Bone mineral density and geometric morphometrics: Indicators of growth in the immature pars basilaris.

The pars basilaris forms a central component of the immature basicranium and owing to its resilience to post-mortem and taphonomic changes, holds significance across evolutionary, clinical, and forensic contexts. While size and shape parameters of the pars basilaris have been investigated, little is known about the influence of the underlying bone mineral density on the morphometry of this bone during growth. This study aimed to investigate the development and growth of the pars basilaris with specific reference to changes in bone density patterning and development of osteological features, during the prenatal and early postnatal periods of life. A total of 109 pars basilari were sourced from the Johannesburg Forensic Paediatric Collection, University of the Witwatersrand, South Africa. The study sample was subdivided into early prenatal (<30 gestational weeks), prenatal (30-40 gestational weeks) and postnatal (birth to 7.5 months) groups and micro-CT scanned to assess bone mineral density patterns across seven regions of interest. Size and shape changes were analysed using 11 digitized landmarks and geometric morphometrics. When comparing across age groups, the assessed dimensions increased with growth manifesting as a deepening at the anterior border of the foramen magnum, development of the lateral angles and widening of the bone at the lateral projections and spheno-occipital synchondrosis. However, no significant changes in the distribution of bone mineral density were observed. An appreciation of morphological changes and bone quality at specific growth sites in the pars basilaris is essential when analyzing remains of unknown provenance for the purposes of identification in disaster victim settings.

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.

Assessing the morphology and bone mineral density of the immature pars lateralis as an indicator of age.

Age estimation is crucial when the state of personhood is a mitigating factor in the identification of immature human remains. The maturation sequence of immature bones is a valuable alternative to dental development and eruption standards. Bordering the foramen magnum and pars basilaris, the pars lateralis is somewhat understudied. The aim of this study was to comprehensively describe the morphology of the immature human pars lateralis bone. Human pars laterali were sourced from the crania of 103 immature individuals of unknown provenance from the Johannesburg Forensic Paediatric Collection (JFPC), University of the Witwatersrand (HREC-Medical: M210855). The study sample was subdivided into early prenatal (younger than 30 gestational weeks; n = 32), prenatal (30-40 gestational weeks, n = 41) and postnatal (birth to 7.5 months, n = 30) age groups. The morphology of the pars laterali was studied using a combination of bone mineral density pattern assessments, geometric morphometrics and stereomicroscopy. Bone mineral density in postnatal individuals was lower when compared with the prenatal individuals. No statistically significant differences between density points were noted. The overall shape of the pars lateralis changed from a triangular shape in the early prenatal individuals to a fan-like quadrilateral bone in postnatal individuals. The angulation of the medial border for the foramen magnum highlighted a change in shape between straight in the early prenatal cohort to V-shaped in the postnatal individuals. The various technical approaches used in the current study provided detailed descriptions of the pars lateralis which establishes a valuable foundation for diagnostic criteria employing morphological predictors for biological profiling.

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.

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.

Validation of the GetReal Trial Tool - Facilitating discussion and understanding more pragmatic design choices and their implications.

BACKGROUND: The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while taking into account the risk of bias, precision, acceptability and operational feasibility. This study describes the validation of the GetReal Trial Tool. METHODS: Twelve experts took part in the GetReal Trial tool validation using the protocols of 6 trials conducted with pragmatic elements. The tool entails 7 domains with a total of 43 questions. A pooled Kappa statistic (95% CI) using random effects model was estimated using Open Meta (analyst) software. The possible operational challenges were collated and discussed with the trialists that conducted the trials. RESULTS: Agreement in the design choices made for the trial protocols was >50% for all the trials and all teams reached consensus during discussion. The pooled Kappa statistic (95% CI) was 0.236 (0.154-0.318). The GetReal Trial tool highlighted several operational challenges, of which almost half had been experienced previously by the trialists. Out of 25 additional operational challenges mentioned by the trialists, 76% were already highlighted by the tool. The tool was considered helpful to optimize trials right from the design stage. CONCLUSION: The GetReal Trial Tool helps to scrutinize the choice of study design in the light of Real World Evidence generation. The tool identifies most of the operational challenges experienced by trialists to date. The tool serves the intended purpose of facilitating discussion and understanding more pragmatic design choices and their implications.

A cross-sectional survey on the early impact of COVID-19 on the uptake of decentralised trial methods in the conduct of clinical trials.

BACKGROUND: The COVID-19 pandemic significantly impacted the conduct of clinical trials through delay, interruption or cancellation. Decentralised methods in clinical trials could help to continue trials during a pandemic. This paper presents the results of an exploratory study conducted early in the pandemic to gain insight into and describe the experiences of organisations involved in clinical trials, with regard to the impact of COVID-19 on the conduct of trials, and the adoption of decentralised methods prior to, and as mitigation for the impact, of COVID-19. METHODS: A survey with 11 open-ended and four multiple choice questions was conducted in June 2020 among member organisations of the public-private "Trials@Home" consortium. The survey investigated (1) the impact and challenges of COVID-19 on the continuation of ongoing clinical trials, (2) the adoption of decentralised methods in clinical trials prior to and as a mitigation strategy for COVID-19, (3) the challenges of conducting clinical trials during COVID-19, (4) the expected permanency of COVID-19-driven changes to the adoption of decentralised methods in clinical trials, and (5) lessons learned from conducting clinical trials during the COVID-19 pandemic. A thematic, inductive analysis of open survey questions was performed, complemented with descriptive statistics (frequencies and distributions). RESULTS: The survey had a response rate of 81%. All organisations included in the analysis (n = 18) implemented (some) decentralised methods in their clinical trials prior to COVID-19, and 15 (83%) implemented decentralised methods as mitigation for COVID-19. Decentralised methods for IMP supply, patient-health care provider interaction and communication, clinic visits and source document verification were used more often as mitigation strategies than they were used prior to COVID-19. Many respondents expect to maintain those decentralised methods they implemented during COVID-19 in ongoing trials, as well as implement them in future trials. CONCLUSIONS: Decentralised methods are a widely implemented mitigation strategy for trial conduct in the face of the COVID-19 pandemic. The results of this survey show that there is an interest to continue the use of decentralised methods in future trials, but important points of attention have been identified that need solutions to help guide the transition from the traditional trial model to a more decentralised trial model.

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.

The GetReal Trial Tool: design, assess and discuss clinical drug trials in light of Real World Evidence generation.

Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake of these methods is slow for several reasons, including uncertainty about acceptability of trial results, lack of experience with the methodology and operational challenges. We developed the "GetReal Trial Tool," an easy-to-use online interface, which allows users to assess the impact of design choices on generalizability to routine clinical practice, while taking into account risk of bias, precision, acceptability and operational feasibility. The tool is grounded in the scientific literature combined with knowledge of experts from academia, pharmaceutical companies, HTA bodies, patient organizations, and regulators. The aim is to help researchers optimize trial design and facilitate translation of evidence from pragmatic trials to clinical practice. In this paper we describe the development, structure and application of the GetReal Trial Tool.

Influenza A viruses circulating in dogs: A review of the scientific literature.

Influenza A viruses (IAV) cause persistent epidemics and occasional human pandemics, leading to considerable economic losses. The ecology and epidemiology of IAV are very complex and the emergence of novel zoonotic pathogens is one of the greatest challenges in the healthcare. IAV are characterized by genetic and antigenic variability resulting from a combination of high mutation rates and a segmented genome that provides the ability to rapidly change and adapt to new hosts. In this context, available scientific evidence is of great importance for understanding the epidemiology and evolution of influenza viruses. The present review summarizes original research papers and IAV infections reported in dogs all over the world. Reports of interspecies transmission of equine influenza viruses H3N2 from birds to dogs, as well as double and triple reassortant strains resulting from reassortment of avian, human, and canine strains have amplified the genetic variety of canine influenza viruses. A total of 146 articles were deemed acceptable by PubMed and the Google Scholar database and were therefore included in this review. The largest number of research articles (n = 68) were published in Asia, followed by the Americas (n = 44), Europe (n = 31), Africa (n = 2), and Australia (n = 1). Publications are conventionally divided into three categories. The first category (largest group) included modern articles published from 2011 to the present (n = 93). The second group consisted of publications from 2000 to 2010 (n = 46). Single papers of 1919, 1931, 1963, 1972, 1975, and 1992 were also used, which was necessary to emphasize the history of the study of the ecology and evolution of the IAV circulating among various mammalian species. The largest number of publications occurred in 2010 (n = 18) and 2015 (n = 11), which is associated with IAV outbreaks observed at that time in the dog population in America, Europe, and Asia. In general, these findings raise concerns that dogs may mediate the adaptation of IAVs to zoonotic transmission and therefore serve as alternative hosts for genetic reassortment of these viruses. The global concern and significant threat to public health from the present coronavirus diseases 2019 pandemic confirms the necessity for active surveillance of zoonotic viral diseases with pandemic potential.

Coding-Complete Genome Sequence of Swine Influenza Virus Isolate A/Swine/Karaganda/04/2020 (H1N1) from Kazakhstan.

Here, we report the coding-complete genome sequence of a clinical sample of influenza virus obtained from a pig at a livestock farm in Karaganda, Central Kazakhstan, during a pig study in 2020. Isolate A/Swine/Karaganda/04/2020 (H1N1) belongs to clade 1A.3.2.2 lineage 1A, which includes the 2009 H1N1 pandemic strains.

Introduction of a community health worker diabetes coach improved glycemic control in an urban primary care clinic.

The burden of diabetes is higher in urban areas and among racial and ethnic minorities. The purpose of this research was to evaluate the effectiveness of extending a diabetes intervention program (DIP) by engaging a team, including a community health worker (CHW), to provide care for patients to meet glycemic control, specifically in a predominantly urban, minority patient population. The DIP enrolled diabetic patients from an internal medicine clinic. A CHW facilitated the collection of glucose meter readings. The CHW coached patients on glycemic control while the CHW's registered nurse partner titrated the patient's recommended insulin dose. Subsequent HbA1c values for participants were compared to those seen at the same clinic who were not enrolled. The DIP was deployed for nine months. One hundred forty-four patients were enrolled in the DIP and 348 patients constituted the comparator group. Ninety-three DIP participants had pre- and post-intervention HbA1c values and were compared to 348 non-DIP participants. Propensity score weighted adjusted analyses suggest that participants were more likely to reduce their HbA1c values by at least 1.0% and have HbA1c values of less than 8.0% (64 mmol/mol) than non-participants (adjusted odds ratio = aOR = 1.47, 95% CI 1.26-1.71, and aOR = 1.23, 95% CI 1.06-1.43, respectively). CHW coaches as part of a team in a clinical setting improved glycemic control in a predominantly urban, minority patient population.

Synthetic hybrids of six yeast species.

Allopolyploidy generates diversity by increasing the number of copies and sources of chromosomes. Many of the best-known evolutionary radiations, crops, and industrial organisms are ancient or recent allopolyploids. Allopolyploidy promotes differentiation and facilitates adaptation to new environments, but the tools to test its limits are lacking. Here we develop an iterative method of Hybrid Production (iHyPr) to combine the genomes of multiple budding yeast species, generating Saccharomyces allopolyploids of at least six species. When making synthetic hybrids, chromosomal instability and cell size increase dramatically as additional copies of the genome are added. The six-species hybrids initially grow slowly, but they rapidly regain fitness and adapt, even as they retain traits from multiple species. These new synthetic yeast hybrids and the iHyPr method have potential applications for the study of polyploidy, genome stability, chromosome segregation, and bioenergy.

Women in Translational Medicine: Tools to Break the Glass Ceiling.

Despite the recent movements for female equality and empowerment, few women occupy top positions in scientific decision-making. The challenges women face during their career may arise from societal biases and the current scientific culture. We discuss the effect of such biases at three different levels of the career and provide suggestions to tackle them. At the societal level, gender roles can create a negative feedback loop in which women are discouraged from attaining top positions and men are discouraged from choosing a home-centred lifestyle. This loop can be broken early in life by providing children with female role models that have a work-centred life and opening up the discussion about gender roles at a young age. At the level of hiring, unconscious biases can lead to a preference for male candidates. The introduction of (unbiased) artificial intelligence algorithms and gender champions in the hiring process may restore the balance and give men and women an equal chance. At the level of coaching and evaluation, barriers that women face should be addressed on a personal level through the introduction of coaching and mentoring programmes. In addition, women may play a pivotal role in shifting the perception of scientific success away from bibliometric outcomes only towards a more diverse assessment of quality and societal relevance. Taken together, these suggestions may break the glass ceiling in the scientific world for women; create more gender diversity at the top and improve translational science in medicine.

Series: Pragmatic trials and real world evidence: Paper 5. Usual care and real life comparators.

Pragmatic trials may deliver real-world evidence on the added value of new medications compared with usual care and inform decision making earlier in development. This fifth paper in a series on pragmatic trials in the Journal discusses usual care as a comparator and the allocation of treatment strategies. The allocation and implementation of treatment strategies should resemble clinical practice as closely as possible. Randomization at the level of the site, as opposed to at the individual level, may be preferred. Data analysis according to the intention-to-treat principle is recommended, and crossover between treatment arms and strong treatment preferences may be accounted for in the study design in specific situations. Although usual care is the comparator of choice, this may differ substantially between centers and countries complicating comparator choice. Using clinical guidelines to define usual care can be helpful in standardizing comparator treatments; however, this may decrease the applicability of the results to real-life settings. Conversely, using multiple usual-care treatment arms will increase the complexity of the study. The specific objectives of the trial and design choices should be discussed with all stakeholders to realize the full potential of the pragmatic trial.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent.

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

Series: Pragmatic trials and real world evidence: Paper 1. Introduction.

This is the introductory paper in a series of eight papers. In this series, we integrate the theoretical design options with the practice of conducting pragmatic trials. For most new market-approved treatments, the clinical evidence is insufficient to fully guide physicians and policy makers in choosing the optimal treatment for their patients. Pragmatic trials can fill this gap, by providing evidence on the relative effectiveness of a treatment strategy in routine clinical practice, already in an early phase of development, while maintaining the strength of randomized controlled trials. Selecting the setting, study population, mode of intervention, comparator, and outcome are crucial in designing pragmatic trials. In combination with monitoring and data collection that does not change routine care, this will enable appropriate generalization to the target patient group in clinical practice. To benefit from the full potential of pragmatic trials, there is a need for guidance and tools in designing these studies while ensuring operational feasibility. This paper introduces the concept of pragmatic trial design. The complex interplay between pragmatic design options, feasibility, stakeholder acceptability, validity, precision, and generalizability will be clarified. In this way, balanced design choices can be made in pragmatic trials with an optimal chance of success in practice.