Closed Treatment of the Internal Nasal Valve.

The internal nasal valve, the narrowest portion of the nasal airway, is prone to collapse and is often targeted for improvement in nasal reconstruction and rhinoplasty. Endonasal techniques can reduce surrounding trauma and reduce operative times compared to traditional open methods. Options include the use of spreader, butterfly and alar batten grafts, suspension and flaring sutures, and Z-plasty for scarring.

Development and Optimization of Oligonucleotide Ligation Assay (OLA) Probes for Detection of HIV-1 Resistance to Dolutegravir.

The WHO currently recommends dolutegravir (DTG)-based ART for persons living with HIV infection in resource-limited-settings (RLS). To expand access to testing for HIV drug resistance (DR) to DTG in RLS, we developed probes for use in the oligonucleotide ligation assay (OLA)-Simple, a near-point of care HIV DR kit. Genotypic data from clinical trials and case reports were used to determine the mutations in HIV-1 integrase critical to identifying individuals with DTG-resistance at virologic failure of DTG-based ART.

Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging.

Impact of Human Immunodeficiency Virus Drug Resistance Mutations Detected in Women Prior to Antiretroviral Therapy With Efavirenz + Tenofovir Disoproxil Fumarate + Lamivudine (or Emtricitabine).

Background: Two large studies suggest that resistance mutations to only nonnucleoside reverse transcriptase inhibitors (NNRTI) did not increase the risk of virologic failure during antiretroviral therapy (ART) with efavirenz/tenofovir disoproxil fumarate/lamivudine (or emtricitabine). We retrospectively evaluated a third cohort to determine the impact of NNRTI resistance on the efficacy of efavirenz-based ART.

Methods: Postpartum women living with human immunodeficiency virus (HIV) were studied if they initiated efavirenz-based ART because of the World Health Organization's recommendation for universal ART.

Structured bubbling in vibrated gas-fluidized beds of binary granular particles: experiments and simulations.

Mixing and segregation of granular particles on the basis of size and density from vertical vibration or upward gas flow is critical to a wide range of industrial, agricultural and natural processes. Recently, combined vibration and gas flow under certain conditions has been shown to create periodically repeating structured bubbling patterns within a fluidized bed of spherical, monodisperse particles. Here, we demonstrate with experiments and simulations that structured bubbling can form in binary mixtures of particles with different size and density, but with similar minimum fluidization velocities.

Vayu bubble continuous positive airway pressure is a promising solution with favorable treatment outcomes for respiratory distress syndrome in newborns: a qualitative study in Bangladesh.

Background: According to Bangladesh Demographic and Health Survey (2022), neonatal mortality, comprising 67% of under-5 deaths in Bangladesh, is significantly attributed to prematurity and low birth weight (LBW), accounting for 32% of neonatal deaths. Respiratory distress syndrome (RDS) is a prevalent concern among preterm and LBW infants, leading to substantial mortality. The World Health Organization (WHO) recommends bubble continuous positive airway pressure (bCPAP) therapy, but the affordability and accessibility of conventional bCPAP devices for a large number of patients become major hurdles in Bangladesh due to high costs and resource intensiveness.

Listening Sessions to Shape the Innovative NIH ComPASS Common Fund Program to Advance Health Equity.

The National Institutes of Health (NIH) recognized the need for a research program to address the underlying structural factors that impact health. To inform the development of the NIH Common Fund Community Partnerships to Advance Science for Society (ComPASS) Program, NIH obtained input through community listening sessions. Through its design, ComPASS recognizes the essential role of community organizations as the lead in addressing persistent structural and social challenges to accelerate progress toward advancing health equity.

Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease.

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor.

Management of Idiopathic Vocal Process Granuloma: A Survey of Academic Laryngologists.

Objectives: Vocal process granulomas (VPGs) are benign laryngeal lesions that may manifest as ulcerated regions of the vocal fold or nodular polypoid lesions. Gold standard treatments for idiopathic VPG are yet to be established at this time. This study evaluated clinical decision-making and outcomes in the treatment of VPG patients based on experiences of academic laryngologists across the United States.

Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial.

Background: Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1.

Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation.

Faraday wave instability analog in vibrated gas-fluidized granular particles.

Granular materials are critical to many natural and industrial processes, yet the chaotic flow behavior makes granular dynamics difficult to understand, model, and control, causing difficulties for natural disaster mitigation as well as scale-up and optimization of industrial devices. Hydrodynamic instabilities in externally excited grains often resemble those in fluids, but have different underlying mechanisms, and these instabilities provide a pathway to understand geological flow patterns and control granular flows in industry. Granular particles subject to vibration have been shown to exhibit Faraday waves analogous to those in fluids; however, waves can only form at high vibration strengths and in shallow layers.

Evaluating Spray Drying and Co-Precipitation as Manufacturing Processes for Amorphous Solid Dispersions of a Low T API.

Amorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (T) can pose challenges to this approach.

What we talk about when we talk about the long-term carbon cycle.

The terrestrial biota is a crucial part of the long-term carbon cycle via the deposition of biomass as coal and other sedimentary organic matter and the impact of plants, fungi, and microbial life on the weathering of silicate minerals. Understanding these processes and their changes through time requires both geochemical modeling of the system as well as expertise in the living and fossil biotas and their ecological interactions, but details of these components are often lost in translation between disciplines. Here, we highlight misconceptions of the long-term carbon cycle that most frequently infiltrate the literature and hamper progress: mass balance requirements, the nature and duration of perturbations, opposing timescale constraints on biological and geological processes, and the role of models.

The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria.

Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX).

Do Misconceptions About Health-Related Quality of Life Affect General Population Valuations of Health States?

Objectives: Healthcare resource allocation decisions are often informed by the expected gains in patients' quality-adjusted life-years. Misconceptions about ill-health's consequences for quality of life (QOL) may however affect evaluations of health states by the general population and hence affect resource allocation decisions informed by quality-adjusted life-years. We examine whether people selectively misestimate the QOL consequences of moderate anxiety or depression compared with other dimensions of health, and we test whether informing people of actual changes in QOL associated with health states changes appraisals of their relative undesirability.

Assessment of minority frequency pretreatment HIV drug-resistant variants in pregnant women and associations with virologic non-suppression at term.

Objective: To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term.

Design: A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls.

Methods: HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing.

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus.

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus . Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M.

Nitrogen-based symbioses, phosphorus availability, and accounting for a modern world more productive than the Paleozoic.

Evolution of high-productivity angiosperms has been regarded as a driver of Mesozoic ecosystem restructuring. However, terrestrial productivity is limited by availability of rock-derived nutrients such as phosphorus for which permanent increases in weathering would violate mass balance requirements of the long-term carbon cycle. The potential reality of productivity increases sustained since the Mesozoic is supported here with documentation of a dramatic increase in the evolution of nitrogen-fixing or nitrogen-scavenging symbioses, including more than 100 lineages of ectomycorrhizal and lichen-forming fungi and plants with specialized microbial associations.

Simultaneous monitoring of HIV viral load and screening of SARS-CoV-2 employing a low-cost RT-qPCR test workflow.

The COVID-19 pandemic interrupted routine care for individuals living with HIV, putting them at risk of virologic failure and HIV-associated illness. Often this population is at high risk for exposure to SARS-CoV-2 infection, and once infected, for severe disease. Therefore, close monitoring of HIV plasma viral load (VL) and screening for SARS-CoV-2 infection are needed.

A Rayleigh-Bénard convection instability analog in vibrated gas-fluidized granular particles.

Granular particles subject to both vertical gas flow and vertical vibration are shown experimentally to exhibit structured convection cells in a densely packed yet fluidized state without gas voids traveling through the particles. Continuum gas-granular simulations reproduce the phenomenon and demonstrate that the convection occurs due to buoyant force arising from a positive vertical gradient in bulk solid density competing with viscous force created by interparticle friction. Simulations further show that convection structures persist in a controllable manner when increasing system width.

Analysis of Population Differences in Digital Conversations About Cancer Clinical Trials: Advanced Data Mining and Extraction Study.

Background: Racial and ethnic diversity in clinical trials for cancer treatment is essential for the development of treatments that are effective for all patients and for identifying potential differences in toxicity between different demographics. Mining of social media discussions about clinical trials has been used previously to identify patient barriers to enrollment in clinical trials; however, a comprehensive breakdown of sentiments and barriers by various racial and ethnic groups is lacking.

Objective: The aim of this study is to use an innovative methodology to analyze web-based conversations about cancer clinical trials and to identify and compare conversation topics, barriers, and sentiments between different racial and ethnic populations.