Regulatory readiness to facilitate the appropriate use of innovation in clinical trials: The case of decentralized clinical trial approaches.

Methodological and operational clinical trial innovation is needed to address key challenges associated with clinical trials, including limited generalizability and (s)low recruitment rates. In this article, we discuss how appropriate implementation of innovative clinical trial approaches can be facilitated by a timely identification of, and response to, emerging situations and innovation by regulators (i.e. regulatory readiness) using decentralized clinical trial (DCT) approaches - in which trial activities are moved closer to participants and away from the investigative sites - as a case study example. Specifically, we discuss how explorative research (e.g. using regulatory sandboxes) can enable the collection of data on the usefulness of DCT approaches. Additionally, we argue that DCT approaches should be evaluated similarly to conventional clinical trials.

The prevalence of polypharmacy in older Europeans: A multi-national database study of general practitioner prescribing.

AIMS: The aims of this study were to measure the prevalence of polypharmacy and describe the prescribing of selected medications known for overuse in older people with polypharmacy in primary care. METHODS: This was a multinational retrospective cohort study across six countries: Belgium, France, Germany, Italy, Spain and the UK. We used anonymized longitudinal patient-level information from general practice databases hosted by IQVIA. Patients ≥65 years were included. Polypharmacy was defined as having 5-9 and ≥10 distinct drug classes (ATC Level 3) prescribed during a 6-month period. Selected medications were: opioids, antipsychotics, proton pump inhibitors (PPI), benzodiazepines (ATC Level 5). We included country experts on the healthcare context to interpret findings. RESULTS: Age and gender distribution was similar across the six countries (mean age 75-76 years; 54-56% female). The prevalence of polypharmacy of 5-9 drugs was 22.8% (UK) to 58.3% (Germany); ≥10 drugs from 11.3% (UK) to 28.5% (Germany). In the polypharmacy population prescribed ≥5 drugs, opioid prescribing ranged from 11.5% (France) to 27.5% (Spain). Prescribing of PPI was highest with almost half of patients receiving a PPI, 42.3% (Germany) to 65.5% (Spain). Benzodiazepine prescribing showed a marked variation between countries, 2.7% (UK) to 34.9% (Spain). The healthcare context information explained possible underreporting for selected medications. CONCLUSIONS: We have found a high prevalence of polypharmacy with more than half of the older population being prescribed ≥5 drugs in four of the six countries. Whilst polypharmacy may be appropriate in many patients, worryingly high usage of PPIs and benzodiazepines supports current efforts to improve polypharmacy management across Europe.

Heart Failure With Reduced Ejection Fraction in a Patient With Erdheim-Chester Disease on Dabrafenib.

A 54-year-old woman with a diagnosis of Erdheim-Chester disease under therapy with dabrafenib presents with clinical signs of heart failure. After discontinuing the offending medication and initiating guideline-directed medical therapy for heart failure with reduced ejection fraction, the clinical picture improved.

Atmospheric corrosion of carbon steel: Results of one-year exposure in an andean tropical atmosphere in Colombia.

In this study was examined the response of carbon steel to atmospheric corrosion after one-year exposure in Valle de Aburrá, a subregion located in northwestern Colombia. The study involved the assessment of material mass loss and corrosion rate, the characterization of atmospheric aggressiveness, and the analysis of the morphology and composition of corrosion products in five different sites. Climatological and meteorological factors were assessed by testing for chloride content, sulfur dioxide levels, and time of wetness (TOW). The analysis of corrosion products was conducted using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. Based on corrosion rates, two sites exhibited a more aggressive environment, with a corrosivity category of C3, while the remaining sites were categorized as C2. The study confirmed the presence of lepidocrocite and goethite phases on the surface of carbon steel at all test sites. Data analysis revealed that both the TOW and the industrial activity significantly influence the corrosion of this metal.

Opportunities and Challenges for Decentralized Clinical Trial Approaches: European Health Technology Assessment Perspective.

OBJECTIVES: Decentralized clinical trial (DCT) approaches are clinical trials in which some or all trial activities take place closer to participants' proximities instead of a traditional investigative site. Data from DCTs may be used for clinical and economic evaluations by health technology assessment (HTA) bodies to support reimbursement decision making. This study aimed to explore the opportunities and challenges for DCT approaches from an HTA perspective by interviewing representatives from European HTA bodies. METHODS: We conducted semistructured interviews with 25 European HTA representatives between September 2022 and February 2023, and transcripts were analyzed after thematic analysis. RESULTS: Two main themes were identified from the data relating to (1) DCT approaches in HTA and (2) trial-level acceptance and relevance. Experience with assessing DCTs was limited and a variety of knowledge about DCTs was observed. The respondents recognized the opportunity of DCTs to reduce recall bias when participant-reported outcome data can be collected more frequently and conveniently from home. Concerns were expressed about the data quality when participants become responsible for data collection. Despite this challenge, the respondents recognized the potential of DCTs to increase the generalizability of results because data can be collected in a setting reflective of the everyday situation potentially from a more diverse participant group. CONCLUSIONS: DCTs could generate relevant results for HTA decision making when data are collected in a real-world setting from a diverse participant group. Increased awareness of the opportunities and challenges could help HTA assessors in their appraisal of DCT approaches.

Exploring the Minnesota Multiphasic Personality Inventory (MMPI)-3 in a transgender and gender diverse sample.

Comparisons of transgender and gender diverse (TGD) individuals' mental health functioning with that of cisgender individuals rely almost exclusively on screening measures. The limited research with TGD individuals and omnibus assessment measures has primarily used previous iterations of the Minnesota Multiphasic Personality Inventories (MMPIs). This study sought to examine the psychometric functioning of the MMPI-3 with a TGD community sample (n = 97) and compare mean scores across TGD and cisgender subsamples. We expected MMPI-3 substantive scale reliability to be comparable across all samples and subsamples. Individual MMPI-3 scales were expected to demonstrate appropriate convergent and discriminant validity with relevant criterion measures in the TGD sample. Results generally supported MMPI-3 scale score reliability and validity with TGD individuals. Next, three sets of mean score comparisons were conducted across all MMPI-3 substantive scales: (a) TGD individuals not currently in mental health treatment and the MMPI-3 normative sample, (b) TGD individuals not currently in mental health treatment and TGD individuals currently in mental health treatment, and (c) TGD individuals currently in mental health treatment and an outpatient mental health sample. Fewer differences were found between TGD individuals in our sample who were not currently in mental health treatment and the MMPI-3 normative sample compared to previous work. This initial study indicates that MMPI-3 scales largely have appropriate psychometric properties when administered to a TGD sample and that the test may be helpful in identifying mental health needs of TGD individuals. Needs and directions for further research are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Bringing an end to diabetes stigma and discrimination: an international consensus statement on evidence and recommendations.

People with diabetes often encounter stigma (ie, negative social judgments, stereotypes, prejudice), which can adversely affect emotional, mental, and physical health; self-care, access to optimal health care; and social and professional opportunities. To accelerate an end to diabetes stigma and discrimination, an international multidisciplinary expert panel (n=51 members, from 18 countries) conducted rapid reviews and participated in a three-round Delphi survey process. We achieved consensus on 25 statements of evidence and 24 statements of recommendations. The consensus is that diabetes stigma is driven primarily by blame, perceptions of burden or sickness, invisibility, and fear or disgust. On average, four in five adults with diabetes experience diabetes stigma and one in five experience discrimination (ie, unfair and prejudicial treatment) due to diabetes, such as in health care, education, and employment. Diabetes stigma and discrimination are harmful, unacceptable, unethical, and counterproductive. Collective leadership is needed to proactively challenge, and bring an end to, diabetes stigma and discrimination. Consequently, we achieved unanimous consensus on a pledge to end diabetes stigma and discrimination.

Clinician perspectives on technology-enhanced in vivo exposures during prolonged exposure therapy for PTSD.

OBJECTIVE: To investigate clinicians' perceptions regarding the use of mobile technology tools during prolonged exposure (PE) therapy to allow for monitoring and enhancing in-vivo exposures (IVEs). METHODS: Clinicians with training in PE therapy (N = 32; average of 9 years of practice) completed surveys asking about their perspectives on the utility of virtually attending IVEs with patients while simultaneously having access to real-time subjective and physiological data (i.e., heart rate, galvanic skin conductance) to guide exposure exercises and assure optimal stimulus engagement. RESULTS: Findings showed clinicians to have a favorable view of applying technology devices and systems to enhance IVEs of PE therapy. Most clinicians (93.8%) believed that real-time monitoring of IVEs-particularly monitoring patients' subjective distress and completion of and duration of time in the IVE-would be useful and significantly enhance PE therapy. CONCLUSION: The positive perceptions toward integrating technology into IVEs in this study have important implications for the development and implementation of technology-enhanced PE therapy. A mobile technology system that incorporates real-time indicators of engagement (i.e., both subjective and physiological) during IVEs and allows clinicians to review recordings of, or virtually accompany, patients during IVEs has the potential to innovate and transform PE and other exposure-based treatments. Clinicians also believed that technology-enhanced IVEs may help reduce early termination from PE.

Unintended impact of pharmacovigilance regulatory interventions: A systematic review.

AIMS: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe. METHODS: We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used. RESULTS: In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose-lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%). CONCLUSION: The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines.

Acute pulmonary tumour embolism and right systolic dysfunction in a hidden intrahepatic cholangiocarcinoma: case report.

Background: Pulmonary tumour embolism is a rare entity that can arise from a wide variety of neoplasms. It can initially manifest as a pulmonary embolism with right heart failure and be refractory to thrombolytic therapy. Cholangiocarcinoma is a rare malignancy that arises from the epithelium of the biliary tree, representing 3% of all the gastrointestinal malignancies, being the intrahepatic cholangiocarcinoma the second most common liver tumour after hepatocellular carcinoma. Case summary: This case regards a patient that presented to our centre with acute pulmonary embolism, deep vein thrombosis, and unrevealing previous medical history. Imaging studies revealed pulmonary embolism, an ovarian mass, and multiple hepatic hypodensities. Throughout the hospitalization, the patient's haemodynamic state and right heart failure worsened, eventually leading to multi-organ failure and death. Post-mortem evaluation revealed cholangiocarcinoma cells on the pulmonary arteries. Discussion: Pulmonary tumour embolism is a rare pathology that can present with acute right heart failure. The diagnosis of occult cancer can be challenging, and the appropriate treatment for this entity remains an unexplored subject.

Direct-to-participant investigational medicinal product supply in clinical trials in Europe: Exploring the experiences of sponsors, site staff and couriers.

AIMS: Insights into the current practice of direct-to-participant (DtP) supply of investigational medicinal product (IMP) in the context of clinical trials conducted in Europe are needed, as regulations are unharmonized. This study is set out to explore how DtP IMP supply has been employed in Europe and what the advantages and disadvantages and barriers and facilitators of its implementation are. METHODS: We conducted semi-structured interviews with representatives from sponsor companies, courier services and site study staff involved in the IMP dispensing and delivery process in Europe. Interviews were conducted between May and November 2021, and data were analysed following thematic analysis. RESULTS: Sixteen respondents participated in one of the 12 interviews. Respondents had experience with different models of DtP IMP supply including shipment from the investigative site, a central pharmacy (a depot under the control of a pharmacist) and a local pharmacy-aiming to reduce trial participation burden. The respondents indicated that investigative site-to-participant shipment is not affected by regulatory barriers, but could burden site staff. Shipment from central locations was considered most efficient, but possible regulatory barriers related to maintaining participants' privacy and investigator oversight were identified. The respondents indicated that the involvement of local pharmacies to dispense IMP can be considered when the IMP is authorized. CONCLUSIONS: Several DtP IMP supply models are implemented in clinical trials conducted in Europe. In this study, three main DtP IMP models were identified, which can be referenced when describing these approaches for regulatory approval.

Atmospheric deterioration of ceramic building materials and future trends in the field: a review.

Multiple techniques have been developed and implemented around the world to monitor structures and minimize the costs of repairing, maintaining, and losing ceramic building materials due to environmental factors. Understanding the different degradation phenomena that affect ceramic building materials and evaluating their condition can help reduce material losses caused by deterioration and the need for interventions. This study reviews the main forms of atmospheric degradation that affect ceramic materials and the commonly employed methods to evaluate their deterioration. The aim is to illustrate the different types of atmospheric deterioration that affect ceramic materials and to demonstrate the current monitoring methods and testing. In addition to a literature review, a bibliometric analysis was conducted to highlight the available tools to counter atmospheric deterioration. The analysis shows that CO2, sulfates, and temperature are the most important types of degradation for ceramic construction materials. It was also discovered that due to their porous nature, ceramic construction materials require careful control as contaminants and water can easily penetrate them. The two most severe types of deterioration identified in this analysis for reinforced concrete were chloride-induced corrosion and carbonation.

Decentralised, patient-centric, site-less, virtual, and digital clinical trials? From confusion to consensus.

There is increasing interest in clinical trials that use technologies and other innovative operational approaches to organise trial activities around trial participants instead of investigator sites. A range of terms has been introduced to refer to this operational clinical trial model, including virtual, digital, remote, and decentralised clinical trials (DCTs). However, this lack of standardised terminology can cause confusion over what a particular trial model entails and for what purposes it can be used, hampering discussions by stakeholders on its acceptability and suitability. Here, we review the different terms described in the scientific literature, advocate the consistent use of a unified term, 'decentralised clinical trial,' and provide a detailed definition of this term.

Parylene-Sealed Perovskite Nanocrystals Down-Shifting Layer for Luminescent Spectral Matching in Thin Film Photovoltaics.

The present contribution aims to enhance solar cells' performance via the development of advanced luminescent down-shifting based on encapsulated nanostructured perovskite materials. Here, thin films of inorganic lead halide (CsPbBr3) perovskite nanocrystal luminophores were synthetized, by hot-injection, deposited on glass substrates by spin-coating, and encapsulated with parylene type C, via chemical vapor deposition, to protect and stabilize the films. The optical properties of these thin films were characterized by absorption, emission and 2D contour spectra, their structure by X-ray diffraction and X-ray photoelectron spectroscopy, and the morphology by Scanning Transmission Electron microscopy. I-V curve and spectral response nanocrystalline silicon photovoltaic (nc-Si:H PV) cells were studied in the absence and presence of the perovskite and parylene luminescent down-shifting layers. The incorporation of the CsPbBr3 nanocrystals and their encapsulation with the parylene type C polymeric coating led to an increase in the current generated and the spectral response of the PV cells in the regime of the nanocrystals' fluorescence emission. A 3.1% increase in the short circuit current density and a 5.6% increase in the power conversion efficiency were observed.

Atmospheric corrosion maps as a tool for designing and maintaining building materials: A review.

Atmospheric corrosion maps can be used to conduct a fast and graphical assessment of material deterioration in specific geographic environments. These maps are a key tool for selecting the most adequate materials in terms of corrosion resistance, maintenance, and cost-efficiency in outdoor constructions. Several studies have evaluated the effects of environmental factors and pollutants on building materials at local, regional, national, and international levels. However, not enough atmospheric corrosion maps are readily available, possibly due to the complexity of the variables that should be considered to construct them, which include weather, meteorological, and pollution-related factors that vary in space and time. This article presents a thorough literature review of atmospheric corrosion maps published between 1971 and 2021 mainly indexed in the Scopus database. It is complemented with a detailed review of books, journals, and projects by research centers that focuses on the methodologies, parameters, and tools that have been used to construct said maps. Most of the available maps are outdated, which highlights the need for new maps that reflect recent global changes in atmospheric pollution and temperature that can intensify metal deterioration in some places.

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.

BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

Which decentralised trial activities are reported in clinical trial protocols of drug trials initiated in 2019-2020? A cross-sectional study in ClinicalTrials.gov.

OBJECTIVES: Decentralised clinical trial activities-such as participant recruitment via social media, data collection through wearables and direct-to-participant investigational medicinal product (IMP) supply-have the potential to change the way clinical trials (CTs) are conducted and with that to reduce the participation burden and improve generalisability. In this study, we investigated the decentralised and on-site conduct of trial activities as reported in CT protocols with a trial start date in 2019 or 2020. DESIGN: We ascertained the decentralised and on-site conduct for the following operational trial activities: participant outreach, prescreening, screening, obtaining informed consent, asynchronous communication, participant training, IMP supply, IMP adherence monitoring, CT monitoring, staff training and data collection. Results were compared for the public versus private sponsors, regions involved, trial phases and four time periods (the first and second half of 2019 and 2020, respectively). SETTING: Phases 2, 3 and 4 clinical drug trial protocols with a trial start date in 2019 or 2020 available from ClinicalTrials.gov. OUTCOME MEASURES: The occurrence of decentralised and on-site conduct of the predefined trial activities reported in CT protocols. RESULTS: For all trial activities, on-site conduct was more frequently reported than decentralised conduct. Decentralised conduct of the individual trial activities was reported in less than 25.6% of the 254 included protocols, except for decentralised data collection, which was reported in 68.9% of the protocols. More specifically, 81.9% of the phase 3 protocols reported decentralised data collection, compared with 73.3% and 47.0% of the phase 2 and 4 protocols, respectively. For several activities, including prescreening, screening and consenting, upward trends in reporting decentralised conduct were visible over time. CONCLUSIONS: Decentralised methods are used in CTs, mainly for data collection, but less frequently for other activities. Sharing best practices and a detailed description in protocols can drive the adoption of decentralised methods.

Ethics review of decentralized clinical trials (DCTs): Results of a mock ethics review.

Decentralized clinical trials (DCTs) can be a valuable addition to the clinical trial landscape. However, the practice of DCTs is dependent on a regulatory system designed for conventional (site-based) trials. This study provides insight into the ethics review of DCTs. A 'mock ethics review' was performed in which members of European ethics committees (ECs) and national competent authorities (NCAs) discussed and reviewed a DCT protocol. Respondents expressed hesitancy toward DCTs and focused on potential risks and burdens. We advise to address these aspects explicitly when submitting a DCT protocol. We propose that both the benefits and risks of DCTs should be carefully monitored to advance the review and practice of this innovative approach to ethically optimize drug development.

Opportunities and Challenges for Decentralized Clinical Trials: European Regulators' Perspective.

Decentralized clinical trials (DCTs) have the potential to improve accessibility, diversity, and retention in clinical trials by moving trial activities to participants' homes and local surroundings. In this study, we conducted semi-structured interviews with 20 European regulators to identify regulatory challenges and opportunities for the implementation of DCTs in the European Union. The key opportunities for DCTs that were recognized by regulators include a reduced participation burden, which could facilitate the participation of underserved patients. In addition, regulators indicated that data collected in DCTs are expected to be more representative of the real world. Key challenges recognized by regulators for DCTs include concerns regarding investigator oversight and participants' safety when physical examinations and face-to-face contact are limited. To facilitate future learning, hybrid clinical trials with both on-site and decentralized elements are proposed by the respondents.