Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Now is the time to fix the clinical research workforce crisis.

The clinical and translational research enterprise is recognized by many as the "evidence generation system." While there have been several calls to revolutionize this enterprise to more effectively deliver the fruits of biomedical science to patients and society, significant issues across the clinical research workforce are pervasive. Perhaps the most visible sign is the widening gap between supply and demand for competent staff. Underpinning this, is a perfect storm of complex issues. Now reaching crisis point, this problem is far bigger than a staffing issue and ultimately jeopardizes the "engine" of drug and device development. With the current perilous state of the workforce, proposed enterprise fixes are likely to languish far out of reach, given that even "business as usual" is under threat. In fact, a glaring disconnect is evident between the visionary discourse on how to revolutionize the clinical research enterprise and the sober recognition that operationalization of any such vision rests on the shoulders of a workforce that's in dire straits. In this article, we provide a brief forensic analysis of the workforce problem and an initial indication of where solutions may lie.

The International Fragile X Premutation Registry: building a resource for research and clinical trial readiness.

FMR1 premutation cytosine-guanine-guanine repeat expansion alleles are relatively common mutations in the general population that are associated with a neurodegenerative disease (fragile X-associated tremor/ataxia syndrome), reproductive health problems and potentially a wide range of additional mental and general health conditions that are not yet well-characterised. The International Fragile X Premutation Registry (IFXPR) was developed to facilitate and encourage research to better understand the FMR1 premutation and its impact on human health, to facilitate clinical trial readiness by identifying and characterising diverse cohorts of individuals interested in study participation, and to build community and collaboration among carriers, family members, researchers and clinicians around the world. Here, we describe the development and content of the IFXPR, characterise its first 747 registrants from 32 countries and invite investigators to apply for recruitment support for their project(s). With larger numbers, increased diversity and potentially the future clinical characterisation of registrants, the IFXPR will contribute to a more comprehensive and accurate understanding of the fragile X premutation in human health and support treatment studies.

Flea and tick treatment satisfaction, preference, and adherence of dog owners in the United States, United Kingdom, and Australia who treated their dog with fluralaner.

Background: An extended duration flea and tick medication of the isoxazoline class (fluralaner) was introduced in 2014 in the United States and other countries. A survey was developed in 2016 to gauge dog owner adherence with veterinary recommendations around the administration of preventive flea and tick medications. Current fluralaner-using dog owners were also asked to compare their experience with opinions on monthly flea and tick products. Aim: To survey dog owners who were current users of fluralaner on their opinions, experiences, and attitudes around the administration of flea and tick medications to their dogs in light of current veterinarian recommendations. Methods: Dog owners in the United States (US), United Kingdom (UK), and Australia that gave fluralaner oral chews to their dogs were asked to compare their experience using fluralaner (12-week dosing) and monthly flea and tick medications. The survey responses of dog owners in the UK and Australia were compared against responses to a similar survey conducted in the US in 2017. Surveys were completed by dog owners who were in the clinic for any reason other than a sickness visit. Additionally, veterinarians that prescribed fluralaner from all three countries provided their annual flea and tick treatment recommendation for dogs. Results: A sample of veterinarians from the US, UK, and Australia that prescribe fluralaner recommend that dog owners obtain approximately 12 months of flea protection per year and 9-12 months of tick protection per year. A variable proportion of owners (22%-90%) reported that their dog participates in outdoor and social activities associated with an increased flea and tick exposure risk. A similarly variable proportion of owners reported prior experience of finding fleas (24%-50%) or ticks (18%-35%) on their dogs. All participating owners treated their dogs currently with fluralaner and most (68%-77%) had previously treated their dog with monthly flea and tick products. The convenience of 12-week dosing and less frequent dosing were the most frequently identified product qualities associated with their choice of an extended effect flea and tick treatment. Conclusion: Most veterinarians surveyed in this survey recommended year-round use of a flea and tick medication for dogs in the US, UK, and Australia. Dog owners recalled the veterinary recommendation for flea and tick prevention as 8-10 months per year. Most dog owners from the clinics in the US, UK, and Australia had used shorter-acting (monthly) flea/tick medications previously. The majority of those who currently gave fluralaner doses to their dogs were "satisfied" or "very satisfied" with the extended duration flea and tick product. Preference for a 12-week duration medication over monthly re-treatment was also high (82%-92%) in all three countries and was associated with convenience.

Use of Big Data to Aid Patient Recruitment for Clinical Trials Involving Biosimilars and Rare Diseases.

Patient recruitment and retention are arguably the greatest challenges to the timely execution of clinical trials. This is particularly true in the case of trials involving biosimilars and those focused on rare diseases. For biosimilars, recruitment success typically hinges on difficulty of access to reimbursement for the originator product and may be hindered by competition from studies with other biosimilars and those with new chemical entities. For rare diseases, recruitment success depends not only on finding enough patients but also on retaining them for the duration of the trial. Historical success with patient recruitment-in addition to site qualifications-needs to be considered in parallel with current market competition and results in an ever-changing patient recruitment environment. Multiple companies supporting the biopharmaceutical industry, such as Contract Research Organizations, have begun to leverage sophisticated data modeling tools and techniques to find additional patients for biosimilar and rare disease trials and/or to find patients more quickly. In addition, these companies seek to better understand the population of interest and refine their statistical assumptions when conducting clinical trials or real-world analyses. The largest and most well-established companies that support the biopharmaceutical industry now have unparalleled access to big data from clinical trials, electronic health records, medical claims, laboratory tests, and prescriptions. This paper will discuss how big data can be harnessed to aid patient recruitment with a focus on clinical trials for biosimilars and orphan rare diseases.