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

Viral-toxin interactions and Parkinson’s disease: poly(I:C) priming enhanced the neurodegenerative effects of paraquat

<p><b>Abstract</b></p> <p><b>Background</b></p> <p>Parkinson’s disease (PD) has been linked with exposure to a variety of environmental and immunological insults (for example, infectious pathogens) in which inflammatory and oxidative processes seem to be involved. In particular, epidemiological studies have found that pesticide exposure and infections may be linked with the incidence of PD. The present study sought to determine whether exposure to a viral mimic prior to exposure to pesticides would exacerbate PD-like pathology.</p> <p><b>Methods</b></p> <p>Mice received a supra-nigral infusion of 5 μg of the double-stranded RNA viral analog, polyinosinic: polycytidylic acid (poly(I:C)), followed 2, 7 or 14 days later by administration of the pesticide, paraquat (nine 10 mg/kg injections over three weeks).</p> <p><b>Results</b></p> <p>As hypothesized, poly(I:C) pre-treatment enhanced dopamine (DA) neuron loss in the substantia nigra pars compacta elicited by subsequent paraquat treatment. The augmented neuronal loss was accompanied by robust signs of microglial activation, and by increased expression of the catalytic subunit (gp91) of the NADPH oxidase oxidative stress enzyme. However, the paraquat and poly(I:C) treatments did not appreciably affect home-cage activity, striatal DA terminals, or subventricular neurogenesis.</p> <p><b>Conclusions</b></p> <p>These findings suggest that viral agents can sensitize microglial-dependent inflammatory responses, thereby rendering nigral DA neurons vulnerable to further environmental toxin exposure.</p

Evaluation of preference and purpose of utilisation of cone beam computed tomography (CBCT) compared to orthopantomogram (OPG) by dental practitioners : a cross-sectional study

BACKGROUND: Cone beam computed tomography (CBCT) has become a reliable adjunctive tool for both diagnosis and treatment planning in the field of dentistry. There are numerous advantages of CBCT over 2D imaging techniques (OPG). There is a need to evaluate the changing trend of preference and purpose of utilisation of these imaging modalities by dental practitioners. This study was carried out to evaluate and compare the purpose and preference of utilisation of CBCT and OPG by various dental practitioners in their clinical practice. MATERIAL AND METHODS: A retrospective, cross-sectional study was carried out on CBCT and OPG data of 620 different cases treated by different dental practitioners from imaging centres in the twin cities of Telangana (Hyderabad & Secunderabad). For comparisons, we used the Mann-Whitney U test (Z test). RESULTS: The analysis of data showed that among the dental practitioners OPG was more commonly ordered by general dentists (31%) followed by prosthodontists (30%), whereas CBCT was more advocated by general dental practitioners (25%) followed by OMFS (23%). OPG preference was greater for fixed partial denture planning (FPD) 59%, whereas CBCT was highly preferred for implant planning 61%. CONCLUSIONS: The present study showed that general dentists preferred OPG and CBCT compared to other dental practitioners, and OPG was advocated for FPD planning, whereas CBCT was advocated for implant planning. Moreover, and it was found that there had been a drastic increase in the preference of CBCT over OPG in recent times

AE burden supplementary information

Supplemental Figures and Table

Data from: Autoimmune encephalitis: a costly condition

Objective: To assess the inpatient hospitalization burden and costs of patients with autoimmune encephalitis (AE) at a tertiary care institution. Methods: Adult inpatients with AE were identified retrospectively from July 1, 2005 – June 30, 2015. Demographic and clinical data were collected and analyzed. Billing data were compared to that of patients with herpes simplex encephalitis (HSE). Charges were adjusted for inflation. Results: Of 244 admissions for encephalitis reviewed, 63 patients met criteria for probable or definite AE. Thirty-one (49%) patients were antibody-positive, and twenty-seven (43%) were admitted to the intensive care unit (ICU). Median hospital charges per AE patient were over $70k, median length of stay (LOS) was 15 days, and in hospital mortality was 6$173k/ admission vs. non-ICU $50k/ admission, p<0.001). LOS was strongly associated with charges and was driven by delay in diagnosis of AE, prolonged treatment courses, and lack of response to therapy. In comparison with HSE, median hospital charges per AE patient were nearly 4 times higher, median AE LOS was 3 times higher, and total charges over the study period were nearly twice as high. Conclusions: AE patients utilized more inpatient healthcare resources per patient during a ten-year period than HSE at our institution. ICU-admitted AE patients were responsible for a substantially higher financial burden than non-ICU-admitted AE patients. Our data underscore the need for the development of novel diagnostic and therapeutic modalities to improve patient outcomes and decrease hospital burden in AE

Frailty predicts worse outcomes after intracranial meningioma surgery irrespective of existing prognostic factors

OBJECTIVE: Frailty has been recognized as a predictor of adverse surgical outcomes across multiple surgical disciplines, but until now the relationship between frailty and intracranial meningioma surgery has not been studied. The goal of the present study was to determine the relationship between increasing frailty (determined using the modified Frailty Index [mFI]) and intracranial meningioma resection outcomes (including hospital length of stay [LOS], discharge location, and reoperation and readmission rates). METHODS: This is a single-center retrospective cohort study of patients who underwent intracranial meningioma resection between August 2012 and May 2018. Seventy-six patients met the inclusion criteria. RESULTS: Frailty was associated with increased hospital LOS (p = 0.0218), increased reoperation rate (p = 0.029), and discharge to a higher level of care: an inpatient rehabilitation facility or a skilled nursing facility (p = 0.0002). After multivariable analysis, frailty was determined to be an independent risk factor for increased LOS, worse discharge disposition, and subsequent readmission. CONCLUSIONS: Frailty is an independent risk factor for worse outcomes following intracranial meningioma resection, including increased LOS, reoperations, and worse discharge disposition. Frailty may help stratify preoperative surgical risk, and thus may provide important clinical information to help neurosurgeons and elderly patients weigh the risks and benefits of resection

Frailty Predicts Worse Outcomes After Intracranial Meningioma Surgery Irrespective of Existing Prognostic Factors

OBJECTIVE: Frailty has been recognized as a predictor of adverse surgical outcomes across multiple surgical disciplines, but until now the relationship between frailty and intracranial meningioma surgery has not been studied. The goal of the present study was to determine the relationship between increasing frailty (determined using the modified Frailty Index [mFI]) and intracranial meningioma resection outcomes (including hospital length of stay [LOS], discharge location, and reoperation and readmission rates). METHODS: This is a single-center retrospective cohort study of patients who underwent intracranial meningioma resection between August 2012 and May 2018. Seventy-six patients met the inclusion criteria. RESULTS: Frailty was associated with increased hospital LOS (p = 0.0218), increased reoperation rate (p = 0.029), and discharge to a higher level of care: an inpatient rehabilitation facility or a skilled nursing facility (p = 0.0002). After multivariable analysis, frailty was determined to be an independent risk factor for increased LOS, worse discharge disposition, and subsequent readmission. CONCLUSIONS: Frailty is an independent risk factor for worse outcomes following intracranial meningioma resection, including increased LOS, reoperations, and worse discharge disposition. Frailty may help stratify preoperative surgical risk, and thus may provide important clinical information to help neurosurgeons and elderly patients weigh the risks and benefits of resection

Contribution of microRNA-27b-3p to synovial fibrotic responses in knee osteoarthritis

OBJECTIVES: Synovial fibrosis contributes to osteoarthritis (OA) pathology but the underlying mechanisms remain unknown. We have observed increased microRNA (miR)-27b-3p levels in synovial fluid of late-stage radiographic knee OA patients. Here, we determined the contribution of miR-27b-3p to synovial fibrosis. METHODS: Synovium sections obtained from Kellgren-Lawrence-graded knee OA patients and a mouse model of knee OA (destabilization of medial meniscus; DMM) were stained for miR-27b-3p using in situ hybridization. Effects of intra-articular injections of miR-27b-3p mimic into naïve mouse knee joints, and miR-27b-3p inhibitor in the DMM model were also examined. MiR-27b-3p mimic or inhibitor transfection experiments were performed on human OA fibroblast-like synoviocytes (FLS) using RT-qPCR array, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence and migration assays. RESULTS: MiR-27b-3p expression increased in the synovium of knee OA patients and after DMM surgery in mice. Intra-articular injections of miR-27b-3p mimic injected in mouse knee joints induced a synovial fibrosis-like phenotype with increased synovitis scores and increased COL1A1 and α-SMA expression. In the DMM model, miR-27b-3p inhibitor decreased α-SMA with unchanged COL1A1 expression and synovitis scores. MiR-27b-3p mimic treatment of human OA FLS induced pro-fibrotic responses including increased migration and expression of key extracellular matrix (ECM) genes, while inhibitor transfection had opposite effects. RNA-sequencing identified a PPARG/ADAMTS8 signaling axis regulated by miR-27b-3p in OA FLS. MiR-27b-3p mimic-transfected OA FLS treated with the PPARG agonist rosiglitazone or ADAMTS8-siRNA exhibited altered expression of select ECM genes. CONCLUSIONS: This study demonstrates a key role of miR-27b-3p in ECM regulation associated with synovial fibrosis during OA