Immunotherapeutic Strategies as Potential Treatment Options for Cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL), caused by protozoan parasites of the genus, is prevalent in tropical and subtropical regions, with important morbidity, particularly in low- to middle-income countries. Current systemic treatments, including pentavalent antimonials and miltefosine, are associated with significant toxicity, reduced efficacy, and are frequently ineffective in cases of severe or chronic CL. Immunotherapies leverage the immune system to combat microbial infection and offer a promising adjunct or alternative approach to the current standard of care for CL.

Correction: Facing the escalating burden of dengue: Challenges and perspectives.

[This corrects the article DOI: 10.1371/journal.pgph.

Further preclinical characterization of molnupiravir against SARS-CoV-2: Antiviral activity determinants and viral genome alteration patterns.

The SARS-CoV-2 pandemic has highlighted the need for broad-spectrum antiviral drugs to respond promptly to viral emergence. We conducted a preclinical study of molnupiravir (MOV) against SARS-CoV-2 to fully characterise its antiviral properties and mode of action. The antiviral activity of different concentrations of MOV was evaluated on human airway epithelium (HAE) and in a hamster model at three escalating doses (150, 300 and 400 mg/kg/day) according to three different regimens (preventive, pre-emptive and curative).

Synthesis and Anti- Activity of 3-Cyanopyridine Derivatives.

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents.

Equine Headshaking Syndrome: Triggers, Seasonality, and Treatment Efficacy in Australia.

Equine headshaking syndrome is a poorly understood neuropathic pain condition presenting as uncontrollable shaking, flicking, or striking of the head. Therapeutic options are limited, and treatments are only partially successful. Currently, epidemiological information on headshaking in the Southern Hemisphere is lacking.

Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens.

Direct acting antivirals (DAAs) represent critical tools for combating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that have escaped vaccine-elicited spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging to evaluate therapeutic efficacy of DAAs that target SARS-CoV-2 RNA-dependent RNA polymerase (favipiravir, molnupiravir) or main protease (nirmatrelvir) against Delta or Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best efficacy followed by molnupiravir and favipiravir in suppressing viral loads in the lung.

Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains.

Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid®) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova®), has been developed.

Facing the escalating burden of dengue: Challenges and perspectives.

Dengue is the most rapidly emerging mosquito-borne infection and, due to climate change and unplanned urbanization, it is predicted that the global burden of dengue will rise further as the infection spreads to new geographical locations. Dengue-endemic countries are often unable to cope with such increases, with health care facilities becoming overwhelmed during each dengue season. Furthermore, although dengue has been predominantly a childhood illness in the past, it currently mostly affects adults in many countries, with higher incidence of severe disease and mortality rates in pregnant women and in those with comorbidities.

Biomechanical Performance of Total Wrist Arthrodesis Plates With and Without Arthrodesis of the Carpometacarpal Joint.

Background: It is unknown whether total wrist arthrodesis (TWA) should be performed with or without arthrodesis of the carpometacarpal joint (CMCJ). The aim of this study is to compare CMCJ-spanning TWA plates using 3D printed wrist arthrodesis model with and without arthrodesis of the CMCJ.

Methods: Total wrist arthrodesis plates mounted to 3D printed models were tested under a 4-N bending load at 4 Hz for 50 000 cycles, increased by 15% every 10 000 cycles until failure.

Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice.

Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that evolve to escape spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging to evaluate therapeutic efficacy of DAAs that target SARS-CoV-2 RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta or Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best efficacy followed by molnupiravir and favipiravir in suppressing viral loads in the lung.

Evasion of toll-like receptor recognition by is mediated via population level regulation of flagellin production.

Uropathogenic is a major cause of urinary tract infections. Analysis of the innate immune response in immortalized urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defenses. A panel of 48 clinical uro-associated .

Title: Obesogenic microbial signatures and the development of obesity in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer with survival exceeding 90% for standard-risk groups. A debilitating side-effect of treatment is the development of overweight/obesity (OW/OB), which develops in approximately 40% of children by the end of treatment. The microbiome has been associated with the development of OW/OB.

Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an Model of Infection.

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against , the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds and , which were profiled further in pharmacokinetic studies and in an model of infection. Compound demonstrated clear reduction of parasitemia in the setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease.

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity.

Longitudinal use of patient reported outcomes in pediatric leukemia and lymphoma reveals clinically relevant symptomatic adverse events.

Background: Leukemia and lymphoma (LL) are the most common cancer diagnoses of childhood with high survival rates, but not without impact on the child's functioning and quality of life. This study aimed to use patient-reported data to describe the symptomatic adverse event (AE) experiences among children with LL diagnoses.

Methods: Two hundred and fifty seven children and adolescents aged 7-18 years with a first LL diagnosis completed the Pediatric Patient-Reported version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE) and Patient-Reported Outcome Measurement Information System (PROMIS) Pediatric measures before starting a treatment course (T1) and after the treatment (T2).

Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19.

In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.

Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2.

Background: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy.

Methods: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2.

Findings: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2.

[NTD Drug Discovery Booster, Achievements and Next Steps].

The Neglected Tropical Disease (NTD) Drug Discovery Booster is a collaborative project in early small molecule drug discovery running since 2015 between Drugs for Neglected Diseases initiative (DNDi) and pharmaceutical partners across the globe, including Astellas Pharma Ltd., Eisai Co., Ltd.

Comfort with Pharmacogenetic Testing Amongst Pediatric Oncology Providers and Their Patients.

Pharmacogenetic (PGx) testing, a component of personalized medicine, aims to ensure treatment efficacy while reducing side effects and symptoms. Before this testing becomes routine in the pediatric oncology population, nurses need to understand the knowledge and concerns of providers, patients, and family members with regard to the timing, extent, interpretation, and incorporation of PGx testing. As part of a comprehensive PGx study (larger study) for children diagnosed with cancer, we surveyed providers and caregivers of children with cancer about their knowledge of and comfort with PGx testing.

The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks.

The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays.

Multidrug-resistant Uro-associated Populations and Recurrent Urinary Tract Infections in Patients Performing Clean Intermittent Self-catheterisation.

Background: The AnTIC trial linked continuous low-dose antibiotic prophylaxis treatments to a lower incidence of symptomatic urinary tract infections (UTIs) among individuals performing clean intermittent self-catheterisation (CISC).

Objective: To explore potential mechanisms underlying the protective effects of low-dose antibiotic prophylaxis treatments, blood and urine samples and uro-associated isolates from AnTIC participants were analysed.

Design Setting And Participants: Blood samples ( = 204) were analysed for gene polymorphisms associated with UTI susceptibility and multiple urine samples ( = 558) were analysed for host urogenital responses.