Designing multi-arm multi-stage clinical trials using a risk-benefit criterion for treatment selection

Multi-arm clinical trials that compare several active treatments to a common control have been proposed as an efficient means of making an informed decision about which of several treatments should be evaluated further in a confirmatory study. Additional efficiency is gained by incorporating interim analyses and in particular, seamless Phase II/III designs have been the focus of recent research. Common to much of this work is the constraint that selection and formal testing should be based on a single efficacy endpoint, despite the fact that in practice, safety considerations will often play a central role in determining selection decisions. Here we develop a multi-arm multistage design for a trial with an efficacy and safety endpoint. The safety endpoint is explicitly considered in the formulation of the problem, selection of experimental arm and hypothesis testing. The design extends group-sequential ideas and considers the scenario where a minimal safety requirement is to be fulfilled and the treatment yielding the best combined safety and efficacy trade-off satisfying this constraint is selected for further testing. The treatment with the best trade-off is selected at the first interim analysis while the whole trial is allowed to comprise of J analyses. We show that the design controls the familywise error rate in the strong sense and illustrate the method through an example and simulation. We find that the design is robust to misspecification of the correlation between the endpoints and requires similar numbers of subjects to a trial based on efficacy alone for moderately correlated endpoints

"The Frailest Leaves of Me": A Study of the Text and Music for Whitman\u27s "To What You Said"

Examines in depth a little-known Whitman poem, "To What You Said," examining the manuscript of the poem and offering "a re-examination of crucial biographical events, an extensive comparative textual analysis" and a "response to the subtleties revealed when the written word is sung" in the musical setting of the poem composed by Leonard Bernstein; written by the world-renowned baritone and his personal assistant

Extrapolation of efficacy and other data to support the development of new medicines for children:a systematic review of methods

Objective When developing new medicines for children, the potential to extrapolate from adult data to reduce the experimental burden in children is well recognised. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. We reviewed the literature to identify statistical methods that could be used to optimise extrapolations in paediatric drug development programmes. Methods Web of Science was used to identify papers proposing methods relevant for using data from a ‘source population’ to support inferences for a ‘target population’. Four key areas of methods development were targeted: paediatric clinical trials, trials extrapolating efficacy across ethnic groups or geographic regions, the use of historical data in contemporary clinical trials and using short-term endpoints to support inferences about long-term outcomes. Results Searches identified 626 papers of which 52 met our inclusion criteria. From these we identified 102 methods comprising 58 Bayesian and 44 frequentist approaches. Most Bayesian methods (n = 54) sought to use existing data in the source population to create an informative prior distribution for a future clinical trial. Of these, 46 allowed the source data to be down-weighted to account for potential differences between populations. Bayesian and frequentist versions of methods were found for assessing whether key parameters of source and target populations are commensurate (n = 34). Fourteen frequentist methods synthesised data from different populations using a joint model or a weighted test statistic. Conclusions Several methods were identified as potentially applicable to paediatric drug development. Methods which can accommodate a heterogeneous target population and which allow data from a source population to be down-weighted are preferred. Methods assessing the commensurability of parameters may be used to determine whether it is appropriate to pool data across age groups to estimate treatment effects

Brain connectivity Patterns Dissociate action of specific Acupressure Treatments in Fatigued Breast cancer survivors

Funding This work was supported by grants R01 CA151445 and 2UL1 TR000433-06 from the National Institutes of Health. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We thank the expert assistance by Dr. Bradley Foerster in acquisition of 1H-MRS and fMRI data.Peer reviewedPublisher PD

El valor del acompañamiento

La amistad y el acompañamiento compasivo para con los más vulnerables es un tipo de servicio humanitario importante que prioriza el acompañamiento personal

No Biological Evidence of XMRV Infection in Cervical Smears from HIV/ HPV Positive and Negative Kenyan Women

BACKGROUND: XMRV (xenotropic murine leukaemia virus-related virus) is a gammaretrovirus first discovered in human prostate carcinomas and later linked to chronic fatigue syndrome (CFS). Emerging conflicting data and lack of reproducibility of results within the scientific community has now led to the association of XMRV with CFS being discounted. Indeed the case for an involvement with any human disease has been questioned with the suggestion that XMRV is a laboratory generated recombinant virus. The fact that not all published positive findings can be easily explained as contamination artefacts coupled with the observation that XMRV may have a sexually transmitted mode of infectivity and can be infectious for primates, where it preferential resides in cells of the reproductive tract, prompted us to look for evidence of XMRV in the cervical cells of a cohort of Kenyan women both with and without pre-existing HIV/HPV infections. RESULTS: Using a highly sensitive and selective triplex PCR approach we analysed DNA from the liquid based cytology (LBC) cervical smears of 224 Kenyan women. There was no evidence of XMRV expression in any of the sample population irrespective of HPV and/or HIV status. CONCLUSIONS: The data presented show no indication of XMRV infection in any of the cervical samples screened in this study. Approximately 50% of the women were HIV positive but this did not influence the findings signifying that XMRV does not act as an opportunistic infection in this cohort nor is it related to HPV status. Our results therefore support the findings that XMRV is confined to the laboratory and does not currently represent an infectious agent for humans, with a cautionary adage that such potential zoonotic viruses should be carefully monitored in the future

No Pay, No Profession? Why Aren’t Educational Expedition Leaders Professional?

Professionalism is a social construct with multiple definitions across a variety of occupations. Meaning, it is concept that has been created and widely accepted by society; the central point of inquiry for this research being, does the educational expedition sector have a definition of professionalism? Briefly, the educational expedition sector is a subsect of the outdoor industry which specialises in the delivery of experiential education and education in remote wilderness environments. The predominant understanding of professionalism seemingly refers to the accepted behaviours within an occupation. Previous research has often relied on the examination of these behaviours along with characteristics and attributes demonstrated by the individual and accepted by the wider occupational field. Consequently, researchers typically develop a list of what they interpret to be professional while alluding to three common conceptions: 1. a preference for professionalism to be founded in traditionalism; 2. ambition for professional status enforces a power differential among the occupations at varying sociological levels; 3. how professional identities are affected by the internalisation and an unconscious assimilation to professional ideals enforced by an occupation. However, though the lists and literature share some commonalities, there is no fixed definition of professionalism. Further, the contextualised investigation of professionalism as a sociological phenomenon is more commonly conducted within more traditional professions (medicine, law, accountancy, education etc.) as opposed to occupations which may strive for similar recognition and status. Therefore, through phenomenological principles this thesis aims to achieve three objectives with the purpose of informing the current understanding of professionalism and professional practice within the educational expedition sector. These are: 1. to examine the interpretations of professionalism adopted by experienced educational expedition leaders who have worked for the British ExploringSociety (BES) as they have the potential to influence the definition of the outdoor professional; 2. to explore competing definitions of professionalism taken from established professions, thus informing differing interpretations of professional identity; 3. to develop a learning model that demonstrates a strategy informing notions of professionalism that could be accepted within a scheme of Higher Education (HE). By analysing competing interpretations from established professions, it is hoped that this research project may begin to assist the educational expedition sector to move away from traditionalised methods of professionalism and begin modernising its commonly held principles. That is, to take a step towards becoming known as a profession, and not pejoratively as an ‘industry’, or ‘sector’, or trade. To achieve the aims a qualitative methodological approach was used. Data had been collected via field observations, focus groups, and semi-structured interviews. Due to the Covid-19 pandemic, expedition-based field observations could not be conducted, yet the premise and potential influence of this method is still discussed. Contrary to previous research, this study refrained from developing a strict definition of professionalism, as might be derived from the data collected. Instead, it concentrated on exploring concepts pertinent to its understanding within the educational expedition sector. The key findings were: 1. The existence and potential implications of the hidden curriculum on aspiring leaders; 2. The effects of an implicit struggle for status, prestige and sociological hierarchy enforced by meritocracy; 3. The development of a learning model illustrating the socialisation of aspiring leaders, and the effects of the aforementioned common conceptions on their professional identities

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis