Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.

Background: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.

Methods: We conducted a systematic review and individual participant data meta-analysis.

Vedolizumab Clearance as a Surrogate Marker for Remission in Inflammatory Bowel Disease Patients: Insights from Real-World Pharmacokinetics.

Vedolizumab (VDZ) is approved in the treatment of patients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD). VDZ exhibits considerable variability in its pharmacokinetic (PK) profile, and its exposure-response relationship is not yet fully understood. The aim was to investigate the variability in VDZ trough levels and PK parameters, to assess the relationship between VDZ PK and biochemical response, as well as clinical and endoscopic outcomes.

Optimizing Lumefantrine Dosing for Young Children in High-Malaria-Burden Countries Using Pharmacokinetic-Pharmacodynamic Simulations.

Background: Artemether-lumefantrine is the most widely used treatment for uncomplicated malaria and it is dosed based on weight bands according to World Health Organization (WHO) guidelines. However, children are vulnerable to underdosing. Inadequate dosing can lead to treatment failure and drug resistance.

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis.

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events.

Desmopressin dosing in children using real-world data and pharmacokinetic/pharmacodynamic model simulations.

Background: Variability in pediatric dosing of desmopressin (ddAVP) in AVP-deficiency (AVP-D) is well-documented but dosing recommendations are limited. This study evaluates and optimizes ddAVP dosing regimens in children with AVP-D using pharmacokinetic and pharmacodynamic (PK/PD) simulations.

Methods: Retrospective electronic health record review was done to identify children (<18 years) with AVP-D on ddAVP evaluated in the outpatient setting using ICD 9 and 10 codes.

Pork quality and histological properties of longissimus muscle from boars and early and late immunocastrated pigs.

Immunocastration has been introduced in pig production to reduce boar taint. However, there is not much information on how different schedule of immunocastration affects meat quality, especially muscle histological properties. In this study, carcass and meat quality characteristics, histological properties of the longissimus dorsi muscle, sensory characteristics and fatty acid composition of meat and fat from entire males (EM), late immunocastrated (LIC, first dose 8 weeks before slaughter, second dose 4 weeks before slaughter) and early immunocastrated pigs (EIC, first dose 13 weeks before slaughter, second dose 8 weeks before slaughter) were compared.

Linezolid Pharmacokinetic-Anemia Modeling in Children With Rifampicin-Resistant Tuberculosis.

Background: Linezolid, a component of rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) treatment, is associated with treatment-limiting toxicities, including anemia. Patient-level and linezolid pharmacokinetic risk factors for anemia have not been well described in children treated for RR/MDR-TB.

Methods: We evaluated the pharmacokinetics of linezolid and longitudinal hemoglobin data to validate an existing population linezolid pharmacokinetic model.

Prospectively predicting BPaMZ phase IIb/III trial outcomes using a translational mouse-to-human platform.

Despite known treatments, tuberculosis (TB) remains the world's top infectious killer, highlighting the pressing need for new drug regimens. To prioritize the most efficacious drugs for clinical testing, we previously developed a PK-PD translational platform with bacterial dynamics that reliably predicted short-term monotherapy outcomes in Phase IIa trials from preclinical mouse studies. In this study, we extended our platform to include PK-PD models that account for drug-drug interactions in combination regimens and bacterial regrowth in our bacterial dynamics model to predict cure at the end of treatment and relapse 6 months post-treatment.

Percent of lung involved in disease on chest X-ray predicts unfavorable treatment outcome in pulmonary tuberculosis.

Unlabelled: Radiology may better define tuberculosis (TB) severity and guide duration of treatment. We aimed to systematically study baseline chest X-rays (CXR) and their association with TB treatment outcome using real-world data. We used logistic regression to associate TB treatment outcomes with CXR findings, including percent of lung involved in disease (PLI), cavitation, and Timika score, alone or in combination with other clinical characteristics, stratifying by drug resistance status and HIV (n = 2,809).

Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen.

TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid.

Exploring the Potential of a Smart Ring to Predict Postoperative Pain Outcomes in Orthopedic Surgery Patients.

Poor pain alleviation remains a problem following orthopedic surgery, leading to prolonged recovery time, increased morbidity, and prolonged opioid use after hospitalization. Wearable device data, collected during postsurgical recovery, may help ameliorate poor pain alleviation because a patient's physiological state during the recovery process may be inferred from sensor data. In this study, we collected smart ring data from 37 inpatients following orthopedic surgery and developed machine learning models to predict if a patient had postsurgical poor pain alleviation.

Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles.

Bio-based resources: systemic & circular solutions for (agro)environmental services.

The global promotion of decarbonisation through the circular solutions and (re)use of bio-based resources (BBR), waste streams, notably from the agricultural, forest and municipal sectors has steadily increased in recent decades. Among the transformative solutions offered by BBR, biosolids (BS), biochars (BC), and bioashes (BA) specifically attract scientific attention due to their highly complex organo-mineral matrices, which present significant potential for recovery in the agro-/forest-ecosystems. These materials enhance various soil (i) chemical (pH, macro/micro nutrient concentrations, organic matter content), (ii) physical (porosity, water-air relations, compaction) or (iii) microbial (diversity, activity) properties.

Pharmacokinetic-pharmacodynamic modeling of tuberculosis time to positivity and colony-forming unit to assess the response to dose-ranging linezolid.

Unlabelled: According to the World Health Organization, the number of tuberculosis (TB) infections and the drug-resistant burden worldwide increased by 4.5% and 3.0%, respectively, between 2020 and 2021.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized Controlled Clinical Trial.

Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes.

Base Characteristics, Preservation Methods, and Assessment of the Genetic Diversity of Autochthonous Breeds of Cattle, Sheep and Pigs in Serbia: A Review.

Preserving local autochthonous domestic animal populations and the products derived from them is a crucial aspect of managing human utilization of the biosphere. This management approach aims to ensure sustainable benefits for both present and future generations. The diversity of autochthonous domestic animal populations plays a vital role in the functionality and sustainability of the food production system.

Prolonged Opioid Use Is Associated With Poor Pain Alleviation After Orthopaedic Surgery.

Introduction: Severe pain after orthopaedic surgery is common and often results in chronic postsurgical pain and chronic opioid use (COU). Poor pain alleviation (PPA) after surgery is a well-described modifiable risk factor of COU. Although PPA's role in inducing COU is recognized in other areas, it is not well defined in orthopaedic surgery.

Twice-Daily Dolutegravir-Based Antiretroviral Therapy With 1 Month of Daily Rifapentine and Isoniazid for Tuberculosis Prevention.

Background: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for tuberculosis prevention in people with human immunodeficiency virus (HIV). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. AIDS Clinical Trials Group A5372 evaluated the effect of 1HP on the pharmacokinetics of twice-daily dolutegravir.

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

The Role of Model Master Files for Sharing, Acceptance, and Communication with FDA.

With the evolving role of Model Integrated Evidence (MIE) in generic drug development and regulatory applications, the need for improving Model Sharing, Acceptance, and Communication with the FDA is warranted. Model Master File (MMF) refers to a quantitative model or a modeling platform that has undergone sufficient model Verification & Validation to be recognized as sharable intellectual property that is acceptable for regulatory purposes. MMF provides a framework for regulatorily acceptable modeling practice, which can be used with confidence to support MIE by both the industry and the U.

Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

Background: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.

Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children.

A meta-analysis of genetic and phenotypic diversity of European local pig breeds reveals genomic regions associated with breed differentiation for production traits.

Background: Intense selection of modern pig breeds has resulted in genetic improvement of production traits while the performance of local pig breeds has remained lower. As local pig breeds have been bred in extensive systems, they have adapted to specific environmental conditions, resulting in a rich genotypic and phenotypic diversity. This study is based on European local pig breeds that have been genetically characterized using DNA-pool sequencing data and phenotypically characterized using breed level phenotypes related to stature, fatness, growth, and reproductive performance traits.

Target product profiles: tests for tuberculosis treatment monitoring and optimization.

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment.