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Journalism’s societal role hinges on effective communication, demanding proficient language skills. This study assesses a South African University of Technology’s Department of Journalism, probing existing selection methods’ efficacy in predicting success in two English modules. Concerns persist about these methods accurately identifying students with essential language proficiency. The research explores alternatives for better assessing language abilities crucial for journalistic proficiency. The literature review underscores language proficiency’s significance in journalism education, especially in African contexts, observing challenges faced by South African universities. Current practices, relying on high school English grades and standardised tests, may not precisely reflect required journalism-specific language skills. Using a non-experimental quantitative design, the study analyses correlations between selection methods and student performance in English modules. Findings indicate a weak correlation, advocating for a more comprehensive approach with alternative assessments. Proposed alternatives include writing samples, portfolio reviews, and situational judgement tests for a holistic selection process. The study suggests future research directions, emphasising broader generalisability and exploring correlations with practical skills and critical thinking. The study emphasises the imperative for journalism departments to reevaluate and enhance selection criteria, aligning them with dynamic professional demands. Contribution: This article contributes to journalism education by illuminating the shortcomings of current selection methods in assessing potential for success in English language-related modules. It proposes alternatives and advocates for a holistic approach, providing practical insights for journalism departments aiming to align their selection criteria with the evolving demands of the profession. Ultimately, this contribution aids in the development of skilled journalists.

Background The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilized in TB treatment to date. Methods Based on inhibitory concentration, oral bioavailability, and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, and flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin, and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index. Results The order of activity of beta-lactams was cefadroxil > tebipenem > cephradine > cephalexin > cefdinir > penicillin V > flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine, and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin, or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin, and cefdinir/moxifloxacin. Conclusions Beta-lactam synergy may provide viable combination therapies for the treatment of TB. [ABSTRACT FROM AUTHOR]

Aims Evidence on the impact of screening for cardiovascular diseases (CVDs) on health-related quality of life (HRQoL) is important for policy decisions about screening implementation and to uncover teachable moments to motivate healthy lifestyle choices. It is unknown whether screening by cardiac computed tomography (CT) scan has a stronger impact on HRQoL than screening by traditional risk prediction models. The study aims to investigate differences in HRQoL across the screening process between participants who were randomized to CVD risk estimation by coronary artery calcium score or Systematic COronary Risk Evaluation. Methods and results A subset of 2687 ROBINSCA participants filled in questionnaires at (T0) randomization, (T1) invitation, (T2) 1–3 days before screening, (T3) 1–3 days after, and (T4) screening result. Generic HRQoL (SF-12; EQ-5D) and anxiety (STAI-6) were measured. We investigated the differences in changes in HRQoL across the screening process with linear mixed models. We found comparable levels of HRQoL at all screening moments for the two intervention groups. Mental health scores were worse at invitation and randomization than at the later time points, irrespective of screening group (all P < 0.001). A result indicating a heightened CVD risk was associated with increased anxiety in the CT screening group. Conclusion Computed tomography screening for CVD risk has no detrimental impact on HRQoL and anxiety levels compared to screening by traditional risk assessment. Receiving an invitation to screenning or a result implying increased CVD risk could function as teachable moments for high-risk individuals. Registration ROBINSCA trial registration number: NTR6471 in Dutch Trial Register (NTR). [ABSTRACT FROM AUTHOR]

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype‐predicted‐phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose‐corrected voriconazole plasma concentration and C‐reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype‐predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose‐corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose‐corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes. [ABSTRACT FROM AUTHOR]

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used to adjust and individualise drug regimens until predefined pharmacokinetic exposure targets are achieved. Minimum inhibitory concentration (drug susceptibility) is the best available pharmacodynamic parameter but is associated with many limitations. Identification of other pharmacodynamic parameters is necessary. Repurposing diagnostic biomarkers as pharmacodynamic parameters to evaluate treatment response is attractive. When combined with therapeutic drug monitoring, it could facilitate making more informed dosing decisions. We believe the approach has potential and justifies further research. [ABSTRACT FROM AUTHOR]

Abstract Background Surrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint. Methods Using real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance. Results In the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation. Conclusion Partial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint.

Introduction: The direct reimplantation of autologous primary articular chondrocytes in a single-stage procedure for knee cartilage lesions is a novel approach, yet to be extensively reported. This study aimed to evaluate the clinical outcomes and reinterventions over a 5-year period post-surgery. Methods: A prospective case series involving 16 patients (4 female, 12 male) with single or multiple focal knee cartilage lesions was conducted. The mean age at baseline was 36.8 (±11.5) years. The mean total lesion size was 4.5 (±2.3) cm2 Patients underwent surgery where articular chondrocytes and mononuclear bone marrow cells were isolated, mixed, and seeded onto a hyaluronan-based scaffold within the lesion. A structured physical therapy regimen was followed, and patients were assessed using Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) Subjective questionnaires at various intervals. Overall, patient-reported outcomes improved over the first 3 years post-surgery, with slight declines thereafter. Results: Significant improvements over baseline were noted for various KOOS parameters and IKDC Subjective scores at different follow-up points. Reinterventions were required for two patients, one receiving intra-articular injections with mesenchymal stromal cells and another undergoing knee washout for septic arthritis while a meniscus implant was removed. Patient satisfaction at final follow-up was generally favorable. Despite a significant intraoperative cell isolation time of approximately 1.5 hours, the procedure demonstrated safety and efficacy, with an average of ±0.9 million articular chondrocytes obtained per case. Conclusions: This study underscores the potential of coimplantation of intraoperatively isolated articular chondrocytes and bone marrow cells on a hyaluronan scaffold as a promising strategy for treating symptomatic knee cartilage lesions.

Objective To explore associations between general health-related problems and subclinical coronary artery disease (CAD), determined by CT coronary calcium score (CT-CCS), in a general population.Design A cross-sectional design.Setting This study was performed in a prospective population-based cohort, examining the health and health-related behaviour of individuals living in the Northern Netherlands.Participants The initial cohort comprised 6763 participants ≥45 years of age who underwent CT-scanning. Participants were included for the current analysis if they filled in three validated questionnaires (Symptomatic Checklist-90, Research and Development Survey-36 and Reviving the Early Diagnosis of CardioVascular Diseases questionnaire (RED-CVD)) and did not have a history of cardiovascular disease. The final analysis included 6530 participants.Primary outcome measure Backward-stepwise and forward-stepwise logistic regression analyses were performed to determine associations between general health-related problems and subclinical CAD (CCS≥100 and ≥300).Results The median age was 53 years (25th, 75th percentile: 48, 58); 57% were women. CRCS≥100 was found in 1236 (19%) participants, 437 (12%) in women and 799 (29%) men and CCS≥300 in 643 (9.9%) participants of which 180 (4.8%) were women and 463 (16.6%) men. In univariate analysis, in women the expectation of health to worsen (OR=1.13, 95% CI: 1.05 to 1.21), and in men reduced exercise intolerance (OR=1.14, 95% CI: 1.06 to 1.23) were associated with CCS≥100. The total RED-CVD score in women (OR=1.06, (95% CI: 1.05 to 1.08) and men (OR=1.07, 95% CI: 1.06 to 1.09), and in men also reduced exercise intolerance (OR=1.15, 95% CI: 1.06 to 1.25) and headache (OR=0.55, 95% CI: 0.38 to 0.79) were associated with CCS≥300. In multivariate analyses, only general health expectation in women was still significantly associated with subclinical CAD (CCS≥300) (OR=1.92, 95% CI: 1.56 to 2.37).Conclusion Only a few general health-related problems were associated with the presence of subclinical CAD in the general population, however, these problems showed no strong association. Therefore, using health-related symptoms does not seem useful to pre-select for CT-CCS.Trial registration number CCMO Register, NL17981.042.07 and NL58592.042.16.

Abstract Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype‐predicted‐phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose‐corrected voriconazole plasma concentration and C‐reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype‐predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose‐corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose‐corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used to adjust and individualise drug regimens until predefined pharmacokinetic exposure targets are achieved. Minimum inhibitory concentration (drug susceptibility) is the best available pharmacodynamic parameter but is associated with many limitations. Identification of other pharmacodynamic parameters is necessary. Repurposing diagnostic biomarkers as pharmacodynamic parameters to evaluate treatment response is attractive. When combined with therapeutic drug monitoring, it could facilitate making more informed dosing decisions. We believe the approach has potential and justifies further research.

Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07–1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06–1.16), treatment success (aRR, 1.07; 95% CI, 1.03–1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14–1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0–24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens.

Introduction: Pyrazinamide, one of the first-line antituberculosis drugs, displays variability in drug exposure that is associated with treatment response. A simple, low-cost assay may be helpful to optimize treatment. This study aimed to develop and validate a point-of-care assay to quantify the concentration of pyrazinamide in saliva., Methods: All measurements were conducted using the nano-volume drop function on the mobile ultraviolet (UV) spectrophotometer (NP80, Implen, Germany). Assay development involved applying second derivative spectroscopy in combination with the Savitzky-Golay filter between wavelengths of 200-300 nm to increase spectral resolution. Assay validation included assessing selectivity, linearity, accuracy, precision, carry-over and matrix effects. Specificity was also analysed by evaluating the impact of co-administered medications on pyrazinamide results. Sample stability was measured at various temperatures up to 40°C., Results: The calibration curve (7.5-200 mg/L) was linear (R2 = 0.9991). The overall accuracy (bias%) and precision (CV%) ranged from -0.66% to 5.15%, and 0.56% to 4.95%, respectively. Carry-over and matrix effects were both acceptable with a bias% of <±4% and CV% of <7.5%. Commonly co-administered medications displayed negligible interferences. Levofloxacin displayed analytical interference (bias% = -10.21%) at pyrazinamide concentrations < 25 mg/L, but this will have little clinical implications. Pyrazinamide was considered stable in saliva after 7 days in all storage conditions with a CV% of <6.5% and bias% of <±10.5% for both low- and high-quality control concentrations., Conclusions: A saliva-based assay for pyrazinamide has been successfully developed and validated using the mobile UV spectrophotometer., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objective: To explore associations between general health-related problems and subclinical coronary artery disease (CAD), determined by CT coronary calcium score (CT-CCS), in a general population., Design: A cross-sectional design., Setting: This study was performed in a prospective population-based cohort, examining the health and health-related behaviour of individuals living in the Northern Netherlands., Participants: The initial cohort comprised 6763 participants ≥45 years of age who underwent CT-scanning. Participants were included for the current analysis if they filled in three validated questionnaires (Symptomatic Checklist-90, Research and Development Survey-36 and Reviving the Early Diagnosis of CardioVascular Diseases questionnaire (RED-CVD)) and did not have a history of cardiovascular disease. The final analysis included 6530 participants., Primary Outcome Measure: Backward-stepwise and forward-stepwise logistic regression analyses were performed to determine associations between general health-related problems and subclinical CAD (CCS≥100 and ≥300)., Results: The median age was 53 years (25th, 75th percentile: 48, 58); 57% were women. CRCS≥100 was found in 1236 (19%) participants, 437 (12%) in women and 799 (29%) men and CCS≥300 in 643 (9.9%) participants of which 180 (4.8%) were women and 463 (16.6%) men. In univariate analysis, in women the expectation of health to worsen (OR=1.13, 95% CI: 1.05 to 1.21), and in men reduced exercise intolerance (OR=1.14, 95% CI: 1.06 to 1.23) were associated with CCS≥100. The total RED-CVD score in women (OR=1.06, (95% CI: 1.05 to 1.08) and men (OR=1.07, 95% CI: 1.06 to 1.09), and in men also reduced exercise intolerance (OR=1.15, 95% CI: 1.06 to 1.25) and headache (OR=0.55, 95% CI: 0.38 to 0.79) were associated with CCS≥300. In multivariate analyses, only general health expectation in women was still significantly associated with subclinical CAD (CCS≥300) (OR=1.92, 95% CI: 1.56 to 2.37)., Conclusion: Only a few general health-related problems were associated with the presence of subclinical CAD in the general population, however, these problems showed no strong association. Therefore, using health-related symptoms does not seem useful to pre-select for CT-CCS., Trial Registration Number: CCMO Register, NL17981.042.07 and NL58592.042.16., Competing Interests: Competing interests: RV has received institutional research grants from Siemens Healthineers, and PvdH has received grant support by Siemens Healthineers and Guerbet. The other authors did not report any potential conflict of interest relevant to this article., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Data on childhood and adolescent multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in Indonesia are lacking. We aimed to assess clinical features, adverse events (AEs) and treatment outcomes of childhood and adolescent MDR/RR-TB., Methods: A retrospective cohort study was performed in children and adolescents aged <18 years treated for MDR/RR-TB at Hasan Sadikin General Hospital in Bandung, Indonesia, between June 2016 and March 2024. Multivariable logistic regression analyses were used to calculate adjusted odds ratios (aOR) for predictors of all-cause mortality., Results: Among 84 included patients, 69 (82%) were adolescents aged 10-17 years, 54 (64%) were female, 54 (64%) were malnourished and 55 (65%) had culture-confirmed disease. Among 69 (82%) patients with known outcomes, 48 (70%) were successfully treated, 14 (20%) died (including 5 pretreatment deaths) and 7 (10%) were lost to follow-up (LTFU) (including 5 pretreatment LTFU). Predictors of all-cause mortality included shortness of breath on admission [aOR: 6.4, 95% confidence interval (CI): 1.3-49.1], high bacillary burden on Xpert MTB/RIF assay (aOR: 17.0, 95% CI: 1.6-260.5) and the presence of lung cavities on chest radiograph (aOR: 4.8, 95% CI: 1.1-23.3). Among 74 patients who initiated treatment, 39 (53%) had at least one grade 1-2 AE, and 4 (5%) had one grade 3-4 AE each, including hepatotoxicity, QT prolongation, hearing loss and rash/hyperpigmentation., Conclusion: Younger children were underrepresented among those treated for MDR/RR-TB, indicating reduced access to care. Severe AEs were uncommon during MDR/RR-TB treatment. Baseline indicators of extensive disease were associated with all-cause mortality. The high proportion of pre-treatment mortality and LTFU may reflect complex patient pathways limiting access to care., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Heart failure (HF) registries provide valuable insights into patient management and quality of care. However, healthcare professionals face challenges due to the administrative burden of participation in registries. This study aims to evaluate the impact of education through an engagement toolkit on HF nurse practitioners' participation rate and data completeness in a national registry: the Netherlands Heart Registration-Heart Failure (NHR-HF) registry., Methods and Results: Engage-HF is an observational study (intervention at the HF nurse level) with a pretest-posttest design within the participating hospitals. Between December 2022 and April 2024, 28 HF nurse practitioners from 12 hospitals will participate in a 24-week educational programme using the Engage-HF engagement toolkit. The main interaction platform in this toolkit is a gamified smartphone-based educational application called BrightBirds. The complete toolkit includes this educational application with weekly challenges, interactive posters, pop-ups, and alert messages, and a follow-up call at Week 4. The primary endpoints are the NHR-HF participation rates and data completeness at 1 and 6 months after using the toolkit. Additionally, we will analyse the experience of participants with the toolkit concerning their HF registry and knowledge of ESC 2021 HF guidelines., Conclusion: The Engage-HF study is the first to explore the impact of education through a gamified engagement toolkit to boost participation rates in a HF registry (NHR-HF) and test participant knowledge of the ESC 2021 HF guidelines. This innovative approach addresses challenges in the rollout of healthcare registries and the implementation of guidelines by providing a contemporary support base and a time-efficient method for education., Competing Interests: Conflict of interest: J.S. received payment for lectures/presentations/consultancy outside the scope of the submitted work from Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, General Electric, and Novo Nordisk. R.M.A.v.d.B. received an independent research grant and speaker fees from Abbott to the institute outside the scope of the submitted work. J.J.B. received an independent research grant for ISS from Abbott to the institute and has had speaker engagement or advisory boards in the past 5 years with AstraZeneca, Abbott, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Novartis, and Vifor. L.M.H. received a grant from the Dutch Heart Foundation (2020T058), Netherlands CardioVascular Research Initiative (CVON; 2020B008), and a Vifor Pharma investigator-initiated grant. Furthermore, he received speaker/consultancy fees from Novartis, Boehringer Ingelheim, Daiichi Sankyo, Vifor Pharma, AstraZeneca, Bayer, MSD, Abbott, and Quin, all not related to this work. J.W.C.B. received speaker fees from Abbott, AstraZeneca, Boehringer Ingelheim, and Novartis. R.v.K. received speaker fees from Novartis and Bayer. F.W.A. and D.v.V., as a representative of the Heart4Data consortium, received funding from the Dutch Heart Foundation and ZonMw (2021-B2015) to the institute as a part of the funding for this study. C.E.E.v.O.-H. is a board member of NVVC, audit committee in FMS, and ESC Heart Academy Alumni. R.P. received grants from NovoNordisk to the institution outside the scope of this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Polymorphisms in the KIR and HLA genes contribute to the diversity of the NK cell repertoire. Extrinsic factors also play a role in modifying this repertoire. The best example is cytomegalovirus, which promotes the expansion of memory-like NK cells. However, the mechanisms governing this phenotypic structure are poorly understood. Furthermore, the influence of age and sex has been understudied., Methods: In this study, we examined these parameters in a cohort of 200 healthy volunteer blood donors, focusing on the major inhibitory KIR receptors and CD94/NKG2A, as well as the differentiation marker CD57 and the memory-like population marker NKG2C. Flow cytometry and two joint analyses, unsupervised and semi-supervised, helped define the impact of various intrinsic and extrinsic markers on the phenotypic structure of the NK cell repertoire., Results: In the KIR NK cell compartment, the KIR3DL1 gene is crucial, as unexpressed alleles lead to a repertoire dominated by KIR2D interacting only with HLA-C ligands, whereas an expressed KIR3DL1 gene allows for a greater diversity of NK cell subpopulations interacting with all HLA class I ligands. KIR2DL2 subsequently favors the KIR2D NK cell repertoire specific to C1/C2 ligands, whereas its absence promotes the expression of KIR2DL1 specific to the C2 ligand. The C2C2Bw4+ environment, marked by strong -21T motifs, favors the expansion of the NK cell population expressing only CD57, whereas the absence of HLA-A3/A11 ligands favors the population expressing only NKG2A, a population highly represented within the repertoire. The AA KIR genotype favors NK cell populations without KIR and NKG2A receptors, whereas the KIR B+ genotypes favor populations expressing KIR and NKG2A. Interestingly, we showed that women have a repertoire enriched in CD57- NK cell populations, while men have more CD57+ NK cell subpopulations., Discussion: Overall, our data demonstrate that the phenotypic structure of the NK cell repertoire follows well-defined genetic rules and that immunological history, sex, and age contribute to shaping this NK cell diversity. These elements can contribute to the better selection of hematopoietic stem cell donors and the definition of allogeneic NK cells for cell engineering in NK cell-based immunotherapy approaches.cters are displayed correctly., Competing Interests: The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Ferron, David, Willem, Legrand, Salameh, Anquetil, Walencik, Gendzekhadze, Gagne and Retière.)