Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Sustainable lignin‐based polyols as promising thermal energy storage materials

Six lignin-based polyols (LBPs) have been prepared by cationic ring opening polymerization of an oxirane in the presence of an organosolv lignin in tetrahydrofuran (THF) as reaction media and co-monomer. The prepared LBPs have been characterized and tested for the first time as phase change materials (PCMs) for thermal energy storage (TES) at low temperature. It was found a strong influence of the LBPs composition on their performance to storage thermal energy. Thus, LBPs with higher THF wt% content and lower oxirane/THF mass ratio exhibit the highest latent heats. Furthermore, a clear inversely proportional trend between the oxirane/THF mass ratio and the melting temperatures of the prepared LBPs was noticed. Among the prepared LBPs, the highest obtained latent heat was 53.7 J/g demonstrating the potential application of lignin as feedstock for PCMs preparation. To the best of our knowledge, this is the first time that a biomass derived PCM based on lignin has been studied and considered for TES applications at low temperature. LBPs show energetic solid–liquid transitions that point out their promising potential as bio-PCMs. This work paves the way to introduce new bio-based PCMs from lignin in TES systems, for example, in a more sustainable construction sector

Clinic of vascular access: Results after implementing a multidisciplinary approach adding routine Doppler ultrasound

Background: A multidisciplinary approach and Doppler ultrasound (DU) assessment for the creation and maintenance of arteriovenous fistulas (AVF) for haemodialysis can improve prevalence and patency. The aim of this study was to analyze the impact of a new multidisciplinary vascular access (VA) clinic with routine DU. Material and methods: We analyzed the VA clinic results from 2014 and 2015, before and after the implementation of a multidisciplinary team protocol (vascular surgeon/nephrologist) with routine DU in preoperative mapping and prevalent AVF. Results: We analyzed 345 and 364 patients from 2014 and 2015 respectively. The number of surgical interventions was similar in both periods (p = .289), with a trend toward an increase in preventive surgical repair of AVF in 2015 (17 vs. 29, p = .098). 155 vs. 169 new AVF were performed in 2014 and 2015, with a significantly lower primary failure rate in 2015 (26.4 vs. 15.3%, p = .015), and a non-significant increase in radiocephalic AVF, 25.8 vs. 33.2% (n = 40 vs. 56), p = .159. The concordance between the indication at the clinic and the surgery performed also increased (81.3 vs. 93.5%, p = .001). Throughout 2015 fewer complementary imaging test were requested from the clinic (78 vs. 35, p < .001), with a corresponding reduction in costs (€ 87,716 vs. € 59,445). Conclusions: Multidisciplinary approach with routine DU can improve VA results, with a decrease in primary failure rate, higher likelihood of radiocephalic AVF, better management of dis-functioning AVF and lower radiological test costs. Resumen: Antecedentes y objetivo: El abordaje multidisciplinar y el uso de ecografía doppler (ED) en la creación y vigilancia del acceso vascular (AV) puede mejorar la prevalencia y permeabilidad de las fístulas arteriovenosas (FAV) para hemodiálisis. El objetivo de este estudio es analizar el impacto de una nueva consulta multidisciplinar (CMD) de AV con ED de rutina. Material y métodos: Evaluamos los resultados de la consulta de AV en 2014 (pre-CMD) y 2015 (CMD), antes y después de la implantación de un equipo multidisciplinar (cirujano vascular/nefrólogo) con ED de rutina en mapeo prequirúrgico y FAV prevalente. Resultados: Se evaluaron 345 pacientes en 2014 (pre-CMD) y 364 pacientes en 2015 (CMD). En ambos periodos se realizó un número similar de cirugías, 172 vs. 198, p = 0,289, con tendencia a aumentar las cirugías preventivas de reparación de FAV en el periodo CMD, 17 vs. 29 (p = 0,098). En FAV de nueva creación (155 vs. 169), disminuyó la tasa de fallo primario en el periodo CMD, 26,4 vs. 15,3%, p = 0,015 y aumentó de forma no significativa la realización de FAV radiocefálicas distales, 25,8 vs. 33,2% (n = 40 vs. 56), p = 0,159. También aumentó la concordancia entre la indicación quirúrgica en la consulta y la cirugía realizada (81,3 vs. 93,5%, p = 0,001). En el periodo CMD se solicitaron menos exploraciones radiológicas desde la consulta, 78 vs. 35 (p < 0,001), con una reducción del gasto sanitario (81.716€ vs. 59.445€). Conclusiones: El manejo multidisciplinar y la utilización del ED de rutina permiten mejorar los resultados de AV, con disminución de la tasa de fallo primario de FAV, más opciones de FAV distal nativa, mejor manejo de la FAV prevalente disfuncionante y menor coste en exploraciones radiológicas. Keywords: Vascular access, Doppler ultrasound, Arteriovenous fistula, Primary failure, Palabras clave: Acceso vascular, Ecografía doppler, Fístula arteriovenosa, Fallo primari

Consulta de acceso vascular: resultados antes y después de la instauración de un programa multidisciplinar con realización de ecografía doppler de rutina

Resumen: Antecedentes y objetivo: El abordaje multidisciplinar y el uso de ecografía doppler (ED) en la creación y vigilancia del acceso vascular (AV) puede mejorar la prevalencia y permeabilidad de las fístulas arteriovenosas (FAV) para hemodiálisis. El objetivo de este estudio es analizar el impacto de una nueva consulta multidisciplinar (CMD) de AV con ED de rutina. Material y métodos: Evaluamos los resultados de la consulta de AV en 2014 (pre-CMD) y 2015 (CMD), antes y después de la implantación de un equipo multidisciplinar (cirujano vascular/nefrólogo) con ED de rutina en mapeo prequirúrgico y FAV prevalente. Resultados: Se evaluaron 345 pacientes en 2014 (pre-CMD) y 364 pacientes en 2015 (CMD). En ambos periodos se realizó un número similar de cirugías, 172 vs. 198, p =0,289, con tendencia a aumentar las cirugías preventivas de reparación de FAV en el periodo CMD, 17 vs. 29 (p = 0,098). En FAV de nueva creación (155 vs. 169), disminuyó la tasa de fallo primario en el periodo CMD, 26,4 vs. 15,3%, p = 0,015 y aumentó de forma no significativa la realización de FAV radiocefálicas distales, 25,8 vs. 33,2% (n = 40 vs. 56), p = 0,159. También aumentó la concordancia entre la indicación quirúrgica en la consulta y la cirugía realizada (81,3 vs. 93,5%, p = 0,001). En el periodo CMD se solicitaron menos exploraciones radiológicas desde la consulta, 78 vs. 35 (p< 0,001), con una reducción del gasto sanitario (81.716€ vs. 59.445€). Conclusiones: El manejo multidisciplinar y la utilización del ED de rutina permiten mejorar los resultados de AV, con disminución de la tasa de fallo primario de FAV, más opciones de FAV distal nativa, mejor manejo de la FAV prevalente disfuncionante y menor coste en exploraciones radiológicas. Abstract: Background: A multidisciplinary approach and Doppler ultrasound (DU) assessment for the creation and maintenance of arteriovenous fistulas (AVF) for haemodialysis can improve prevalence and patency. The aim of this study was to analyse the impact of a new multidisciplinary vascular access (VA) clinic with routine DU. Material and methods: We analysed the VA clinic results from 2014 and 2015, before and after the implementation of a multidisciplinary team protocol (vascular surgeon/nephrologist) with routine DU in preoperative mapping and prevalent AVF. Results: We analysed 345 and 364 patients from 2014 and 2015 respectively. The number of surgical interventions was similar in both periods (p = .289), with a trend towards an increase in preventive surgical repair of AVF in 2015 (17 vs. 29, p = .098). 155 vs. 169 new AVF were performed in 2014 and 2015, with a significantly lower primary failure rate in 2015 (26.4 vs. 15.3%, p = .015), and a non-significant increase in radiocephalic AVF, 25.8 vs. 33.2% (n = 40 vs. 56), p = .159. The concordance between the indication at the clinic and the surgery performed also increased (81.3 vs. 93.5%, p = .001). Throughout 2015 fewer complementary imaging test were requested from the clinic (78 vs. 35, p < .001), with a corresponding reduction in costs (€87,716 vs. €59,445). Conclusions: Multidisciplinary approach with routine DU can improve VA results, with a decrease in primary failure rate, higher likelihood of radiocephalic AVF, better management of dis-functioning AVF and lower radiological test costs. Palabras clave: Acceso vascular, Ecografía doppler, Fístula arteriovenosa, Fallo primario, Keywords: Vascular access, Doppler ultrasound, Arteriovenous fistula, Primary failur

A randomized trial of planned cesarean or vaginal delivery for twin pregnancy

Background: Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy.\ud \ud Methods: We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison.\ud \ud Results: A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P = 0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P = 0.49).\ud \ud Conclusion: In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN