Investigating the relationship between mutations and response to artemisinin-based treatment for uncomplicated falciparum malaria: a protocol for a systematic review and individual patient data meta-analysis.

Introduction: Artemisinin-based combination therapies (ACTs) remain the WHO-recommended treatment for uncomplicated malaria. However, the emergence and spread of artemisinin resistance (ART-R) threatens ACT efficacy. ART-R is phenotypically expressed as delayed parasite clearance, which can facilitate ACT partner drug resistance.

Does mass chloroquine treatment have any role in the elimination of Plasmodium vivax ?

Countries in the Greater Mekong sub-region (GMS) have been encouraged to deploy mass chloroquine treatments given monthly for four months to reduce the burden of vivax malaria. This paper summarizes briefly current knowledge on Plasmodium vivax epidemiology, the biology of vivax relapse and previous experience using dihydroartemisinin-piperaquine mass treatments in the GMS to show why this approach would be extremely cost-ineffective. Around 800 full treatment courses in 200 people would be needed to prevent one symptomatic case.

Tuberculosis preventive therapy: scientific and ethical considerations for trials of ultra-short regimens.

Preventive therapy remains key to the elimination of tuberculosis and is typically offered to people with presumptive Mycobacterium tuberculosis infection to prevent active disease. Although the duration of tuberculosis preventive therapy has been reduced substantially over time, it remains long in absolute terms, and uptake remains low. Treatment-shortening trials using non-inferiority designs have so far led to the implementation of effective regimens of 1-4 months' duration.

Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV).

Background: The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity , and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in therapeutic guidelines and their antiviral activity has not been characterised.

Methods: PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos.

Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2.

Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes.

Modeling the within-host dynamics of hypnozoite activation: An analysis of the SPf66 vaccine trial.

parasites can lie dormant in the liver as hypnozoites, activating weeks to months after sporozoite inoculation to cause relapsing malarial illness. It is not known what biological processes govern hypnozoite activation. We use longitudinal data from the most detailed cohort study ever conducted in an area where both and were endemic to fit a simple within-host mathematical model of hypnozoite activation.

The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment.

DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface.

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

Background: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use.

Methods And Findings: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention.

Lineage-informative microhaplotypes for recurrence classification and spatio-temporal surveillance of Plasmodium vivax malaria parasites.

Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences.

Transmission-blocking activities of artesunate, chloroquine, and methylene blue on gametocytes.

is now the main cause of malaria outside Africa. The gametocytocidal effects of antimalarial drugs are important to reduce malaria transmissibility, particularly in low-transmission settings, but they are not well characterized for . The transmission-blocking effects of chloroquine, artesunate, and methylene blue on gametocytes were assessed.

Clinical guideline highlights for the hospitalist: International consensus criteria for pediatric sepsis and septic shock.

International Consensus Criteria for Pediatric Sepsis and Septic Shock RELEASE DATE: January 21, 2024 PRIOR VERSION(S): International Pediatric Sepsis Consensus Conference: Definitions for Sepsis and Organ Dysfunction in Pediatrics (2005) DEVELOPER: Society of Critical Care Medicine FUNDING SOURCE: Society of Critical Care Medicine (grant R01HD105939 from the National Institute of Child Health and Human Development) TARGET POPULATION: Children with sepsis and septic shock.

Comparison of WHO versus national COVID-19 therapeutic guidelines across the world: not exactly a perfect match.

Background: The COVID-19 pandemic affected all WHO member states. We compared and contrasted the COVID-19 treatment guidelines of each member state with the WHO COVID-19 therapeutic guidelines.

Methods: Ministries of Health or accessed National Infectious Disease websites and other relevant bodies and experts were contacted to obtain national guidelines (NGs) for COVID-19 treatment.

Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB.

The relationship between viral clearance rates and disease progression in early symptomatic COVID-19: a systematic review and meta-regression analysis.

Background: Effective antiviral drugs accelerate viral clearance in acute COVID-19 infections; the relationship between accelerating viral clearance and reducing severe clinical outcomes is unclear.

Methods: A systematic review was conducted of randomized controlled trials (RCTs) of antiviral therapies in early symptomatic COVID-19, where viral clearance data were available. Treatment benefit was defined clinically as the relative risk of hospitalization/death during follow-up (≥14 days), and virologically as the SARS-CoV-2 viral clearance rate ratio (VCRR).

Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of malaria: An individual patient data meta-analysis'.

In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.

Primaquine in glucose-6-phosphate dehydrogenase deficiency: an adaptive pharmacometric assessment of ascending dose regimens in healthy volunteers.

Background: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd).

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial.

Unlabelled: In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance.

Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive.

[A global core outcome measurement set for snakebite clinical trials].

Background: Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation.

Method: A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials.