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.
Since its earliest days, the effective use of anticoagulation for prevention of stroke and other thromboembolic events has been limited by the risk and fear of bleeding, which was long believed to be ...inevitable. However, new understanding of the coagulation cascade suggests that, by targeting factor XI, it may be possible to protect patients from pathological thrombosis without significantly affecting physiological haemostasis, and thus greatly reduce the risk of bleeding. The AZALEA-TIMI 71 trial is the first study to provide definitive evidence that factor XI inhibition substantially reduces bleeding compared to a standard-of-care direct oral anticoagulant (DOAC). Based on an interview with Principal Investigator Christian T. Ruff, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Boston, Massachusetts, USA, this article explains the significance of the AZALEA-TIMI 71 trial results, which showed an unprecedented reduction in the rate of bleeding with abelacimab, an investigational dual-acting factor XI/XIa inhibitor, compared with the DOAC rivaroxaban in patients with atrial fibrillation (AF) at moderate-to-high risk of stroke.
This continuing medical education-accredited symposium, held at the 2023 International Society for Thrombosis and Haemostasis (ISTH) congress in Montréal, Canada, focused on current unmet needs in ...anticoagulation, especially in the atrial fibrillation (AF) population, and reflected on the promise of the emerging class of Factor XI inhibitors for stroke prevention (SPAF) in susceptible patients. The faculty agreed that, although direct oral anticoagulants (DOAC) have represented a major advance compared with vitamin K antagonists, their utilisation remains suboptimal, often due to the prevailing fear of bleeding in many types of patients. Older age alone can be a reason for withholding anticoagulation, due to the risk and implications of bleeding. Frailty and comorbidities, such as chronic kidney disease (CKD), which can adversely affect the bioavailability of DOACs, are also deterrents to optimal anticoagulant use. Clinicians may try to avoid or mitigate bleeding by inappropriately prescribing low doses of DOACs, an off-label practice that has been found to fail to protect patients from thrombotic risk, without attenuating the risk of bleeding. In addition, the potential for drug-drug interactions and poor adherence also limit the optimal use of DOACs in real-world clinical practice. A recent patient survey focusing on the topic of ‘minor bleeding’, often referred to by clinicians as ‘nuisance bleeding’, and typically not well captured in clinical trials, revealed the far-reaching impact of ongoing problems with bleeding on quality of life, and the possibility that these experiences may deter patients from adherence to their prescribed anticoagulant regimen. Factor XI represents a promising new target for anticoagulation, which may minimise the risk of bleeding by pharmacologically ‘uncoupling’ the clotting pathway, leading to pathological thrombosis from the cascade largely responsible for physiological haemostasis. Phase II research with investigational Factor XI inhibitors has established their antithrombotic and safety potential, and some of these agents may also avoid other practical drawbacks of DOACs. Phase III evaluation of Factor XI inhibition is ongoing in a number of clinical settings.
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.
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.
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.
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.
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.
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
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.
The premutation of the fragile X messenger ribonucleoprotein 1 (
) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased ...levels of
mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations,
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
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.
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.
Mice were inoculated with herpes simplex virus in the skin of the snout or by scarification on the cornea and then examined for eye disease using a slit lamp. Whole mounts of corneal epithelium were ...stained for virus antigens by the peroxidase-antiperoxidase method, and infectious virus was isolated from eyewashings. Antigens were present one day after corneal inoculation, but after inoculation of the snout, there was a delay of three days before antigens were seen. This delay and the distribution of antigens were evidence of zosteriform spread from the snout to the eye via the nervous system. Disease of the cornea varied in severity and timing depending on the site of inoculation. The peroxidase-antiperoxidase method was more sensitive than isolation of virus from eyewashings and allowed the site and distribution of infected cells to be seen.
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD ...exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission.
To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations.
The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration FEV1 to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023.
Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol.
The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions.
Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean SD age, 68 7.9 years; 274 men 53%; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96).
Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both.
isrctn.org Identifier: ISRCTN10497306.
Background Statins lower cholesterol and also exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory ...conditions. Objective To evaluate the in vivo therapeutic potential of simvastatin as an anti-inflammatory agent in patients with asthma. Methods Potential signal from treatment effect was optimized by withdrawing all anti-inflammatory treatment for the duration of the study. Participants received 1 month of daily simvastatin and 1 month of daily placebo in a randomized, double-blind crossover trial. A total of 16 patients completed per protocol. Asthmatic inflammation was evaluated by measuring exhaled tidal nitric oxide, alveolar nitric oxide, sputum and peripheral eosinophil count, methacholine hyperresponsiveness, salivary eosinophilic cationic protein, and C-reactive protein. Measurements of dynamic and static lung volumes and of cholesterol were also made. Results After initial withdrawal of usual asthma medication, there was a 1.43 geometric mean fold increase (ie, 43% difference) in fraction of exhaled nitric oxide (95% CI, 1.15 to 1.78; P = .004). Compared with placebo, simvastatin led to a 0.86 geometric mean fold decrease (95% CI, 0.7 to 1.04; P = .15) in exhaled nitric oxide (ie, a 14% difference), and a −0.18 doubling dilution shift (95% CI, −1.90 to 1.55; P = 1.0) in methacholine hyperresponsiveness. There were no significant differences in other inflammatory outcomes, lung volumes, or airway resistance between simvastatin and placebo. Treatment with simvastatin led to a significant reduction ( P < .005) of total and low-density lipoprotein cholesterol. Conclusion There is no evidence to suggest simvastatin has anti-inflammatory activity in patients with asthma. Clinical implications Simvastatin is not useful for the treatment of asthma.
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