Remote monitoring of patients with implantable cardioverter-defibrillators: Can results from large clinical trials be transposed to clinical practice?

SummaryBackgroundRemote monitoring (RM) is increasingly used to follow up patients with implantable cardioverter-defibrillators (ICDs). Randomized control trials provide evidence for the benefit of this intervention, but data for RM in daily clinical practice with multiple-brands and unselected patients is lacking.AimsTo assess the effect of RM on patient management and clinical outcome for recipients of ICDs in daily practice.MethodsWe reviewed ICD recipients followed up at our institution in 2009 with RM or with traditional hospital only (HO) follow-up. We looked at the effect of RM on the number of scheduled ambulatory follow-ups and urgent unscheduled consultations, the time between onset of asymptomatic events to clinical intervention and the clinical effectiveness of all consultations. We also evaluated the proportion of RM notifications representing clinically relevant situations.ResultsWe included 355 patients retrospectively (RM: n=144, HO: n=211, 76.9% male, 60.3±15.2years old, 50.1% with ICDs for primary prevention and mean left ventricular ejection fraction 35.5±14.5%). Average follow-up was 13.5months. The RM group required less scheduled ambulatory follow-up consultations (1.8 vs. 2.1/patient/year; P<0.0001) and a far lower median time between the onset of asymptomatic events and clinical intervention (7 vs. 76days; P=0.016). Of the 784 scheduled ambulatory follow-up consultations carried out, only 152 (19.4%) resulted in therapeutic intervention or ICD reprogramming. We also found that the vast majority of RM notifications (61.9%) were of no clinical relevance.ConclusionRM allows early management of asymptomatic events and a reduction in scheduled ambulatory follow-up consultations in daily clinical practice, without compromising safety, endorsing RM as the new standard of care for ICD recipients

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

Impact of prenatal exposure to pesticides on neurophysiological functions of preterm neonates

Notre étude avait pour objectifs d'évaluer l'exposition chronique du fœtus aux pesticides et d'en étudier l'impact sur ses fonctions neurophysiologiques du nouveau-né prématuré. L'évaluation de l'exposition aux pesticides des enfants a été réalisée par questionnaire d'exposition maternelle et par le dosage de certains pesticides dans le méconium des nouveau-nés. Les paramètres hypniques et cardiovasculaires ont été obtenus lors d’une polysomnographie nocturne. La sensibilité des chémorécepteurs périphériques a été évaluée par un test hypoxique (15% O2) réalisé dans chacun des stades de sommeil. 100% des nouveau-nés présentaient au moins un des pesticides recherchés dans leur méconium, et pour 58,3% d’entre eux, plus de 3 substances ont été retrouvées. Nos résultats ont montré un impact des pesticides sur la structure du sommeil avec un temps de sommeil plus court (DMP), et une proportion de sommeil agité plus importante et de sommeil calme plus faible (DEP). Les enfants avaient également un sommeil plus fractionné lorsque les mamans étaient exposées aux pesticides par l'alimentation. La ventilation de base était plus élevée en présence de DEP (+18%) mais plus faible en présence de DMDTP (-14%). La sensibilité des chémorécepteurs périphériques était également plus faible chez les enfants exposés au DMDTP. Enfin, la balance sympatho-vagale était perturbée par l'exposition aux pesticides. Nos résultats suggèrent que l'exposition chronique in utero aux pesticides pourrait entrainer des dysfonctionnements des fonctions neurovégétatives du nouveau-né prématuré les rendant plus vulnérables face à divers stress cardio-ventilatoiresFirst we aimed to assess chronic pesticides exposure of the fetus. Then, we investigated the impact of pesticide exposure on vital neurophysiological functions of preterm neonates such as sleep, ventilation and its control, as well as cardiovascular control. We assessed pesticides exposure of neonates using a maternal exposure questionnaire, completed by a multi-residue analysis of pesticides in meconium in order to identify and quantify some pesticides and their metabolites. Cardiovascular and sleep parameters were obtained by polysomnography. Peripheral chemoreceptors sensitivity was measured using a hypoxic test (15% O2) during each sleep state. All newborns had at least one pesticide in their meconium and 58.3% of them, had more than 3 substances detected. Our results showed an impact of pesticides exposure on sleep structure as sleep duration was shortened (DMP), active sleep proportion was higher, and quiet sleep proportion was lower. Neonates also had a more fractionated sleep when their mothers were exposed to pesticides through dietary habits. With regards to ventilation, our results showed heterogeneous effects. Indeed, ventilation was higher when DEP was detected (+18%) but lower when DMDTP was identified (-14%). Peripheral chemoreceptors sensitivity was also weaker for neonates exposed to DMDTP. Finally, the sympatho-vagal balance were altered by pesticides exposure. Our results suggest that chronic pesticide exposure in utero could lead to a disruption of neurophysiological functions in preterm neonates (sleep, ventilation, cardiovascular system) making them even more vulnerable to various cardiorespiratory challenge

Impact de l'exposition in utero aux pesticides sur les fonctions neurophysiologiques du nouveau-né prématuré

First we aimed to assess chronic pesticides exposure of the fetus. Then, we investigated the impact of pesticide exposure on vital neurophysiological functions of preterm neonates such as sleep, ventilation and its control, as well as cardiovascular control. We assessed pesticides exposure of neonates using a maternal exposure questionnaire, completed by a multi-residue analysis of pesticides in meconium in order to identify and quantify some pesticides and their metabolites. Cardiovascular and sleep parameters were obtained by polysomnography. Peripheral chemoreceptors sensitivity was measured using a hypoxic test (15% O2) during each sleep state. All newborns had at least one pesticide in their meconium and 58.3% of them, had more than 3 substances detected. Our results showed an impact of pesticides exposure on sleep structure as sleep duration was shortened (DMP), active sleep proportion was higher, and quiet sleep proportion was lower. Neonates also had a more fractionated sleep when their mothers were exposed to pesticides through dietary habits. With regards to ventilation, our results showed heterogeneous effects. Indeed, ventilation was higher when DEP was detected (+18%) but lower when DMDTP was identified (-14%). Peripheral chemoreceptors sensitivity was also weaker for neonates exposed to DMDTP. Finally, the sympatho-vagal balance were altered by pesticides exposure. Our results suggest that chronic pesticide exposure in utero could lead to a disruption of neurophysiological functions in preterm neonates (sleep, ventilation, cardiovascular system) making them even more vulnerable to various cardiorespiratory challengesNotre étude avait pour objectifs d'évaluer l'exposition chronique du fœtus aux pesticides et d'en étudier l'impact sur ses fonctions neurophysiologiques du nouveau-né prématuré. L'évaluation de l'exposition aux pesticides des enfants a été réalisée par questionnaire d'exposition maternelle et par le dosage de certains pesticides dans le méconium des nouveau-nés. Les paramètres hypniques et cardiovasculaires ont été obtenus lors d’une polysomnographie nocturne. La sensibilité des chémorécepteurs périphériques a été évaluée par un test hypoxique (15% O2) réalisé dans chacun des stades de sommeil. 100% des nouveau-nés présentaient au moins un des pesticides recherchés dans leur méconium, et pour 58,3% d’entre eux, plus de 3 substances ont été retrouvées. Nos résultats ont montré un impact des pesticides sur la structure du sommeil avec un temps de sommeil plus court (DMP), et une proportion de sommeil agité plus importante et de sommeil calme plus faible (DEP). Les enfants avaient également un sommeil plus fractionné lorsque les mamans étaient exposées aux pesticides par l'alimentation. La ventilation de base était plus élevée en présence de DEP (+18%) mais plus faible en présence de DMDTP (-14%). La sensibilité des chémorécepteurs périphériques était également plus faible chez les enfants exposés au DMDTP. Enfin, la balance sympatho-vagale était perturbée par l'exposition aux pesticides. Nos résultats suggèrent que l'exposition chronique in utero aux pesticides pourrait entrainer des dysfonctionnements des fonctions neurovégétatives du nouveau-né prématuré les rendant plus vulnérables face à divers stress cardio-ventilatoire

The hypoxic test in preterm neonates reinvestigated

International audienceAim: We currently lack a suitable gold-standard method for implementation on modern equipment to assess peripheral chemoreceptor sensitivity. The aim of the present study was to develop an accurate and reproducible method for assessing peripheral chemoreceptors sensitivity in sleeping preterm neonates. Methods: A poïkilocapnic hypoxic test was performed twice during rapid eye movement sleep (REM sleep) and non-rapid eye movement sleep (nonREM sleep). The infant breathed hypoxic gas (15% O 2) for 60 s. The ventilatory response to hypoxia was assessed by comparing minute ventilation during the control period (21% O 2) with successive 4-cycles sequences during hypoxia. We detected the first statistically significant increase in minute ventilation and recorded the corresponding response time

Isolated hypospadias: The impact of prenatal exposure to pesticides, as determined by meconium analysis

International audienceAlthough endocrine-disrupting chemicals (EDCs, including pesticides) are thought to increase the risk of hypospadias, no compounds have been formally identified in this context. Human studies may now be possible via the assessment of meconium as a marker of chronic prenatal exposure. The objective of the present study was to determine whether or not prenatal exposure to pesticides (as detected in meconium) constitutes a risk factor for isolated hypospadias. In a case-control study performed between 2011 and 2014 in northern France, male newborns with isolated hypospadias (n = 25) were matched at birth with controls (n = 58). Newborns with obvious genetic or hormonal anomalies, undescended testis, micropenis, a congenital syndrome or a family history of hypospadias were not included. Neonatal and parental data were collected. Foetal exposure was assessed by determining the meconium concentrations of the pesticides or metabolites (organophosphates, carbamates, phenylurea, and phenoxyherbicides) most commonly used in the region. Risk factors were assessed in a multivariate analysis. The pesticides most commonly detected in meconium were organophosphates (in up to 98.6% of samples, depending on the substance) and phenylurea (>85.5%). A multivariate analysis revealed an association between isolated hypospadias and the presence in meconium of the phenylurea herbicide isoproturon and of the phenoxyherbicide 2-methyl-4-chlorophenoxyacetic acid (odds ratio [95% confidence interval]: 5.94 [1.03-34.11] and 4.75 [1.20-18.76]) respectively). We conclude that prenatal exposure to these two herbicides (as assessed by meconium analysis) was correlated with the occurrence of isolated hypospadias. The results of our case-control study (i) suggest that prenatal exposure to pesticides interferes with the development of the male genitalia, and (ii) emphasize the importance of preventing pregnant women from being exposed to EDCs in general and pesticides in particular