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Point-of-care ultrasonography is increasingly being used to facilitate accurate abstract and timely diagnoses and to guide procedures. It is important for pediatric emergency medicine (PEM) physicians caring for patients in the emergency department to receive adequate and continued point-of-care ultrasonography training for those indications used in their practice setting. Emergency departments should have credentialing and quality assurance programs. PEM fellowships should provide appropriate training to physician trainees. Hospitals should provide privileges to physicians who demonstrate competency in point-of-care ultrasonography. Ongoing research will provide the necessary measures to define the optimal training and competency assessment standards. Requirements for credentialing and hospital privileges will vary and will be specific to individual departments and hospitals. As more physicians are trained and more research is completed, there should be one national standard for credentialing and privileging in point-of-care ultrasonography for PEM physicians.

Abstract Background Characterizing root system architecture (RSA) is essential to understanding the development and function of vascular plants. Identifying RSA-associated genes also represents an underexplored opportunity for crop improvement. Software tools are needed to accelerate the pace at which quantitative traits of RSA are estimated from images of root networks. Results We have developed GiA Roots (General Image Analysis of Roots), a semi-automated software tool designed specifically for the high-throughput analysis of root system images. GiA Roots includes user-assisted algorithms to distinguish root from background and a fully automated pipeline that extracts dozens of root system phenotypes. Quantitative information on each phenotype, along with intermediate steps for full reproducibility, is returned to the end-user for downstream analysis. GiA Roots has a GUI front end and a command-line interface for interweaving the software into large-scale workflows. GiA Roots can also be extended to estimate novel phenotypes specified by the end-user. Conclusions We demonstrate the use of GiA Roots on a set of 2393 images of rice roots representing 12 genotypes from the species Oryza sativa. We validate trait measurements against prior analyses of this image set that demonstrated that RSA traits are likely heritable and associated with genotypic differences. Moreover, we demonstrate that GiA Roots is extensible and an end-user can add functionality so that GiA Roots can estimate novel RSA traits. In summary, we show that the software can function as an efficient tool as part of a workflow to move from large numbers of root images to downstream analysis.

Abstract Background It is generally acknowledged that a disparity between knowledge and its implementation is adversely affecting quality of care. An example commonly cited is the failure of clinicians to follow clinical guidelines. A guiding assumption of this view is that adherence should be gauged by a standard of conformance. At least some guideline developers dispute this assumption and claim that their efforts are intended to inform and assist clinical practice, not to function as standards of performance. However, their ability to assist and inform will remain limited until an alternative to the conformance criterion is proposed that gauges how evidence-based guidelines are incorporated into clinical decisions. Methods The proposed investigation has two specific aims to identify the processes that affect decisions about incorporating clinical guidelines, and then to develop ad test a strategy that promotes the utilization of evidence-based practices. This paper focuses on the first aim. It presents the rationale, introduces the clinical paradigm of treatment-resistant schizophrenia, and discusses an exemplar of clinician non-conformance to a clinical guideline. A modification of the original study is proposed that targets psychiatric trainees and draws on a cognitively rich theory of decision-making to formulate hypotheses about how the guideline is incorporated into treatment decisions. Twenty volunteer subjects recruited from an accredited psychiatry training program will respond to sixty-four vignettes that represent a fully crossed 2 × 2 × 2 × 4 within-subjects design. The variables consist of criteria contained in the clinical guideline and other relevant factors. Subjects will also respond to a subset of eight vignettes that assesses their overall impression of the guideline. Generalization estimating equation models will be used to test the study's principal hypothesis and perform secondary analyses. Implications The original design of phase two of the proposed investigation will be changed in recognition of newly published literature on the relative effectiveness of treatments for schizophrenia. It is suggested that this literature supports the notion that guidelines serve a valuable function as decision tools, and substantiates the importance of decision-making as the means by which general principles are incorporated into clinical practice.

Abstract Background Cognitive deficits in various domains have been consistently replicated in patients with schizophrenia. Most studies looking at the relationship between cognitive dysfunction and functional disability are from developed countries. Studies from developing countries are few. The purpose of the present study was to compare the neurocognitive function in patients with schizophrenia who were in remission with that of normal controls and to determine if there is a relationship between measures of cognition and functional disability. Methods This study was conducted in the Psychiatric Unit of a General Hospital in Mumbai, India. Cognitive function in 25 patients with schizophrenia in remission was compared to 25 normal controls. Remission was confirmed using the brief psychiatric rating scale (BPRS) and scale for the assessment of negative symptoms (SANS). Subjects were administered a battery of cognitive tests covering aspects of memory, executive function and attention. The results obtained were compared between the groups. Correlation analysis was used to look for relationship between illness factors, cognitive function and disability measured using the Indian disability evaluation and assessment scale. Results Patients with schizophrenia showed significant deficits on tests of attention, concentration, verbal and visual memory and tests of frontal lobe/executive function. They fared worse on almost all the tests administered compared to normal controls. No relationship was found between age, duration of illness, number of years of education and cognitive function. In addition, we did not find a statistically significant relationship between cognitive function and scores on the disability scale. Conclusion The data suggests that persistent cognitive deficits are seen in patients with schizophrenia under remission. The cognitive deficits were not associated with symptomatology and functional disability. It is possible that various factors such as employment and family support reduce disability due to schizophrenia in developing countries like India. Further studies from developing countries are required to explore the relationship between cognitive deficits, functional outcome and the role of socio-cultural variables as protective factors.

Objectives: Although the incidence of malaria is increased in women in endemic areas after delivery compared to non-pregnant women, no studies have assessed the benefit of presumptive antimalarial treatment given postpartum., Methods: A randomised controlled trial investigating the efficacy of antimalarial treatment in preventing postpartum malaria was performed in healthy Papua New Guinea mothers immediately following delivery. Participants were randomised 1:1 to no treatment (n = 90) or artemisinin combination therapy (ACT), with further 1:1 ACT randomisation to artemether-lumefantrine (AL; n = 45) or dihydroartemisinin-piperaquine (DP; n = 45). Standardised reviews were conducted monthly for 6 months, including clinical assessment, malaria screening and haemoglobin measurement. The primary endpoint was incidence of slide-positive malaria within 6 months of delivery., Results: Of 183 recruited participants, 151 completed study procedures and were included in per-protocol analyses (no treatment n = 71, AL n = 40, DP, n = 40). Those allocated to ACT were significantly less likely to develop slide-positive malaria during the 6-month follow-up period compared to those who were untreated (n = 17 (21%) vs n = 27 (38%); P = 0.016; hazard ratio 0.49 (95% confidence intervals 0.27-0.90). There was no significant difference in malaria incidence between the two ACT groups., Conclusion: A treatment course of ACT at time of delivery halved the incidence of malaria infection during the first 6-month postpartum., Competing Interests: Declarations of competing interest 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 article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate the physicochemical compatibility of caffeine citrate and caffeine base injections with 43 secondary intravenous (IV) drugs used in Neonatal Intensive Care Unit (NICU) settings., Methods: Caffeine citrate (20 mg/mL or 10 mg/mL) or caffeine base injection (10 mg/mL) were mixed in a volume ratio of 1:1 with the secondary drug solution to simulate Y-site co-administration procedures in NICUs. Physical compatibility was evaluated based on visual observation for 2 h, against a black and white background and under polarised light, for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from caffeine concentration measurements, using a validated high-performance liquid chromatography assay., Results: Six of the 43 secondary drugs tested (aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine) were physically incompatible with caffeine citrate undiluted injection (20 mg/mL), at their high-end, clinically relevant concentrations for NICU settings. However, when tested at lower concentrations, hydrocortisone (1 mg/mL) was physicochemically compatible, whereas furosemide (0.2 mg/mL) was physically incompatible with caffeine citrate. The six drugs which showed physical incompatibility with caffeine citrate 20 mg/mL injection were also physically incompatible with caffeine citrate 10 mg/mL solution. All 43 secondary drugs tested were physicochemically compatible with caffeine base injection., Conclusions: Most secondary test drugs, except aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine, were physicochemically compatible with caffeine citrate injection. Caffeine base injection was physicochemically compatible with all 43 test drugs tested., (© 2024. The Author(s).)

Sildenafil is used to treat pulmonary hypertension in neonatal intensive care unit (NICU) settings. As multiple intravenous (IV) medications are co-administered in NICU settings, we sought to investigate the physicochemical compatibility of sildenafil with a range of IV drugs. Sildenafil 600 mcg/mL or 60 mcg/mL was mixed 1:1 with the secondary drug solution to simulate Y-site co-administration procedures. Physical compatibility was evaluated by visual observation against a black and white background and under polarized light for two hours for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from sildenafil concentrations, using a validated, stability-indicating high-performance liquid chromatography assay. Sildenafil 600 mcg/mL was physicochemically compatible with 29 of the 45 drugs tested at 'high-end' clinical concentrations and physically incompatible with 16 drugs and six '2-in-1' parenteral nutrition solutions. Sildenafil 600 mcg/mL was compatible with lower, clinically relevant concentrations of calcium gluconate, heparin and hydrocortisone. Aciclovir, amoxicillin, ampicillin, ibuprofen lysine, indometacin, phenobarbitone and rifampicin were incompatible with sildenafil 600 mcg/mL, however these IV medications were compatible with sildenafil 60 mcg/mL. Sildenafil 600 mcg/mL and 60 mcg/mL were incompatible with amphotericin, flucloxacillin, furosemide, ibuprofen, meropenem and sodium bicarbonate. Sildenafil compatibility with commonly used syringe filters was also investigated. Sildenafil solution was compatible with nylon syringe filters, however, absorption/adsorption loss occurred with polyethersulfone and cellulose ester filters.

Syphilis is an important global health threat and little has changed in its treatment since the mid-20th century. For late-latent or syphilis infection of unknown duration, the standard treatment of multiple intramuscular injections of benzathine penicillin G (BPG) are associated with significant pain and distress to clients and caregivers, negatively impacting on treatment completion. Based on pharmacokinetic modelling from a Phase I study of subcutaneous infusion of high dose BPG (SCIP), we present its feasibility, safety and tolerability for treatment of syphilis in a single infusion. SCIP leads to more sustained penicillin concentrations above the desired target with less reported pain and reduced clinic visits.

Our objective was to establish and test a machine learning-based screening process that would be applicable to systematic reviews in pharmaceutical sciences. We used the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) model, a broad search strategy, and a machine learning tool (Research Screener) to identify relevant references related to y-site compatibility of 95 intravenous drugs used in neonatal intensive care settings. Two independent reviewers conducted pilot studies, including manual screening and evaluation of Research Screener, and used the kappa-coefficient for inter-reviewer reliability. After initial deduplication of the search strategy results, 27 597 references were available for screening. Research Screener excluded 1735 references, including 451 duplicate titles and 1269 reports with no abstract/title, which were manually screened. The remainder (25 862) were subject to the machine learning screening process. All eligible articles for the systematic review were extracted from <10% of the references available for screening. Moderate inter-reviewer reliability was achieved, with kappa-coefficient ≥0.75. Overall, 324 references were subject to full-text reading and 118 were deemed relevant for the systematic review. Our study showed that a broad search strategy to optimize the literature captured for systematic reviews can be efficiently screened by the semi-automated machine learning tool, Research Screener., (© 2024 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order ( t 1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD., Competing Interests: The authors declare no conflict of interest.

Half of all pregnancies at risk of malaria worldwide occur in the Asia-Pacific region, where Plasmodium falciparum and Plasmodium vivax co-exist. Despite substantial reductions in transmission, malaria remains an important cause of adverse health outcomes for mothers and offspring, including pre-eclampsia. Malaria transmission is heterogeneous, and infections are commonly subpatent and asymptomatic. High-grade antimalarial resistance poses a formidable challenge to malaria control in pregnancy in the region. Intermittent preventive treatment in pregnancy reduces infection risk in meso-endemic New Guinea, whereas screen-and-treat strategies will require more sensitive point-of-care tests to control malaria in pregnancy. In the first trimester, artemether-lumefantrine is approved, and safety data are accumulating for other artemisinin-based combinations. Safety of novel antimalarials to treat artemisinin-resistant P falciparum during pregnancy, and of 8-aminoquinolines during lactation, needs to be established. A more systematic approach to the prevention of malaria in pregnancy in the Asia-Pacific is required., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To survey paediatric eye care providers to identify current patterns of prescribing for hyperopia., Methods: Paediatric eye care providers were invited, via email, to participate in a survey to evaluate current age-based refractive error prescribing practices. Questions were designed to determine which factors may influence the survey participant's prescribing pattern (e.g., patient's age, magnitude of hyperopia, patient's symptoms, heterophoria and stereopsis) and if the providers were to prescribe, how much hyperopic correction would they prescribe (e.g., full or partial prescription). The response distributions by profession (optometry and ophthalmology) were compared using the Kolmogorov-Smirnov cumulative distribution function test., Results: Responses were submitted by 738 participants regarding how they prescribe for their hyperopic patients. Most providers within each profession considered similar clinical factors when prescribing. The percentages of optometrists and ophthalmologists who reported considering the factor often differed significantly. Factors considered similarly by both optometrists and ophthalmologists were the presence of symptoms (98.0%, p = 0.14), presence of astigmatism and/or anisometropia (97.5%, p = 0.06) and the possibility of teasing (8.3%, p = 0.49). A wide range of prescribing was observed within each profession, with some providers reporting that they would prescribe for low levels of hyperopia while others reported that they would never prescribe. When prescribing for bilateral hyperopia in children with age-normal visual acuity and no manifest deviation or symptoms, the threshold for prescribing decreased with age for both professions, with ophthalmologists typically prescribing 1.5-2 D less than optometrists. The threshold for prescribing also decreased for both optometrists and ophthalmologists when children had associated clinical factors (e.g., esophoria or reduced near visual function). Optometrists and ophthalmologists most commonly prescribed based on cycloplegic refraction, although optometrists most commonly prescribed based on both the manifest and cycloplegic refraction for children ≥7 years., Conclusion: Prescribing patterns for paediatric hyperopia vary significantly among eye care providers., (© 2023 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

Objectives: To assess the pharmacokinetics, safety, and tolerability of two high-dose, short-course primaquine (PQ) regimens compared with standard care in children with Plasmodium vivax infections., Methods: We performed an open-label pediatric dose-escalation study in Madang, Papua New Guinea (Clinicaltrials.gov NCT02364583). Children aged 5-10 years with confirmed blood-stage vivax malaria and normal glucose-6-phosphate dehydrogenase activity were allocated to one of three PQ treatment regimens in a stepwise design (group A: 0.5 mg/kg once daily for 14 days, group B: 1 mg/kg once daily for 7 days, and group C: 1 mg/kg twice daily for 3.5-days). The study assessments were completed at each treatment time point and fortnightly for 2 months after PQ administration., Results: Between August 2013 and May 2018, 707 children were screened and 73 met the eligibility criteria (15, 40, and 16 allocated to groups A, B, and C, respectively). All children completed the study procedures. The three regimens were safe and generally well tolerated. The pharmacokinetic analysis indicated that an additional weight adjustment of the conventionally recommended milligram per kilogram PQ doses is not necessary to ensure the therapeutic plasma concentrations in pediatric patients., Conclusions: A novel, ultra-short 3.5-day PQ regimen has potential benefits for improving the treatment outcomes in children with vivax malaria that warrants further investigation in a large-scale clinical trial., Competing Interests: Declarations of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We aimed to assess safety, tolerability, and Plasmodium vivax relapse rates of ultra-short course (3.5 days) high-dose (1 mg/kg twice daily) primaquine (PQ) for uncomplicated malaria because of any Plasmodium species in children randomized to early- or delayed treatment., Methods: Children aged 0.5 to 12 years with normal glucose-6-phosphate-dehydrogenase (G6PD) activity were enrolled. After artemether-lumefantrine (AL) treatment, children were randomized to receive PQ immediately after (early) or 21 days later (delayed). Primary and secondary endpoints were the appearance of any P. vivax parasitemia within 42 or 84 days, respectively. A non-inferiority margin of 15% was applied (ACTRN12620000855921)., Results: A total of 219 children were recruited, 70% with Plasmodium falciparum and 24% with P. vivax. Abdominal pain (3.7% vs 20.9%, P <0.0001) and vomiting (0.9% vs 9.1%, P = 0.01) were more common in the early group. At day 42, P. vivax parasitemia was observed in 14 (13.2%) and 8 (7.8%) in the early and delayed groups, respectively (difference, -5.4%; 95% confidence interval -13.7 to 2.8). At day 84, P. vivax parasitemia was observed in 36 (34.3%) and 17 (17.5%; difference -16.8%, -28.6 to -6.1)., Conclusion: Ultra-short high-dose PQ was safe and tolerated without severe adverse events. Early treatment was non-inferior to delayed treatment in preventing P. vivax infection at day 42., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Epidemiology has been transformed by the advent of Bayesian phylodynamic models that allow researchers to infer the geographic history of pathogen dispersal over a set of discrete geographic areas [1, 2]. These models provide powerful tools for understanding the spatial dynamics of disease outbreaks, but contain many parameters that are inferred from minimal geographic information (i.e., the single area in which each pathogen was sampled). Consequently, inferences under these models are inherently sensitive to our prior assumptions about the model parameters. Here, we demonstrate that the default priors used in empirical phylodynamic studies make strong and biologically unrealistic assumptions about the underlying geographic process. We provide empirical evidence that these unrealistic priors strongly (and adversely) impact commonly reported aspects of epidemiological studies, including: 1) the relative rates of dispersal between areas; 2) the importance of dispersal routes for the spread of pathogens among areas; 3) the number of dispersal events between areas, and; 4) the ancestral area in which a given outbreak originated. We offer strategies to avoid these problems, and develop tools to help researchers specify more biologically reasonable prior models that will realize the full potential of phylodynamic methods to elucidate pathogen biology and, ultimately, inform surveillance and monitoring policies to mitigate the impacts of disease outbreaks.

Summary: Phylodynamic methods are central to studies of the geographic and demographic history of disease outbreaks. Inference under discrete-geographic phylodynamic models-which involve many parameters that must be inferred from minimal information-is inherently sensitive to our prior beliefs about the model parameters. We present an interactive utility, PrioriTree, to help researchers identify and accommodate prior sensitivity in discrete-geographic inferences. Specifically, PrioriTree provides a suite of functions to generate input files for-and summarize output from-BEAST analyses for performing robust Bayesian inference, data-cloning analyses and assessing the relative and absolute fit of candidate discrete-geographic (prior) models to empirical datasets., Availability and Implementation: PrioriTree is distributed as an R package available at https://github.com/jsigao/prioritree, with a comprehensive user manual provided at https://bookdown.org/jsigao/prioritree&#95;manual/., (© The Author(s) 2023. Published by Oxford University Press.)

Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns. Healthy volunteers from Papua New Guinea received a 3-day course of DHA-PQP (2.1/17.1 mg/kg) monthly for 3 consecutive months in a single arm longitudinal study. Plasma PQP concentrations were measured after the third dose of each course (at 52-54 h) and at 0 h of course 3. Twelve-lead electrocardiographic readings were conducted at 0 h, 48 h, 52 h, and day 7 of each course. QT interval corrected by Fridericia's formula (QTcF) was measured at each time point. A pharmacokinetic-pharmacodynamic model using nonlinear mixed effects models was developed to correlate PQP concentrations with QTcF. Ten thousand female and 10,000 male individuals were simulated at each treatment course. Eighty-two participants were included; mean age was 28.3 years (standard deviation [SD] ±12.3 years), and 36 (44%) were female. Pharmacokinetic-pharmacodynamic models were determined with 290 PQP concentrations and 868 QTcF observations. The average baseline QTcF was 392 ms with a between-subject variability SD ±14.4 ms and between-occasion variability SD ±3.64 ms. From the population modeled, only 0.08% of males and 0.45% of females would be at risk of an absolute QTcF of >500 ms. DHA-PQP is safe at standard doses in consecutive months, and the likelihood of severe cardiac events occurring during an MDA campaign is very low. This study has been registered at ClinicalTrials.gov under identifier NCT02605720.

Phylodynamic methods reveal the spatial and temporal dynamics of viral geographic spread, and have featured prominently in studies of the COVID-19 pandemic. Virtually all such studies are based on phylodynamic models that assume-despite direct and compelling evidence to the contrary-that rates of viral geographic dispersal are constant through time. Here, we: (1) extend phylodynamic models to allow both the average and relative rates of viral dispersal to vary independently between pre-specified time intervals; (2) implement methods to infer the number and timing of viral dispersal events between areas; and (3) develop statistics to assess the absolute fit of discrete-geographic phylodynamic models to empirical datasets. We first validate our new methods using simulations, and then apply them to a SARS-CoV-2 dataset from the early phase of the COVID-19 pandemic. We show that: (1) under simulation, failure to accommodate interval-specific variation in the study data will severely bias parameter estimates; (2) in practice, our interval-specific discrete-geographic phylodynamic models can significantly improve the relative and absolute fit to empirical data; and (3) the increased realism of our interval-specific models provides qualitatively different inferences regarding key aspects of the COVID-19 pandemic-revealing significant temporal variation in global viral dispersal rates, viral dispersal routes, and the number of viral dispersal events between areas-and alters interpretations regarding the efficacy of intervention measures to mitigate the pandemic., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Since there are inconsistent data relating to the effect of haemoglobinopathies on disposition of artemisinin antimalarial combination therapy, and none in sickle cell trait (SCT) or sickle cell disease (SCD), the aim of this study was to characterize the pharmacokinetic properties of artemether-lumefantrine (ARM-LUM) in children with SCD/SCT. Thirty-eight Tanzanian children aged 5-10 years with normal (haemoglobin AA; n = 12), heterozygous (haemoglobin AS; n = 14) or homozygous (haemoglobin SS; n = 12) sickle genotypes received six ARM-LUM doses (1.7 mg/kg plus 10 mg/kg, respectively) over 3 days. Sparse venous and mixed-capillary dried blood spot (DBS) samples were taken over 42 days. Plasma and DBS ARM and LUM, and their active metabolites dihydroartemisinin (DHA) and desbutyl-lumefantrine (DBL), were assayed using validated liquid chromatography-mass spectrometry. Multi-compartmental pharmacokinetic models were developed using a population approach. Plasma but not DBS concentrations of ARM/DHA were assessable. The majority (85%) of the 15 measurable values were within 95% prediction intervals from a published population pharmacokinetic ARM/DHA model in Papua New Guinean children of similar age without SCD/SCT who had uncomplicated malaria, and there was no clear sickle genotype clustering. Plasma (n = 38) and corrected DBS (n = 222) LUM concentrations were analysed using a two-compartment model. The median [inter-quartile range] LUM AUC 0-∞ was 607,296 [426,480-860,773] μg.h/L, within the range in published studies involving different populations, age-groups and malaria status. DBS and plasma DBL concentrations correlated poorly and were not modelled. These data support use of the conventional ARM-LUM treatment regimen for uncomplicated malaria in children with SCT/SCD., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Pacific longnose parrotfish, Hipposcarus longiceps, is a medium- to large-bodied scarine labrid that is among the most commonly harvested species in mixed reef fisheries across the Indo-Pacific. Despite its ecological and fisheries importance, assessments of stock status and development of appropriate management strategies for the species have been limited by an absence of biological information. To date, the only detailed studies of the biology of H. longiceps have occurred in tropical regions. This study examined the biology of H. longiceps in southern New Caledonia, towards the southernmost extent of the species' distribution. In addition, resulting estimates of longevity and asymptotic length were compared against those derived for the species elsewhere in the Pacific, and regional patterns in these parameters were explored for correlation with sea surface temperature (SST). A total of 212 H. longiceps were collected from commercial fishers or fish markets between September 2015 and March 2017. Sampled individuals ranged from 28.2 cm fork length (L F ) to 57.3 cm L F , and from 424 g to 3773 g. Examination of sectioned otoliths showed a clear pattern in increment formation, with opaque zones forming annually in most individuals between July and August (i.e., austral winter). Estimated longevities were similar between sexes, at ~18 years for females and ~19 years for males. These estimates extend the reported longevity of H. longiceps by at least 5 years. Despite this species being a diandric protogynous hermaphrodite, sex ratios were only slightly female biased, with 1 female:0.6 males. Primary males (i.e., those individuals that are male at first sexual maturity) constituted 30% of all sampled individuals and 79% of all males. A clearly defined, yet protracted, spawning season was evident, with peak spawning occurring from December-February, extending from November to April in some individuals. The estimated median length (L 50 ) and age (A 50 ) at female maturity were 38.9 cm L F and 5.7 years, respectively, while the estimated length at which females changed sex to secondary males was 52.5 cm L F . Reported longevity and asymptotic length were found to exhibit considerable regional variation, and both were negatively associated with SST. The results highlight the importance of geographically disparate studies into the species' biology, inform future assessments for the species, provide key baseline information for comparative work and improve understanding of spatial patterns of the life history of parrotfish species., (© 2022 The Author. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

The aim of this narrative review is to summarise efficacy and pharmacokinetic data for Plasmodium vivax in children. The burden of P. vivax malaria in children continues to remain a significant public health issue, and the need for improved treatment regimens for this vulnerable population is critical. Relapse after re-activation of dormant liver-stage hypnozoites poses additional challenges for treatment, elimination, and control strategies for P. vivax. Whilst it is recognised that paediatric pharmacology may be significantly influenced by anatomical and physiological changes of childhood, dosing regimens often continue to be extrapolated from adult data, highlighting the need for antimalarial dosing in children to be evaluated in early phase clinical trials. This will ensure that globally recommended treatment regimens do not result in suboptimal dosing in children. Furthermore, the development of affordable paediatric formulations to enhance treatment acceptability and widespread G6PD testing to facilitate use of anti-hypnozoite treatment such as primaquine and tafenoquine, should be further prioritised. As the world prepares for malaria elimination, a renewed focus on P. vivax malaria provides an ideal opportunity to harness momentum and ensure that all populations, including children have access to safe, efficacious, and correctly dosed antimalarial therapies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial., Methods and Findings: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high., Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RMF is employed currently by AstraZeneca but has no financial stake in the results of the current study. EAA and NJW are Academic Editors on PLOS Medicine's editorial board, and IM was previously an Academic Editor.

Ceftriaxone is widely used for respiratory and urinary infections in elderly and frail patients, but there are few pharmacokinetic studies. A prospective population pharmacokinetic study of ceftriaxone in adults over 65 years old was undertaken. Dried blood spots collected at baseline (predose) and 0.5, 1, 4, 8, and 24 h after administration of 1 g of ceftriaxone were assayed using a validated liquid chromatography-mass spectroscopy analytical method. Frailty was classified using the Edmonton frailty scale and grip strength via a hand dynamometer. Estimates of glomerular filtration rate were determined using creatinine-based and cystatin C-based equations. Of 26 patients recruited, 23 (88%) were vulnerable or very frail. Estimates of drug clearance improved significantly with a cystatin C-based estimate of renal function that accounted for frailty. Simulations indicate that the combined effects of ranges of size and renal function resulted in a 6-fold range in peak ceftriaxone concentrations and 9-fold range in total exposure (area under the concentration-time curve [AUC]). For elderly patients with moderate or severe renal impairment, 48-h dosing results in greater trough concentrations and total exposure than the trough concentrations and total exposure in patients with normal renal function receiving 24-h dosing. Cystatin C-based measures of renal function improved predictions of ceftriaxone clearance in elderly patients., (Copyright © 2020 American Society for Microbiology.)

Introduction: The association between pregnancy and altered drug pharmacokinetic (PK) properties is acknowledged, as is its impact on drug plasma concentrations and thus therapeutic efficacy. However, there have been few robust PK studies of antimalarial use in pregnancy. Given that inadequate dosing for prevention or treatment of malaria in pregnancy can result in negative maternal/infant outcomes, along with the potential to select for parasite drug resistance, it is imperative that reliable pregnancy-specific dosing recommendations are established., Areas Covered: PK studies of antimalarial drugs in pregnancy. The present review summarizes the efficacy and PK properties of WHO-recommended therapies used in pregnancy, with a focus on PK studies published since 2014., Expert Opinion: Changes in antimalarial drug disposition in pregnancy are well described, yet pregnant women continue to receive treatment regimens optimized for non-pregnant adults. Contemporary in silico modeling has recently identified a series of alternative dosing regimens that are predicted to provide optimal therapeutic efficacy for pregnant women.