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

BACKGROUND: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. METHODS: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. RESULTS: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. CONCLUSIONS: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

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

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.

Using symbiotic empirical ethics to explore the significance of relationships to clinical ethics: findings from the Reset Ethics research project.

BACKGROUND: At the beginning of the coronavirus (Covid-19) pandemic, many non-Covid healthcare services were suspended. In April 2020, the Department of Health in England mandated that non-Covid services should resume, alongside the continuing pandemic response. This 'resetting' of healthcare services created a unique context in which it became critical to consider how ethical considerations did (and should) underpin decisions about integrating infection control measures into routine healthcare practices. We draw on data collected as part of the 'NHS Reset Ethics' project, which explored the everyday ethical challenges of resetting England's NHS maternity and paediatrics services during the pandemic. METHODS: Healthcare professionals and members of the public participated in interviews and focus group discussions. The qualitative methods are reported in detail elsewhere. The focus of this article is our use of Frith's symbiotic empirical ethics methodology to work from our empirical findings towards the normative suggestion that clinical ethics should explicitly attend to the importance of relationships in clinical practice. This methodology uses a five-step approach to refine and develop ethical theory based on a naturalist account of ethics that sees practice and theory as symbiotically related. RESULTS: The Reset project data showed that changed working practices caused ethical challenges for healthcare professionals, and that infection prevention and control measures represented harmful barriers to the experience of receiving and offering care. For healthcare professionals, offering care as part of a relational interaction was an ethically important dimension of healthcare delivery. CONCLUSIONS: Our findings suggest that foregrounding the importance of relationships across a hospital community will better promote the ethically important multi-directional expression of caring between healthcare professionals, patients, and their families. We offer two suggestions for making progress towards such a relational approach. First, that there is a change of emphasis in clinical ethics practice to explicitly acknowledge the importance of the relationships (including with their healthcare team) within which the patient is held. Second, that organisational decision-making should take into account the moral significance afforded to caring relationships by healthcare professionals, and the role such relationships can play in the negotiation of ethical challenges.

Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis.

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.

QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.

Pharmacokinetics and optimized dosing of dispersible and non-dispersible levofloxacin formulations in young children.

BACKGROUND: Levofloxacin is used for treatment and prevention of rifampicin-resistant (RR)-TB in children. Recent data showed higher exposures with 100 mg dispersible compared with non-dispersible tablet formulations with potentially important dosing implications in children. We aimed to verify and better characterize this finding. METHODS: We conducted a crossover pharmacokinetic trial in children aged ≤5 years receiving levofloxacin RR-TB preventive therapy. Pharmacokinetic sampling was done after 15-20 mg/kg doses of levofloxacin with 100 mg dispersible and crushed 250 mg non-dispersible levofloxacin formulations. A population pharmacokinetic model was developed. RESULTS: Twenty-five children were included, median (IQR) weight and age 12.2 (10.7-15.0) kg and 2.56 (1.58-4.03) years, respectively. A two-compartment model with first-order elimination and transit compartment absorption best described levofloxacin pharmacokinetics. Allometric scaling adjusted for body size, and maturation of clearance with age was characterized. Typical clearance in a 12 kg child was estimated at 4.17 L/h. Non-dispersible tablets had 21.5% reduced bioavailability compared with the dispersible formulation, with no significant differences in other absorption parameters.Dosing simulations showed that current recommended dosing for both formulations result in median exposures below adult-equivalent exposures at a 750 mg daily dose, mainly in children >6 months. Higher levofloxacin doses of 16-30 mg/kg for dispersible and 20-38 mg/kg for crushed non-dispersible tablets may be required in children >6 months. CONCLUSIONS: The dispersible paediatric levofloxacin formulation has improved bioavailability compared with the crushed non-dispersible adult formulation, but exposures remain below those in adults. We propose optimized age- and weight-based dosing for levofloxacin, which require further evaluation.

Donating a Kidney to a Stranger: Are Healthcare Professionals Facilitating the Journey? Results From the BOUnD Study.

Unspecified kidney donors (UKDs) are approached cautiously by some transplant professionals. The aim of this study was to interrogate the views of UK transplant professionals towards UKDs and identify potential barriers. A purposely designed questionnaire was validated, piloted and distributed amongst transplant professionals at each of the 23 UK transplant centres. Data captured included personal experiences, attitudes towards organ donation, and specific concerns about UKD. 153 responses were obtained, with representation from all UK centres and professional groups. The majority reported a positive experience with UKDs (81.7%; p < 0.001) and were comfortable with UKDs undergoing major surgery (85.7%; p < 0.001). 43.8% reported UKDs to be more time consuming and 52% felt that a mental health assessment should take place before any medical tests. 77% indicated the need for a lower age limit. The suggested age range was broad (16-50 years). Adjusted mean acceptance scores did not differ by profession (p = 0.68) but higher volume centres were more accepting (46.2 vs. 52.9; p < 0.001). This is the first quantitative study of acceptance by transplant professionals to a large national UKD programme. Support is broad, however potential barriers to donation have been identified, including lack of training. Unified national guidance is needed to address these.

Exploring Staff Attitudes Towards Unspecified Kidney Donors in the United Kingdom: Results From the BOUnD Study.

Unspecified kidney donation (UKD) has made substantial contributions to the UK living donor programme. Nevertheless, some transplant professionals are uncomfortable with these individuals undergoing surgery. This study aimed to qualitatively explore the attitudes of UK healthcare professionals towards UKD. An opportunistic sample was recruited through the Barriers and Outcomes in Unspecified Donation (BOUnD) study covering six UK transplant centres: three high volume and three low volume centres. Interview transcripts were analysed using inductive thematic analysis. The study provided comprehensive coverage of the UK transplant community, involving 59 transplant professionals. We identified five themes: staff's conception of the ethics of UKD; presence of the known recipient in the donor-recipient dyad; need for better management of patient expectations; managing visceral reactions about the "typical" unspecified kidney donor; complex attitudes toward a promising new practice. This is the first in-depth qualitative study of attitudes of transplant professionals towards UKD. The data uncovered findings with strong clinical implications for the UKD programme, including the need for a uniform approach towards younger candidates that is adhered to by all transplant centres, the need to equally extend the rigorous assessment to both specified and unspecified donors, and a new approach to managing donor expectations.

Proposal to support making decisions about the organ donation process.

In this paper, we propose a novel approach to permit members of the public opportunity to record more nuanced wishes in relation to organ donation. Recent developments in organ donation and procurement have made the associated processes potentially more multistaged and complex than ever. At the same time, opt-out legislation has led to a more simplistic recording of wishes than ever. We argue that in order to be confident that a patient would really wish to go ahead with the various interventions and procedures that now accompany organ donation, more nuanced information than a simple 'yes' or 'no' may be required. This is of particular importance for donation after circulatory death, where some interventions to facilitate donation occur when the patient is still alive. We propose the implementation of an online form to allow people to record more nuanced wishes in relation to donation, including an indication of competing wishes and how these should be weighed into decision-making. We argue that this approach will promote autonomous decision-making for the public, potentially reduce difficulties that family members encounter at the time of organ donation, and should make medical staff more confident that they are truly acting according to the wishes and best interests of their patients.

RELATIONSHIPS, RIGHTS, AND RESPONSIBILITIES: (RE)VIEWING THE NHS CONSTITUTION FOR THE POST-PANDEMIC 'NEW NORMAL'.

Action needs to be taken to map out the fairest way to meet the needs of all NHS stakeholders in the post-pandemic 'new normal'. In this article, we review the NHS Constitution, looking at it from a relational perspective and suggesting that it offers a useful starting point for such a project, but that new ways of thinking are required to accommodate the significant changes the pandemic has made to the fabric of the NHS. These new ways of thinking should encompass concepts of solidarity, care, and (reciprocal) responsibility, grounded in an acceptance of the importance of relationships in society. To this end, we explore and emphasise the importance of our interconnections as NHS stakeholders and 're-view' the NHS Constitution from a relational perspective, concentrating on the rights and responsibilities it describes for patients and the public as NHS stakeholders. We argue that the NHS Constitution, of which most stakeholders are probably unaware, can be used as a tool to engage us, and to catalyse conversation about how our responsibilities as NHS stakeholders should change in the post-pandemic 'new normal'.

Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children.

BACKGROUND: Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS: Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. RESULTS: Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16-kg child. Stunting and HIV increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. CONCLUSIONS: Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. METHODS: In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation. CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Pharmacokinetics and Dose Optimization Strategies of Para-Aminosalicylic Acid in Children with Rifampicin-Resistant Tuberculosis.

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.

Impact of Opioid Administration in the Intensive Care Unit and Subsequent Use in Opioid-Naïve Patients.

BACKGROUND: Opioids are a mainstay of therapy for patients in the intensive care unit (ICU) as part of the analgesia-first approach to sedation. Despite knowledge of acute consequences of opioid based analgosedation, less is known about the potential long-term consequences, including the effect of opioid administration in the ICU on subsequent opioid use in opioid-naïve patients. OBJECTIVE: To evaluate the relationship between ICU opioid administration to opioid-naïve patients and subsequent opioid use following discharge. METHODS: A query of the electronic medical record was performed to identify opioid-naïve adult patients admitted directly to an ICU. Patients who received continuous intravenous infusion of fentanyl, hydromorphone, or morphine were screened for inclusion into the analysis. RESULTS: Of the 342 patients included for analysis, 164 (47.1%) received an opioid at hospital discharge. In total, 17 of the 342 patients (5.0%) became long-term users, noted to be more common in patients who received an opioid prescription at discharge (8.7% vs 1.6%; P = 0.006). Neither total ICU morphine milligram equivalent (MME) nor average daily ICU MME administration were found to correlate with daily MME prescription quantity at discharge (R2 = 0.008 and R2 = 0.03, respectively). Following control for potentially confounding variables, total ICU MME administration remained an insignificant predictor of subsequent receipt of an opioid prescription at discharge and long-term opioid use. CONCLUSION AND RELEVANCE: This study failed to find a significant relationship between ICU opioid use in opioid-naïve patients and subsequent opioid use. These findings highlight the need to focus on transitions points between the ICU and discharge as potential opportunities to reduce inappropriate opioid continuation.

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial.

BACKGROUND: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. OBJECTIVES: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. PATIENTS AND METHODS: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose]. RESULTS: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. CONCLUSIONS: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.

Evaluation of artificial intelligence clinical applications: Detailed case analyses show value of healthcare ethics approach in identifying patient care issues.

This paper is one of the first to analyse the ethical implications of specific healthcare artificial intelligence (AI) applications, and the first to provide a detailed analysis of AI-based systems for clinical decision support. AI is increasingly being deployed across multiple domains. In response, a plethora of ethical guidelines and principles for general AI use have been published, with some convergence about which ethical concepts are relevant to this new technology. However, few of these frameworks are healthcare-specific, and there has been limited examination of actual AI applications in healthcare. Our ethical evaluation identifies context- and case-specific healthcare ethical issues for two applications, and investigates the extent to which the general ethical principles for AI-assisted healthcare expressed in existing frameworks capture what is most ethically relevant from the perspective of healthcare ethics. We provide a detailed description and analysis of two AI-based systems for clinical decision support (Painchek® and IDx-DR). Our results identify ethical challenges associated with potentially deceptive promissory claims, lack of patient and public involvement in healthcare AI development and deployment, and lack of attention to the impact of AIs on healthcare relationships. Our analysis also highlights the close connection between evaluation and technical development and reporting. Critical appraisal frameworks for healthcare AIs should include explicit ethical evaluation with benchmarks. However, each application will require scrutiny across the AI life-cycle to identify ethical issues specific to healthcare. This level of analysis requires more attention to detail than is suggested by current ethical guidance or frameworks.

Population Pharmacokinetics and Dosing of Ethionamide in Children with Tuberculosis.

Ethionamide has proven efficacy against both drug-susceptible and some drug-resistant strains of Mycobacterium tuberculosis Limited information on its pharmacokinetics in children is available, and current doses are extrapolated from weight-based adult doses. Pediatric doses based on more robust evidence are expected to improve antituberculosis treatment, especially in small children. In this analysis, ethionamide concentrations in children from 2 observational clinical studies conducted in Cape Town, South Africa, were pooled. All children received ethionamide once daily at a weight-based dose of approximately 20 mg/kg of body weight (range, 10.4 to 25.3 mg/kg) in combination with other first- or second-line antituberculosis medications and with antiretroviral therapy in cases of HIV coinfection. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. The MDR-PK1 study contributed data for 110 children on treatment for multidrug-resistant tuberculosis, while the DATiC study contributed data for 9 children treated for drug-susceptible tuberculosis. The median age of the children in the studies combined was 2.6 years (range, 0.23 to 15 years), and the median weight was 12.5 kg (range, 2.5 to 66 kg). A one-compartment, transit absorption model with first-order elimination best described ethionamide pharmacokinetics in children. Allometric scaling of clearance (typical value, 8.88 liters/h), the volume of distribution (typical value, 21.4 liters), and maturation of clearance and absorption improved the model fit. HIV coinfection decreased the ethionamide bioavailability by 22%, rifampin coadministration increased clearance by 16%, and ethionamide administration by use of a nasogastric tube increased the rate, but the not extent, of absorption. The developed model was used to predict pediatric doses achieving the same drug exposure achieved in 50- to 70-kg adults receiving 750-mg once-daily dosing. Based on model predictions, we recommend a weight-banded pediatric dosing scheme using scored 125-mg tablets.

Donating a Kidney to a Stranger: A Review of the Benefits and Controversies of Unspecified Kidney Donation.

OF BACKGROUND DATA: Unspecified kidney donation (UKD) describes living donation of a kidney to a stranger. The practice is playing an increasingly important role within the transplant programme in the United Kingdom, where these donors are commonly used to trigger a chain of transplants; thereby amplifying the benefit derived from their donation. The initial reluctance to accept UKD was in part due to uncertainty about donor motivations and whether the practice was morally and ethically acceptable. OBJECTIVES: This article provides an overview of UKD and answers common questions regarding the ethical considerations, clinical assessment, and how UKD kidneys are used to maximize utility. Existing literature on outcomes after UKD is also discussed, along with current controversies. CONCLUSIONS: We believe UKD is an ethically acceptable practice which should continue to grow, despite its controversies. In our experience, these donors are primarily motivated by a desire to help others and utilization of their kidney as part of a sharing scheme means that many more people seek to benefit from their very generous donation.

Changes in quality of life, health status and other patient-reported outcomes following simultaneous pancreas and kidney transplantation (SPKT): a quantitative and qualitative analysis within a UK-wide programme.

We examined quality of life (QoL) and other patient-reported outcome measures (PROMs) in 95 simultaneous pancreas and kidney transplant (SPKT) recipients and 41 patients wait-listed for SPKT recruited to the UK Access to Transplantation and Transplant Outcome Measures (ATTOM) programme. Wait-listed patients transplanted within 12 months of recruitment (n = 22) were followed 12 months post-transplant and compared with those still wait-listed (n = 19) to examine pre- to post-transplant changes. Qualitative interviews with ten SPKT recipients 12 months post-transplant were analysed thematically. Cross-sectional analyses showed several better 12-month outcomes for SPKT recipients compared with those still wait-listed, a trend to better health utilities but no difference in diabetes-specific QoL or diabetes treatment satisfaction. Pre- to post-transplant, SPKT recipients showed improved treatment satisfaction, well-being, self-reported health, generic QoL and less negative impact on renal-specific QoL (ps < 0.05). Health utility values were better overall in transplant recipients and neither these nor diabetes-specific QoL changed significantly in either group. Pre-emptive transplant advantages seen in 12-month cross-sectional analyses disappeared when controlling for baseline values. Qualitative findings indicated diabetes complications, self-imposed blood glucose monitoring and dietary restrictions continued to impact QoL negatively post-transplant. Unrealistic expectations of SPKT caused some disappointment. Measuring condition-specific PROMs over time will help in demonstrating the benefits and limitations of SPKT.