Inadequate Lopinavir Concentrations With Modified 8-hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV

Background: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. // Methods: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. // Results: Of 20 children enrolled; 15, 1–7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve0–24 55.32mg/h/L [0.30–398.7mg/h/L]; Cmax 3.04mg/L [0.03–18.6mg/L]; C8hr 0.90mg/L [0.01–13.7mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve24 121.63mg/h/L [2.56–487.3mg/h/L]; Cmax 9.45mg/L [0.39–26.4mg/L]; C12hr 3.03mg/L [0.01–17.7mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. // Conclusions: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation

Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial

Background: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. Methods/design: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. Discussion: Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smearnegative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020. Trial registration: International Standard Randomised Controlled Trials Number: ISRCTN63579542, 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379, 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events

Ash dosage and concentration risk dataset

This dataset was generated at the University of Reading (UK) and was funded by NERC under the Environmental Risks to Infrastructure Innovation Programme. The dataset provides data sufficient to plot Figures 2, 3, 4, 5, 7 and 8 presented in Prata et al. (2018). The dataset includes NAME dispersion model output for a control run of a hypothetical Katla eruption, processed data that represent model agreement and risk maps, waypoints produced using flightCode for an air-route from New York (JFK) to London (LHR) return and processed data that represent ash dosage, concentration, model agreement and risk calculated along an air-route from New York (JFK) to London (LHR) return. Reference: Prata A. T., H. F. Dacre, E. A. Irvine, E. Mathieu, K. P. Shine and R. J. Clarkson (2018), Calculating and communicating ensemble-based volcanic ash dosage and concentration risk for aviation, Under Review, Meteorol. Apps

The rise of cholesterol testing: how much is unnecessary?

Background: Laboratory testing has increased dramatically over recent decades, which is a consequence particularly of repeat testing or monitoring, as either a response to treatment or follow-up. Aim: To assess rates of measurement of lipid levels (total cholesterol, high-density lipoprotein, triglyceride) for diagnosis and monitoring over the last 20 years. Design of study: Audit of electronic database. Setting: A single region in the UK (Oxfordshire). Method: Specimens from individual patients were matched over time. All tests that were the third or more in a 3-year period were considered to be for monitoring, while the first and second were considered to be for diagnosis. As recent evidence-based recommendations suggest that frequent monitoring of cholesterol may reflect measurement error rather than true changes, between one and three tests in each 3-year period were considered to be 'necessary'. Results: Over the 20 years from 1987 there has been a more than 15-fold rise in the overall number of lipid tests requested. After a small decline in the early 1990s, testing rose steadily after publication of several large statin trials, particularly tests requested in primary rather than secondary care. Repeat testing (likely to be for monitoring) rose from 24% of tests (1933-1995) to 61% (2005-2007), with between 42% and 79% of tests in 2005-2007 possibly being unnecessary. Mean cholesterol values declined over time from 1996 onwards. Conclusion: In the last decade, the number of cholesterol tests performed in Oxfordshire has risen dramatically. Much of this appears to be for monitoring purposes rather than case finding or risk assessment. The majority of cholesterol tests requested may be unnecessary

Direct Arylation Polymerization of Degradable Imine-based Conjugated Polymers

The development and optimization of reliable polymerization methods are needed for the synthesis of degradable imine-based conjugated polymers, which are attractive materials for transient electronics. Direct arylation polymerization (DArP) has emerged as a sustainable and atom-economical synthetic method for the preparation of well-defined conjugated polymers. Compared to polymerization methods such as imine polycondensation or Stille cross-coupling polymerization which require monomer functionalization, direct arylation proceeds via C-H activation and thereby reduces synthetic complexities and toxic by-products. Here we report the first use of DArP for the synthesis of an imine-based indacenodithiophene (IDT) copolymer, p(IDT-TIT). Polymers prepared via DArP can result in branched or cross-linked polymer chains due to the reactivity of C-H bonds in the monomers. In this report, we demonstrate a systematic study focusing on the reaction conditions needed to prepare p(IDT-TIT) via DArP with tetramethylethylenediamine as a co-ligand. The degradable polymer is characterized via nuclear magnetic resonance spectroscopy, high-temperature gel permeation chromatography, and ultraviolet- visible-near-infrared spectroscopy. With the simplicity of monomer preparation and reaction conditions, we anticipate this efficient synthetic protocol will lead to higher synthetic adoption in the research community to aid the exploration of high-performance imine-based degradable materials

Optimal strategies for identifying kidney disease in diabetes:properties of screening tests, progression of renal dysfunction and impact of treatment - Systematic review and modelling of progression and cost-effectiveness

BACKGROUND: Annual screening for adults with type 2 diabetes to detect the early onset of kidney disease is widely recommended, but the recommendations are based on a limited methodological approach. In addition, there are continuing uncertainties about underlying rates of progression of the condition and the benefits of treatments with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. OBJECTIVES: We aimed to estimate the clinical value and cost-effectiveness of different screening intervals to diagnose early diabetic kidney disease. DATA SOURCES: We used the following databases for the literature review (searched January 2005 to August 2010): MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews. Individual patient data were obtained from the Oxford Regional Prospective Diabetes Study and the Collaborative Atorvastatin Diabetes Study. METHODS: Data from systematically identified randomised trials reporting the impact on renal outcomes of angiotensin-converting enzyme inhibitors and angiotensin 2 receptor blockers for type 1 and type 2 diabetes patients with normoalbuminuria and microalbuminuria were pooled to derive estimates of effect. Individual patient data for type 1 and type 2 diabetes patients were used to obtain parameters describing progression and variability of measurement over time for the albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate. Based on accepted diagnostic thresholds, we modelled whether these tests accurately identified patients who were developing early diabetic kidney disease and required intensification of treatment. Cost-effectiveness analyses were carried out using simulation outcome models to estimate the incremental costs per quality-adjusted life-year (QALY) for different screening intervals. RESULTS: In total, 49 trials (n = 34,082 patients) were eligible for inclusion in the systematic review. For type 1 diabetes, pooled estimates of urinary albumin excretion (UAE) for treated patients with microalbuminuria were on average 67% [95% confidence interval (CI) 54% to 77%] lower at the end of the trial than for untreated patients. There was no significant treatment effect for patients with normoalbuminuria (p interaction = 0.006). For treated patients with type 2 diabetes and normoalbuminuria or microalbuminuria, UAE was lower by, on average, 21% (95% CI 97% to 32%) or 27% (95% CI 15% to 38%), respectively. The proportion (95% CI) of men and women with type 1 diabetes screened annually for microalbuminuria over 6 years and inaccurately identified as having microalbuminuria would be 48% (43% to 53%) and 55% (48% to 61%), respectively. The corresponding proportions for type 2 diabetes are 36% (32% to 42%) and 48% (41% to 55%). Decreasing the screening interval to 3-yearly would reduce this for men with type 1 diabetes to 38% (33% to 44%), with an increase in those not identified over 6 years from 1.5% (95% CI 1% to 2%) to 4% (95% CI 3% to 5%). For type 1 diabetes, incremental cost per QALY [standard deviation (SD)] of a 5-yearly compared with a 4-yearly screening interval was £3612 (£6586), increasing to £9601 (£34,112) for annual compared with 2-yearly screening. The probability that the intervention is cost saving is around 25%, and it has around an 80% chance of being below a cost-effectiveness threshold of £30,000. For type 2 diabetes, incremental cost per QALY (SD) of a yearly compared with a 2-yearly screening interval was £606 (£1782). The intervention is almost certainly below a cost-effectiveness threshold of £5000. CONCLUSIONS: These results support current UK guidance, which recommends annual screening with ACR to identify early kidney disease in patients with diabetes, despite a high false-positive rate leading to, at worst, unnecessary or, at best, early therapeutic intervention. For type 1 diabetes, screening costs for annual compared with 2-yearly screening are well within the bounds of accepted cost-effectiveness. Annual screening is even more cost-effective in type 2 diabetes than in type 1 diabetes. Identification of alternative markers for developing diabetic nephropathy may improve targeting of treatment for those at high risk. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Impact of perturbations of nitrogen oxide emissions from global aviation

The atmospheric response to perturbations in NOx emissions from global air traffic is investigated by performing a coherent set of sensitivity experiments. The importance of cruise altitude, size of the emission perturbation and geographical distribution of emissions is systematically analyzed using two global chemistry transport models and an off-line radiative transfer model. NOx emissions from a contemporary aircraft inventory have been used to assess the impact of global air traffic on ozone and methane. In further experiments the NOx emissions are perturbed, in turn, in 16 cruise altitude bands between 5 and 15 km altitude. In the p-TOMCAT model we diagnose an annual mean ozone increase of up to 6 ppbv and a decrease in the methane lifetime of 3% due to global air traffic in 2002. Associated radiative forcings of 30 mWm(-2) for ozone and -19 mWm(-2) for methane are diagnosed; a simple method is used to estimate the forcing due to the methane-induced ozone change and this yields an additional -11 mWm(-2). Results show that up to the tropopause, ozone production efficiency and resulting impacts increase per emitted mass of NOx with the altitude of the perturbation. Between 11 and 15 km we find that the geographical location of the NOx emissions plays a crucial role in the potential O-3 impact and lifetime change of CH4. We show that changes in flight routing in this altitude range can have significant consequences for O-3 and CH4 concentrations. Overall, we demonstrate a linear relationship in the atmospheric response to small emission changes which can be used to predict the importance of perturbations about the reference aircraft emissions profile, provided the geographical distribution of the emissions is not altered significantly