Oceanic influence on southernmost South American precipitation

The potential oceanic influence on southernmost South American precipitation since 1930 is analyzed in this study. The aim is to define oceanic characteristics that can produce wetter or drier conditions over the mentioned region on different time scales. Results suggest important precipitation-oceanic links in decadal and interdecadal oscillations. The eastern and central subtropical Indian, western tropical Pacific and western and central subtropical Pacific could be forcing the precipitation on decadal time scale. Moreover, the eastern tropical and western subtropical Indian and western and central subtropical Pacific could be forcing the variability of precipitation on interdecadal time scale. Although the research was focused in forcing of precipitation, relations among different regions of the Indian and Pacific oceans on decadal and interdecadal time scales have also been detected. Therefore, results presented here can be useful in describing new aspects of the remote influence of both oceans on regional climate.En este trabajo se analiza la posible influencia oceánica en la variabilidad de la precipitación sobre el extremo sur de Sudamérica desde 1930. El objetivo es definir características oceánicas que pueden producir condiciones de más o menos lluvia en diferentes escalas de tiempo en la mencionada región. Los resultados sugieren importantes relaciones entre los océanos y la precipitación en oscilaciones decadales e interdecadales. El este y centro del índico subtropical, el oeste del Pacífico tropical y el oeste y centro del Pacífico subtropical podrían estar influenciando la precipitación en escala decadal. Por otra parte, la región este tropical y oeste subtropical del índico, y el oeste y centro del Pacífico subtropical podrían influenciar la variabilidad de la precipitación en escala interdecadal. Si bien el estudio se enfocó en la variabilidad de la precipitación, relaciones entre diferentes regiones de los océanos Índico y Pacífico en escalas decadal e interdecadal han sido también detectadas. Por lo tanto, los resultados aquí presentados pueden también ser útiles para describir nuevos aspectos de la influencia remota de ambos océanos en el clima regional.Fil: Berman, Ana Laura. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Silvestri, Gabriel Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmosfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmosfera; ArgentinaFil: Compagnucci, Rosa Hilda. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Velasco Herrera, Victor. Universidad Nacional Autónoma de México. Instituto de Geofísica; Méxic

Co-variabilidad de la temperatura superficial del mar entre cuencas del Hemisferio sur

En este trabajo se estudian relaciones estadísticas entre diferentes regiones de los océanos del Hemisferio Sur en todo el espacio tiempo-frecuencia durante los últimos cincuenta años aplicando la metodología de transformada ondeletas de coherencia a promedios anuales de anomalías mensuales de temperatura superficial del mar. Entre los resultados más relevantes encontrados debe mencionarse que las regiones del oeste y centro del Pacífico tropical tienen una estrecha relación en oscilaciones menores a 8 años y en oscilaciones alrededor de 12 años pero notables desacoples son detectados en el resto del espacio de frecuencias. Por otra parte, la relación entre las regiones del oeste y del este del Pacífico tropical es significativa sólo en oscilaciones menores a 8 años con una clara interrupción durante la década de 1980. Importantes conexiones en oscilaciones interdecadales son detectadas entre las regiones del oeste y centro del Pacifico subtropical. En el Océano Atlántico se encuentran relaciones significativas en un amplio rango de frecuencias entre las regiones del oeste y, especialmente, entre las regiones tropicales mientras que en el Océano Indico solo se observan relaciones importantes entre áreas subtropicales en oscilaciones decadales e interdecadales. El análisis también revela fuertes conexiones entre las tres cuencas oceánicas en diferentes bandas de frecuencia.Relations among different regions of the Southern Hemisphere oceans in the whole time-frequency space during the last fifty years are studied applying the methodology of Wavelet Coherence Analysis to annual means of monthly anomalies of sea surface temperature. Among the most relevant results, it must be mentioned that the western and central regions of the tropical Pacific have a close relation in oscillations shorter than 8 years and in oscillations around 12 years but important disconnections are detected in the rest of the space of frequencies. Moreover, the relation among the western and eastern regions of the tropical Pacific is significant only in oscillations shorter than 8 years with a clear interruption during the 1980s. Important connections in interdecadal oscillations are detected among the western and central regions of the subtropical Pacific. Significant relations in a wide range of frequencies among the western and, specially, among the tropical regions of the Atlantic Ocean are found. In the Indian Ocean, the relations among subtropical areas in decadal and interdecadal scales are the only ones important. The analysis also reveals strong connections among the three oceanic basins in different bands of frequencies.Asociación Argentina de Geofísicos y Geodesta

Análisis en tiempo-frecuencia de la conexión entre la atmósfera y el Océano Pacífico Tropical

En este trabajo son exploradas las relaciones entre el Indice de Oscilación Sur (SOI) y la temperatura de la superficie del mar (TSM) tanto del Pacifico tropical como de la región subtropical del Pacífico Sur para las diferentes bandas del espacio de tiempo-frecuencia mediante la transformada de ondeleta (transformada wavelet). En el Pacífico tropical central, los resultados muestran que el conocido sistema acoplado El Niño-Oscilación Sur (ENOS) caracterizado por simultáneas anomalías positivas (negativas) del SOI y negativas (positivas) de la TSM ocurre en todo el espacio de frecuencias. Sin embargo, estas relaciones significativas con el SOI se interrumpen en el océano tropical oeste en oscilaciones alrededor de 8 años cerca del destacado cambio climático de 1976/77. En las periodicidades más largas, el SOI tiene una débil relación con las áreas del océano tropical oeste y no tiene conexión con las regiones del este. Los índices de TSM subtropical exhiben relaciones complejas con el SOI. Estas son significativas pero no estacionarias con la TSM de la región del oeste, con la región central son detectadas solo estrechas conexiones en específicas periodicidades y en la región este prácticamente desaparecen.El análisis de series reconstruidas para periodos preinstrumental revela que las esporádicas desconexiones entre el SOI y el Pacifico tropical fueron comunes durante los últimos siglos.Relations between the Southern Oscillation Index (SOI) and the sea surface temperature (SST) in the tropical and subtropical South Pacific are explored in this paper for different bands of the timefrequency space using the wavelet transform. In the tropical central Pacific, results show that the widely know coupled system El Niño-Southern Oscillation (ENSO) characterized by simultaneous positive (negative) SOI anomalies and negative (positive) SST anomalies occurs in the entire range of frequency. However, these significant links with the SOI are interrupted in the western tropical ocean in oscillations around 8 yrs near the extensively described 1976/77 climate shift. In the largest periodicities, the SOI has a weak relation with the western tropical areas and it does not have connection with the eastern regions. The indexes of subtropical SST exhibit complex relationships with the SOI. The links are significant but non-stationary with the western regions, close connections only occur in specific periodicities in the central areas and they vanish to the east. The analysis performed for reconstructed series for pre-instrumental times reveals that the sporadic disconnections between the SOI and the tropical Pacific were usual during the last centuries.Asociación Argentina de Geofísicos y Geodesta

Activation of Type 1 Cannabinoid Receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures

The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R) activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ) stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive), neurons and astrocytes. Stimulation of the CB1R by (R)-(+)-Methanandamide (R-m-AEA) increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation), at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca2+](i)) in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.Fundacao para a Ciencia e a Tecnologia - Portugal [POCTI/SAU-NEU/68465/2006, PTDC/SAU-NEU/104415/2008, PTDC/SAU-NEU/101783/2008, POCTI/SAU-NEU/110838/2009]; Fundacao Calouste Gulbenkian [96542]; Fundacao para a Ciencia e Tecnologiainfo:eu-repo/semantics/publishedVersio

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial

BACKGROUND Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). METHODS SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. FINDINGS Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm$^{3}$ (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm$^{3}$ (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m$^{2}$ (95% CI: 0.3, 1.0; p < 0.001)]. INTERPRETATION In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. FUNDING Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir

COVID-19 Vaccination Responses with Different Vaccine Platforms in Patients with Inborn Errors of Immunity

Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina. The study cohort included adults and pediatric IEI patients (n = 118) and age-matched healthy controls (HC) (n = 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry. No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (p < 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (p < 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection. In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.Fil: Erra, Lorenzo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Uriarte, Ignacio. Universidad Nacional de Mar del Plata; Argentina. Hospital Interzonal Especializado Materno Infantil Don Victorio Tetamanti (hiemi Victorio Tetamanti) ; Gobierno de la Provincia de Buenos Aires;Fil: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Paolini, María Virginia. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Seminario, Gisela. No especifíca;Fil: Fernández, Julieta Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Tau, Lorena. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Laboratorio de Salud Pública; ArgentinaFil: Bernatowiez, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Moreira, Ileana. No especifíca;Fil: Vishnopolska, Sebastián Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Rumbo, Martín. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Laboratorio de Salud Pública; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cassarino, María Chiara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Vijoditz, Gustavo. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: López, Ana Laura. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Curciarello, Renata. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Laboratorio de Salud Pública; ArgentinaFil: Rodríguez, Diego. Universidad Nacional de Mar del Plata; Argentina. Hospital Interzonal Especializado Materno Infantil Don Victorio Tetamanti (hiemi Victorio Tetamanti) ; Gobierno de la Provincia de Buenos Aires;Fil: Rizzo, Gaston Pascual. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Laboratorio de Salud Pública; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Ferreyra Compagnucci, Malena María. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Laboratorio de Salud Pública; ArgentinaFil: Ferreyra Mufarregue, Leila Romina. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Badano, Maria Noel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Quiroga, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Baré, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ibañez, Lorena Itatí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Pozner, Roberto Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Docena, Guillermo H.. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Laboratorio de Salud Pública; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bezrodnik, Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Conversion to secondary progressive multiple sclerosis: patient awareness and needs. results from an online survey in Italy and Germany

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders.Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified.Methods: Participants were consenting adults with SPMS since &lt;= 5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs.Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p &lt; 0.001).Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients).All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: "physiotherapy" and "active patient care involvement." The other two differed across countries: "an individualized health care plan" and "information on social rights and policies" in Italy, and "psychological support" and "cognitive rehabilitation" in Germany.Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries

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