Implementing pharmacogenetics in clinical trials: considerations about current methodological, ethical, and regulatory challenges.

INTRODUCTION: The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in obtaining actionable information with a sufficient level of evidence to enable its integration into routine clinical practice. AREAS COVERED: We discuss the current status of pharmacogenetics integration in clinical trials, underscore the associated challenges, and make some suggestions on the aspects to address in any clinical trial including a pharmacogenetic evaluation. We conducted a literature review, thoroughly reviewed the applicable regulations and available guidelines, and assessed the application dossiers submitted for evaluation to the Ethics committee of Hospital La Paz (Madrid, Spain) to extract information related to inclusion of pharmacogenetics evaluations. EXPERT OPINION: The integration of pharmacogenetics into clinical trials is becoming increasingly common. However, several regulatory, methodological and ethical aspects involved are insufficiently addressed. There is a need for specific and transparent guidelines that establish unified and compliant criteria for methodology, proper handling of samples in compliance with regulations, and the protection of data privacy and confidentiality. Participants should receive complete and appropriate information regarding the purpose, handling, storage, and transfer of their samples and data, and should have the right to decide about their processing.

Advancing pharmacogenetic testing in a tertiary hospital: a retrospective analysis after 10 years of activity.

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice.

Identifying biomarkers of treatment response to ciclosporin in atopic dermatitis through multiomic predictive modelling: DERMATOMICS study protocol.

INTRODUCTION: There is a need to optimise the management of atopic dermatitis (AD), improving the efficacy of treatments and reducing the toxicity associated with them. Although the efficacy of ciclosporine (CsA) in the treatment of AD has been thoroughly documented in the literature, the optimal dose has not been yet established. The use of multiomic predictive models of treatment response could optimise CsA therapy in AD. METHODS AND ANALYSIS: The study is a low-intervention phase 4 trial to optimise the treatment of patients with moderate-severe AD requiring systemic treatment. The primary objectives are to identify biomarkers that could allow for the selection of responders and non-responders to first-line treatment with CsA and to develop a response prediction model to optimise the CsA dose and treatment regimen in responding patients based on these biomarkers. The study is divided into two cohorts: the first comprised of patients starting treatment with CsA (cohort 1), and the second, of patients already receiving or who have received CsA therapy (cohort 2). ETHICS AND DISSEMINATION: The study activities began following authorisation by the Spanish Regulatory Agency (AEMPS) and the Clinical Research Ethics Committee of La Paz University Hospital approval. Trial results will be submitted for publication in an open access peer-reviewed medical speciality-specific publication.Trial registration of this study can be located at the EU Clinical Trials Register, available from https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en. Our clinical trial was registered in the website before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according the WHO. Once our trial was included in a primary and official registry, in order to extend the accessibility to our research, we also registered it retrospectively in clinicaltrials.gov; however, this is not mandatory as per our regulation. TRIAL REGISTRATION NUMBER: NCT05692843.

Melatonin in the Prophylaxis of SARS-CoV-2 Infection in Healthcare Workers (MeCOVID): A Randomised Clinical Trial.

We evaluated in this randomised, double-blind clinical trial the efficacy of melatonin as a prophylactic treatment for prevention of SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Healthcare workers fulfilling inclusion criteria were recruited in five hospitals in Spain and were randomised 1:1 to receive melatonin 2 mg administered orally for 12 weeks or placebo. The main outcome was the number of SARS-CoV-2 infections. A total of 344 volunteers were screened, and 314 were randomised: 151 to placebo and 163 to melatonin; 308 received the study treatment (148 placebo; 160 melatonin). We detected 13 SARS-CoV-2 infections, 2.6% in the placebo arm and 5.5% in the melatonin arm (p = 0.200). A total of 294 adverse events were detected in 127 participants (139 in placebo; 155 in melatonin). We found a statistically significant difference in the incidence of adverse events related to treatment: 43 in the placebo arm and 67 in the melatonin arm (p = 0.040), and in the number of participants suffering from somnolence related to treatment: 8.8% (n = 14) in the melatonin versus 1.4% (n = 2) in the placebo arm (p = 0.008). No severe adverse events related to treatment were reported. We cannot confirm our hypothesis that administration of melatonin prevents the development of SARS-CoV-2 infection in healthcare workers.

What do biomarkers add: Mapping quantitative imaging biomarkers research.

PURPOSE: To understand the contribution of the concept of "biomarker" to quantitative imaging research. METHOD: The study consists of a bibliometric and a network analysis of quantitative imaging biomarkers research based on publication data retrieved from the Web of Science (WoS) for the period 1976-2017. Co-authorship is used as a proxy for scientific collaboration among research groups. Research groups are disambiguated and assigned to an institutional sector and to a medical specialty or academic discipline. Co-occurrence maps of specialties are built to delineate the collaborative network structure of this emerging field. RESULTS: Two very distinct growth patterns emerged from the 5432 publications retrieved from WoS. Scientific production on «quantitative imaging biomarkers¼ (QIB) began 20 years after the first publications on «quantitative imaging¼ (QI). The field of QIB has exhibited rapid growth becoming the most used term since 2011. Among the 12,882 institutions identified, 56% include the term QIB and 44% include the term QI; among the 14,734 different research groups identified, 60% include the term QIB and 40% the term QI. QIB is characterized by a well-established community of researchers whose largest contributors are in medical specialties (radiology 17%, neurology 16%, mental 10%, oncology 10%), while QI shows a more fragmented and diverse community (radiology 13%, engineering 13%, physics 10%, oncology 9%, neurology 6%, biology 4%, nuclear 3%, computing 3%). This suggests a qualitative difference between QIB and QI networks. CONCLUSIONS: Adding biomarkers to quantitative imaging suggests that medical imaging is rapidly evolving, driven by the efforts to translate quantitative imaging research into clinical practice.

Valproic Acid-Induced Liver Injury: A Case-Control Study from a Prospective Pharmacovigilance Program in a Tertiary Hospital.

INTRODUCTION: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. METHODS: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring program, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related liver injury but who did not meet the DILI criteria, matched for date, age and sex. RESULTS: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild liver injury. Mean age for the cases was 45.7 years, 4 (26.7%) were women and 5 (33.34%) were children under 18 years, of them 3 (20%) were fatal. Polytherapy with other antiepileptic drugs (p = 0.047) and alcohol consumption (p < 0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p < 0.001). The cases developed hepatocellular liver injury (p < 0.001), while the mild hepatic damage controls had a higher rate of cholestatic liver injury (p < 0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p = 0.033 and p = 0.039). CONCLUSIONS: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.

Health Care Workers' Reasons for Choosing Between Two Different COVID-19 Prophylaxis Trials in an Acute Pandemic Context: Single-Center Questionnaire Study.

BACKGROUND: In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). OBJECTIVE: This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. METHODS: Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. RESULTS: In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited "to contribute to scientific knowledge" (n=80, 53.0%), followed by "to avoid SARS-CoV-2 infection" (n=33, 21.9%) and "the interest to be tested for SARS-CoV-2" (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). CONCLUSIONS: Health care workers' reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

The Reading Signatures of Agreement Attraction.

The comprehension of subject-verb agreement shows "attraction effects," which reveal that number computations can be derailed by nouns that are grammatically unlicensed to control agreement with a verb. However, previous results are mixed regarding whether attraction affects the processing of grammatical and ungrammatical sentences alike. In a large-sample eye-tracking replication of Lago et al. (2015), we support this "grammaticality asymmetry" by showing that the reading profiles associated with attraction depend on sentence grammaticality. In ungrammatical sentences, attraction affected both fixation durations and regressive eye-movements at the critical disagreeing verb. Meanwhile, both grammatical and ungrammatical sentences showed effects of the attractor noun number prior to the verb, in the first- and second-pass reading of the subject phrase. This contrast suggests that attraction effects in comprehension have at least two different sources: the first reflects verb-triggered processes that operate mainly in ungrammatical sentences. The second source reflects difficulties in the encoding of the subject phrase, which disturb comprehension in both grammatical and ungrammatical sentences.

A case report of a drug-induced liver injury (DILI) caused by multiple antidepressants with causality established by the updated Roussel Uclaf causality assessment method (RUCAM) and in vitro testing.

A 56-year-old female patient was hospitalized because of a lack of response and poor tolerance to multiple antidepressants, which included an episode of DILI. During hospitalization, the patient suffered another episode of DILI. Causality was assessed both by RUCAM and Lymphocyte Transformation Test, allowing to identify a safer medication.

A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Secondary objectives: To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection.To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial.To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection.To evaluate seroconversion timing post-symptom onset. Exploratory objectives:To compare severity of COVID-19 between men and women.To evaluate the influence of sleep and diet on prevention from SARS-CoV-2 infection.To evaluate the effect of melatonin on the incidence and characteristics of lymphopenia and increase of inflammatory cytokines related to COVID-19. TRIAL DESIGN: This is a two-arm parallel randomised double-blind controlled trial to evaluate the efficacy of melatonin versus placebo in the prophylaxis of coronavirus disease 2019 among healthcare workers. PARTICIPANTS: Inclusion Criteria: Male or female participants ≥ 18 and ≤ 80 years of age.Healthcare workers from the public and private Spanish hospital network at risk of SARS-CoV 2 infection.Not having a previous COVID19 diagnosis.Understanding the purpose of the trial and not having taken any pre-exposure prophylaxis (PrEP) including HIV PrEP from March 1st 2020 until study enrolment.Having a negative SARS-CoV 2 reverse-transcription PCR (RT-PCR) result or a negative serologic rapid test (IgM/IgG) result before randomization.Premenopausal women must have a negative urinary pregnancy test in the 7 days before starting the trial treatment.Premenopausal women and males with premenopausal couples must commit to using a high efficiency anticonceptive method. EXCLUSION CRITERIA: HIV infection.Active hepatitis B infection.Renal failure (CrCl < 60 mL/min/1.73 m2) or need for hemodialysis.Osteoporosis.Myasthenia gravis.Pre-existent maculopathy.Retinitis pigmentosa.Bradycardia (less than 50 bpm).Weight less than 40 Kg.Participant with any immunosuppressive condition or hematological disease.Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone.Hereditary intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption.Treatment with fluvoxamine.Treatment with benzodiazepines or benzodiazepine analogues such as zolpidem, zopiclone or zaleplon.Pregnancy.Breastfeeding.History of potentially immune derived diseases such as: lupus, Crohn's disease, ulcerative colitis, vasculitis or rheumatoid arthritis.Insulin-dependent diabetes mellitus.Known history of hypersensitivity to the study drug or any of its components.Patients that should not be included in the study at the judgment of the research team. Participants will be recruited from the following eight hospitals in Madrid, Spain: Hospital Universitario La Paz, Hospital Ramón y Cajal, Hospital Infanta Sofía, Hospital 12 de Octubre, Hospital Clínico San Carlos, Hospital Central de la defensa Gómez Ulla,Hospital de La Princesa and Hospital Infanta Leonor. INTERVENTION AND COMPARATOR: Experimental: Melatonin (Circadin®, Exeltis Healthcare, Spain): 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo (Laboratorios Liconsa, Spain) orally before bedtime for 12 weeks. MAIN OUTCOMES: Number of SARS-CoV-2 (COVID-19) symptomatic infections confirmed by polymerase chain reaction (PCR) test or serologic test or according to each centre diagnosis protocol. Primary outcome will be measured until the end of treatment for each participant (until the date of the last dose taken by each patient). RANDOMISATION: Patients who meet all inclusion and no exclusion criteria will be randomised, stratified by centres, sex and age (<50 and ≥ 50 years old). The randomisation sequence was created using SAS version 9.4 statistical software (procedure 'PROC PLAN') with a 1:1 allocation. No randomisation seed was specified. The randomisation seed was generated taking the hour of the computer where the program was executed. Randomization will be done centrally through the electronic system RedCAP® in order to conceal the sequence until interventions are assigned BLINDING (MASKING): Participants, caregivers, and those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 450 participants are planned to be enrolled in this clinical trial, 225 in the experimental arm and 225 in the placebo arm. TRIAL STATUS: Protocol version 3.0, 17th of April 2020. Recruitment ongoing. First participant was recruited on the 21st of April 2020. The final participant is anticipated to be recruited on the 31st of May 2020. As of May 18th, 2020, a total of 312 participants have been enrolled (154 at Hospital La Paz, 85 at Hospital Infanta Sofía and 73 at Hospital 12 de Octubre). TRIAL REGISTRATION: EU Clinical Trials Register: 2020-001530-35; Date of trial registration: 13th of April 2020; https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001530-35/ES FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Broca's area plays a causal role in morphosyntactic processing.

Although there is strong evidence that Broca's area is important for syntax, this may simply be a by-product of greater working memory and/or cognitive control demands for more complex syntactic structures. Here we report an experiment with event-related transcranial magnetic stimulation (TMS) to investigate whether Broca's area plays a causal role in morphosyntactic processing when both working memory and cognitive control demands are low. Participants were presented with word pairs that could either agree or disagree in grammatical number or gender while receiving stimulation to Broca's area or to the right intraparietal sulcus (a control site). Stimulation of Broca's area significantly reduced the advantage for grammatical relative to ungrammatical word pairs. In contrast, stimulation of control site left this grammaticality advantage unchanged. The interaction between grammaticality and stimulation was specific to Broca's area, suggesting a clear involvement of the region in morphosyntactic processing.

Processing ambiguous Spanish se in a minimal chain.

The recovery of pieces of information that are not linguistically expressed is a constant feature of the process of language comprehension. In the processing literature, such missing information is generally referred to as "gaps". Usually, one resolves gaps by finding "fillers" in either the sentence or the context. For instance, in Peter seemed to be upset, Peter is really the subject of being upset but appears as surface subject of seems. Sometimes constituents move, leaving gaps behind. Various Romance languages such as Spanish or Italian have a grammatical particle se/si, which, as it is extremely ambiguous, licenses different sorts of gaps. In Spanish, se can encode at least reflexive, impersonal, and passive meanings. In an eye-tracking experiment we contrast reflexive structures containing postverbal subjects with impersonal structures with no subjects (GAP se vendó apresuradamente el corredor/"the runner bandaged himself hurriedly" vs. GAP se vendó apresuradamente al corridor/"(someone) bandaged the runner hurriedly"). In a second manipulation we contrast the presence of an extra argument with se-passives (GAP se vendó el tobillo el corredor/"the runner bandaged his ankle" vs. GAP se vendó el tobillo al corridor/"the runner's ankle was bandaged"). Our comparisons involve contrasting standard transitive structures with nonstandard word order (postverbal subject and a preverbal subject gap) against inherently complex and less habitual structures such as impersonals (with no subject) or se-passives (with subjects in canonical object position). We evaluate the minimal chain principle (de Vincenzi, 1991), according to which displacement is costly because it entails complex (derivational) "chains" that must be undone before phrasal packaging can commence. We show the minimal chain principle to be essentially correct when contrasting more complex but more frequent structures with less complex but less frequent structures. A noteworthy feature of this research is that the gaps appear before the fillers in the structures that we analyse.

Total persistence of thyroglossal duct with direct communication between cyst and foramen caecum.

During embryonic development the thyroid gland migrates through the thyroglossal duct from the pharyngeal endoderm to the anterior cervical region. The final step in this process is the total obliteration of the thyroglossal duct. A case is presented of a patient with a thyroglossal cyst together with a complete failure of the obliteration of the duct, which caused regurgitations of mucopurulent material after the expression of the cyst. This indicates a complete failure of the obliterative process. To the best of our knowledge, this phenomenon has not been described previously in the literature.

Early and late processes in syllogistic reasoning: evidence from eye-movements.

An eye-movement monitoring experiment was carried out to examine the effects of the difficulty of the problem (simple versus complex problems) and the type of figure (figure 1 or figure 4) on the time course of processing categorical syllogisms. The results showed that the course of influence for these two factors is different. We found early processing effects for the figure but not for the difficulty of the syllogism and later processing effects for both the figure and the difficulty. These results lend support to the Model Theory (Johnson-Laird, P. N., Byrne, R. M. J. (1991). Deduction. Hillsdale, New Jersey: LEA.) as opposed to other theories of reasoning (Chater, N., Oaksford, M. (1999). The probability heuristics model of syllogistic reasoning. Cognitive Psychology, 38, 191-258; Rips, L. J. (1994). The psychology of proof. Cambridge, MA: MIT Press; Rips, L. J. (1994). The psychology of proof. Cambridge, MA: MIT Press).

Double tumor of the larynx: a case report.

A case is described of a double laryngeal tumor with simultaneous evolution but different histological patterns: a chondrosarcoma and an epidermoid carcinoma "in situ" involving both vocal cords. To our knowledge, only one previous case has been reported in the literature.

Overt reanalysis strategies and eye movements during the reading of mild garden path sentences.

In an eye movement experiment, we examined the use of reanalysis strategies during the reading of locally ambiguous but globally unambiguous Spanish sentences. Among other measures, we examined regressive eye movements made while readers were recovering in reading mild garden path sentences. The sentences had an adverbial clause that, depending on the mood (indicative vs. subjunctive) of the subordinate clause verb, could attach high (to the main verb of the sentence) or low (to the verb in the subordinate clause). Although Spanish speakers favor low attachment, the high attachment version was quite easy to understand. Readers predominately used two alternative strategies to recover from the mild garden path in our sentences. In the more common reanalysis strategy, their eyes regressed from the last region (disambiguation+ 1) directly to the main verb in the sentence. Following this, they reread the rest of the sentence, fixating the next region and the adverb (the beginning of the ambiguous part of the sentence). Less frequently, readers regressed from the last region (disambiguation+1) directly to the adverb. We argue that both types of strategies are consistent with a selective reanalysis process as described by Frazier and Rayner (1982).

Eye movements and processing stages in reading: relative contribution of visual, lexical, and contextual factors.

The independent and the combined influence of word length, word frequency, and contextual predictability on eye movements in reading was examined across processing stages under two priming-context conditions. Length, frequency, and predictability were used as predictors in multiple regression analyses, with parafoveal, early, late, and spillover eye movement measures as the dependent variables. There were specific effects of: (a) length, both on where to look (how likely a word was fixated and in which location) and how long to fixate, across all processing stages; (b) frequency, on how long to fixate a word, but not on where to look, at an early processing stage; and (c) predictability, both on how likely a word was fixated and for how long, in late processing stages. The source of influence for predictability was related to global rather than to local contextual priming. The contribution of word length was independent of contextual source. These results are relevant to determine both the time course of the influence of visual, lexical, and contextual factors on eye movements in reading, and which main component of eye movements, that is, location or duration, is affected.