Monitoring advances including consent: learning from COVID-19 trials and other trials running in UKCRC registered clinical trials units during the pandemic.

The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home.Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK.The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring.Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future.The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use

Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol

Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access

Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis

Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood

The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown

Perspectives of 360-Degree Cinematic Virtual Reality: Interview Study Among Health Care Professionals

BackgroundThe global market for medical education is projected to increase exponentially over the next 5 years. A mode of delivery expected to drive the growth of this market is virtual reality (VR). VR simulates real-world objects, events, locations, and interactions in 3D multimedia sensory environments. It has been used successfully in medical education for surgical training, learning anatomy, and advancing drug discovery. New VR research has been used to simulate role-playing and clinical encounters; however, most of this research has been conducted with health professions students and not current health care professionals. Thus, more research is needed to explore how health care professionals experience VR with role-playing and clinical encounters. ObjectiveThe aim of this study was to explore health care professionals’ experiences with a cinematic VR (cine-VR) training program focused on role-playing and clinical encounters addressing social determinants of health, Appalachian culture, and diabetes. Cine-VR leverages 360-degree video with the narrative storytelling of cinema to create an engaging educational experience. MethodsWe conducted in-depth telephone interviews with health care professionals who participated in the cine-VR training. The interviews were audio recorded and transcribed verbatim. A multidisciplinary team coded and analyzed the data using content and thematic analyses with NVivo software. ResultsWe conducted 24 in-depth interviews with health care professionals (age=45.3, SD 11.3, years; n=16, 67%, women; n=22, 92%, White; and n=4, 17%, physicians) to explore their experiences with the cine-VR training. Qualitative analysis revealed five themes: immersed in the virtual world: seeing a 360-degree sphere allowed participants to immerse themselves in the virtual world; facilitated knowledge acquisition: all the participants accurately recalled the culture of Appalachia and listed the social determinants of health presented in the training; empathized with multiple perspectives: the cine-VR provided a glimpse into the real life of the main character, and participants described thinking about, feeling, and empathizing with the character’s frustrations and disappointments; perceived ease of use of cine-VR: 96% (23/24) of the participants described the cine-VR as easy to use, and they liked the 360-degree movement, image resolution, and sound quality but noted limitations with the buttons on the headsets and risk for motion sickness; and perceived utility of cine-VR as a teaching tool: participants described cine-VR as an effective teaching tool because it activated visual and affective learning for them. ConclusionsParticipants emphasized the realism of the cine-VR training program. They attributed the utility of the cine-VR to visual learning in conjunction with the emotional connection to the VR characters. Furthermore, participants reported that the cine-VR increased their empathy for people. More research is needed to confirm an association between the level of immersion and empathy in cine-VR training for health care professionals

Using virtual reality to improve health care providers⇔ cultural self-efficacy and diabetes attitudes: pilot questionnaire study

Background: In southeastern Appalachian Ohio, the prevalence of diabetes is 19.9%, nearly double that of the national average of 10.5%. Here, people with diabetes are more likely to have a delayed diagnosis, limited access to health care, and lower health literacy. Despite the high rates of diabetes in the region, the availability of endocrinologists and certified diabetes care and education specialists is limited. Therefore, innovative strategies to address the growing diabetes care demands are needed. One approach is to train the primary care workforce in new and emerging therapies for type 2 diabetes to meet the increasing demands and complexity of diabetes care. Objective: The aim of this study was to assess the effectiveness of a virtual reality training program designed to improve cultural self-efficacy and diabetes attitudes. Methods: Health care providers and administrators were recruited from large health care systems, private practices, university-owned hospitals or clinics, Federally Qualified Health Centers, local health departments, and AmeriCorps. Providers and administrators participated in a 3-hour virtual reality training program consisting of 360-degree videos produced in a professional, cinematic manner; this technique is called virtual reality cinema (cine-VR). Questionnaires measuring cultural self-efficacy, diabetes attitudes, and presence in cine-VR were administered to providers and administrators before and after the program. Results: A total of 69 participants completed the study. The mean age of the sample was 42.2 years (SD 13.7), 86% (59/69) identified as female, 83% (57/69) identified as White, 86% (59/69) identified as providers, and 25% (17/69) identified as nurses. Following the training program, we observed positive improvements in all three of the cultural self-efficacy subscales: Cognitive (mean change –1.29; t65=–9.309; P\u3c.001), Practical (mean change –1.85; t65=–9.319; P\u3c.001), and Affective (mean change –0.75; t65=–7.067; P\u3c.001). We observed the largest magnitude of change with the subscale, with a Cohen d of 1.16 indicating a very large effect. In addition, we observed positive improvements in all five of the diabetes attitude subscales: Need for special training (mean change –0.21; t67=–6.154; P\u3c.001), Seriousness of type 2 diabetes (mean change –0.34; t67=–8.114; P\u3c.001), Value of tight glucose control (mean change –0.13; t67=–3.029; P=.001), Psychosocial impact of diabetes (mean change –0.33; t67=–6.610; P\u3c.001), and Attitude toward patient autonomy (mean change –0.17; t67=–3.889; P\u3c.001). We observed the largest magnitude of change with the Psychosocial impact of diabetes subscale, with a Cohen d of 0.87 indicating a large effect. We observed only one significant correlation between presence in cine-VR (ie, Interface Quality) and a positive change score (ie, Affective self-efficacy) (r=.285; P=.03). Conclusions: Our findings support the notion that cine-VR education is an innovative approach to improve cultural self-efficacy and diabetes attitudes among health care providers and administrators. The long-term impact of cine-VR education on cultural self-efficacy and diabetes attitudes needs to be determined

Mediation : Practice, Policy, and Ethics

https://larc.cardozo.yu.edu/faculty-books/1060/thumbnail.jp