Integrator Complex Subunit 3 Knockdown Has Minimal Effect on Lytic Herpes Simplex Virus Type-1 Infection in Fibroblast Cells.

Proteomic analysis of viral and cellular proteins that copurify with the herpes simplex virus type-1 (HSV-1) genome revealed that the cellular Integrator complex associates with viral DNA throughout infection. The Integrator complex plays a key role in the regulation of transcription of cellular coding and non-coding RNAs. We therefore predicted that it may regulate transcription of viral genes. Here, we demonstrate that knockdown of the Integrator complex subunit, Ints3, has minimal effect on HSV-1 infection. Despite reducing viral yield during low multiplicity infection, Ints3 knockdown had no effect on viral DNA replication, mRNA expression, or yield during high multiplicity infection.

Unpacking the nudge muddle.

Libertarian paternalism initially focused on policy domains in which the state was prohibited from interfering coercively in decision making out of respect for individual autonomy. Because adjustment of the s-frame was not an option, achieving better outcomes through manipulation of the i-frame seemed attractive. This original motivation was unfortunately lost in the transition from libertarian paternalism to the nudge framework.

Ethical Issues in Physician Billing Under Fee-For-Service Plans.

Medical ethics has become an important and recognized component of physician training. There is one area, however, in which medical students receive little guidance. There is practically no discussion of the financial aspects of medical practice. My objective in this paper is to initiate a discussion about the moral dimension of physician billing practices. I argue that physicians should expand their conception of professional responsibility in order to recognize that their moral obligations toward patients include a commitment to honest and forthright billing practices. I argue that physicians should aspire to a standard of clinical accuracy-not legal adequacy-in describing their activities. More generally, physicians should strive to promote an integrity-based professional culture, first and foremost by stigmatizing rather than celebrating creative billing practices, as well as condemning the misguided sense of solidarity that currently makes it taboo for physicians to criticize each other on this score.

The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: A cross-sectional study of products authorised 2011-2018.

BACKGROUND: In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies. METHODS AND FINDINGS: We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway. CONCLUSIONS: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

Seasonal Influenza Vaccination amongst Medical Students: A Social Network Analysis Based on a Cross-Sectional Study.

INTRODUCTION: The Chief Medical Officer for England recommends that healthcare workers have a seasonal influenza vaccination in an attempt to protect both patients and NHS staff. Despite this, many healthcare workers do not have a seasonal influenza vaccination. Social network analysis is a well-established research approach that looks at individuals in the context of their social connections. We examine the effects of social networks on influenza vaccination decision and disease dynamics. METHODS: We used a social network analysis approach to look at vaccination distribution within the network of the Lancaster Medical School students and combined these data with the students' beliefs about vaccination behaviours. We then developed a model which simulated influenza outbreaks to study the effects of preferentially vaccinating individuals within this network. RESULTS: Of the 253 eligible students, 217 (86%) provided relational data, and 65% of responders had received a seasonal influenza vaccination. Students who were vaccinated were more likely to think other medical students were vaccinated. However, there was no clustering of vaccinated individuals within the medical student social network. The influenza simulation model demonstrated that vaccination of well-connected individuals may have a disproportional effect on disease dynamics. CONCLUSIONS: This medical student population exhibited vaccination coverage levels similar to those seen in other healthcare groups but below recommendations. However, in this population, a lack of vaccination clustering might provide natural protection from influenza outbreaks. An individual student's perception of the vaccination coverage amongst their peers appears to correlate with their own decision to vaccinate, but the directionality of this relationship is not clear. When looking at the spread of disease within a population it is important to include social structures alongside vaccination data. Social networks influence disease epidemiology and vaccination campaigns designed with information from social networks could be a future target for policy makers.

Anorexia nervosa, autoimmunity and the hygiene hypothesis.

The hypothesis proposed is that anorexia nervosa (AN) is an autoimmune disease caused by delayed exposure to common micro-organisms in which auto-antibodies to regulatory peptides and hypothalamic neurons, which cross react with microbial antigens, disturb appetite and lead to decreased intake of food. IgG, IgA and IgM auto-antibodies to a range of regulatory peptides concerned with appetite and mood are found in patients with AN. The regulatory peptides show sequence homology with common micro-organisms of the microbial flora. Auto-antibodies to α melanocyte stimulating hormone (αMSH) are positively correlated with AN psychopathology. But patients with bulimia nervosa (BN) and normal healthy controls also have a similar range of auto-antibodies at comparable levels. The incidence of AN is rising in developed countries, the disease is more common in females than in males, the peak incidence is in the teenage years, there is seasonal variation in the month of birth and the disease is more common in higher socio-economic groups. These are all features which are consistent with the hygiene hypothesis. But there is no evidence that the disease is more common in first born than in later born children. There is a paucity of data on early life events such as attendance at nursery and exposure to pets. Genetic factors are important but the data on major histocompatibility complex (MHC) gene polymorphisms are contradictory. The epidemiological and serological data are consistent with the hypothesis under investigation but key questions in relation to the hygiene hypothesis have not been posed. A large case control study of AN epidemiology is indicated. MHC gene polymorphisms should be assessed. There is, however, sufficient evidence to justify a trial of pooled immunoglobulin therapy in patients with life threatening AN.