CD4 T cell counts are inversely correlated with anti-cluster A antibodies in antiretroviral therapy-treated PLWH.

While antiretroviral therapy efficiently suppresses viral replication, inflammation and immune dysfunction persist in some people living with HIV-1 (PLWH). Soluble gp120 (sgp120) has been detected in PLWH plasma and its presence is linked to immune dysfunction. It was reported that sgp120 binding to CD4 on uninfected bystander CD4 T cells sensitizes them to antibody-dependent cellular-cytotoxicity (ADCC) mediated by non-neutralizing antibodies present in PLWH plasma.

Formulation development of dual-compartment topical inserts combining tenofovir alafenamide and elvitegravir for flexible on-demand HIV prevention.

Pre-exposure prophylaxis (PrEP) has emerged as a prominent approach for the prevention of HIV infections. While the latest advances have resulted in effective oral and injectable product options, there are still gaps in on-demand, event-driven, topical products for HIV prevention that are safe and effective. Here we describe the formulation development of a dual-compartment topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) that may be administered when needed, vaginally or rectally, pre- or post-coitus, for flexible HIV prophylaxis.

Preclinical and Early Clinical Development of Tenofovir Alafenamide/Elvitegravir Topical Inserts for Effective On-Demand Vaginal and Rectal HIV Prevention.

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus.

Role of Preoperative Intra-Articular Corticosteroid Injections on Periprosthetic Joint Infection in Total Hip Arthroplasty and Its Association With Preoperative Timing: A Single-Center Series of 5,909 Hips.

Background: Preoperative intra-articular corticosteroid injections to the hip joint increase the risk of periprosthetic joint infection (PJI) during primary total hip arthroplasty (THA). This study aimed to determine the relationship between preoperative timing of intra-articular corticosteroid injections and PJI risk following THA using data from a single-center hospital.

Methods: This single-center, retrospective cohort study included patients who underwent a THA between 2014 and 2020.

Extended Postexposure Protection Against Vaginal Simian/Human Immunodeficiency Virus Infection With Tenofovir Alafenamide Fumarate/Elvitegravir Inserts in Macaques.

Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20 mg) and elvitegravir (EVG, 16 mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.

Accurate magnification determination for cryoEM using gold.

Determining the correct magnified pixel size of single-particle cryoEM micrographs is necessary to maximize resolution and enable accurate model building. Here we describe a simple and rapid procedure for determining the absolute magnification in an electron cryomicroscope to a precision of <0.5%.

Employing Feature Selection Algorithms to Determine the Immune State of Mice Model of Rheumatoid Arthritis.

The immune response is a dynamic process by which the body determines whether an antigen is self or nonself. The state of this dynamic process is defined by the relative balance and population of inflammatory and regulatory actors which comprise this decision making process. The goal of immunotherapy as applied to, e.

Exponentially decreasing exposure of antigen generates anti-inflammatory T-cell responses.

Rheumatoid Arthritis (RA) is a chronic debilitating disease characterized by auto-immune reaction towards self-antigen such as collagen type II. In this study, we investigated the impact of exponentially decreasing levels of antigen exposure on pro-inflammatory T cell responses in the collagen-induced arthritis (CIA) mouse model. Using a controlled delivery experimental approach, we manipulated the collagen type II (CII) antigen concentration presented to the immune system.

Integral Quadratic Constraints with Infinite-Dimensional Channels.

Modern control theory provides us with a spectrum of methods for studying the interconnection of dynamic systems using input-output properties of the interconnected subsystems. Perhaps the most advanced framework for such input-output analysis is the use of Integral Quadratic Constraints (IQCs), which considers the interconnection of a nominal linear system with an unmodelled nonlinear or uncertain subsystem with known input-output properties. Although these methods are widely used for Ordinary Differential Equations (ODEs), there have been fewer attempts to extend IQCs to infinite-dimensional systems.

Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies.

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation.

Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.

Background: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities.

Methods: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg).

Pharmacokinetics and efficacy of topical inserts containing tenofovir alafenamide fumarate and elvitegravir administered rectally in macaques.

Background: Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques.

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges.

Introduction: Poor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting (LA) antiretrovirals (ARVs) in conjunction with advances in controlled release technologies has enabled LA ARV drug delivery systems (DDS) capable of providing extended dosing intervals and overcome the challenge of suboptimal drug adherence with daily oral dosing.

Areas Covered: This review discusses the current state of the LA PrEP field, recent advances, and emerging technologies, including ARV prodrug modifications and new DDS.

Corticosteroids Use and Incidence of Severe Infections in People Living with HIV Compared to a Matched Population.

Background: People living with HIV (PLWH) have been shown to have an increased risk of autoimmune diseases. Corticosteroids are the cornerstone of autoimmune diseases treatment, but their use is associated with an increased risk of infections. It is unclear how HIV status affects the risk of infection associated with corticosteroids use.

On the reduction in the effects of radiation damage to two-dimensional crystals of organic and biological molecules at liquid-helium temperature.

We have studied the fading of electron diffraction spots from two-dimensional (2D) crystals of paraffin (CH), purple membrane (bacteriorhodopsin) and aquaporin 4 (AQP4) at stage temperatures between 4K and 100K. We observed that the diffraction spots at resolutions between 3 Å and 20 Å fade more slowly at liquid-helium temperatures compared to liquid-nitrogen temperatures, by a factor of between 1.2 and 1.

Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring.

Background: A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported.

Objective: CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK.

Unraveling antimicrobial resistance using metabolomics.

The emergence of antimicrobial resistance (AMR) in bacterial pathogens represents a global health threat. The metabolic state of bacteria is associated with a range of genetic and phenotypic resistance mechanisms. This review provides an overview of the roles of metabolic processes that are associated with AMR mechanisms, including energy production, cell wall synthesis, cell-cell communication, and bacterial growth.

Formulation Development for Transdermal Delivery of Raloxifene, a Chemoprophylactic Agent against Breast Cancer.

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal delivery system (TDS) for the sustained delivery of RLX to enhance the therapeutic effectiveness, increase adherence, and reduce side effects.

Agreement and Reliability of Median Neurodynamic Test 1 and Resting Scapular Position.

Objective: The purposes of this study were to determine whether there are differences between the dominant and nondominant arms for the Median Neurodynamic Test 1 (MNT 1); whether there are differences between men and women on the MNT 1; the reliability of an assessment of resting scapular position; the reliability of the MNT 1; and the frequency and percentage of sensory responses that are present during the MNT 1 in the asymptomatic population.

Methods: This was a reliability and agreement study. It included asymptomatic students enrolled in the college of health professions and the college of nursing at a university.

Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP.

The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å.

Heterogeneous Hydrogel Structures with Spatiotemporal Reconfigurability using Addressable and Tunable Voxels.

Stimuli-responsive hydrogels can sense environmental cues and change their volume accordingly without the need for additional sensors or actuators. This enables a significant reduction in the size and complexity of resulting devices. However, since the responsive volume change of hydrogels is typically uniform, their robotic applications requiring localized and time-varying deformations have been challenging to realize.

Reliability of the beighton score and impact of generalized joint mobility and resting scapular position on Median Neurodynamic Test 1.

Introduction: There is a lack of understanding of the impact of generalized joint mobility, joint hypermobility, and resting scapular position on neurodynamic testing of the median nerve. The objectives of the study were to determine: 1) the reliability of the Beighton score (BS) with and without the cutoff score for general joint hypermobility (GJH); 2) if there are differences in the Median Neurodynamic Test 1 (MNT 1) based on the Beighton cutoff score for GJH; 3) if there are differences in the MNT 1 based on an assessment of resting scapular position; 4) if there are relationships between the BS with and without the cutoff score for GJH, resting scapular position, and MNT 1.

Methods: Testing was performed by two testers at two-time intervals at least 1 week apart.

Pharmacokinetics of a weekly transdermal delivery system of tenofovir alafenamide in hairless rats.

Tenofovir alafenamide (TAF) is a potent prodrug of tenofovir (TFV) for HIV prophylaxis, and HIV and HBV treatment. Compared to oral daily doses, transdermal administration of TAF may be more advantageous for long-term adherence by offering sustained drug delivery and reduced dosing frequency. Here, we described the plasma pharmacokinetics (PK) of an optimized once-weekly suspension transdermal delivery system (TDS) for TAF (96 mg/25 cm of TDS) in female hairless rats.