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Successful antimicrobial therapy depends on achieving optimal drug concentrations within individual patients. Inter-patient variability in pharmacokinetics (PK) and differences in pathogen susceptibility (reflected in the minimum inhibitory concentration, [MIC]) necessitate personalised approaches. Dose individualisation strategies aim to address this challenge, improving treatment outcomes and minimising the risk of toxicity and antimicrobial resistance. Therapeutic drug monitoring (TDM), with the application of population pharmacokinetic (popPK) models, enables model-informed precision dosing (MIPD). PopPK models mathematically describe drug behaviour across populations and can be combined with patient-specific TDM data to optimise dosing regimens. The integration of machine learning (ML) techniques promises to further enhance dose individualisation by identifying complex patterns within extensive datasets. Implementing these approaches involves challenges, including rigorous model selection and validation to ensure suitability for target populations. Understanding the relationship between drug exposure and clinical outcomes is crucial, as is striking a balance between model complexity and clinical usability. Additionally, regulatory compliance, outcome measurement, and practical considerations for software implementation will be addressed. Emerging technologies, such as real-time biosensors, hold the potential for revolutionising TDM by enabling continuous monitoring, immediate and frequent dose adjustments, and near patient testing. The ongoing integration of TDM, advanced modelling techniques, and ML within the evolving digital health care landscape offers a potential for enhancing antimicrobial therapy. Careful attention to model development, validation, and ethical considerations of the applied techniques is paramount for successfully optimising antimicrobial treatment for the individual patient., (© 2024. The Author(s).)

Data published on the oral clavulanic acid pharmacokinetics in the pediatric population is lacking. This research aimed to describe clavulanic acid disposition following oral and intravenous administration and to provide insights into clavulanic acid exposure based on threshold concentrations for (pre-)term neonates and infants. This pooled population pharmacokinetic study combined four datasets for analysis in NONMEM v7.4.3. Clavulanic acid exposure was simulated using the percentage of time above the threshold concentrations (%fT > C T ). Multiple dosage regimens and amoxicillin/clavulanic acid dosage ratios were evaluated. The cohort consisted of 89 (42 oral, 47 intravenous) subjects (403 samples) with a median (range) postnatal age 54.5 days (0-365), gestational age 37.4 weeks (23.0-41.7), and current bodyweight 3.9 kg (0.6-9.0). A one-compartment model with first-order absorption best described clavulanic acid pharmacokinetics with postnatal age as a covariate on the inter-individual variability of clearance. Oral bioavailability was 24.4% in neonates up to 10 days of age. An oral dosing regimen 90 mg/kg/day amoxicillin/clavulanic acid (4:1 ratio) resulted in 40.2% of simulated patients achieving 100% fT > C T,2mg/L . An amoxicillin/clavulanic acid ratio of 4:1 is preferred for neonatal oral regimens due to the higher exposure along the entire %fT > C T range (0-100%) as ratios higher than 4:1 might result in inadequate exposure. Our results highlight substantial exposure differences (%fT > C T ) when using threshold concentrations of 1 mg/L vs. 2 mg/L. This first population pharmacokinetic model for clavulanic acid in neonates may serve as a foundational step for future research, once more precise clavulanic acid targets become available., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Chemsex refers to the use of psychoactive substances with sex. We carried out a systematic scoping review of methodological characteristics of chemsex research among men who have sex with men (MSM), published between 2010 and 2020. For inclusion, chemsex had to be the main focus, and studies had to specify GHB/GBL, stimulant (amphetamine, crystal meth, ecstasy/MDMA, cathinones, cocaine) and/or ketamine use with sex as a variable. From 7055 titles/abstracts, 108 studies were included, mostly cross-sectional, and from Western countries. About one-third of studies recruited exclusively from clinical settings. A majority of these recruited from sexually transmitted infection (STI) clinics. The included quantitative studies analyzed possible associations between chemsex and STI health (40%), mental health (15%), drug health (12%), sexological health (10%), and post-diagnostic HIV health (7%). Most studies included GHB/GBL and crystal meth in their operationalization of chemsex. Definitions and operationalizations of chemsex vary greatly in the literature, and researchers of chemsex among MSM should consider ways in which this variation impacts the validity of their results. More studies are needed among MSM in non-high income and non-Western countries, and examination of possible links between chemsex and post-diagnostic HIV health, sexological health, and mental health.

Objectives: WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam., Methods: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination., Results: We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required., Conclusions: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Opioid Maintenance Treatment (OMT) is the gold standard for people with opioid dependence. However, drop-out rates are high, and many patients do not reach desired outcomes. Understanding patients' and healthcare providers' experiences with the treatment can provide valuable information to improve the quality of OMT and to increase acceptability and accessibility of services. The aim of this systematic review is to explore and synthesise the experiences of OMT among persons with opioid dependence and health care providers, to inform policy makers and practitioners on how to improve OMT outcomes., Methods: We conducted a qualitative evidence synthesis. We systematically searched in electronic databases (CINAHL, Embase, MEDLINE, and nordic databases) and searched for grey literature. As we identified many studies that met our inclusion criteria, we purposively sampled a manageable number of studies to include in this review. Two researchers independently extracted and coded data from the included studies and used the Andersen's healthcare utilization model to organize and develop codes. We assessed the methodological limitations of the studies, and our confidence in the findings using GRADE CERQual., Results: We retrieved 56 relevant studies and purposively sampled 24 qualitative studies of patients' and healthcare providers' experiences with OMT. Our analyses resulted in six main themes: (1) External stigma prevents engagement and retention in treatment, (2) Being identified as in OMT contributed to an increased experience of stigma (3) Inadequate knowledge and expertise among healthcare providers affected patients' treatment experiences, (4) Quality of communication between personnel and patients impacts patients' engagement with treatment and treatment outcomes, (5) Patients wanted help with many aspects of their lives not just medication, and (6) Balancing positive expectations of OMT with treatment stigma. We found that stigma was an overarching theme across these themes., Conclusion: Our findings suggest that OMT could be more beneficial for patients if treatment programs prioritize efforts to diminish societal and OMT provider stigma and find strategies to better address patient needs. Initiatives should focus on improving treatment knowledge among providers, encouraging the use of client perspectives, considering the context of family members, and establishing a more holistic and flexible treatment environment., (© 2024. The Author(s).)

Word-finding difficulties for naming everyday objects are often prevalent in aphasia. Traditionally, treating these difficulties has involved repeated drilling of troublesome items with a therapist. Spaced repetition schedules can improve the efficiency of such training. However, spaced repetition in a therapy environment can be both difficult to implement and time-consuming. The current study evaluated the potential utility of automated, asynchronous, online spaced repetition training for the treatment of word-finding difficulties in individuals with aphasia. Twenty-one participants completed a two-week training study, completing approximately 60 minutes per day of asynchronous online drilling. The training items were identified using a pretest, and word-finding difficulties were evaluated both at the end of training (i.e., a post-test) and four weeks later (i.e., a retention test). The trained items were separated into three different spaced-repetition schedules: (1) Short-spacing; (2) Long-spacing; and (3) Adaptive-spacing. At the retention-test, all trained items outperformed non-trained items in terms of accuracy and reaction time. Further, preliminary evidence suggested a potential reaction time advantage for the adaptive-spacing condition. Overall, online, asynchronous spaced repetition training appears to be effective in treating word-finding difficulties in aphasia. Further research will be required to determine if different spaced repetition schedules can be leveraged to enhance this effect.

Internet-delivered Cognitive-Behavioural Therapy (ICBT) aims to support people with mental health concerns using online treatment materials. Client stories (either real or a composite based on many clients) are often used in ICBT to facilitate learning. However, these stories remain understudied in terms of how they are perceived by clients, as well as their relationship to ICBT engagement, satisfaction, and outcomes. Among a sample of 324 clients enrolled in transdiagnostic ICBT targeting symptoms of depression and anxiety, we examined client perceptions of stories through mixed-method qualitative (open-ended) and quantitative (closed-ended) data collection. Specifically, 234 (72.22 %) clients responded to questions about stories at 4 weeks and 221 (68.21 %) responded to questions at 8 weeks. Most clients who responded to questions endorsed reviewing at least some stories (79.06 % at 4 weeks, 71.95 % at 8 weeks). Moreover, they rated stories positively in terms of being relatable, making clients feel less alone, increasing knowledge, providing ideas for how to use skills, and motivating clients to use skills. These perceptions of stories remained stable over the course of treatment. Stories were perceived more positively among those with lower symptom severity at 8 weeks as well as those who were more satisfied with ICBT at 8 weeks. Story perceptions at 4 weeks were predictive of decreased post-treatment anxiety symptom severity but not depression while controlling for baseline scores, age, and education. 26.49 % of clients at 4 weeks who reviewed stories and 33.33 % at 8 weeks provided suggestions about how to improve stories. In a qualitative analysis, we found 5 categories of suggestions including increasing the variety of issues and relatability of stories, ensuring the stories are realistic, refining the formatting, and making the stories shorter. Overall, this study provides insights into how client stories could be improved to play a more significant role in future ICBT programs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Objectives: Antibiotic dosing is not optimal in the ICU. Our recent trial investigated the effect of model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin and showed no significant differences in clinical outcomes in all patients. This study aimed to identify subgroups of patients in which the MIPD of these antibiotics could be beneficial for clinical outcomes., Methods: We analysed data from the DOLPHIN randomized controlled trial, which compared MIPD to standard dosing of beta-lactam antibiotics and ciprofloxacin in 388 ICU patients. We divided patients into subgroups based on baseline characteristics and assessed the effect of MIPD on 28-day mortality, 6-month mortality, change in sequential organ failure assessment (delta-SOFA), and ICU length of stay (LOS)., Results: We found a lower 28-day mortality in patients with a SOFA below 8 randomized to MIPD (OR 0.40; 95% CI 0.17-0.88). However, patients with a higher SOFA show an increased 28-day mortality (OR 1.94; 95% CI 1.07-3.59) in the MIPD group. ICU LOS was increased in patients receiving MIPD with a SOFA below 8 (IRR 1.36; 95% CI 1.01-1.83) and those receiving MIPD for ceftriaxone (IRR 1.76; 95% CI 1.24-2.51). Patients receiving a dose recommendation within 24 hours show a trend towards decreased ICU LOS (IRR 0.77; 95% CI 0.52-1.16) and higher delta-SOFA (estimate -1.19; 95% CI -2.98-0.60)., Conclusions: ICU patients with a SOFA below 8 using MIPD had an increased ICU LOS but a lower 28-day mortality. Fast dose recommendations using MIPD of beta-lactam antibiotics and ciprofloxacin needs to be investigated in ICU patients., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Drain-associated intracerebral infections are life-threatening emergencies. Their treatment is challenging due to the limited penetration of antibiotics to the site of infection, resulting in potentially inadequate exposure. The emergence of multidrug-resistant pathogens might force the use of off-label intrathecal (IT) doses of antibiotics. We reviewed the literature on general aspects determining intrathecal dosing regimen, using pharmacometric knowledge. We summarised clinical experience with IT doses of antibiotics that are usually not used intrathecally, as well as the outcome of the cases and concentrations reached in the cerebrospinal fluid (CSF). Factors determining the IT regimen are the size of the ventricle system and the CSF drainage volume. With regard to pharmacometrics, pharmacokinetic/pharmacodynamic indices are likely similar to those in non-cerebral infections. The following number (N) of cases were described: benzylpenicillin (>50), ampicillin (1), ceftazidime (2), cephaloridine (56), ceftriaxone (1), cefotiam (1), meropenem (57), linezolid (1), tigecycline (15), rifampicin (3), levofloxacin (2), chloramphenicol (3) and daptomycin (8). Many side effects were reported for benzylpenicillin in the 1940-50s, but for the other antibiotics, when administered correctly, all side effects were minor and reversible. These data might help when choosing an IT dosing regimen in case there is no alternative option due to antimicrobial resistance., Competing Interests: The authors declare no conflict of interest.

Purpose: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied., Methods: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated., Results: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively)., Conclusion: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects., (© 2023. The Author(s).)

Purpose: A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets., Methods: Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC 24h /MIC of 83 and 75%T >MIC ) and bacteriostatic (AUC 24h /MIC of 25) plasma targets and bacteriostatic (AUC 24h /MIC of 3994) urine target., Results: A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L., Conclusion: For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T >MIC target than intermittent infusion., (© 2023. The Author(s).)

Background: Standard antibiotic dosing is not suitable for critically ill patients, due to altered pharmacokinetics (PK) in these patients. Knowledge of protein binding is important for optimizing antibiotic exposure because only the unbound fraction is pharmacologically active. If unbound fractions can be predicted, minimal sampling techniques and less costly methods can be routinely used., Methods: Data from the DOLPHIN trial, a prospective randomized clinical trial that included critically ill patients, were used. Total and unbound ceftriaxone concentrations were determined using a validated UPLC-MS/MS method. A non-linear saturable binding model was made using 75% of the trough concentrations and validated on the remaining data. Our model and previously published models were tested for their performance for subtherapeutic (<1 mg/L) and high (>10 mg/L) unbound concentrations., Results: In total, 113 patients were sampled [Acute Physiology And Chronic Health Evaluation version 4 (APACHE IV) score 71 (IQR 55-87), albumin 28 g/L (IQR 24-32)]. This resulted in 439 samples (trough = 224, peak = 215). Unbound fractions were significantly different between samples taken at trough and peak times [10.9% (IQR 7.9-16.4) versus 19.7% (IQR 12.9-26.6), P < 0.0001], which was not explained by concentration differences. Our model and most literature models showed good sensitivity and low specificity to determine high and subtherapeutic ceftriaxone trough concentrations using only the total ceftriaxone and albumin concentrations., Conclusions: Ceftriaxone protein binding is not concentration related in critically ill patients. Existing models show good ability to predict high concentrations, but low specificity in predicting subtherapeutic concentrations., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Although polymyxin B has been in use since the late 1950s, there have been limited studies done to unravel its pharmacokinetics (PK) and pharmacodynamics (PD) index., Methods: We determined, in neutropenic infected mice, the PK, plasma protein binding and PK/PD index best correlating with efficacy for Escherichia coli and Klebsiella pneumoniae strains., Results: The pharmacokinetic profile showed non-linear PK; dose was significantly correlated with absorption rate and clearance. The inhibitory sigmoid dose-effect model for the fCmax/MIC index of E. coli fitted best, but was only modestly higher than the R2 of %fT>MIC and fAUC/MIC (R2 0.91-0.93). For K. pneumoniae the fAUC/MIC index had the best fit, which was slightly higher than the R2 of %fT>MIC and fCmax/MIC (R2 0.85-0.91). Static targets of polymyxin B fAUC/MIC were 27.5-102.6 (median 63.5) and 5.9-60.5 (median 11.6) in E. coli and in K. pneumoniae isolates, respectively. A 1 log kill effect was only reached in two E. coli isolates and one K. pneumoniae. The PTA with the standard dosing was low for isolates with MIC >0.25 mg/L., Conclusions: This study confirms that fAUC/MIC can describe the exposure-response relationship for polymyxin B. The 1 log kill effect was achieved in the minority of the isolates whereas polymyxin B PK/PD targets cannot be attained for the majority of clinical isolates with the standard dosing regimen, indicating that polymyxin B may be not effective against serious infections as monotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Temocillin is used for the treatment of various infections caused by Enterobacterales . The pharmacokinetic (PK)/pharmacodynamic (PD) index that is best correlated with the activity of beta-lactams is the percentage of time that the unbound concentration exceeds the MIC (% f T>MIC). However, the % f T>MIC needed for a bacteriostatic or killing effect of temocillin is unknown in thigh and lung infection models. In the present study, we studied the temocillin PK in plasma and epithelial lining fluid (ELF) of infected neutropenic mice and determined the plasma exposure-response relationships for Escherichia coli and Klebsiella pneumoniae. Neutropenic murine thigh and lung infection models were used. The bacterial loads in the thighs or lungs were determined. A sigmoid maximum-effect model was used to fit the plasma exposure-response relationship. A one-compartment model with first-order absorption best described temocillin PK (clearance [CL], 1.03 L/h/kg; volume of distribution [ V ], 0.457 L/kg). Protein binding was 78.2% ± 1.3% across different plasma concentrations. A static effect was achieved for all strains in both the thigh and lung infection models. However, the median % f T>MIC needed for a static effect was much lower in the lung infection model (27.8% for E. coli and 38.2% for K. pneumoniae) than in the thigh infection model (65.2% for E. coli and 64.9% for K. pneumoniae). A 1-log kill was reached for all strains in the lung infection model (median % f T>MIC values of 42.1% for E. coli and 44.1% for K. pneumoniae) and 7 out of 8 strains in the thigh infection model (median % f T>MIC values of 85.4% for E. coli and 74.5% for K. pneumoniae). These data support the use of temocillin in patients with pneumonia.

The number of pharmacokinetic (PK) models of meropenem is increasing. However, the daily role of these PK models in the clinic remains unclear, especially for critically ill patients. Therefore, we evaluated the published meropenem models on real-world ICU data to assess their suitability for use in clinical practice. All models were built in NONMEM and evaluated using prediction and simulation-based diagnostics for the ability to predict the subsequent meropenem concentrations without plasma concentrations (a priori), and with plasma concentrations (a posteriori), for use in therapeutic drug monitoring (TDM). Eighteen PopPK models were included for evaluation. The a priori fit of the models, without the use of plasma concentrations, was poor, with a prediction error (PE)% of the interquartile range (IQR) exceeding the ±30% threshold. The fit improved when one to three concentrations were used to improve model predictions for TDM purposes. Two models were in the acceptable range with an IQR PE% within ±30%, when two or three concentrations were used. The role of PK models to determine the starting dose of meropenem in this population seems limited. However, certain models might be suitable for TDM-based dose adjustment using two to three plasma concentrations.

Aims: To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus., Methods: Five samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NONMEM (v7.4.2). The percentage of patients reaching 100% fT>MIC ECOFF was used to compare different dosage regimens for Enterobacterales and S. aureus., Results: This study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h -1 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h -1 for S. aureus resulted in a minimum of 99% PTA., Conclusion: Cefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h -1 was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h -1 would be preferred if eGFR and albumin concentration exceed 80 mL min -1 and 40 g L -1 respectively., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Machine learning (ML) tools exist that can reduce or replace human activities in repetitive or complex tasks. Yet, ML is underutilized within evidence synthesis, despite the steadily growing rate of primary study publication and the need to periodically update reviews to reflect new evidence. Underutilization may be partially explained by a paucity of evidence on how ML tools can reduce resource use and time-to-completion of reviews., Methods: This protocol describes how we will answer two research questions using a retrospective study design: Is there a difference in resources used to produce reviews using recommended ML versus not using ML, and is there a difference in time-to-completion? We will also compare recommended ML use to non-recommended ML use that merely adds ML use to existing procedures. We will retrospectively include all reviews conducted at our institute from 1 August 2020, corresponding to the commission of the first review in our institute that used ML., Conclusion: The results of this study will allow us to quantitatively estimate the effect of ML adoption on resource use and time-to-completion, providing our organization and others with better information to make high-level organizational decisions about ML., (© 2023. The Author(s).)

Purpose: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking., Methods: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment., Results: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes., Conclusions: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation., (© 2022. The Author(s).)

Background: Very limited studies, so far, have been conducted to identify the pharmacodynamic targets of cefepime, a well-established fourth-generation cephalosporin. As a result, conventional targets representing the cephalosporin class are used for cefepime target attainment analysis., Objectives: We employed both a neutropenic murine lung infection model and an in vitro pharmacokinetic model (IVPM) to determine cefepime's pharmacodynamic target [percentage of the dosing interval during which unbound drug concentrations remain higher than the MIC (%fT>MIC)] for bacteriostatic and 1 log10 kill effects., Methods: Ten strains with cefepime MICs ranging from 0.03 to 16 mg/L were studied in the lung infection. In the IVPM, five cefepime-resistant strains with cefepime/tazobactam (fixed 8 mg/L) MICs ranging from 0.25 to 8 mg/L were included. Through 24 h dose fractionation, both in lung infection and IVPM (in the latter case, tazobactam 8 mg/L continuous infusion was used to protect cefepime), varying cefepime exposures and corresponding pharmacodynamic effect scenarios were generated to identify the pharmacodynamic targets., Results: Using a non-linear sigmoidal maximum-effect (Emax) model, the cefepime's plasma fT>MIC for 1 log10 kill in lung infection ranged from 17% to 53.7% and a combined exposure-response plot yielded 30%. In the case of IVPM, T>MIC ranged from 6.9% to 75.4% with a mean value of 34.2% for 1 log10 kill., Conclusions: Both in vivo and in vitro studies showed that cefepime's pharmacodynamic requirements are lower than generally reported for cephalosporins (50%-70% fT>MIC). The lower requirement for cefepime could be linked with factors such as cefepime's better permeation properties and multiple PBP affinity-driven enhanced bactericidal action., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients., Objectives: To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU., Methods: Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill-Langmuir equation taking ligand depletion into account., Results: Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (Bmax) was 1.2-2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%-29%, 23%-42% and 32%-52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2-3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction., Conclusions: Temocillin PPB is saturable, 2-4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose This study aimed to synthesise the available knowledge on how participant engagement in supported employment (SE) interventions is presented, defined, and conceptualised. We also aimed to develop a working definition of participant engagement in SE based on the results of our study. Methods This systematic scoping review was conducted following the PRISMA extension for scoping reviews. The following databases were systematically searched: EBSCO, SCOPUS, Social Care Online, and JSTOR. We included peer-reviewed publications in English based on empirical studies. Results Sixteen articles met the inclusion criteria and were included in the final analysis. Thematic framework analysis resulted in three themes conveying the concept of participant engagement: self-determined choice, empowerment, and collaboration/working alliance. We suggest that participant engagement in SE is an active multifaceted process that involves the empowerment of participants, participants' exercise of self-determined informed choice, and their collaboration with SE practitioners in a working alliance. Conclusions Participant empowerment, self-determined choice, and collaboration are important aspects of participant engagement in SE. The study results will appeal to SE practitioners and make significant contributions to the broader field of other vocational services supporting people in (re-)entering the competitive labour market., (© 2021. The Author(s).)

Introduction: Currently, antibiotic treatment is often a standard dosing regimen in bone and joint infections (BJI). However, it remains unknown if exposure at the target-site is adequate. The aim of this review is to gain more insight in the relationship between the target site concentration of antibiotic and the minimal inhibitory concentration to target the bacteria in bone and joint infections (BJI)., Areas Covered: A literature search was performed by Erasmus MC Medical library. Bone, bone tissue and synovial concentration of antibiotics were covered in humans. In addition, we reported number of patients, dose, sampling method, analytical method and tissue and plasma concentrations. We used the epidemiological cutoff value (ECOFF) values of the targeted micro-organisms. If more than 3 publications were available on the antibiotic, we graphically presented ECOFFS values against reported antibiotic concentrations., Expert Opinion: For most antibiotics, the literature is sparse. In addition, a lot of variable and total antibiotic concentrations are published. Ciprofloxacin, cefazolin, cefuroxime, vancomycin and linezolid seem to have adequate average exposure if correlating total concentration to ECOFF, when standard dosing is used. With regard to other antibiotics, results are inconclusive. More extensive pharmacokinetic/pharmacodynamic modeling in BJI is needed.

For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates were measured to determine the wild-type distribution. The PD of 8 S. aureus, 1 S. pyogenes, and 1 S. agalactiae isolates were evaluated in a neutropenic murine thigh infection model. Two S. aureus isolates were used in a dose-fractionation study and a dose−response analysis was performed additionally in the in vivo model. Data were analyzed with a population PK and sigmoid maximum effect model. The end of the wild-type distribution was 1 mg/L. The percentage of time the unbound concentration was above MIC (%fT > MIC) was best correlated with efficacy. For S. aureus, median %fT > 0.25 × MIC required for 1-log reduction was 15%. The value for S. pyogenes was 10%fT > MIC and for S. agalactiae 22%fT > 0.25xMIC for a 1-log reduction. The effect of flucloxacillin reached a 2-log reduction of S. aureus at 20%fT > 0.25xMIC and also for S. pyogenes and S. agalactiae, a reduction was reached. These data may serve to optimize dosing regimens currently used in humans.

Background: Recent studies demonstrated that failure of achieving pharmacodynamic targets of commonly used antibiotics is common in critically ill patients. Therapeutic drug monitoring (TDM) can contribute to optimize the exposure of beta-lactams and ciprofloxacin. While evidence for TDM of these antibiotics is growing, translation into clinical implementation remains limited. Therefore, perceived barriers and facilitators are important for implementing TDM in this population. The primary aim of this study was to identify healthcare professionals' barriers and facilitators for the implementation of TDM of beta-lactams and ciprofloxacin in Dutch intensive care units (ICU)., Methods: We conducted a nationwide cross-sectional online survey among healthcare professionals (HCPs) involved in antibiotic treatment of ICU patients. An adapted version of the Measurement Instrument for Determinants of Innovations was sent out. Items were considered barriers when ≥ 20% of participants responded with a negative answer. If ≥ 80% of the participants responded with a positive answer, the item was considered a facilitator., Results: Sixty-four HCPs completed the survey, of which 14 were from academic hospitals, 25 from general hospitals, and 25 from teaching hospitals. Most participants were hospital pharmacists (59%) or medical specialists (23%). Eleven barriers and four facilitators for implementation of TDM of beta-lactams were identified; 17 barriers for TDM of ciprofloxacin and no facilitators. The most important barriers were a lack of conclusive evidence, organizational support, and low availability of assays. Additional barriers were a lack of consensus on which specific patients to apply TDM and which pharmacodynamic targets to use. Identified facilitators for beta-lactam TDM implementation are low complexity and high task perception, combined with the perception that TDM is important to prevent side effects and to adequately treat infections. Twenty-eight percent of participants reported that flucloxacillin could be analyzed in their hospital. Assay availability of other beta-lactams and ciprofloxacin was lower (3-17%)., Conclusion: Several barriers were identified that could obstruct the implementation of TDM of beta-lactams and ciprofloxacin in the ICU. In particular, education, clear guidelines, and organizational support should be considered when creating tailored implementation strategies. Finally, evidence of beneficial clinical outcomes on TDM of beta-lactams and ciprofloxacin can enhance further implementation., (© 2022. The Author(s).)

Background: One lesson from the current COVID-19 pandemic is the need to optimize health care provision outside of traditional settings, and potentially over longer periods of time. An important strategy is remote patient monitoring (RPM), allowing patients to remain at home, while they transmit health data and receive follow-up services. Materials and Methods: We conducted an overview of the latest systematic reviews that had included randomized controlled trials with adult patients with chronic diseases. We summarized results and displayed these in forest plots, and used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) to assess our certainty of the evidence. Results: We included 4 systematic reviews that together reported on 11 trials that met our definition of RPM, each including patients with diabetes and/or hypertension. RPM probably makes little to no difference on HbA1c levels. RPM probably leads to a slight reduction in systolic blood pressure, with questionable clinical meaningfulness. RPM probably has a small negative effect on the physical component of health-related quality of life, but the clinical significance of this reduction is uncertain. We have low confidence in the finding that RPM makes no difference to the remaining five primary outcomes. Conclusion: Most of our findings are consistent with reviews of other, broader definitions of RPM. The type of RPM examined in this review is as effective as standard treatment for patients with diabetes/hypertension. If this or other types of RPM are to be used for "long covid" patients or for other chronic disease groups post-pandemic, we need to understand why RPM may negatively affect quality of life.

Background: Machine learning and automation are increasingly used to make the evidence synthesis process faster and more responsive to policymakers' needs. In systematic reviews of randomized controlled trials (RCTs), risk of bias assessment is a resource-intensive task that typically requires two trained reviewers. One function of RobotReviewer, an off-the-shelf machine learning system, is an automated risk of bias assessment., Methods: We assessed the feasibility of adopting RobotReviewer within a national public health institute using a randomized, real-time, user-centered study. The study included 26 RCTs and six reviewers from two projects examining health and social interventions. We randomized these studies to one of two RobotReviewer platforms. We operationalized feasibility as accuracy, time use, and reviewer acceptability. We measured accuracy by the number of corrections made by human reviewers (either to automated assessments or another human reviewer's assessments). We explored acceptability through group discussions and individual email responses after presenting the quantitative results., Results: Reviewers were equally likely to accept judgment by RobotReviewer as each other's judgement during the consensus process when measured dichotomously; risk ratio 1.02 (95% CI 0.92 to 1.13; p = 0.33). We were not able to compare time use. The acceptability of the program by researchers was mixed. Less experienced reviewers were generally more positive, and they saw more benefits and were able to use the tool more flexibly. Reviewers positioned human input and human-to-human interaction as superior to even a semi-automation of this process., Conclusion: Despite being presented with evidence of RobotReviewer's equal performance to humans, participating reviewers were not interested in modifying standard procedures to include automation. If further studies confirm equal accuracy and reduced time compared to manual practices, we suggest that the benefits of RobotReviewer may support its future implementation as one of two assessors, despite reviewer ambivalence. Future research should study barriers to adopting automated tools and how highly educated and experienced researchers can adapt to a job market that is increasingly challenged by new technologies., (© 2022. The Author(s).)

Background: Opioid use has increased globally in the recent decade. Although pain remains a significant problem among older adults, susceptibility to opioid-related harms highlights the importance of careful opioid therapy monitoring on individual and societal levels. We aimed to describe the trends of prescription opioid utilisation among residents aged ≥65 in all Nordic countries during 2009-2018., Methods: We conducted cross-sectional measurements of opioid utilisation in 2009-2018 from nationwide registers of dispensed drugs in Denmark, Finland, Iceland, Norway, and Sweden. The measures included annual opioid prevalence, defined daily doses (DDDs) per 1000 inhabitants per day (DIDs), and morphine milligram equivalents (MMEs) per user per day., Results: From 2009 to 2018, an average of 808,584 of adults aged ≥65 used opioids yearly in all five countries; an average annual prevalence of 17.0%. During this time period, the prevalence decreased in Denmark, Norway, and Sweden due to declining codeine and/or tramadol use. Iceland had the highest opioid prevalence in 2009 (30.2%), increasing to 31.7% in 2018. In the same period, DIDs decreased in all five countries, and ranged from 28.3 in Finland to 58.5 in Denmark in 2009, and from 23.0 in Finland to 54.6 in Iceland in 2018. MMEs/user/day ranged from 4.4 in Iceland to 19.6 in Denmark in 2009, and from 4.6 in Iceland to 18.8 in Denmark in 2018. In Finland, Norway, and Sweden, MMEs/user/day increased from 2009 to 2018, mainly due to increasing oxycodone utilisation., Conclusions: The stable or decreasing opioid utilisation prevalence among a majority of older adults across the Nordic countries coincides with an increase in treatment intensity in 2009-2018. We found large cross-national differences despite similarities across the countries' cultures and healthcare systems. For the aged population, national efforts should be placed on improving pain management and monitoring future trends of especially oxycodone utilisation., (© 2022. The Author(s).)

Systematic reviews are resource-intensive. The machine learning tools being developed mostly focus on the study identification process, but tools to assist in analysis and categorization are also needed. One possibility is to use unsupervised automatic text clustering, in which each study is automatically assigned to one or more meaningful clusters. Our main aim was to assess the usefulness of an automated clustering method, Lingo3G, in categorizing studies in a simplified rapid review, then compare performance (precision and recall) of this method compared to manual categorization. We randomly assigned all 128 studies in a review to be coded by a human researcher blinded to cluster assignment (mimicking two independent researchers) or by a human researcher non-blinded to cluster assignment (mimicking one researcher checking another's work). We compared time use, precision and recall of manual categorization versus automated clustering. Automated clustering and manual categorization organized studies by population and intervention/context. Automated clustering failed to identify two manually identified categories but identified one additional category not identified by the human researcher. We estimate that automated clustering has similar precision to both blinded and non-blinded researchers (e.g., 88% vs. 89%), but higher recall (e.g., 89% vs. 84%). Manual categorization required 49% more time than automated clustering. Using a specific clustering algorithm, automated clustering can be helpful with categorization of and identifying patterns across studies in simpler systematic reviews. We found that the clustering was sensitive enough to group studies according to linguistic differences that often corresponded to the manual categories., (© 2021 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Given the concerns raised regarding the effects of prenatal exposure to methadone and buprenorphine on the developmental outcomes of the children, this study assessed mental health and use of services in a national sample of school-aged children (N = 78) born to women enrolled in opioid maintenance treatment during pregnancy, compared with a group of foster children (N = 140). The majority of the opioid-exposed children lived with their birth parent(s) at the time of assessment (N = 62), while 16 lived in foster homes. Caregivers completed the Strengths and Difficulties Questionnaire (SDQ) and the Reactive Attachment Disorder scale. Teachers completed the SDQ. Three kinds of services were included in measuring service use: school-based education services, child mental health services, and hospital-based habilitation services. The main finding of the study is that children prenatally exposed to methadone or buprenorphine living with their family of origin had significantly better mental health status than their foster-placed counterparts and that of the comparison group of foster children. In addition, the exposed children living at home had less child welfare involvement, and only half of them were using any of the three services measured. The odds for using services increased significantly in accordance with increasing mental health problems, independent of group affiliation, indicating a need-based access to services. In line with other studies, we found that the odds for using one or more services was 2.3 times greater for boys than for girls. Our results contribute to a more-nuanced understanding of the developmental outcomes of prenatal exposure to methadone and buprenorphine, and factors associated with increased service use in groups of at-risk children., (© 2021. The Author(s).)

Background: With increasing knowledge of beta-lactam pharmacodynamics and interpatient and intrapatient variability in pharmacokinetics, the usefulness of therapeutic drug monitoring (TDM) is becoming increasingly clear. However, little research has been conducted to identify potential barriers and facilitators in the clinical implementation of beta-lactam TDM. This study provides an overview of the current practices of beta-lactam TDM and barriers and facilitators in its implementation., Methods: A systematic search was conducted using the Ovid MEDLINE database in April 2021, without restrictions on the publication date. All studies reporting the implementation of beta-lactam antibiotic TDM in critically ill patients through questionnaires or surveys were included in this review., Results: Six eligible studies were identified from 215 records, all of which were cross-sectional. All studies identified barriers and facilitators in the implementation of beta-lactam TDM in critically ill patients. The main barriers were insufficient knowledge about various aspects regarding the implementation of beta-lactam TDM and the unavailability of assays. Furthermore, a delay in the acquisition of TDM results reduces the probability of physicians altering drug dosages. Finally, doubts about the cost-effectiveness and clinical effectiveness of beta-lactam TDM in critically ill patients hinder broad implementation. Moreover, to improve the willingness of physicians to use beta-lactam TDM, collaboration between physicians and clinical pharmacists and clinical microbiologists should be strengthened., Conclusions: Although the evidence for application of beta-lactam TDM continues to grow, its clinical implementation remains limited. To enable optimal implementation of these antibiotics in critically ill patients, several barriers need to be overcome regarding logistics, equipment availability, clinical evidence, and proof of cost-effectiveness., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Guidelines do not distinguish between 50 mg or 100 mg nitrofurantoin as daily prophylaxis for recurrent urinary tract infection (UTI), although 50 mg might have a better safety profile. Our objective was to compare the effectiveness and safety of both regimens., Methods: Data were retrospectively collected from 84 Dutch GP practices between 2013 and 2020. Nitrofurantoin prescriptions of 100 mg and 50 mg every 24 hours in women were included. Cox proportional hazard regression analysis was used to calculate hazard ratios on first episode of UTI, pyelonephritis and (adverse) events. Patients were followed for the duration of consecutive repeated prescriptions, assuming non-informative right censoring, up to 1 year., Results: Nitrofurantoin prophylaxis was prescribed in 1893 patients. Median lengths of follow up were 90 days (interquartile range (IQR) 37-179 days) for 100 mg (n = 551) and 90 days (IQR 30-146 days) for 50 mg (n = 1342) with few differences in baseline characteristics between populations. Under 100 mg and 50 mg, 82/551 (14.9%) and 199/1342 (14.8%) developed UTI and 46/551 (8.3%) and 81/1342 (6.0%) developed pyelonephritis, respectively. Adjusted HRs of 100 mg versus 50 mg were 1.01 (95% CI 0.78-1.30) on first UTI, 1.37 (95% CI 0.95-1.98) on first pyelonephritis episode, 1.82 (95% CI 1.20-2.74) on first consultation for cough, 2.68 for dyspnoea (95% CI 1.11-6.45) and 2.43 for nausea (95% CI 1.03-5.74)., Conclusion: Daily prophylaxis for recurrent UTI with 100 mg instead of 50 mg nitrofurantoin was associated with an equivalent hazard on UTI or pyelonephritis, and a higher hazard on cough, dyspnoea and nausea. We recommend 50 mg nitrofurantoin as daily prophylaxis., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Optimizing beta-lactam antibiotic treatment is a promising method to reduce the length of intensive care unit (ICU) stay and therefore reduce ICU costs. We used data from the EXPAT trial to determine whether beta-lactam antibiotic target attainment is a cost determinant in the ICU., Methods: Patients included in the EXPAT trial were divided into target attainment and target nonattainment based on serum antibiotic levels. All hospital costs were extracted from the hospital administration system and categorized., Results: In total, 79 patients were included in the analysis. Target attainment showed a trend toward higher total ICU costs (€44,600 versus €28,200, P = 0.103). This trend disappeared when correcting for ICU length of stay (€2680 versus €2700). Renal replacement therapy was the most important cost driver., Conclusions: Target attainment for beta-lactam antibiotics shows a trend toward higher total costs in ICU patients, which can be attributed to the high costs of a long stay in the ICU and renal replacement therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Purpose: Early initiation of antibiotics is essential for ameliorating infections in critically ill patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure. Critically ill patients have altered pharmacokinetic parameters and are often infected by less susceptible microorganisms. Differences in drug disposition are not considered with standard doses of antibiotics. This can lead to suboptimal antibiotic exposure in critically ill patients. To overcome this problem of suboptimal dosing, therapeutic drug monitoring (TDM) is a strategy commonly used to support individualized dosing of antibiotics. It is routinely used for vancomycin and aminoglycosides in clinical practice. In recent years, it has become apparent that TDM may also be used in other antibiotics., Methods: This review summarizes the evidence for TDM of antibiotics in critically ill patients, focuses on clinical outcomes, and summarizes possibilities for optimized TDM in the future., Results and Conclusion: After reviewing the literature, we can conclude that general TDM implementation is advised for glycopeptides and aminoglycosides, as evidence of the relationship between TDM and clinical outcome is present. For antibiotics, such as beta-lactams, fluoroquinolones, and linezolid, it seems rational to perform TDM in specific patient cases. TDM involving other antibiotics is supported by individual cases, specifically to decrease toxicity. When focusing on future possibilities to improve TDM of antibiotics in critically ill patients, implementation of model-informed precision dosing should be investigated because it can potentially streamline the TDM process. The logistics of TDM, such as turnaround time and available equipment, are challenging but may be overcome by rapid bioanalytical techniques or real-time monitoring of drug concentrations through biosensors in the future. Education, clinical information on targets, and clinical outcome studies are other important factors that facilitate TDM implementation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90-120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.

Purpose of Review: To summarize the most recent evidence regarding nonprescribed androgen use among women and trans men., Recent Findings: Fourteen heterogeneous studies met inclusion criteria. Three provided lifetime prevalence estimates among particular subgroups (from 0.5 to 8%), whereas one longitudinal study found adverse childhood experiences predicted later nonprescribed androgen use. Mental health and substance problems appear to correlate with severity of use, but evidence is mixed as to whether female users had lower or equal mental health burdens compared to male users. Studies that discuss motivation highlighted the dynamic risk management that underlies decisions to continue use; benefits have to outweigh undesired effects, whereas some sexual side effects are re-framed to be positive. Finally, a theme among qualitative studies is the gendered experiences of nonprescribed androgen use, and the search for knowledge and communities created by women., Summary: Prevalence, side effects, and trajectories of use appear to be different for women than men. Women users need gender-specific information, although some are able to navigate male-dominated knowledge sources and are creating a female ethnopharmacology that privileges women's experiences. Health research, including epidemiology, gravely needs a gender perspective when examining nonprescribed androgen use, and one that is inclusive of transgender people., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression-free survival (PFS) in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real-world benefit of first-line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors., Methods: This study included HR-positive, HER2-negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression-free survival (PFS) was determined using Kaplan-Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil-to-lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time-dependent variable., Results: In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93-NR). Median PFS for patients with bone-only metastases (n = 54) was not reached (95% CI 18.21-NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33-33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71-0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97-1.18, p = 0.203)., Conclusion: The effectiveness of palbociclib and endocrine therapy in the treatment of HR-positive, HER2-negative mBC in the real-world setting is similar to the efficacy reported in the PALOMA-2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The Living Evidence Map Project at the Norwegian Institute of Public Health (NIPH) gives an updated overview of research results and publications. As part of NIPH's mandate to inform evidence-based infection prevention, control and treatment, a large group of experts are continously monitoring, assessing, coding and summarising new COVID-19 publications. Screening tools, coding practice and workflow are incrementally improved, but remain largely manual., Results: This paper describes how deep learning methods have been employed to learn classification and coding from the steadily growing NIPH COVID-19 dashboard data, so as to aid manual classification, screening and preprocessing of the rapidly growing influx of new papers on the subject. Our main objective is to make manual screening scalable through semi-automation, while ensuring high-quality Evidence Map content., Conclusions: We report early results on classifying publication topic and type from titles and abstracts, showing that even simple neural network architectures and text representations can yield acceptable performance., (© 2021. The Author(s).)