1. Fukuhara H, Yamamoto S, Lai HW, Karashima T, Kurabayashi A, Furihata M, Inoue K. Real-world experience with 5-aminolevulinic acid for photodynamic diagnosis of bladder cancer (2nd report): Reduced bladder recurrence after PDD-TURBT. Photodiagnosis and photodynamic therapy. 2022; 38: 102757.

BACKGROUND: Photodynamic diagnosis (PDD) with administration of oral aminolevulinic acid (ALA) prior to transurethral resection of bladder tumor (TURBT) can now be used for non-muscle invasive bladder cancer (NMIBC) in clinical settings in Japan. Since ALA was first marketed, a limited number of reports have described PDD-TURBT outcomes, and the effects of resecting false-positive tissue on outcomes have not been clarified. METHODS: This study compared tumor recurrence among NMIBC patients who underwent TURBT under either white light cystoscopy (WL) or PDD. In addition, the frequency of recurrence was compared between patients with or without false-positive lesions at the time of PDD-TURBT. RESULTS: The frequency of recurrence in NMIBC patients (cumulative number of recurrences/cumulative number of follow-up days, number of recurrences/10,000 days), including progression to muscle-invasive bladder cancer (MIBC), was 12.80 in the WL-TURBT group and 5.82 in the PDD-TURBT group (p < 0.05). Tumor recurrence after TURBT was seen in 29 of 88 patients (33.0%) in the WL-TURBT group and 21 of 105 patients (20.0%) in the PDD-TURBT group (p < 0.05). Mean (± standard deviation) time to first recurrence was 249 ± 140 days in the WL-TURBT group and 419 ± 219 days in the PDD-TURBT group (p < 0.05). The frequency of recurrence in PDD-TURBT-group NMIBC patients was significantly lower in patients with resection of false-positive tissue (4.19/10,000 days) than in those without (9.00/10,000 days, p < 0.05). CONCLUSION: The frequency of recurrence was lower and the time to recurrence was longer in the PDD-TURBT group than in the WL-TURBT group. The frequency of recurrence decreased with resection of false-positive resection.

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2. Jacob S, Veenstra-VanderWeele J, Murphy D, McCracken J, Smith J, Sanders K, Meyenberg C, Wiese T, Deol-Bhullar G, Wandel C, Ashford E, Anagnostou E. Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial. The lancet Psychiatry. 2022; 9(3): 199-210.

BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual’s baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27•6 years (SD 9•7) and mean IQ score was 104•8 (18•1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67•2 (SD 15•3) in the balovaptan group and 66•2 (17•7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2•91 (SE 1•52) in the balovaptan group (n=79) and 4•75 (1•60) in the placebo group (n=71; estimated treatment difference -1•84 [95% CI -5•15 to 1•48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4•56 (SD 10•85) in the balovaptan group (n=111) and 6•83 (12•18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.

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3. Karlsson H, Sjöqvist H, Brynge M, Gardner R, Dalman C. Childhood infections and autism spectrum disorders and/or intellectual disability: a register-based cohort study. Journal of neurodevelopmental disorders. 2022; 14(1): 12.

OBJECTIVE: To explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID), and their co-occurrence. METHODS: The association between specialized care for any infection, defined by ICD-codes, and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987-2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders children’s characteristics, family socioeconomic factors, obstetric complications, and parental histories of treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with the exclusion of congenital causes of ASD/ID and documented risk for infections were also performed. RESULTS: Crude estimates indicated that infections during childhood were associated with later ASD and ID with the largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population, and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later « ASD without ID » (HR 1.24, 95%CI 1.15-1.33), « ASD with ID » (1.57, 1.35-1.82), and « ID without ASD » (2.01, 1.76-2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID. CONCLUSIONS: Infections during childhood may contribute to a later diagnosis of ID and ASD.

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4. Loth E. Placebo effects and participant heterogeneity in clinical trials of autism spectrum disorder. The lancet Psychiatry. 2022; 9(3): 184-5.

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5. Vanclooster S, Bissell S, van Eeghen AM, Chambers N, De Waele L, Byars AW, Capal JK, Cukier S, Davis P, Flinn J, Gardner-Lubbe S, Gipson T, Heunis TM, Hook D, Kingswood JC, Krueger DA, Kumm AJ, Sahin M, Schoeters E, Smith C, Srivastava S, Takei M, Waltereit R, Jansen AC, de Vries PJ. The research landscape of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)-a comprehensive scoping review. Journal of neurodevelopmental disorders. 2022; 14(1): 13.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. METHODS: The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. RESULTS: Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low-middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder-like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). CONCLUSIONS: Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.

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