction, with emerging clinical implications. In this preliminary phase of our study, we introduce a pilot test of innovative virtual reality technology designed for tracking head and eye movements among healthy individuals. This tool was developed to assess the presence of mild traumatic brain injury (mTBI), given the frequent association of oculomotor function deficits with such injuries. Alongside eye-tracking, we also integrated fMRI due to the complementary nature of these techniques, offering insights into both neural activation patterns and behavioural responses, thereby providing a comprehensive understanding of oculomotor function. We used fMRI with tasks evaluating oculomotor functions: Smooth Pursuit (SP), Saccades, Anti-Saccades, and Optokinetic Nystagmus (OKN). Prior to the scanning, the testing with a system of VR goggles with integrated eye and head tracking was used where subjects performed the same tasks as those used in fMRI. 31 healthy adult controls (HCs) were tested with the purpose of identifying brain regions associated with these tasks and collecting preliminary norms for later comparison with concussed subjects. HCs' fMRI results showed following peak activation regions: SP-cuneus, superior parietal lobule, paracentral lobule, inferior parietal lobule (IPL), cerebellartonsil (CT); Saccades-middle frontal gyrus (MFG), postcentral gyrus, medial frontal gyrus; Anti-saccades-precuneus, IPL, MFG; OKN-middle temporal gyrus, ACC, postcentral gyrus, MFG, CT. These results demonstrated brain regions associated with the performance on oculomotor tasks in healthy controls and most of the highlighted areas are corresponding with those affected in concussion. This suggests that the involvement of brain areas susceptible to mTBI in implementing oculomotor evaluation, taken together with commonly reported oculomotor difficulties post-concussion, may lead to finding objective biomarkers using eye-tracking tasks.

Challenges of Integrating APOL1 Genetic Test Results into the Electronic Health Record.

OBJECTIVES: Integrating genetic test results into the electronic health record (EHR) is essential for integrating genetic testing into clinical practice. This article describes the organizational challenges of integrating discrete apolipoprotein L1 (APOL1) genetic test results into the EHR for a research study on culturally sensitive genetic counseling for living kidney donors. METHODS: We convened a multidisciplinary team across three institutions (Northwestern University, Northwestern Memorial HealthCare [NMHC], and OHSU Knight Diagnostic Laboratories [KDL]), including researchers, physicians, clinical information technology, and project management. Through a series of meetings over a year between the team and the genetic testing laboratory, we explored and adjusted our EHR integration plan based on regulatory and budgetary constraints. RESULTS: Our original proposal was to transmit results from KDL to NMHC as structured data sent via Health Level Seven (HL7) v2 message. This was ultimately deemed infeasible given the time and resources required to establish the interface, and the low number of samples to be processed for the study (n = 316). We next explored the use of Epic's Care Everywhere interoperability platform, but learned it was not possible as a laboratory test ordered for a research study; even though our intent was to study the APOL1 genetic test result's clinical use and impact, test results were still considered "research results." Faced with two remaining options-downloading a PDF from the KDL laboratory portal or scanning a faxed result from KDL-only a PDF of the APOL1 test result could be integrated into the EHR, reinforcing the status quo. CONCLUSION: Even with early and ongoing stakeholder engagement, dedicated project management, and funding, unanticipated implementation challenges-especially for research projects-can result in drastic design tradeoffs.

Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment.

Hepatic and renal insufficiency due to co-infection, alcoholism, diabetes mellitus, family history, adverse effects of antiretrovirals and other factors are commonly seen in HIV-infected patients. Therefore, the use of antiretrovirals in this patient setting requires attention to the pharmacokinetic issues that clinicians must consider when prescribing highly active antiretroviral therapy for these patients. This review summarizes the current knowledge of the use of antiretrovirals in patients with hepatic or renal impairment, and makes dosing recommendations for this subpopulation of HIV-infected patients.

Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with fosamprenavir-ritonavir in opioid-dependent subjects.

STUDY OBJECTIVE: To compare steady-state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg-ritonavir 100 mg twice/day. DESIGN: Open-label, single-sequence, two-period crossover, drug-interaction study. SETTING: Two university-affiliated research centers. SUBJECTS: Twenty-six opioid-dependent, methadone-maintained, healthy adults. INTERVENTION: Subjects received their usual daily dose of methadone alone for 4 days (period 1). Subjects then received the same daily dose of methadone plus fosamprenavir 700 mg-ritonavir 100 mg twice/day for 14 days (period 2). MEASUREMENTS AND MAIN RESULTS: Blood was collected on days 1-4 (period 1) and on days 11-14 (period 2) for plasma R- and S-methadone concentrations; amprenavir concentrations were assessed during period 2. Opioid-effect measures were assessed in each study period. Subjects served as their own controls for comparison of period 1 with period 2. Coadministration of fosamprenavir-ritonavir with methadone reduced plasma total R-methadone area under the plasma concentration-time curve over the dosing interval at steady state (AUC tau-ss) by 18%, maximum concentration at steady state (Cmax-ss) by 21%, and concentration at the end of the dosing interval at steady state (Ctau-ss) by 11%; time to reach Cmax-ss (Tmax) was delayed by 1.75 hours. Coadministration of fosamprenavir-ritonavir with methadone also reduced plasma total S-methadone AUC tau-ss and Cmax-ss by 43% each, Ctau-ss by 41%, and delayed Tmax by 0.85 hours. Fosamprenavir-ritonavir administered with methadone did not alter plasma amprenavir pharmacokinetics compared with historical control data; nor did it alter the unbound R-methadone at 2 and 6 hours after methadone dosing. Pharmacodynamic indexes remained essentially unchanged after adding fosamprenavir-ritonavir to methadone. No subject demonstrated opioid intoxication or withdrawal, or requested methadone dosage modification. CONCLUSION: No adjustment in the dosages of either methadone or fosamprenavir 700 mg-ritonavir 100 mg twice/day is required during coadministration, on the basis of the small reduction in total R-methadone exposure, no change in unbound R-methadone, no clinically important opioid effects, and no change in amprenavir exposure.

Cyclic nucleotide-gated ion channels in rod photoreceptors are protected from retinoid inhibition.

In vertebrate rods, photoisomerization of the 11-cis retinal chromophore of rhodopsin to the all-trans conformation initiates a biochemical cascade that closes cGMP-gated channels and hyperpolarizes the cell. All-trans retinal is reduced to retinol and then removed to the pigment epithelium. The pigment epithelium supplies fresh 11-cis retinal to regenerate rhodopsin. The recent discovery that tens of nanomolar retinal inhibits cloned cGMP-gated channels at low [cGMP] raised the question of whether retinoid traffic across the plasma membrane of the rod might participate in the signaling of light. Native channels in excised patches from rods were very sensitive to retinoid inhibition. Perfusion of intact rods with exogenous 9- or 11-cis retinal closed cGMP-gated channels but required higher than expected concentrations. Channels reopened after perfusing the rod with cellular retinoid binding protein II. PDE activity, flash response kinetics, and relative sensitivity were unchanged, ruling out pharmacological activation of the phototransduction cascade. Bleaching of rhodopsin to create all-trans retinal and retinol inside the rod did not produce any measurable channel inhibition. Exposure of a bleached rod to 9- or 11-cis retinal did not elicit channel inhibition during the period of rhodopsin regeneration. Microspectrophotometric measurements showed that exogenous 9- or 11-cis retinal rapidly cross the plasma membrane of bleached rods and regenerate their rhodopsin. Although dark-adapted rods could also take up large quantities of 9-cis retinal, which they converted to retinol, the time course was slow. Apparently cGMP-gated channels in intact rods are protected from the inhibitory effects of retinoids that cross the plasma membrane by a large-capacity buffer. Opsin, with its chromophore binding pocket occupied (rhodopsin) or vacant, may be an important component. Exceptionally high retinoid levels, e.g., associated with some retinal degenerations, could overcome the buffer, however, and impair sensitivity or delay the recovery after exposure to bright light.

Drug interactions between proton pump inhibitors and antiretroviral drugs.

Gastroesophageal reflux disease and other related symptoms are common comorbidities for HIV-infected patients. Therefore, concurrent use of proton pump inhibitors and antiretrovirals is a common practice in the clinical setting. However, this practice may alter antiretroviral pharmacokinetics and lead to treatment failure due to inadequate drug exposure. Clinician awareness of these complex interactions is essential for optimal HIV management. This review summarizes the current knowledge on the interactions between proton pump inhibitors and antiretrovirals, and makes recommendations for the coadministration of proton pump inhibitors.

All-trans-retinal is a closed-state inhibitor of rod cyclic nucleotide-gated ion channels.

Rod vision begins when 11-cis-retinal absorbs a photon and isomerizes to all-trans-retinal (ATR) within the photopigment, rhodopsin. Photoactivated rhodopsin triggers an enzyme cascade that lowers the concentration of cGMP, thereby closing cyclic nucleotide-gated (CNG) ion channels. After isomerization, ATR dissociates from rhodopsin, and after a bright light, this release is expected to produce a large surge of ATR near the CNG channels. Using excised patches from Xenopus oocytes, we recently showed that ATR shuts down cloned rod CNG channels, and that this inhibition occurs in the nanomolar range (aqueous concentration) at near-physiological concentrations of cGMP. Here we further characterize the ATR effect and present mechanistic information. ATR was found to decrease the apparent cGMP affinity, as well as the maximum current at saturating cGMP. When ATR was applied to outside-out patches, inhibition was much slower and less effective than when it was applied to inside-out patches, suggesting that ATR requires access to the intracellular surface of the channel or membrane. The apparent ATR affinity and maximal inhibition of heteromeric (CNGA1/CNGB1) channels was similar to that of homomeric (CNGA1) channels. Single-channel and multichannel data suggest that channel inhibition by ATR is reversible. Inhibition by ATR was not voltage dependent, and the form of its dose-response relation suggested multiple ATR molecules interacting per channel. Modeling of the data obtained with cAMP and cGMP suggests that ATR acts by interfering with the allosteric opening transition of the channel and that it prefers closed, unliganded channels. It remains to be determined whether ATR acts directly on the channel protein or instead alters channel-bilayer interactions.

All-trans-retinal shuts down rod cyclic nucleotide-gated ion channels: a novel role for photoreceptor retinoids in the response to bright light?

In retinal rods, light-induced isomerization of 11-cis-retinal to all-trans-retinal within rhodopsin triggers an enzyme cascade that lowers the concentration of cGMP. Consequently, cyclic nucleotide-gated (CNG) ion channels close, generating the first electrical response to light. After isomerization, all-trans-retinal dissociates from rhodopsin. We now show that all-trans-retinal directly and markedly inhibits cloned rod CNG channels in excised patches. 11-cis-retinal and all-trans-retinol also inhibited the channels, but at somewhat higher concentrations. Single-channel analysis suggests that all-trans-retinal reduces average open probability of rod CNG channels by inactivating channels for seconds at a time. At physiological cGMP levels, all-trans-retinal inhibited in the nanomolar range. Our results suggest that all-trans-retinal may be a potent regulator of the channel in rods during the response to bright light, when there is a large surge in the concentration of all-trans-retinal.