YAT2150 is irresistible in Plasmodium falciparum and active against Plasmodium vivax and Leishmania clinical isolates.

We recently characterized the potent antiplasmodial activity of the aggregated protein dye YAT2150, whose presumed mode of action is the inhibition of protein aggregation in the malaria parasite. Using single-dose and ramping methods, assays were done to select Plasmodium falciparum parasites resistant to YAT2150 concentrations ranging from 3× to 0.25× the in vitro IC of the compound (in the two-digit nM range) and performed a cross-resistance assessment in P.

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs.

β-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling.

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline was orally efficacious in -infected mice and that it showed low cross-resistance between susceptible and four different drug-resistant strains.

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Phosphatidylinositol-4-kinase and Hemozoin Formation with Efficacy.

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of () phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of .

The role of microstructure in the thermal fatigue of solder joints.

Thermal fatigue is a common failure mode in electronic solder joints, yet the role of microstructure is incompletely understood. Here, we quantify the evolution of microstructure and damage in Sn-3Ag-0.5Cu joints throughout a ball grid array (BGA) package using EBSD mapping of localised subgrains, recrystallisation and heavily coarsened AgSn.

Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons With HIV Receiving Tenofovir Alafenamide and Emtricitabine-Based Antiretroviral Therapy (QUANTI-TAF).

Background: QUANTI-TAF aimed to establish tenofovir-diphosphate (TFV-DP)/emtricitabine-triphosphate (FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with human immunodeficiency virus (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART).

Methods: For 16 weeks, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TFV-DP and FTC-TP in DBS were quantified and summarized at steady-state (week 12 or 16) as median (interquartile range).

Nanowired human cardiac organoid transplantation enables highly efficient and effective recovery of infarcted hearts.

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium.

Modeling Microplastic Transport in the Marine Environment: Testing Empirical Models of Particle Terminal Sinking Velocity for Irregularly Shaped Particles.

Microplastic (mP) pollution has been indicated as an area of concern in the marine environment. However, there is no consensus on their potential to cause significant ecological harm, and a comprehensive risk assessment of mP pollution is unattainable due to gaps in our understanding of their transport, uptake, and exchange processes. This research considers drag models that have been proposed to calculate the terminal settling velocity of regularly and irregularly shaped particles to assess their applicability in a mP modeling context.

Demographic and Clinical Characteristics of Persons with HIV with Viral Load:Adherence Mismatch Who Are at Risk of Future Viremia.

The potency of modern antiretroviral therapy (ART) allows for greater forgiveness to missed doses while still achieving, and maintaining, viral suppression. However, imperfect ART adherence, even if sufficient to maintain viral suppression, has been associated with adverse clinical outcomes. ART adherence can be objectively quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), a biomarker of cumulative adherence that is predictive of future viremia-even among persons with HIV (PWH) with an undetectable HIV viral load (VL).

How ready was the US vaccination infrastructure and network of immunization information systems for COVID-19 vaccination campaigns: Recommendations to strengthen the routine vaccination program and prepare for the next pandemic.

Coronavirus disease 2019 (COVID-19) pandemic vaccination campaigns globally have been unlike any effort in history. In the United States, the success of these efforts, in part, has hinged on the timely capture and reporting of an unprecedented amount of data from a significantly greater number of administering providers than for routine vaccinations. The pandemic response has highlighted the need to explore the status and value of vaccination data as the critical glue that connects all aspects of the upstream US vaccine development and downstream vaccination delivery system.

Cumulative tenofovir diphosphate exposure in persons with HIV taking single- vs. multiple-tablet regimens.

Background: We assessed cumulative antiretroviral exposure-using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS)-in persons with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART) as single-tablet regimens (STR) or multiple-tablet regimens (MTR).

Methods: Blood for DBS was prospectively collected in PWH on TDF during 1144 person visits (n = 523). Linear mixed-effects models, adjusted for baseline characteristics, were used to compare TFV-DP in STR versus MTR.

Targeting inhibitor of apoptosis proteins (IAPs) with IAP inhibitors sensitises malignant rhabdoid tumour cells to cisplatin.

Malignant rhabdoid tumour (MRT) is a rare, aggressive paediatric malignancy most commonly diagnosed in those below the age of three. MRTs can arise in soft tissue but are more often associated with the central nervous system or kidney. Unfortunately, the prognosis upon diagnosis with MRT is poor.

Coding Practices in Hand Surgery and Their Relationship to Surgeon Compensation Structure.

Purpose: To evaluate the coding practices of hand surgeons in the American Society for Surgery of the Hand with respect to practice compensation structure using common, representative hand surgery cases.

Methods: We developed a survey of demographic factors and 4 commonly encountered hypothetical hand surgery cases. This survey was emailed to the members of the American Society for Surgery of the Hand.

A single-session behavioral protocol for successful event-related potential recording in children with neurodevelopmental disorders.

Event-related potentials (ERPs) are an ideal tool for measuring neural responses in a wide range of participants, including children diagnosed with neurodevelopmental disorders (NDDs). However, due to perceived barriers regarding participant compliance, much of this work has excluded children with low IQ and/or reduced adaptive functioning, significant anxiety symptoms, and/or sensory processing difficulties, including heterogeneous samples of children with autism spectrum disorder (ASD) and children with fragile X syndrome (FXS). We have developed a behavioral support protocol designed to obtain high-quality ERP data from children in a single session.

Low-Level Viremia Is Associated With Cumulative Adherence to Antiretroviral Therapy in Persons With HIV.

The drivers of low-level viremia (LLV) between 20 and 200 copies/mL remain unclear. In 1042 person-visits from 497 persons with HIV on tenofovir disoproxil fumarate-containing antiretroviral therapy (ART), the association between LLV and cumulative antiretroviral adherence (quantified using tenofovir diphosphate [TFV-DP] in dried blood spots) was assessed. Lower TFV-DP levels were associated with higher odds of LLV.

Using Plasmodium knowlesi as a model for screening Plasmodium vivax blood-stage malaria vaccine targets reveals new candidates.

Plasmodium vivax is responsible for the majority of malaria cases outside Africa. Unlike P. falciparum, the P.

Emtricitabine triphosphate in dried blood spots predicts future viremia in persons with HIV and identifies mismatch with self-reported adherence.

Objective: Emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS), a measure of short-term antiretroviral therapy (ART) adherence, is associated with viral suppression in persons with HIV (PWH). However, its ability to predict future viremia remains unknown.

Design: Prospective, observational cohort (up to three visits in 48 weeks).

Current Challenges and Future Possibilities for Immunization Information Systems.

Immunizations have proven to be an important tool for public health and for reducing the impact of vaccine preventable diseases. To realize the maximum benefits of immunizations, a coordinated effort between public policy, health care providers and health systems is required to increase vaccination coverage and to ensure high-quality data are available to inform clinical and public health interventions. Immunization information systems (IIS) are confidential, population-based, computerized databases that record all immunization doses administered by participating providers to persons residing within a given geopolitical area.

A Brief Training Program to Support the Use of a Digital Pill System for Medication Adherence: Pilot Descriptive Study.

Background: Digital pill systems (DPSs), which comprise ingestible radiofrequency sensors integrated into a gelatin capsule that overencapsulates a medication, can directly measure ingestion events.

Objective: Teaching users to operate a DPS is vital to ensure the collection of actionable ingestion and adherence data. In this study, we aim to develop and pilot a training program, grounded in the Technology Acceptance Model, to instruct individuals on DPS operation.

Targeting HIF-α for robust prevascularization of human cardiac organoids.

Prevascularized 3D microtissues have been shown to be an effective cell delivery vehicle for cardiac repair. To this end, our lab has explored the development of self-organizing, prevascularized human cardiac organoids by co-seeding human cardiomyocytes with cardiac fibroblasts, endothelial cells, and stromal cells into agarose microwells. We hypothesized that this prevascularization process is facilitated by the endogenous upregulation of hypoxia-inducible factor (HIF) pathway in the avascular 3D microtissues.

Higher medication complexity in persons with HIV is associated with lower tenofovir diphosphate in dried blood spots.

Study Objective: To assess the association between tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), a measure of cumulative tenofovir-based antiretroviral (ART) adherence, with medication regimen complexity in persons with human immunodeficiency virus (PWH).

Design: Prospective clinical cohort (up to three visits over 48 weeks).

Setting: Academic-based HIV clinic.

Measurement and improvement as a model to strengthen immunization information systems and overcome data gaps.

Background: IIS are important tools in the public health system and exist to improve and protect the nation's health from vaccine-preventable diseases. A network of 62 independent state, territorial, and jurisdictional immunization information systems (IIS) are operated within the United States. These systems are relied upon to implement an increasingly complex vaccination schedule, consolidate and create comprehensive immunization records, as well as monitor vaccine safety, efficacy, and support vaccine delivery.

Preparing for COVID-19 Vaccination: A Call to Action for Clinicians on Immunization Information Systems.

Immunization information systems (IISs) play a central role in coordinating distribution, administration, documentation, and monitoring of COVID-19 vaccination. In this commentary, the authors provide an introduction to IISs and discuss how clinicians can help maximize their utility in the COVID-19 pandemic.

Associations Between Tenofovir Diphosphate in Dried Blood Spots, Impaired Physical Function, and Fracture Risk.

Background: In this study, we evaluate associations between cumulative antiretroviral adherence/exposure, quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), and human immunodeficiency virus (HIV)-related aging factors.

Methods: This is a cross-sectional analysis of younger (ages 18-35) and older (ages ≥60) persons with HIV (PWH) taking TFV disoproxil fumarate. Tenofovir diphosphate concentrations were quantified in DBS.

Lower Cumulative Antiretroviral Exposure in People Living With HIV and Diabetes Mellitus.

Objective: People living with HIV (PLWH) are living longer and developing more non-AIDS comorbidities, which negatively impact antiretroviral therapy (ART) adherence. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a novel pharmacologic measure of cumulative ART adherence that is predictive of viral suppression and future viremia. However, the relationship between non-AIDS comorbidities and this adherence measure is unknown.