Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.

Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.

Closing the Last Mile Gap in Access to Multimodality Imaging in Rural Settings: Design of the Imaging Core of the Risk Underlying Rural Areas Longitudinal Study.

Achieving optimal cardiovascular health in rural populations can be challenging for several reasons including decreased access to care with limited availability of imaging modalities, specialist physicians, and other important health care team members. Therefore, innovative solutions are needed to optimize health care and address cardiovascular health disparities in rural areas. Mobile examination units can bring imaging technology to underserved or remote communities with limited access to health care services. Mobile examination units can be equipped with a wide array of assessment tools and multiple imaging modalities such as computed tomography scanning and echocardiography. The detailed structural assessment of cardiovascular and lung pathology, as well as the detection of extracardiac pathology afforded by computed tomography imaging combined with the functional and hemodynamic assessments acquired by echocardiography, yield deep phenotyping of heart and lung disease for populations historically underrepresented in epidemiological studies. Moreover, by bringing the mobile examination unit to local communities, innovative approaches are now possible including engagement with local professionals to perform these imaging assessments, thereby augmenting local expertise and experience. However, several challenges exist before mobile examination unit-based examinations can be effectively integrated into the rural health care setting including standardizing acquisition protocols, maintaining consistent image quality, and addressing ethical and privacy considerations. Herein, we discuss the potential importance of cardiac multimodality imaging to improve cardiovascular health in rural regions, outline the emerging experience in this field, highlight important current challenges, and offer solutions based on our experience in the RURAL (Risk Underlying Rural Areas Longitudinal) cohort study.

New Tridentate Ligand Affords a Long-Lived 3MLCT Excited State in a Ru(II) Complex: DNA Photocleavage and 1O2 Production.

Two new complexes, [Ru(tpy)(qdppz)](PF6)2 (1; qdppz = 2-(quinolin-8-yl)dipyrido[3,2-a:2',3'-c]phenazine, tpy = 2,2':6',2″-terpyridine) and [Ru(qdppz)2](PF6)2 (2), were investigated for their potential use as phototherapeutic agents through their ability to photosensitize the production of singlet oxygen, 1O2, upon irradiation with visible light. The complexes exhibit strong Ru(dπ) → qdppz(π*) metal-to-ligand charge transfer (MLCT) absorption with maxima at 485 and 495 nm for 1 and 2 in acetone, respectively, red-shifted from the Ru(dπ) → tpy(π*) absorption at 470 nm observed for [Ru(tpy)2]2+ (3) in the same solvent. Complexes 1 and 3 are not luminescent at room temperature, but 3MLCT emission is observed for 2 with maximum at 690 nm (λexc = 480 nm) in acetone. The lifetimes of the 3MLCT states of 1 and 2 were measured using transient absorption spectroscopy to be ∼9 and 310 ns in methanol, respectively, at room temperature (λexc = 490 nm). The bite angle of the qdppz ligand is closer to octahedral geometry than that of tpy, resulting in the longer lifetime of 2 as compared to those of 1 and 3. Arrhenius treatment of the temperature dependence of the luminescence results in similar activation energies, Ea, from the 3MLCT to the 3LF (ligand-field) state for the two complexes, 2520 cm-1 in 1 and 2400 cm-1 in 2. However, the pre-exponential factors differ by approximately two orders of magnitude, 2.3 × 1013 s-1 for 1 and 1.4 × 1011 s-1 for 2, which, together with differences in the Huang-Rhys factors, lead to markedly different 3MLCT lifetimes. Although both 1 and 2 intercalate between the DNA bases, only 2 is able to photocleave DNA owing to its 1O2 production upon irradiation with ΦΔ = 0.69. The present work highlights the profound effect of the ligand bite angle on the electronic structure, providing guidelines for extending the lifetime of 3MLCT Ru(II) complexes with tridentate ligands, a desired property for a number of applications.

Considerations for Cell and Gene Therapy Programs Entering the Clinical Space.

Cell and gene therapy (CGT) describes a broad category of medicinal products with potential applications to prevent and treat human disease in multiple therapeutic areas. These therapies leverage the use of modified nucleic acids, altered cells or tissue, or both. The modality, mechanism, route of administration, and therapeutic indication for a CGT product will influence the challenges and opportunities for early clinical development, some of which may be highly specific to the product under consideration. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) encourage early interaction between sponsor and health authority to align on key elements of the CGT development program.

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

BACKGROUND: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP). SETTING: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal. RESULTS: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6  cells) were above the PK threshold for all dose levels. CONCLUSION: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1.

Solvent effects on the photooxidation of indolepyrazines.

Photodestruction of 2-(pyrazin-2'-yl)-1H-indole and 2,5-di(1H-indol-2'-yl)pyrazine involves singlet oxygen generation and its rapid insertion into the indole ring with the formation of benzoxazinone derivatives: 2-(pyrazin-2-yl)-4H-3,1-benzoxazin-4-one and 2-[5-(1H-indol-2-yl)pyrazin-2-yl]-4H-3,1-benzoxazin-4-one. The quantum yield of this reaction strongly depends on the environment. It is definitely smaller in protic methanol than in aprotic acetonitrile or n-hexane. The observed effect of photostabilization is explained by formation of hydrogen bonded complexes between the chromophore and alcohol, which results in lower triplet formation efficiency and, in consequence, decrease of singlet oxygen formation quantum yield.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency.

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and to healthy individuals without renal impairment (matched control group; eGFR ≥90 mL/min/1.73 m2). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC0-∞) were ~2-fold and ~5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC0-∞ was ~1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function. (This study has been registered at ClinicalTrials.gov under registration no. NCT04303156.).

Electrocatalytic CO2 Reduction by Molecular Ruthenium Complexes with Polypyridyl Ligands.

Two series of ruthenium complexes with various polypyridyl ligands have been prepared. One series of complexes (5 examples) are featured with tetradentate polypyridyl ligands and two acetonitrile molecules at the axial positions of the coordination sphere; the other series (3 examples) include combinations of a tridentate polypyridyl ligand, one 2,2'-bipyridine (bpy) or two picolines, and one acetonitrile ligand. All these complexes were fully characterized by their NMR spectra as well as X-ray single crystal structures. Their electronic absorption and redox data were measured and reported. Of the 8 complexes, three candidates effectively catalyze electrochemical CO2 reduction reaction (CO2 RR) in wet acetonitrile medium, generating CO as the major product. All these three catalytically active complexes contain a 2,2':6',2'':6'',2'''-quaterpyridine (qpy) ligand scaffold. A maximum turnover frequency (TOFmax ) of>1000 s-1 was achieved for the electrocatalytic CO2 reduction at a modest overpotential. On the basis of electrochemical and spectroelectrochemical evidences, the CO2 substrate was proposed to bind with the ruthenium center at the two-electron reduced state of the complex and then entered the catalytic cycle.

Metalloimmunotherapy with Rhodium and Ruthenium Complexes: Targeting Tumor-Associated Macrophages.

Tumor associated macrophages (TAMs) suppress the cancer immune response and are a key target for immunotherapy. The effects of ruthenium and rhodium complexes on TAMs have not been well characterized. To address this gap in the field, a panel of 22 dirhodium and ruthenium complexes were screened against three subtypes of macrophages, triple-negative breast cancer and normal breast tissue cells. Experiments were carried out in 2D and biomimetic 3D co-culture experiments with and without irradiation with blue light. Leads were identified with cell-type-specific toxicity toward macrophage subtypes, cancer cells, or both. Experiments with 3D spheroids revealed complexes that sensitized the tumor models to the chemotherapeutic doxorubicin. Cell surface exposure of calreticulin, a known facilitator of immunogenic cell death (ICD), was increased upon treatment, along with a concomitant reduction in the M2-subtype classifier arginase. Our findings lay a strong foundation for the future development of ruthenium- and rhodium-based chemotherapies targeting TAMs.

Incorporating protein precipitation to resolve hybrid IP-LC-MS assay interference for ultrasensitive quantification of intact therapeutic insulin dimer in human plasma.

For pharmacokinetics characterization of a therapeutic insulin dimer, an ultrasensitive plasma method was required due to the expected low circulating levels in humans. A bioanalytical strategy combining immunoprecipitation enrichment with liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis of the intact protein offers the opportunity to resolve the analyte from endogenous and exogenous insulin and insulin analogs. Nonetheless, interference from complex background matrix was observed limiting reliable measurements at the low concentration range. A sample preparation approach incorporating protein precipitation and immunoprecipitation was developed and optimized to further reduce sample complexity prior to LC-MS/MS analysis. This approach enabled a deeper level of selectivity and presented a cleaner mass spectrometric detection that may otherwise be confounded. Sample preparation was automated to allow high throughput analysis. The method reached a limit of quantitation at 0.3 ng/mL (25 pM), and a linear dynamic range from 0.3 to 300 ng/mL. Results were highly reproducible, with intra-day and inter-day precision and bias below 11%. Furthermore, the organic solvent treatment involved in protein precipitation is expected to improve assay resistance to the bias introduced by endogenous protein binding such as that exerted by anti-drug antibodies. The method was successfully applied to support clinical pharmacokinetics studies. This approach may potentially be adapted to bioanalysis of low abundance proteins.

A phase 1, open-label study to evaluate the drug interaction between islatravir (MK-8591) and the oral contraceptive levonorgestrel/ethinyl estradiol in healthy adult females.

INTRODUCTION: Hormonal contraceptives are among the most effective forms of reversible contraception, but many other compounds, including some antiretrovirals, have clinically meaningful drug-drug interactions (DDIs) with hormonal contraceptives. Islatravir is a novel human immunodeficiency virus nucleoside reverse transcriptase translocation inhibitor currently in clinical development for treatment and prevention of HIV infection. A phase 1 clinical trial was conducted to evaluate the DDI of islatravir and the combination of oral contraceptive levonorgestrel (LNG)/ethinyl estradiol (EE). METHODS: This was an open-label, two-period, fixed-sequence, DDI clinical trial in healthy, postmenopausal or bilaterally oophorectomized females aged 18 through 65 years in the United States between October 2016 and January 2017. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7-day washout. Islatravir, 20 mg, was then dosed once weekly for 3 weeks; a single dose of LNG 0.15 mg/EE 0.03 mg was given concomitantly with the third dose of islatravir. Pharmacokinetic samples for plasma LNG and EE concentrations were collected pre-dose and up to 120 hours post-dose in each period. Safety and tolerability were assessed throughout the trial by clinical assessments, laboratory evaluations and examination of adverse events. RESULTS AND DISCUSSION: Fourteen participants were enrolled. The pharmacokinetics of LNG and EE were not meaningfully altered by co-administration with islatravir. For the comparison of (islatravir + LNG/EE)/(LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for LNG AUC0-inf and Cmax were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE, the GMRs (90% CI) for AUC0-inf and Cmax were 1.05 (0.981, 1.11) and 1.02 (0.971, 1.08), respectively. Co-administration of all three drugs was generally well tolerated. CONCLUSIONS: The results of this trial support the use of LNG/EE contraceptives in combination with islatravir without dose adjustment.

Electrocatalytic Hydrogen Evolution by Cobalt Complexes with a Redox Non-Innocent Polypyridine Ligand.

Novel cobalt and zinc complexes with the tetradentate ppq (8-(1″,10″-phenanthrol-2″-yl)-2-(pyrid-2'-yl)quinoline) ligand have been synthesized and fully characterized. Electrochemical measurements have shown that the formal monovalent complex [Co(ppq)(PPh3)]+ (2) undergoes two stepwise ligand-based electroreductions in DMF, affording a [Co(ppq)DMF]-1 species. Theoretical calculations have described the electronic structure of [Co(ppq)DMF]-1 as a low-spin Co(II) center coupling with a triple-reduced ppq radical ligand. In the presence of triethylammonium as the proton donor, the cobalt complex efficiently drives electrocatalytic hydrogen evolution with a maximum turnover frequency of thousands per second. A mechanistic investigation proposes an EECC H2-evolving pathway, where the second ligand-based redox process (E), generating the [Co(ppq)DMF]-1 intermediate, initiates proton reduction, and the second proton transfer process (C) is the rate-determining step. This work provides a unique example for understanding the role of redox-active ligands in electrocatalytic H2 evolution by transition metal sites.

Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV.

BACKGROUND: Islatravir (MK-8591) is a novel nucleoside analog in development for the treatment and prevention of HIV-1 infection. Islatravir has potent antiviral activity and a long intracellular half-life. SETTING: A 3-panel, randomized, double-blind, placebo-controlled, multiple-dose study in 36 adults without HIV evaluated the safety, tolerability, and pharmacokinetics of islatravir after daily administration. METHODS: Islatravir or placebo was administered orally once daily for 42 days (5 mg) or 28 days (0.25 mg; 0.75 mg). Blood samples were taken at prespecified time points for pharmacokinetic analysis of islatravir (plasma) and islatravir-triphosphate (ISL-TP; peripheral blood mononuclear cells [PBMCs]). Rectal and vaginal tissue samples were also collected in a subset of participants. Safety and tolerability were evaluated throughout. RESULTS: The pharmacokinetics of islatravir were approximately dose proportional, with concentrations approaching a steady state between days 14 and 21 in plasma and by day 28 for ISL-TP in PBMCs. Plasma exposure accumulation was 1.5-fold to 1.8-fold, and ISL-TP exposure accumulation was ∼10-fold. The apparent terminal half-life of ISL-TP was 177-209 hours. The ISL-TP pharmacokinetic trough threshold-the minimal concentration required for efficacy-of 0.05 pmol/106 cells was achieved after a single administration at all dose levels. Rectal and vaginal tissue also exhibited potentially therapeutic concentrations. Islatravir was generally well tolerated at all doses. CONCLUSIONS: ISL-TP levels in PBMCs were above the threshold projected for antiviral efficacy against wild-type HIV after a single 0.25-mg dose. Multiple once-daily dosing of islatravir in adults without HIV was generally well tolerated up to doses of 5 mg administered for up to 6 weeks.

Lack of a Clinically Meaningful Drug Interaction Between the HIV-1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate.

Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. Because islatravir may be coadministered with other antiretroviral agents, assessment of potential drug-drug interactions are warranted. This phase 1, open-label, fixed-sequence, 2-period trial in adults without HIV (N = 12) assessed the safety and pharmacokinetic interactions of islatravir administered with dolutegravir and tenofovir disoproxil fumarate (TDF). In period 1, participants received a single oral dose of islatravir (20 mg). In period 2, participants received oral doses of dolutegravir (50 mg) and TDF (300 mg) once daily on days 1 through 11, with a single oral dose of islatravir (20 mg) coadministered on day 8. There were no clinically significant changes in islatravir, dolutegravir, or TDF pharmacokinetics following coadministration. Islatravir was generally well tolerated when administered alone or in combination with dolutegravir and TDF. Coadministration of islatravir, dolutegravir, and TDF is supported, with no clinically meaningful effect on pharmacokinetics, safety, or tolerability in participants without HIV.

Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial.

Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.

Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.

Islatravir (MK-8591) is a nucleoside analogue in development for the treatment and prevention of HIV-1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18-60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir-triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high-fat meal. In Study 2, 8 participants per dose received 3 once-weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well-tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half-life was 49-61 h; intracellular islatravir-triphosphate half-life was 118-171 h. Plasma exposure increased in an approximately dose-proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir-triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir-triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

Deep Learning-Based Automated Echocardiographic Quantification of Left Ventricular Ejection Fraction: A Point-of-Care Solution.

BACKGROUND: We have recently tested an automated machine-learning algorithm that quantifies left ventricular (LV) ejection fraction (EF) from guidelines-recommended apical views. However, in the point-of-care (POC) setting, apical 2-chamber views are often difficult to obtain, limiting the usefulness of this approach. Since most POC physicians often rely on visual assessment of apical 4-chamber and parasternal long-axis views, our algorithm was adapted to use either one of these 3 views or any combination. This study aimed to (1) test the accuracy of these automated estimates; (2) determine whether they could be used to accurately classify LV function. METHODS: Reference EF was obtained using conventional biplane measurements by experienced echocardiographers. In protocol 1, we used echocardiographic images from 166 clinical examinations. Both automated and reference EF values were used to categorize LV function as hyperdynamic (EF>73%), normal (53%-73%), mildly-to-moderately (30%-52%), or severely reduced (<30%). Additionally, LV function was visually estimated for each view by 10 experienced physicians. Accuracy of the detection of reduced LV function (EF<53%) by the automated classification and physicians' interpretation was assessed against the reference classification. In protocol 2, we tested the new machine-learning algorithm in the POC setting on images acquired by nurses using a portable imaging system. RESULTS: Protocol 1: the agreement with the reference EF values was good (intraclass correlation, 0.86-0.95), with biases <2%. Machine-learning classification of LV function showed similar accuracy to that by physicians in most views, with only 10% to 15% cases where it was less accurate. Protocol 2: the agreement with the reference values was excellent (intraclass correlation=0.84) with a minimal bias of 2.5±6.4%. CONCLUSIONS: The new machine-learning algorithm allows accurate automated evaluation of LV function from echocardiographic views commonly used in the POC setting. This approach will enable more POC personnel to accurately assess LV function.

A Phase 1 Study to Evaluate the Drug Interaction Between Islatravir (MK-8591) and Doravirine in Adults Without HIV.

BACKGROUND AND OBJECTIVES: Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. METHODS: Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. RESULTS: Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0-24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0-24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. CONCLUSION: These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection.

Utility of a Deep-Learning Algorithm to Guide Novices to Acquire Echocardiograms for Limited Diagnostic Use.

Importance: Artificial intelligence (AI) has been applied to analysis of medical imaging in recent years, but AI to guide the acquisition of ultrasonography images is a novel area of investigation. A novel deep-learning (DL) algorithm, trained on more than 5 million examples of the outcome of ultrasonographic probe movement on image quality, can provide real-time prescriptive guidance for novice operators to obtain limited diagnostic transthoracic echocardiographic images. Objective: To test whether novice users could obtain 10-view transthoracic echocardiographic studies of diagnostic quality using this DL-based software. Design, Setting, and Participants: This prospective, multicenter diagnostic study was conducted in 2 academic hospitals. A cohort of 8 nurses who had not previously conducted echocardiograms was recruited and trained with AI. Each nurse scanned 30 patients aged at least 18 years who were scheduled to undergo a clinically indicated echocardiogram at Northwestern Memorial Hospital or Minneapolis Heart Institute between March and May 2019. These scans were compared with those of sonographers using the same echocardiographic hardware but without AI guidance. Interventions: Each patient underwent paired limited echocardiograms: one from a nurse without prior echocardiography experience using the DL algorithm and the other from a sonographer without the DL algorithm. Five level 3-trained echocardiographers independently and blindly evaluated each acquisition. Main Outcomes and Measures: Four primary end points were sequentially assessed: qualitative judgement about left ventricular size and function, right ventricular size, and the presence of a pericardial effusion. Secondary end points included 6 other clinical parameters and comparison of scans by nurses vs sonographers. Results: A total of 240 patients (mean [SD] age, 61 [16] years old; 139 men [57.9%]; 79 [32.9%] with body mass indexes >30) completed the study. Eight nurses each scanned 30 patients using the DL algorithm, producing studies judged to be of diagnostic quality for left ventricular size, function, and pericardial effusion in 237 of 240 cases (98.8%) and right ventricular size in 222 of 240 cases (92.5%). For the secondary end points, nurse and sonographer scans were not significantly different for most parameters. Conclusions and Relevance: This DL algorithm allows novices without experience in ultrasonography to obtain diagnostic transthoracic echocardiographic studies for evaluation of left ventricular size and function, right ventricular size, and presence of a nontrivial pericardial effusion, expanding the reach of echocardiography to clinical settings in which immediate interrogation of anatomy and cardiac function is needed and settings with limited resources.

Imaging the mitral valve: a primer for the interventional surgeon.

Transcatheter mitral valve interventions (TMVI) have evolved over the past decade as alternatives to open surgical repair for the therapeutic management of patients with severe mitral regurgitation (MR). Concurrent with the development of these technologies, quality multi-modality cardiac imaging has become essential in patient selection and procedural guidance. The former involves assessments of the pathophysiologic mechanisms of regurgitation, valvular anatomy and morphology, as well as objective quantification of the severity of MR. Both transthoracic and transesophageal echocardiography (TEE) are crucial and serve as the gateway to diagnosis and management of mitral valvular disease. Along with multi-detector computed tomography (CT) and cardiac magnetic resonance imaging (CMR), echocardiography plays an important role for preprocedural planning and evaluation of the spatial relationships of the mitral valvular complex with the coronary sinus, circumflex coronary artery and left ventricular (LV) outflow tract. Procedures that target mitral leaflets (e.g., MitraClip, PASCAL) or annulus (e.g., Cardioband, Carillon), or provide chordal (e.g., NeoChord, Harpoon) or valvular replacement, tend to be guided by TEE and assisted by fluoroscopy. As newer devices become available and outcomes of TMVI improve, cardiac imaging will undoubtedly continue to play an essential role in the success of percutaneous mitral valve repair (MVr) and replacement. The interventional surgeon of the future must therefore have a thorough understanding of the various imaging modalities while synthesizing and integrating novel concepts (e.g., neo-LV outflow tract) as applicable to assessing valvular function and pathology.