European Forum for Good Clinical Practice

Plain language resources (PLR) are lay summaries of clinical trial results or plain language summaries of publications, in digital/visual/language formats. They aim to provide accurate information in jargon-free, and easy-to-understand language that can meet the health information needs of the general public, especially patients and caregivers. These are typically developed by the study sponsors or investigators, or by national public health bodies, research hospitals, patient organizations, and non-profit organizations. While the usefulness of PLR seems unequivocal, they have never been analyzed from the perspective of ethics. In this commentary, we do so and reflect on whether PLR are categorically advantageous or if they solve certain issues but raise new problems at the same time. Ethical concerns that PLR can potentially address include but are not limited to individual and community level health literacy, patient empowerment and autonomy. We also highlight the ethical issues that PLR may potentially exacerbate, such as fair balanced presentation and interpretation of medical knowledge, positive publication bias, and equitable access to information. PLR are important resources for patients, with promising implications for individual as well as community health. However, they require appropriate oversight and standards to optimize their potential value. Hence, we also highlight recommendations and best practices from our reading of the literature, that aim to minimize these biases.

Magnetic Resonance-guided high-intensity Focused Ultrasound (MRgFUS) of the thalamic ventral intermediate nucleus (Vim) for tremor has increasingly gained interest as a new non-invasive alternative to standard neurosurgery. Resting state functional connectivity (rs-FC) correlates of MRgFUS have not been extensively investigated yet. A region of interest (ROI)-to-ROI rs-FC MRI “connectomic” analysis focusing on brain regions relevant for tremor was conducted on 15 tremor-dominant patients with Parkinson's disease who underwent MRgFUS. We tested whether rs-FC between tremor-related areas was modulated by MRgFUS at 1 and 3 months post-operatively, and whether such changes correlated with individual clinical outcomes assessed by the MDS-UPDRS-III sub items for tremor. Significant increase in FC was detected within bilateral primary motor (M1) cortices, as well as between bilateral M1 and crossed primary somatosensory cortices, and also between pallidum and the dentate nucleus of the untreated hemisphere. Correlation between disease duration and FC increase at 3 months was found between the putamen of both cerebral hemispheres and the Lobe VI of both cerebellar hemispheres, as well as between the Lobe VI of untreated cerebellar hemisphere with bilateral supplementary motor area (SMA). Drop-points value of MDS-UPDRS at 3 months correlated with post-treatment decrease in FC, between the anterior cingulate cortex and bilateral SMA, as well as between the Lobe VI of treated cerebellar hemisphere and the interpositus nucleus of untreated cerebellum. Tremor improvement at 3 months, expressed as percentage of intra-subject MDS-UPDRS changes, correlated with FC decrease between bilateral occipital fusiform gyrus and crossed Lobe VI and Vermis VI. Good responders (≥50% of baseline tremor improvement) showed reduced FC between bilateral SMA, between the interpositus nucleus of untreated cerebellum and the Lobe VI of treated cerebellum, as well as between the untreated SMA and the contralateral putamen. Good responders were characterized at baseline by crossed hypoconnectivity between bilateral putamen and M1, as well as between the putamen of the treated hemisphere and the contralateral SMA. We conclude that MRgFUS can effectively modulate brain FC within the tremor network. Such changes are associated with clinical outcome. The shifting mode of integration among the constituents of this network is, therefore, susceptible to external redirection despite the chronic nature of PD.

Abstract Host genetics is an emerging theme in COVID-19 and few common polymorphisms and some rare variants have been identified, either by GWAS or candidate gene approach, respectively. However, an organic model is still missing. Here, we propose a new model that takes into account common and rare germline variants applied in a cohort of 1,300 Italian SARS-CoV-2 positive individuals. Ordered logistic regression of clinical WHO grading on sex and age was used to obtain a binary phenotypic classification. Genetic variability from WES was synthesized in several boolean representations differentiated according to allele frequencies and genotype effect. LASSO logistic regression was used for extracting relevant genes. We defined about 100 common driver polymorphisms corresponding to classical “threshold model”. Extracted genes were demonstrated to be gender specific. Stochastic rare more penetrant events on about additional 100 extracted genes, when occurred in a medium or severe background (common within the family), simulate Mendelian inheritance in 14% of subjects (having only 1 mutation) or oligogenic inheritance (in 10% having 2 mutations, in 11% having 3 mutations, etc).The combined effect of common and rare results can be described as an integrated polygenic score computed as: (nseverity − nmildness) + F (mseverity − mmildness)where n is the number of common driver genes, m is the number of driver rare variants and F is a factor for appropriately weighing the more powerful rare variants. We called the model “post-Mendelian”. The model well describes the cohort, and patients are clustered in severe or mild by the integrated polygenic scores, the F factor being calibrated around 2, with a prediction capacity of 65% in males and 70% in females. In conclusion, this is the first comprehensive model interpreting host genetics in a holistic post-Mendelian manner. Further validations are needed in order to consolidate and refine the model which however holds true in thousands of SARS-CoV-2 Italian subjects.

ABSTRACTBackgroundCOVID-19 presentation ranges from asymptomatic to fatal. The variability in severity may be due in part to impaired Interferon type I response due to specific mutations in the host genome or to autoantibodies, explaining about 15% of the cases when combined. Exploring the host genome is thus warranted to further elucidate disease variability.MethodsWe developed a synthetic approach to genetic data representation using machine learning methods to investigate complementary genetic variability in COVID-19 infected patients that may explain disease severity, due to poly-amino acids repeat polymorphisms. Using host whole-exome sequencing data, we compared extreme phenotypic presentations (338 severe versus 300 asymptomatic cases) of the entire (men and women) Italian GEN-COVID cohort of 1178 subjects infected with SARS-CoV-2. We then applied the LASSO Logistic Regression model on Boolean gene-based representation of the poly-amino acids variability.FindingsShorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against a more severe outcome in COVID-19 infection. In the subgroup of males with age <60 years, testosterone was higher in subjects with AR long-polyQ (≥23), possibly indicating receptor resistance (p=0.004 Mann-Whitney U test). Inappropriately low testosterone levels for the long-polyQ alleles predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ (≥23) and age>60 years had increased levels of C Reactive Protein (p=0.018).InterpretationOur results may contribute to design reliable clinical and public health measures and provide a rationale to test testosterone treatment as adjuvant therapy in symptomatic COVID-19 men expressing AR polyQ longer than 23 repeats.FundingMIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020). Private donors for COVID research and charity funds from Intesa San Paolo.BoxesEvidence before this studyWe searched on Medline, EMBASE, and Pubmed for articles published from January 2020 to August 2020 using various combinations of the search terms “sex-difference”, “gender” AND SARS-Cov-2, or COVID. Epidemiological studies indicate that men and women are similarly infected by COVID-19, but the outcome is less favorable in men, independently of age. Several studies also showed that patients with hypogonadism tend to be more severely affected. A prompt intervention directed toward the most fragile subjects with SARS-Cov2 infection is currently the only strategy to reduce mortality. glucocorticoid treatment has been found cost-effective in improving the outcome of severe cases. Clinical algorithms have been proposed, but little is known on the ability of genetic profiling to predict outcome and disclose novel therapeutic strategies.Added-value of this studyIn a cohort of 1178 men and women with COVID-19, we used a supervised machine learning approach on a synthetic representation of the uncovered variability of the human genome due to poly-amino acid repeats. Comparing the genotype of patients with extreme manifestations (severe vs. asymptomatic), we found that the poly-glutamine repeat of the androgen receptor (AR) gene is relevant for COVID-19 disease and defective AR signaling identifies an association between male sex, testosterone exposure, and COVID-19 outcome. Failure of the endocrine feedback to overcome AR signaling defect by increasing testosterone levels during the infection leads to the fact that polyQ becomes dominant to T levels for the clinical outcome.Implications of all the available evidenceWe identify the first genetic polymorphism predisposing some men to develop a more severe disease irrespectively of age. Based on this, we suggest that sizing the AR poly-glutamine repeat has important implications in the diagnostic pipeline of patients affected by life-threatening COVID-19 infection. Most importantly, our studies open to the potential of using testosterone as adjuvant therapy for severe COVID-19 patients having defective androgen signaling, defined by this study as ≥23 PolyQ repeats and inappropriate levels of circulating androgens.

Biomedical research should include plans to communicate complete and accurate results to the scientific community and the public in a timely manner. All too often, however, such planning is lacking until after data have been generated. We developed a collaborative professional statement following review of the indexed biomedical literature and relevant professional society guidelines. Planning for publications before, during and after biomedical research studies are conducted promotes the timely dissemination of accurate and comprehensive results. Effective publication planning accounts for the work of all contributors, encourages full transparency and contributes to overall scientific integrity. Although the most obvious contribution of publication planning is to result dissemination, the best planning may also help improve the overall quality of research study design and the overall integrity of study conduct by keeping the final audience in the forefront of the investigators' attention. Publication planning can help biomedical researchers achieve and maintain high standards of transparency and integrity. Table 1 below highlights briefly some of the aspects to be included in a publication plan.

Background and aims On 2 April 2014 the European Parliament adopted the European Clinical Trials Regulation that replaces the European Clinical Trials Directive of 2001. This paves the way for greater harmonisation of European paediatric research along with setting new rules for engaging clinical trials with vulnerable populations, including children. Methods This paper examines key points in the European Clinical Trial Regulation that will affect the paediatric community in developing new medicines for children as well as impact nearly all areas of European paediatric research. The following important developments are explained: · the distinction between a ‘clinical trial’ and a ‘clinical study’, · the new requirements for registering clinical trials on publicly accessible databases, · requirements to report clinical trials, · new definitions of ‘vulnerable populations’ and how this impacts paediatric research, · informed consent rules, · requirements for ethical review and their potential impact at national and institutions levels, and · the requirements for publishing the results of clinical trials. Results The intended result of the EU Clinical Trial Regulation is to improve the environment for clinical research in Europe. It is also intended to provide greater protections to research subjects while improving the environment for academic research. Conclusions Important hurdles that arose in the context of the previous Clinical Trials Directive have been addressed. New challenges, however, will arise that affect both the ability to organise clinical trials among paediatric research centres as well as financial implications for those leading paediatric research.