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Background. Healthy volunteer wild-type influenza challenge models offer a unique opportunity to evaluate multiple aspects of this important virus. Such studies have not been performed in the United States in more than a decade, limiting our capability to investigate this virus and develop countermeasures. We have completed the first ever wild-type influenza A challenge study under an Investigational New Drug application (IND). This dose-finding study will lead to further development of this model both for A(H1N1)pdm09 and other strains of influenza. Methods. Volunteers were admitted to an isolation unit at the National Institutes of Health Clinical Center for a minimum of 9 days. A reverse genetics, cell-based, Good Manufacturing Practice (GMP)–produced, wild-type A (H1N1)pdm09 virus was administered intranasally. Escalating doses were given until a dose was reached that produced disease in a minimum of 60% of volunteers. Results. An optimal dose of 107 tissue culture infectious dose 50 was reached that caused mild to moderate influenza disease in 69% of individuals with mean viral shedding for 4–5 days and significant rises in convalescent influenza antibody titers. Viral shedding preceded symptoms by 12–24 hours and terminated 2–3 days prior to symptom resolution, indicating that individuals may be infectious before symptom development. As expected, nasal congestion and rhinorrhea were most common, but interestingly, fever was observed in only 10% of individuals. Conclusions. This study represents the first healthy volunteer influenza challenge model using a GMP-produced wild-type virus under an IND. This unique clinical research program will facilitate future studies of influenza pathogenesis, animal model validation, and the rapid, efficient, and cost-effective evaluation of efficacy of novel vaccines and therapeutics.

Severely immunocompromised individuals infected with influenza are different from the influenza infected that are nonimmunocompromised. Issues to consider during medical management include asymptomatic shedding, development of multi-drug resistance during prolonged antiviral therapy, and the potential high risk of pulmonary involvement. Introduction.  Medical advances have led to an increase in the world's population of immunosuppressed individuals. The most severely immunocompromised patients are those who have been diagnosed with a hematologic malignancy, solid organ tumor, or who have other conditions that require immunosuppressive therapies and/or solid organ or stem cell transplants. Materials and methods.  Medically attended patients with a positive clinical diagnosis of influenza were recruited prospectively and clinically evaluated. Nasal washes and serum were collected. Evaluation of viral shedding, nasal and serum cytokines, clinical illness, and clinical outcomes were performed to compare severely immunocompromised individuals to nonimmunocompromised individuals with influenza infection. Results.  Immunocompromised patients with influenza had more severe disease/complications, longer viral shedding, and more antiviral resistance while demonstrating less clinical symptoms and signs on clinical assessment. Conclusions.  Immunocompromised patients are at risk for more severe or complicated influenza induced disease, which may be difficult to prevent with existing vaccines and antiviral treatments. Specific issues to consider when managing a severely immunocompromised host include the development of asymptomatic shedding, multi-drug resistance during prolonged antiviral therapy, and the potential high risk of pulmonary involvement. Clinical trials registration,  ClinicalTrials.gov identifier NCT00533182.

Background. The 2009 influenza A(H1N1) pandemic called attention to the limited influenza treatment options available, especially in individuals at high risk of severe disease. Neuraminidase inhibitor—resistant seasonal H1N1 viruses have demonstrated the ability to transmit well despite early data indicating that resistance reduces viral fitness. 2009 H1N1 pandemic viruses have sporadically appeared containing resistance to neuraminidase inhibitors and the adamantanes, but the ability of these viruses to replicate, transmit, and cause disease in mammalian hosts has not been fully characterized. Methods. Two pretreatment wild-type viruses and 2 posttreatment multidrug-resistant viruses containing the neuraminidase H275Y mutation collected from immunocompromised patients infected with pandemic influenza H1N1 were tested for viral fitness, pathogenicity, and transmissibility in ferrets. Resutls. The pretreatment wild-type viruses and posttreatment resistant viruses containing the H275Y mutation all demonstrated significant pathogenicity and equivalent viral fitness and transmissibility. Conclusions. The admantane-resistant 2009 pandemic influenza A(H1N1) virus can develop the H275Y change in the neuraminidase gene conferring resistance to both oseltamivir and peramivir without any loss in fitness, transmissibility, or pathogenicity. This suggests that the dissemination of widespread multidrug resistance similar to neuraminidase inhibitor resistance in seasonal H1N1 is a significant threat.

To ensure genome stability during mitosis, the mitotic spindle must segregate sister chromosomes accurately. Multiple surveillance mechanisms, collectively referred to as the mitotic checkpoint, function to delay anaphase onset if sister chromosomes are not bound to microtubules from opposite spindle poles. Dominant signaling pathways within the mitotic checkpoint are the Spindle Assembly Checkpoint (SAC), which delays anaphase when kinetochores are not stably attached to microtubules, and the error correction mechanism, which induces detachment when microtubule-kinetochore attachments are not under tension. Together, these mechanisms promote stable, bipolar attachments in which dynamic microtubules can generate tension across sister kinetochores. However, the interdependency of kinetochore-microtubule attachment and tension has proved challenging to understanding whether this model fully explains how the mitotic checkpoint responds to the tension status at kinetochores. Unlike higher eukaryotes, budding yeast kinetochores bind only one microtubule, simplifying the relationship between attachment and tension. To address the role of tension in the mitotic checkpoint, we developed a Taxol-sensitive yeast model to reduce tension by stabilizing microtubules in fully assembled spindles. Our results show that reducing tension on bipolar, attached kinetochores delays anaphase onset. The tension-mediated delay is transient relative to the SAC delay imposed by unattached kinetochores. Furthermore, it requires the SAC proteins Bub1 and Bub3, but persists without Mad1, Mad2 and Mad3 (yeast BubR1). Together, our results demonstrate that reduced tension generates a ‘wait-anaphase’ signal during the mitotic checkpoint that is temporally and mechanistically distinct from that of unattached kinetochores.

Background: Digital mental health interventions stand to play a critical role in managing the mental health impact of the COVID-19 pandemic. Thus, enhancing their uptake is a key priority. General practitioners (GPs) are well positioned to facilitate access to digital interventions, but tools that assist GPs in identifying suitable patients are lacking. Objective: This study aims to evaluate the suitability of a web-based mental health screening and treatment recommendation tool (StepCare) for improving the identification of anxiety and depression in general practice and, subsequently, uptake of digital mental health interventions. Methods: StepCare screens patients for symptoms of depression (9-item Patient Health Questionnaire) and anxiety (7-item Generalized Anxiety Disorder scale) in the GP waiting room. It provides GPs with stepped treatment recommendations that include digital mental health interventions for patients with mild to moderate symptoms. Patients (N=5138) from 85 general practices across Australia were invited to participate in screening. Results: Screening identified depressive or anxious symptoms in 43.09% (1428/3314) of patients (one-quarter were previously unidentified or untreated). The majority (300/335, 89.6%) of previously unidentified or untreated patients had mild to moderate symptoms and were candidates for digital mental health interventions. Although less than half were prescribed a digital intervention by their GP, when a digital intervention was prescribed, more than two-thirds of patients reported using it. Conclusions: Implementing web-based mental health screening in general practices can provide important opportunities for GPs to improve the identification of symptoms of mental illness and increase patient access to digital mental health interventions. Although GPs prescribed digital interventions less frequently than in-person psychotherapy or medication, the promising rates of uptake by GP-referred patients suggest that GPs can play a critical role in championing digital interventions and maximizing the associated benefits.

Objective. In 2015, the Australian Government introduced several mental health reforms, including the requirement that Primary Health Networks (PHNs) provide stepped care services for Australians with mental health needs such as anxiety and depression. This paper reports on the development and feasibility study of StepCare, an online stepped mental healthcare service in general practice that screens patients, provides immediate feedback to patients and general practitioners (GPs), transmits stepped treatment recommendations to GPs and monitors patients' progress, including notification of deterioration. Methods. The present codesign and feasibility study in one PHN examined: (1) the acceptability and feasibility of StepCare to GPs, practice staff and patients; (2) the impact of StepCare on clinical practice; and (3) the barriers to and facilitators of implementation. Results. Thirty-two GPs, 22 practice staff and 418 patients participated in the study. Overall, patients, practice staff and GPs found StepCare acceptable and feasible, commending its privacy, the mental health screening, monitoring and feedback. They also made suggestions for service improvements. GPs reported that StepCare helped with their identification and management of patients with common mental health issues. Conclusions. Preliminary data suggest that StepCare may be acceptable and feasible in Australian general practice, helping GPs identify and manage common mental health problems in their patients. The study provides implications for policy and practice, and points the way to future translational research into stepped mental health care.

Limited research has assessed the “human dimension” of horse care. The aims of this study were to (1) understand horse owner attitudes toward horse welfare when kept outdoors versus indoors and in groups versus individually, (2) compare horse owner attitudes toward horse welfare with the ways in which they house their horses, and (3) explore horse owner reasons for and challenges with their horses’ housing. Seventy-six horse owners in Prince Edward Island, Canada completed a questionnaire. Non-parametric tests and quantitative content analysis were used for data analysis. Consistent with the way horses were kept, most (82–96%) owners agreed that horses’ physical health, mental well-being, and natural living were better when kept outdoors and in groups. Fewer (64–68%) participants agreed that the horses’ standard of care was better when kept outdoors or in groups. Results show associations between owners whose attitudes suggest indoor and/or individual housing is better for horse welfare and keeping their horses indoors part-time and/or individually. Two overarching themes were developed from owners’ responses regarding their reasons and challenges related to the ways in which horses were housed: horse-centered and owner-centered care. The results indicate that horse owners’ choices about their horses’ housing correspond to beliefs about improved horse welfare.

The core premise of evidence-based medicine is that clinical decisions are informed by the peer-reviewed literature. To extract meaningful conclusions from this literature, one must first understand the various forms of biases inherent within the process of peer review. We performed an exhaustive search that identified articles exploring the question of whether survival benefit was associated with maximal high-grade glioma (HGG) resection and analysed this literature for patterns of publication. We found that the distribution of these 108 articles among the 26 journals to be non-random (p<0.01), with 75 of the 108 published articles (69%) appearing in 6 of the 26 journals (25%). Moreover, certain journals were likely to publish a large number of articles from the same medical academic genealogy (authors with shared training history and/or mentor). We term the tendency of certain types of articles to be published in select journals ‘journal bias’ and discuss the implication of this form of bias as it pertains to evidence-based medicine.