Selection of endpoints in breast cancer clinical trials: a qualitative study of key trial stakeholders

Clinical trial endpoints are fundamental for evaluating the safety and efficacy of cancer therapies, yet it is not well understood how they are selected or the role of stakeholder groups in deciding endpoints. This study aimed to explore how clinical trial endpoints are selected in breast cancer trials of anti-cancer drugs through semi structured interviews with purposively selected stakeholders involved in breast cancer clinical trials (clinicians, consumers, pharmaceutical company representatives, and members of drug regulatory agencies). Participants were asked to describe the process of selecting trial endpoints. Interviews were transcribed verbatim and analysed using inductive thematic analysis supported by NVivo software. Saturation of the main themes was reached and the final sample included 25 participants from 14 countries (9 clinicians, 7 consumers, 5 members of regulatory agencies, 4 pharmaceutical company representatives). Pharmaceutical companies were almost always identified as the main decision maker. While most consumers and pharmaceutical company representatives felt clinicians and consumers influenced trial design, some clinicians and regulators reported consumers and clinicians had little influence. Factors identified as important considerations in determining trial endpoints included the main goal of the trial, established standardised endpoints, resources, and the investigational agent studied. All pharmaceutical advisors reported that meeting the requirements for regulatory approval was the major factor considered. Clinical trial endpoint selection is largely decided by the pharmaceutical industry, driven by requirements for regulatory approval. Given the limited influence from clinicians and consumers, guidance by regulatory agencies will be important for future inclusion of novel endpoints in clinical trials.     

Assessment of Rapid MinION Nanopore DNA Virus Meta-Genomics Using Calves Experimentally Infected with Bovine Herpes Virus-1

Bovine respiratory disease (BRD), which is the leading cause of morbidity and mortality in cattle, is caused by numerous known and unknown viruses and is responsible for the widespread use of broad-spectrum antibiotics despite the use of polymicrobial BRD vaccines. Viral metagenomics sequencing on the portable, inexpensive Oxford Nanopore Technologies MinION sequencer and sequence analysis with its associated user-friendly point-and-click Epi2ME cloud-based pathogen identification software has the potential for point-of-care/same-day/sample-to-result metagenomic sequence diagnostics of known and unknown BRD pathogens to inform a rapid response and vaccine design. We assessed this potential using in vitro viral cell cultures and nasal swabs taken from calves that were experimentally challenged with a single known BRD-associated DNA virus, namely, bovine herpes virus 1. Extensive optimisation of the standard Oxford Nanopore library preparation protocols, particularly a reduction in the PCR bias of library amplification, was required before BoHV-1 could be identified as the main virus in the in vitro cell cultures and nasal swab samples within approximately 7 h from sample to result. In addition, we observed incorrect assignment of the bovine sequence to bacterial and viral taxa due to the presence of poor-quality bacterial and viral genome assemblies in the RefSeq database used by the EpiME Fastq WIMP pathogen identification software.     

Australian chiropractic and osteopathic graduates' perceptions of readiness for transition to practice

ObjectiveThis is the second phase of a project. The aim was to explore Australian chiropractic and osteopathic new graduates'' readiness for transition to practice concerning their clinical skills, professional behaviors, and interprofessional abilities. Phase 1 explored final year students'' self-perceptions, and this part uncovered their opinions after 6 months or more in practice.MethodsInterviews were conducted with a self-selecting sample of phase 1 participant graduates from 2 Australian chiropractic and 2 osteopathic programs. Results of the thematic content analysis of responses were compared to the Australian Chiropractic Standards and Osteopathic Capabilities, the authority documents at the time of the study.ResultsInterviews from graduates of 2 chiropractic courses (n = 6) and 2 osteopathic courses (n = 8) revealed that the majority had positive comments about their readiness for practice. Most were satisfied with their level of clinical skills, verbal communication skills, and manual therapy skills. Gaps in competence were identified in written communications such as case notes and referrals to enable interprofessional practice, understanding of professional behaviors, and business skills. These identified gaps suggest that these graduates are not fully cognizant of what it means to manage their business practices in a manner expected of a health professional.ConclusionThis small study into clinical training for chiropractic and osteopathy suggests that graduates lack some necessary skills and that it is possible that the ideals and goals for clinical education, to prepare for the transition to practice, may not be fully realized or deliver all the desired prerequisites for graduate practice.     

Time of Dietary Energy and Nutrient Intake and Body Mass Index in Children: Compositional Data Analysis from the Childhood Obesity Project (CHOP) Trial

Meal timing is suggested to influence the obesity risk in children. Our aim was to analyse the effect of energy and nutrient distributions at eating occasions (EO), including breakfast, lunch, supper, and snacks, on the BMI z-score (zBMI) during childhood in 729 healthy children. BMI and three-day dietary protocols were obtained at 3, 4, 5, 6, and 8 years of age, and dietary data were analysed as the percentage of the mean total energy intake (TEI; %E). Intakes at EOs were transformed via an isometric log–ratio transformation and added as exposure variables to linear mixed-effects models. Stratified analyses by country and recategorization of EOs by adding intake from snacks to respective meals for further analyses were performed. The exclusion of subjects with less than three observations and the exclusion of subjects who skipped one EO or consumed 5% energy or less at one EO were examined in sensitivity analyses. Around 23% of the children were overweight at a given time point. Overweight and normal-weight children showed different distributions of dietary intakes over the day; overweight children consumed higher intakes at lunch and lower intakes of snacks. However, no significant effects of timing of EOs on zBMI were found in regression analyses.     

Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children

The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington’s disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.Subject terms: Retina, Prognostic markers, Retinal diseases, Predictive markers     

Individuals with peripheral vestibulopathy and poor quality of sleep are at a higher risk for falls

IntroductionThere is a lack of scientific studies on the assessment of patients with vestibular disorders associated with sleep quality disorders and its impact on the balance and overall quality of life.Objectivesto assess the impact of the sleep quality on the balance and quality of life of individuals with peripheral vestibulopathies.Methods52 individuals with peripheral vestibulopathies underwent sleep quality assessment through the Pittsburgh sleep quality index, neurotological examination through dizziness handicap inventory and Tetrax posturography (Sunlight Medical Ltd.) in eight sensory conditions. Thirty-two healthy individuals (G3) participated as the control group.ResultsFourteen individuals with vestibulopathy had good quality of sleep (G1) and 38 showed poor quality of sleep (G2) as demonstrated by the Pittsburgh sleep quality index global scores (p = 0.001). The dizziness handicap inventory showed worse impact of the dizziness on the quality of life in G2 when compared to G1 (p  = 0.045). The G₂ showed higher risk of falling in posturography when compared to G3 (p = 0.012) and higher index of postural instability in five sensory conditions in comparison with G3. In the vestibulopathy groups, the worse the sleep quality, the higher the risk of falling (r = 0.352) and the worse the quality of life (r = 0.327).ConclusionIndividuals with peripheral vestibulopathies and poor quality of sleep demonstrate worse balance evidenced by increased postural instability, higher risk of falls and worse perceived quality of life. The quality of sleep is a predictive factor for worse perceived quality of life and for higher risk of falls in individuals with peripheral vestibulopathies.     

Dysphagia in patients with moderate and severe obstructive sleep apnea

IntroductionThere is evidence that trauma caused by snoring in the pharynx could result in dysphagia in patients with obstructive sleep apnea, but the literature is still scarce to define the factors associated with the presence of dysphagia in these patients.ObjectivesTo analyze the occurrence of dysphagia and its clinical and polysomnographic features in patients with moderate and severe obstructive sleep apnea, in addition to verifying the impact of dysphagia on the quality of life of these patients.MethodsSeventy patients with moderate or severe apnea (apnea and hypopnea index – AHI > 15/hour) were selected. The patients underwent a sleep questionnaire, a quality of life in dysphagia questionnaire and a fiberoptic endoscopic evaluation of swallowing.ResultsA total of 70 patients were included in the study, of which 49 were men (70 %), with a mean age of 48.9 years. The fiberoptic endoscopic evaluation of swallowing was altered in 27.3 % and the most frequent alteration was the premature oral leakage with fluid. Comparing the groups with and without dysphagia, the female gender was the only clinical parameter that showed a trend of statistical significance in the group with dysphagia (p = 0.069). There was no statistical difference regarding the polysomnographic features and in the global quality of life score in dysphagia in the comparison between the groups.ConclusionsThe presence of dysphagia in patients with moderate to severe apnea is frequent and subclinical, reinforcing the need to investigate this symptom in this group of patients. However, the presence of dysphagia did not result in worsening in patients' quality of life, suggesting that, although frequent, its effect is mild. There was no relevance regarding the association of clinical and polysomnographic parameters with the presence of dysphagia.     

STUDIES ON THE ETIOLOGY OF RABBIT POX : I. ISOLATION OF A FILTERABLE AGENT: ITS PATHOGENIC PROPERTIES

A filterable agent was isolated from 7 cases of spontaneous rabbit pox by the intratesticular injection in rabbits of a variety of tissues. The virus was transmitted for 15 consecutive testicle to testicle passages in rabbits by Berkefeld V filtrates of testicular tissue emulsions. Unfiltered emulsions were more potent than filtrates. The virulence of the virus was maintained by ice box storage of infected tissues for as long as 127 days. The pathogenic properties of the virus persisted under conditions of animal passage for the 9 months from January to October, 1933, covered by these studies. The reaction produced in rabbits by the inoculation of tissue-virus emulsions was of two principal types, the first of which has been described and analyzed in the present paper. In the case of intratesticular injections, particularly of testicular tissue inocula, an acute fulminating and rapidly fatal condition regularly developed. The outstanding features were a massive hemorrhagic orchitis with marked scrotal edema, fever, and death within a week. The second type of reaction which is taken up in the next paper of this series (1) was observed under conditions in which the animal survived a week or longer. Occasional examples occurred in rabbits of the so called intratesticular series. The reaction was characterized by the development of a disease syndrome with a diversity of clinical manifestations which, it may be stated here for the sake of continuity, was indistinguishable from spontaneous rabbit pox.