Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.

BACKGROUND: Influenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses. METHODS: We did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050. FINDINGS: Between Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis. INTERPRETATION: The tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed. FUNDING: Bill & Melinda Gates Foundation.

Quality indicators to assess a colorectal cancer prevention program.

OBJECTIVES: The aim of this study was to implement a set of indicators to assess the quality of care of a new healthcare model for prevention of colorectal cancer in a high-risk population. METHODS: Information was obtained retrospectively from electronic clinical records, review of documentation, and a survey. The high-risk clinic for colorectal cancer was created in Barcelona (Spain) in 2006. All users at greater risk of colorectal cancer assessed through the new healthcare model were included. Twenty-one indicators were computed using defined formulas and standards. Logistic regression models were computed to analyze factors related to adherence to the screening and surveillance prevention strategies. RESULTS: A total of 1,275 users were included. Eight of seventeen indicators reached the quality standard (80 percent structure, 50 percent process, and 17 percent outcome), whereas four indicators did not have a previously defined standard. The overall adherence to the screening and surveillance program was 67 percent. Users aged 59 and older had almost two times greater probabiblity (95 percent confidence interval [CI], 1.3-3.1) of adherence than younger users; users with surveillance colonoscopies presented a 7.4 times (95 percent CI, 4.6-11.7) greater probability of adherence than those with screening colonoscopies. CONCLUSIONS: The indicators have been shown to be feasible and valid tools to identify areas of improvement in this new model, such as information systems, continuity of care, and communication among professionals. Because this was the first time these indicators were applied to assess the high-risk clinic for colorectal cancer, further implementation is required to improve the interpretability of results.

Patient- and trial-specific barriers to participation in cardiovascular randomized clinical trials.

OBJECTIVES: The purpose of this study was to quantitatively examine the association of patient- and trial-specific factors with participation in cardiovascular randomized clinical trials. BACKGROUND: Randomized clinical trials are central to evidenced-based medicine, but low patient participation rates and potentially modifiable barriers are not well understood. METHODS: At a large U.S. academic health system, we examined screening logs from December 1, 2005, to February 28, 2011, from 15 cardiovascular randomized clinical trials. We identified 655 patients who were screened and potentially eligible for participation in at least 1 trial. We used multivariable Poisson regression to quantify the risk of not participating in a trial associated with patient- and trial-specific factors. RESULTS: The median age was 63 years (interquartile range: 54 to 72), 35% were women, and the median Charlson Index was 2 (interquartile range: 1 to 5). Forty-two percent of patients did not participate in a trial. In multivariable regression (C-Index 0.85), trial-specific factors strongly associated with not participating included intensive trial-related testing (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.63 to 2.20) and anticipated trial participation >6 months (RR: 4.10; 95% CI: 2.30 to 7.29). Patient-specific factors associated with not participating included older age (RR: 1.23; 95% CI: 1.11 to 1.36, per 10-year increase if age ≥65 years), out-of-state residence (RR: 1.26; 95% CI: 1.04 to 1.54), and female sex (RR: 1.17; 95% CI: 1.01 to 1.35). Race was not associated with participation. CONCLUSIONS: While patient-specific factors were associated with not participating in cardiovascular trials, longer trial duration and intensive trial-related testing were most strongly associated with risk for patients not participating. Innovative trial designs fostering convenience may most enhance trial participation.

Smarter regulations: commentary on "Responsible conduct by life scientists in an age of terrorism".

In the United States a rapidly increasing regulatory burden for life scientists has led to questions of whether the increased burden resulting from the Select Agent Program has had adverse effects on scientific advances. Attention has focussed on the regulatory "fit" of the Program and ways in which its design could be improved. An international framework convention to address common concerns about biosecurity and biosafety is a logical next step.

Arthroplasty registers: a review of international experiences.

OBJECTIVES: Registers have proven to be a valuable instrument in the evaluation of arthroplasty procedures and the performance of implants. The aim of this study was to describe the structure, functioning, and content of arthroplasty registers in Europe and other parts of the world. METHODS: A search of technical reports was carried out through the Internet and in Medline/PubMed. The exhaustiveness of the information was confirmed using the links to Web pages of other registers and contacts with key people. Aims, methods in data collection and evaluation, internal structure and organization, participants, validity of the data, and other variables were assessed for each arthroplasty register using a qualitative content analysis of the texts. RESULTS: Fifteen arthroplasty registers were identified which published sufficient information to conduct a comparative analysis. Eight additional registers were identified but no information was available on the Internet or in English. Most registers were initiatives of an orthopaedic society receiving governmental funding. Data were collected using standardized clinical forms and additional information from clinical-administrative datasets or other registers (mortality, implant costs, hip fractures). The main outcome measure of these registers is survival of the prostheses. Registers use the Internet and their annual reports as the main strategy for the dissemination and feed-back of their results. CONCLUSIONS: Scientific or professional societies and the public health administration should collaborate in the development of arthroplasty registers. To adequately assess the results of observational data information on the structure, the process of arthroplasty interventions and patients characteristics should be collected.

Small groups for supporting GPs' professional development in mental health disease--an evaluation.

BACKGROUND: Small groups provide opportunities for education, information sharing, development of clinical skills and peer support. They have been promoted in general practice in Australia, especially for mental health disease, and often by divisions of general practice. METHODS: Minutes from a series of small groups supervised by psychiatrists were analysed to observe the content and themes over 5 years. Additionally, focus groups of general practitioner participants were asked to comment on what they found most valuable. RESULTS: Forty-two GPs attended small groups (mean size 2-3) over 3 years, about half for 10-49 sessions. The most discussed diseases were depression (most frequently at 157 times), psychosis (137), personality disorders (79), drug and alcohol abuse (73), anxiety disorders (68) and suicide (42). Discussion of doctor-patient interpersonal and doctor self care issues increased from under 2% of all statements in 1995 to nearly 10% in 2000. Participating GPs found the small groups empowering, confidence increasing, and useful for addressing psychological and interpersonal issues at work. DISCUSSION: Participating GPs found small groups useful and provided helpful recommendations based on their experiences.

Preliminary comparison of the Essie and PubMed search engines for answering clinical questions using MD on Tap, a PDA-based program for accessing biomedical literature.

MD on Tap, a PDA application that searches and retrieves biomedical literature, is specifically designed for use by mobile healthcare professionals. With the goal of improving the usability of the application, a preliminary comparison was made of two search engines (PubMed and Essie) to determine which provided most efficient path to the desired clinically-relevant information.

Kinetic analysis of the oxidative conversion of the [4Fe-4S]2+ cluster of FNR to a [2Fe-2S]2+ Cluster.

The ability of FNR to sense and respond to cellular O(2) levels depends on its [4Fe-4S](2+) cluster. In the presence of O(2), the [4Fe-4S](2+) cluster is converted to a [2Fe-2S](2+) cluster, which inactivates FNR as a transcriptional regulator. In this study, we demonstrate that approximately 2 Fe(2+) ions are released from the reaction of O(2) with the [4Fe-4S](2+) cluster. Fe(2+) release was then used as an assay of reaction progress to investigate the rate of [4Fe-4S](2+) to [2Fe-2S](2+) cluster conversion in vitro. We also found that there was no detectable difference in the rate of O(2)-induced cluster conversion for FNR free in solution compared to its DNA-bound form. In addition, the rate of FNR inactivation was monitored in vivo by measuring the rate at which transcriptional regulation by FNR is lost upon the exposure of cells to O(2); a comparison of the in vitro and in vivo rates of conversion suggests that O(2)-induced cluster conversion is sufficient to explain FNR inactivation in cells. FNR protein levels were also compared for cells grown under aerobic and anaerobic conditions.

Superoxide destroys the [2Fe-2S]2+ cluster of FNR from Escherichia coli.

The oxygen sensing ability of the transcription factor FNR depends on the presence of a [4Fe-4S]2+ cluster. In the presence of O2, conversion of the [4Fe-4S]2+ cluster to a [2Fe-2S]2+ cluster inactivates FNR, but the fate of the [2Fe-2S]2+ cluster in cells grown under aerobic conditions is unknown. The present study shows that the predominant form of FNR in aerobic cells is apo-FNR (cluster-less FNR) indicating that the [2Fe-2S]2+ cluster, like the [4Fe-4S]2+ cluster, is not stable under these conditions. By quantifying the amount of [2Fe-2S]2+ cluster in 2Fe-FNR in vitro in the presence of various reductants and oxidants (GSH, DTT, cysteine, O2, hydrogen peroxide, and superoxide), we found that superoxide, a byproduct of aerobic metabolism, significantly destabilized the [2Fe-2S]2+ cluster. Mössbauer spectroscopy was used to monitor the effects of superoxide on 2Fe-FNR in vivo; under cellular conditions that favored superoxide production, we observed the disappearance of the signal representative of the [2Fe-2S]2+ cluster. We conclude that the [2Fe-2S]2+ cluster of FNR is labile to superoxide both in vitro and in vivo. This lability may explain the absence of the [2Fe-2S]2+ cluster form of FNR under aerobic growth conditions.

Techniques for studying the oxygen-sensitive transcription factor FNR from Escherichia coli.

A large variety of techniques can be adapted for use with oxygen-sensitive samples. The growth of cells and in vivo analyses, as well as protein purification and in vitro assays, can be executed either by performing necessary steps in anaerobic environments (ranging from simple closed containers to the anaerobic chamber) or by circumventing the need for anaerobiosis with the use of oxygen-resistant protein variants.

Dissociation in adolescent girls with anorexia: relationship to comorbid psychopathology.

This study investigated the relationship between dissociation and psychological symptoms in adolescent girls with anorexia. First, the psychometric properties of the Adolescent Dissociative Experiences Scale (A-DES) were examined using data from 181 nonclinical adolescent boys and girls. Thereafter, A-DES scores and correlations with a range of psychological symptoms were compared across 20 girls with anorexia, 19 mixed clinical girls, and 86 nonclinical girls. The A-DES had a one-factor structure and good psychometric characteristics. Dissociation scores were significantly correlated with level of symptomatology for all groups. Although the group with anorexia did not have significantly higher dissociation scores than the other two groups, dissociation in the anorexic girls was related to psychopathology in a distinct way. Adolescent girls with anorexia appear to use dissociation specifically to avoid processing angry affect with an interpersonal basis, although it is also related to their use of somatization, and obsessive-compulsive features.