ORCID Profile
0000-0002-3236-0807
Current Organisations
University of Aberdeen
,
Institut de Pathologie et de Génétique
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Publications
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
Publisher: Springer Science and Business Media LLC
Date: 16-11-2022
DOI: 10.1038/S41380-022-01852-9
Abstract: Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride roton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 in iduals from 67 families with CLCN4 -related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for in iduals with this diagnosis.
Systematic Review of Active Surveillance for Clinically Localised Prostate Cancer to Develop Recommendations Regarding Inclusion of Intermediate-risk Disease, Biopsy Characteristics at Inclusion and M
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.EURURO.2021.12.007
Abstract: There is uncertainty regarding the most appropriate criteria for recruitment, monitoring, and reclassification in active surveillance (AS) protocols for localised prostate cancer (PCa). To perform a qualitative systematic review (SR) to issue recommendations regarding inclusion of intermediate-risk disease, biopsy characteristics at inclusion and monitoring, and repeat biopsy strategy. A protocol-driven, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-adhering SR incorporating AS protocols published from January 1990 to October 2020 was performed. The main outcomes were criteria for inclusion of intermediate-risk disease, monitoring, reclassification, and repeat biopsy strategies (per protocol and/or triggered). Clinical effectiveness data were not assessed. Of the 17 011 articles identified, 333 studies incorporating 375 AS protocols, recruiting 264 852 patients, were included. Only a minority of protocols included the use of magnetic resonance imaging (MRI) for recruitment (n = 17), follow-up (n = 47), and reclassification (n = 26). More than 50% of protocols included patients with intermediate or high-risk disease, whilst 44.1% of protocols excluded low-risk patients with more than three positive cores, and 39% of protocols excluded patients with core involvement (CI) >50% per core. Of the protocols, ≥80% mandated a confirmatory transrectal ultrasound biopsy 72% (n = 189) of protocols mandated per-protocol repeat biopsies, with 20% performing this annually and 25% every 2 yr. Only 27 protocols (10.3%) mandated triggered biopsies, with 74% of these protocols defining progression or changes on MRI as triggers for repeat biopsy. For AS protocols in which the use of MRI is not mandatory or absent, we recommend the following: (1) AS can be considered in patients with low-volume International Society of Urological Pathology (ISUP) grade 2 (three or fewer positive cores and cancer involvement ≤50% CI per core) or another single element of intermediate-risk disease, and patients with ISUP 3 should be excluded (2) per-protocol confirmatory prostate biopsies should be performed within 2 yr, and per-protocol surveillance repeat biopsies should be performed at least once every 3 yr for the first 10 yr and (3) for patients with low-volume, low-risk disease at recruitment, if repeat systematic biopsies reveal more than three positive cores or maximum CI >50% per core, they should be monitored closely for evidence of adverse features (eg, upgrading) patients with ISUP 2 disease with increased core positivity and/or CI to similar thresholds should be reclassified. We examined the literature to issue new recommendations on active surveillance (AS) for managing localised prostate cancer. The recommendations include setting criteria for including men with more aggressive disease (intermediate-risk disease), setting thresholds for close monitoring of men with low-risk but more extensive disease, and determining when to perform repeat biopsies (within 2 yr and 3 yearly thereafter).
EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an International Collaborative Study (DETEC
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.EURURO.2019.09.020
Abstract: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised. To develop consensus statements for all domains of DAT. A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed. A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%) the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion. Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials. We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers.
What are the unmet supportive care needs of men affected by penile cancer? A systematic review of the empirical evidence
Publisher: Elsevier BV
Date: 10-2020
Study Protocol for the DETECTIVE Study: An International Collaborative Study To Develop Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer
Publisher: Elsevier BV
Date: 04-2019
Related Organisations
University Of Aberdeen
Location: United Kingdom of Great Britain and Northern Ireland
Université De Limoges Faculté Des Sciences Et Techniques
Location: France
Related Funding Activities
No related grants have been discovered for Olivier Monestier.