Antiherpetic drugs: a potential way to prevent Alzheimer’s disease?

Background Considering the growing body of evidence suggesting a potential implication of herpesviruses in the development of dementia, several authors have questioned a protective effect of antiherpetic drugs (AHDs) which may represent a new means of prevention, well tolerated and easily accessible. Subsequently, several epidemiological studies have shown a reduction in the risk of dementia in subjects treated with AHDs, but the biological plausibility of this association and the impact of potential methodological biases need to be discussed in more depth. Methods Using a French medico-administrative database, we assessed the association between the intake of systemic AHDs and the incidence of (i) dementia, (ii) Alzheimer’s disease (AD), and (iii) vascular dementia in 68,291 subjects over 65 who were followed between 2009 and 2017. Regarding potential methodological biases, Cox models were adjusted for numerous potential confounding factors (including proxies of sociodemographic status, comorbidities, and use of healthcare) and sensitivity analyses were performed in an attempt to limit the risk of indication and reverse causality biases. Results 9.7% of subjects (n=6642) had at least one intake of systemic AHD, and 8883 incident cases of dementia were identified. Intake of at least one systemic AHD during follow-up was significantly associated with a decreased risk of AD (aHR 0.85 95% confidence interval [0.75–0.96], p=0.009) and, to a lesser extent with respect to p values, to both dementia from any cause and vascular dementia. The association with AD remained significant in sensitivity analyses. The number of subjects with a regular intake was low and prevented us from studying its association with dementia. Conclusions Taking at least one systemic AHD during follow-up was significantly associated with a 15% reduced risk of developing AD, even after taking into account several potential methodological biases. Nevertheless, the low frequency of subjects with a regular intake questions the biological plausibility of this association and highlights the limits of epidemiological data to evaluate a potential protective effect of a regular treatment by systemic AHDs on the incidence of dementia

A Systematic Review and Recommendations Around Frameworks for Evaluating Scientific Validity in Nutritional Genomics

Background: There is a significant lack of consistency used to determine the scientific validity of nutrigenetic research. The aims of this study were to examine existing frameworks used for determining scientific validity in nutrition and/or genetics and to determine which framework would be most appropriate to evaluate scientific validity in nutrigenetics in the future.Methods: A systematic review (PROSPERO registration: CRD42021261948) was conducted up until July 2021 using Medline, Embase, and Web of Science, with articles screened in duplicate. Gray literature searches were also conducted (June-July 2021), and reference lists of two relevant review articles were screened. Included articles provided the complete methods for a framework that has been used to evaluate scientific validity in nutrition and/or genetics. Articles were excluded if they provided a framework for evaluating health services/systems more broadly. Citing articles of the included articles were then screened in Google Scholar to determine if the framework had been used in nutrition or genetics, or both; frameworks that had not were excluded. Summary tables were piloted in duplicate and revised accordingly prior to synthesizing all included articles. Frameworks were critically appraised for their applicability to nutrigenetic scientific validity assessment using a predetermined categorization matrix, which included key factors deemed important by an expert panel for assessing scientific validity in nutrigenetics.Results: Upon screening 3,931 articles, a total of 49 articles representing 41 total frameworks, were included in the final analysis (19 used in genetics, 9 used in nutrition, and 13 used in both). Factors deemed important for evaluating nutrigenetic evidence related to study design and quality, generalizability, directness, consistency, precision, confounding, effect size, biological plausibility, publication/funding bias, allele and nutrient dose-response, and summary levels of evidence. Frameworks varied in the components of their scientific validity assessment, with most assessing study quality. Consideration of biological plausibility was more common in frameworks used in genetics. Dose-response effects were rarely considered. Two included frameworks incorporated all but one predetermined key factor important for nutrigenetic scientific validity assessment.Discussion/Conclusions: A single existing framework was highlighted as optimal for the rigorous evaluation of scientific validity in nutritional genomics, and minor modifications are proposed to strengthen it further.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=261948, PROSPERO [CRD42021261948].

OP123 The Use Of Surrogate Outcomes In National Institute For Health And Care Excellence (NICE) Highly Specialised Technology Evaluations: A Review Of Published Guidance

IntroductionThe use of surrogate outcomes in health technology assessment (HTA) is increasing and methods for validating surrogate relationships have been published. However, these may not be fully applicable to ultra-rare diseases due to challenges such as scarcity of evidence and heterogenous populations. This study reviews and summarizes the use of surrogate outcomes and committee's considerations in the evaluations within the National Institute for Health and Care Excellence's (NICE) Highly Specialised Technology (HST) programme, which was established in 2013 in response to the challenges associated with the assessment of ultra-rare diseases.MethodsAll HST evaluation documents published before November 2020 were reviewed. Data extracted included surrogate outcomes used, rationales, the committee's considerations on the validity and generalizability of the surrogate relationships, related uncertainties, and other factors considered in decision-making.ResultsSeven out of the eighteen published HST topics used surrogate outcomes. The rationale for most of the surrogate relationships focused on biological plausibility. Common concerns raised by the committee included the generalizability of the surrogate relationship to the condition of interest, the lack of validation, and inability to prove or quantify the magnitude of benefits associated with the surrogate relationships. In some topics, other aspects of the evidence and clinical/patient expert's opinions were also considered by the committee.ConclusionsThe use of surrogate outcomes is common in NICE HST evaluations and the challenges in supporting surrogate relationships with more than biological plausibility are recognized. However, our review indicates that, the committee considers more than just biological plausibility and will take into account other related factors.

AE Reporting and Causality

Adverse effects may be related, unrelated, or unknown in relation to a vaccine and may range from self-limited mild reactions to permanent sequelae. The causal inference of any adverse effect to a vaccine is based on assessing the strength of association, temporal response, consistency and specificity of the association, and biological plausibility. Safety evaluation depends on accurate reporting of adverse events during pre-licensure studies and post-licensure surveillance.

Systematic review of prenatal exposure to endocrine disrupting chemicals and autism spectrum disorder in offspring

Epidemiological studies, which can have inherent methodological limitations, are used to study the relation between endocrine disrupting chemicals and autism spectrum disorder. The objective is to systematically review the treatment of methodological limitations and assess the quality and strength of the findings in the available literature. The quality and strength of the evidence were evaluated using the Navigation Guide Systematic Review Methodology. The overall quality and strength of the available studies were “moderate” and “limited,” respectively. Risk of bias due to the methodological limitations regarding the exclusion of potential confounding factors and the lack of accuracy of exposure assessment methods were the most prevalent and were also considered to arrive at these results. The omnipresence of endocrine disrupting chemicals, their persistence and bioaccumulation, and the biological plausibility of the association between prenatal exposure to these and later development of autism spectrum disorder highlight the need to carry out well-designed epidemiological studies that overcome the methodological limitations observed in the currently available literature in order to be able to inform public policy to prevent exposure to these potentially harmful chemicals. Lay abstract Autism spectrum disorders comprise a complex group with many subtypes of behaviorally defined neurodevelopmental abnormalities in two core areas: deficits in social communication and fixated, restricted, repetitive, or stereotyped behaviors and interests each with potential unique risk factors and characteristics. The underlying mechanisms and the possible causes of autism spectrum disorder remain elusive and while increased prevalence is undoubtable, it is unclear if it is a reflection of diagnostic improvement or emerging risk factors such as endocrine disrupting chemicals. Epidemiological studies, which are used to study the relation between endocrine disrupting chemicals and autism spectrum disorder, can have inherent methodological challenges that limit the quality and strength of their findings. The objective of this work is to systematically review the treatment of these challenges and assess the quality and strength of the findings in the currently available literature. The overall quality and strength were “moderate” and “limited,” respectively. Risk of bias due to the exclusion of potential confounding factors and the lack of accuracy of exposure assessment methods were the most prevalent. The omnipresence of endocrine disrupting chemicals and the biological plausibility of the association between prenatal exposure and later development of autism spectrum disorder highlight the need to carry out well-designed epidemiological studies that overcome the methodological challenges observed in the currently available literature in order to be able to inform public policy to prevent exposure to these potentially harmful chemicals and aid in the establishment of predictor variables to facilitate early diagnosis of autism spectrum disorder and improve long-term outcomes.

Hydrochlorothiazide Use and Risk of Nonmelanoma Skin Cancers: A Biological Plausibility Study

Recent studies reported the association between increased risk of nonmelanoma skin cancers (NMSCs) and the use of hydrochlorothiazide (HCTZ), one of the most commonly prescribed diuretic, antihypertensive drug, over the world. Although HCTZ is known to be photosensitizing, the mechanisms involved in its potential prophotocarcinogenic effects remain unclear. Under acute exposure, therapeutically relevant concentrations of HCTZ (70, 140, and 370 ng/mL) amplified UVA-induced double-strand breaks, oxidative DNA, and protein damage in HaCaT human keratinocytes, and this effect was associated to a defective activity of the DNA repair enzyme, OGG1. Oxidative damage to DNA, but not that to proteins, was reversible within few hours. After chronic, combined exposure to HCTZ (70 ng/mL) and UVA (10 J/cm2), for 9 weeks, keratinocytes acquired a dysplastic-like phenotype characterized by a multilayered morphology and alterations in cell size, shape, and contacts. At the ultrastructural level, several atypical and enlarged nuclei and evident nucleoli were also observed. These transformed keratinocytes were apoptosis resistant, exhibited enhanced clonogenicity capacity, increased DNA damage and inflammation, defective DNA repair ability, and increased expression of the oncogene ΔNp63α and intranuclear β-catenin accumulation (a hallmark of Wnt pathway activation), compared to those treated with UVA alone. None of these molecular, morphological, or functional effects were observed in cells treated with HCTZ alone. All these features resemble in part those of preneoplastic lesions and NMSCs and provide evidence of a biological plausibility for the association among exposure to UVA, use of HCTZ, and increased risk of NMSCs. These results are of translational relevance since we used environmentally relevant UVA doses and tested HCTZ at concentrations that reflect the plasma levels of doses used in clinical practice. This study also highlights that drug safety data should be followed by experimental evaluations to clarify the mechanistic aspects of adverse events.