A Bayesian approach to correct for unmeasured or semi-unmeasured confounding in survival data using multiple validation data sets

Purpose: The existence of unmeasured confounding can clearly undermine the validity of an observational study. Methods of conducting sensitivity analyses to evaluate the impact of unmeasured confounding are well established. However, application of such methods to survival data (“time-to-event” outcomes) have received little attention in the literature. The purpose of this study is to propose a novel Bayesian method to account for unmeasured confounding for survival data.   Methods: The Bayesian method is proposed under an assumption that the supplementary information on unmeasured confounding in the form of internal validation data, external validation data or expert elicited prior distributions is available. The method for incorporating such information to Cox proportional hazard model is described.  Simulation studies are performed based on the recently published instrumental variable method to assess the impact of unmeasured confounding and to illustrate the improvement of the proposed method over the naïve model which ignores unmeasured confounding.   Results: Simulation studies illustrate the impact of ignoring the unmeasured confounding and the effectiveness of our Bayesian approach. The corrected model had significantly less bias and coverage of 95% intervals much closer to nominal.   Conclusion: The proposed Bayesian method provides a useful and flexible tool in incorporating different types of supplemental information on unmeasured confounding to adjust the treatment estimates when the outcome is survival data.  It out-performed the naïve model in simulation studies based on a real world study. &nbsp

Earliest archaeological evidence of persistent hominin carnivory

The emergence of lithic technology by ~2.6 million years ago (Ma) is often interpreted as a correlate of increasingly recurrent hominin acquisition and consumption of animal remains. Associated faunal evidence, however, is poorly preserved prior to ~1.8 Ma, limiting our understanding of early archaeological (Oldowan) hominin carnivory. Here, we detail three large well-preserved zooarchaeological assemblages from Kanjera South, Kenya. The assemblages date to ~2.0 Ma, pre-dating all previously published archaeofaunas of appreciable size. At Kanjera, there is clear evidence that Oldowan hominins acquired and processed numerous, relatively complete, small ungulate carcasses. Moreover, they had at least occasional access to the fleshed remains of larger, wildebeest-sized animals. The overall record of hominin activities is consistent through the stratified sequence ??? spanning hundreds to thousands of years ??? and provides the earliest archaeological evidence of sustained hominin involvement with fleshed animal remains (i.e., persistent carnivory), a foraging adaptation central to many models of hominin evolution.This research was supported by funding from the National Science Foundation, Leakey Foundation, Wenner-Gren Foundation, National Geographic Society, The Leverhulme Trust, University of California, Baylor University, and the City University of New York. Additional logistical support was provided by the Smithsonian Institution???s Human Origins Program and the Peter Buck Fund for Human Origins Research, the British Institute in Eastern Africa, and the National Museums of Kenya. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Incoherent non-Fermi liquid scattering in a Kondo lattice

One of the most notorious non-Fermi liquid properties of both archetypal heavy-fermion systems [1-4] and the high-Tc copper oxide superconductors [5] is an electrical resistivity that evolves linearly with temperature, T. In the heavy-fermion superconductor CeCoIn5 [5], this linear behaviour was one of the first indications of the presence of a zero-temperature instability, or quantum critical point. Here, we report the observation of a unique control parameter of T-linear scattering in CeCoIn5, found through systematic chemical substitutions of both magnetic and non-magnetic rare-earth, R, ions into the Ce sub-lattice. We find that the evolution of inelastic scattering in Ce1-xRxCoIn5 is strongly dependent on the f-electron configuration of the R ion, whereas two other key properties -- Cooper-pair breaking and Kondo-lattice coherence -- are not. Thus, T-linear resistivity in CeCoIn5 is intimately related to the nature of incoherent scattering centers in the Kondo lattice, which provides insight into the anomalous scattering rate synonymous with quantum criticality [7].Comment: 4 pages, 3 figures (published version

How to select a chiropractor for the management of athletic conditions

<p>Abstract</p> <p>Background</p> <p>Chiropractors are an integral part of the management of musculoskeletal injuries. A considerable communication gap between the chiropractic and medical professions exists. Subsequently referring allopathic practitioners lack confidence in picking a chiropractic practitioner with appropriate management strategies to adequately resolve sporting injuries. Subsequently, the question is often raised: "how do you find a good chiropractor?".</p> <p>Discussion</p> <p>Best practice guidelines are increasingly suggesting that musculoskeletal injuries should be managed with multimodal active and passive care strategies. Broadly speaking chiropractors may be subdivided into "modern multimodal" or "classical" (unimodal) in nature. The modern multimodal practitioner is better suited to managing sporting injuries by incorporating passive and active care management strategies to address three important phases of care in the continuum of injury from the acute inflammation/pain phase to the chronic/rehabilitation phase to the injury prevention phase. In contrast, the unimodal, manipulation only and typically spine only approach of the classical practitioner seems less suited to the challenges of the injured athlete. Identifying what part of the philosophical management spectrum a chiropractor falls is important as it is clearly not easily evident in most published material such as Yellow Pages advertisements.</p> <p>Summary</p> <p>Identifying a chiropractic practitioner who uses multimodal treatment of adequate duration, who incorporates active and passive components of therapy including exercise prescription whilst using medical terminology and diagnosis without mandatory x-rays or predetermined treatment schedules or prepaid contracts of care will likely result in selection of a chiropractor with the approach and philosophy suited to appropriately managing athletic conditions. Sporting organizations and associations should consider using similar criteria as a minimum standard to allow participation in health care team selections.</p

How can chiropractic become a respected mainstream profession? The example of podiatry

<p>Abstract</p> <p>Background</p> <p>The chiropractic profession has succeeded to remain in existence for over 110 years despite the fact that many other professions which had their start at around the same time as chiropractic have disappeared. Despite chiropractic's longevity, the profession has not succeeded in establishing cultural authority and respect within mainstream society, and its market share is dwindling. In the meantime, the podiatric medical profession, during approximately the same time period, has been far more successful in developing itself into a respected profession that is well integrated into mainstream health care and society.</p> <p>Objective</p> <p>To present a perspective on the current state of the chiropractic profession and to make recommendations as to how the profession can look to the podiatric medical profession as a model for how a non-allopathic healthcare profession can establish mainstream integration and cultural authority.</p> <p>Discussion</p> <p>There are several key areas in which the podiatric medical profession has succeeded and in which the chiropractic profession has not. The authors contend that it is in these key areas that changes must be made in order for our profession to overcome its shrinking market share and its present low status amongst healthcare professions. These areas include public health, education, identity and professionalism.</p> <p>Conclusion</p> <p>The chiropractic profession has great promise in terms of its potential contribution to society and the potential for its members to realize the benefits that come from being involved in a mainstream, respected and highly utilized professional group. However, there are several changes that must be made within the profession if it is going to fulfill this promise. Several lessons can be learned from the podiatric medical profession in this effort.</p

Development of a Halotolerant Community in the St. Lucia Estuary (South Africa) during a Hypersaline Phase

Background: The St. Lucia Estuary, Africa’s largest estuarine lake, is currently experiencing unprecedented freshwater deprivation which has resulted in a northward gradient of drought effects, with hypersaline conditions in its northern lakes. Methodology/Principal Findings: This study documents the changes that occurred in the biotic communities at False Bay from May 2010 to June 2011, in order to better understand ecosystem functioning in hypersaline habitats. Few zooplankton taxa were able to withstand the harsh environmental conditions during 2010. These were the flatworm Macrostomum sp., the harpacticoid copepod Cletocamptus confluens, the cyclopoid copepod Apocyclops cf. dengizicus and the ciliate Fabrea cf. salina. In addition to their exceptional salinity tolerance, they were involved in a remarkably simple food web. In June 2009, a bloom of an orange-pigmented cyanobacterium (Cyanothece sp.) was recorded in False Bay and persisted uninterruptedly for 18 months. Stable isotope analysis suggests that this cyanobacterium was the main prey item of F. cf. salina. This ciliate was then consumed by A. cf. dengizicus, which in turn was presumably consumed by flamingos as they flocked in the area when the copepods attained swarming densities. On the shore, cyanobacteria mats contributed to a population explosion of the staphylinid beetle Bledius pilicollis. Although zooplankton disappeared once salinities exceeded 130, many taxa are capable of producing spores or resting cysts to bridge harsh periods. The hypersaline community was disrupted by heavy summer rains in 2011, which alleviated drought conditions and resulted in a sharp increase in zooplankton stock an

Protection in Macaques Immunized with HIV-1 Candidate Vaccines Can Be Predicted Using the Kinetics of Their Neutralizing Antibodies

A vaccine is needed to control the spread of human immunodeficiency virus type 1 (HIV-1). An in vitro assay that can predict the protection induced by a vaccine would facilitate the development of such a vaccine. A potential candidate would be an assay to quantify neutralization of HIV-1.We have used sera from rhesus macaques that have been immunized with HIV candidate vaccines and subsequently challenged with simian human immunodeficiency virus (SHIV). We compared neutralization assays with different formats. In experiments with the standardized and validated TZMbl assay, neutralizing antibody titers against homologous SHIV(SF162P4) pseudovirus gave a variable correlation with reductions in plasma viremia levels. The target cells used in the assays are not just passive indicators of virus infection but are actively involved in the neutralization process. When replicating virus was used with GHOST cell assays, events during the absorption phase, as well as the incubation phase, determine the level of neutralization. Sera that are associated with protection have properties that are closest to the traditional concept of neutralization: the concentration of antibody present during the absorption phase has no effect on the inactivation rate. In GHOST assays, events during the absorption phase may inactivate a fixed number, rather than a proportion, of virus so that while complete neutralization can be obtained, it can only be found at low doses particularly with isolates that are relatively resistant to neutralization.Two scenarios have the potential to predict protection by neutralizing antibodies at concentrations that can be induced by vaccination: antibodies that have properties close to the traditional concept of neutralization may protect against a range of challenge doses of neutralization sensitive HIV isolates; a window of opportunity also exists for protection against isolates that are more resistant to neutralization but only at low challenge doses

Contribution of Intrinsic Reactivity of the HIV-1 Envelope Glycoproteins to CD4-Independent Infection and Global Inhibitor Sensitivity

Human immunodeficiency virus (HIV-1) enters cells following sequential activation of the high-potential-energy viral envelope glycoprotein trimer by target cell CD4 and coreceptor. HIV-1 variants differ in their requirements for CD4; viruses that can infect coreceptor-expressing cells that lack CD4 have been generated in the laboratory. These CD4-independent HIV-1 variants are sensitive to neutralization by multiple antibodies that recognize different envelope glycoprotein epitopes. The mechanisms underlying CD4 independence, global sensitivity to neutralization and the association between them are still unclear. By studying HIV-1 variants that differ in requirements for CD4, we investigated the contribution of CD4 binding to virus entry. CD4 engagement exposes the coreceptor-binding site and increases the “intrinsic reactivity” of the envelope glycoproteins; intrinsic reactivity describes the propensity of the envelope glycoproteins to negotiate transitions to lower-energy states upon stimulation. Coreceptor-binding site exposure and increased intrinsic reactivity promote formation/exposure of the HR1 coiled coil on the gp41 transmembrane glycoprotein and allow virus entry upon coreceptor binding. Intrinsic reactivity also dictates the global sensitivity of HIV-1 to perturbations such as exposure to cold and the binding of antibodies and small molecules. Accordingly, CD4 independence of HIV-1 was accompanied by increased susceptibility to inactivation by these factors. We investigated the role of intrinsic reactivity in determining the sensitivity of primary HIV-1 isolates to inhibition. Relative to the more common neutralization-resistant (“Tier 2-like”) viruses, globally sensitive (“Tier 1”) viruses exhibited increased intrinsic reactivity, i.e., were inactivated more efficiently by cold exposure or by a given level of antibody binding to the envelope glycoprotein trimer. Virus sensitivity to neutralization was dictated both by the efficiency of inhibitor/antibody binding to the envelope glycoprotein trimer and by envelope glycoprotein reactivity to the inhibitor/antibody binding event. Quantitative differences in intrinsic reactivity contribute to HIV-1 strain variability in global susceptibility to neutralization and explain the long-observed relationship between increased inhibitor sensitivity and decreased entry requirements for target cell CD4