8 research outputs found
Trials, Tricks and Transparency: How Disclosure Rules Affect Clinical Knowledge
No full textScandals of selective reporting of clinical trial results by pharmaceutical firms have underlined the need for more transparency in clinical trials. We provide a theoretical framework which reproduces incentives for selective reporting and yields three key implications concerning regulation. First, a compulsory clinical trial registry complemented through a voluntary clinical trial results database can implement full transparency (the existence of all trials as well as their results is known). Second, full transparency comes at a price. It has a deterrence effect on the incentives to conduct clinical trials, as it reduces the firms' gains from trials. Third, in principle, a voluntary clinical trial results database without a compulsory registry is a superior regulatory tool; but we provide some qualified support for additional compulsory registries when medical decision-makers cannot anticipate correctly the drug companies' decisions whether to conduct trials.pharmaceutical firms, strategic information transmission, clinical trials, registries, results databases, scientific knowledge.
The need for open source software in machine learning
No full textOpen source tools have recently reached a level of maturity which makes them suitable for building large-scale real-world systems. At the same time, the field of machine learning has developed a large body of powerful learning algorithms for diverse applications. However, the true potential of these methods is not used, since existing implementations are not openly shared, resulting in software with low usability, and weak interoperability. We argue that this situation can be significantly improved by increasing incentives for researchers to publish their software under an open source model. Additionally, we outline the problems authors are faced with when trying to publish algorithmic implementations of machine learning methods. We believe that a resource of peer reviewed software accompanied by short articles would be highly valuable to both the machine learning and the general scientific community
Is more better? Do statewide increases in trauma centers reduce injury-related mortality?
No full textOBJECTIVES: Trauma centers (TCs) are inconsistently distributed throughout the US. It is unclear if new TCs improve care and decrease mortality. We tested the hypothesis that increases in TCs are associated with decreases in injury-related mortality (IRM) at the state level. METHODS: We used data from the American Trauma Society to geolocate every state-designated or ACS-verified TC in all 50 states and DC from 2014–2018. These data were merged with publicly available IRM data from the Centers for Disease Control and Prevention. We used geographic information systems methods to map and study the relationships between TC locations and state-level IRM over time. Regression analysis, accounting for state-level fixed effects, was used to calculate the effect of total statewide number of TC on IRM and year-to-year changes in statewide TC with the IRM (shown as deaths per additional TC per 100,000 population, p-value). RESULTS: Nationwide between 2014 and 2018, the number of TC increased from 2039 to 2153. IRM also increased over time. There was notable interstate variation, from 1 to 284 TCs. Four patterns in statewide TC changes emerged: static (12), increased (29), decreased (5), or variable (4). Of states with TC increases, 26 (90%) had increased IRM between 2014 and 2017, while the remaining 3 saw a decline. Regression analysis demonstrated that having more trauma centers in a state was associated with a significantly higher IRM rate (0.38, p=0.03); adding new trauma centers was not associated with changes in IRM (0.02, p=0.8). CONCLUSION: Having more TC and increasing the number of TC within a state is not associated with decreases in state-level IRM. In this case, more is not better. However, more work is needed identify the optimal number and location of trauma centers to improve IRM. LEVEL OF EVIDENCE: III, Epidemiologi
Characterizing determinants of BK Polyomavirus-specific immune response
No full textBK polyomavirus (BKPyV) is one of now 13 human polyomavirus (HPyV) species detected in humans. BKPyV is only known to infect humans and seroprevalence rates of more than 90% have been reported in adult populations around the world. Following primary infection, BKPyV persists in the renourinary tract without causing any disease as evidenced by urinary shedding in 5% - 10% of healthy immunocompetent blood donors.
In immunocompromised persons, however, BKPyV can cause significant diseases whereby uncontrolled high-level replication may lead to organ invasive pathologies in kidneys, bladder, lungs, vasculature, and the central nervous system. The most consistently found diseases are BKPyV-associated hemorrhagic cystitis (BKPyVHC) in 5%-20% allogeneic hematopoietic stem cells transplant patients, and BKPyV-associated nephropathy (BKPyVAN) in 1%-15% of kidney transplant patients. BKPyVHC is highly symptomatic with pain, anemic bleeding, and increased mortality. BKPyVAN is asymptomatic except for progressive renal failure and premature return to dialysis. Both entities are characterized by high-level viral replication i.e. with urine BKPyV loads of 8-10 log10 Geq/mL, plasma BKPyV loads often above 4 log10 Geq/mL, and an allogeneic constellation between the virus-infected host cell and the available T-cell effectors. Despite these similarities, the clinical manifestations are strikingly different suggesting relevant, but experimentally undefined differences in pathogenesis. Thus, BKPyVHC typically occurs within 4 weeks after allogeneic HSCT and is confined to the bladder, and typically without kidney involvement. By contrast, BKPyVAN is diagnosed around 3-6 months after kidney transplantation and confined to the kidney allograft without causing cystitis. Although high-level BKPyV replication should be formally amenable to antiviral drug treatment, no effective and BKPyV-specific antiviral therapy is currently available. Therefore, a better understanding of the immune alteration in both diseases has been deemed essential to identify patients at risk and to develop prophylactic, preemptive and therapeutic strategies.
The currently recommended strategy for BKPyVAN is to screen kidney transplant patients for BKPyV replication and to promptly reduce immunosuppressive therapy in those with significant replication to facilitate mounting of BKPyV-specific T cell responses and thereby preventing progression to disease. This manoeuver has been linked to expanding BKPyV-specific T cell responses in the peripheral blood of kidney transplant patients. However, this approach may place patients at risk for acute rejection episodes that predispose equally well to premature kidney transplant failure. Although the clinical feasibility of reducing immunosuppression and curtailing BKPyV replication has been shown to be effective in prospective cohort studies for many, but not all of kidney transplant patients, this approach has not been possible in allogeneic HSCT patients because of concurrent or imminent graft-versus host disease. Thus, there are significant gaps in the current understanding of the BKPyV– host interaction in the normal host and in the allogeneic setting, which need to be investigated for a more effective and safer management of these significant viral complications.
In this thesis, the interaction of BKPyV and the immune response has been approached from two different angles. In the first project, potential mechanisms of BKPyV immune evasion were studied. Here, we focused on a small accessory protein called agnoprotein encoded as a leader protein in the late viral early region (LVGR). Although HPyV genomes overall show a very similar genome organization, agnoproteins are only found in the genomes of BKPyV and JCPyV that have a kidney tropisms, but not in any of the other 11 presumably non-renotropic HPyVs. We hypothesized that agnoprotein could play a role in immune evasion by downregulating HLA expression. The effects of agnoprotein were studied on HLA class I and II expression in vitro by flow cytometry following transfection of primary human renal tubular epithelial cells, which are the viral target of BKPyV-associated nephropathy. In addition, transfected human UTA-6 cells were studied as well as UTA-6 cells bearing a tetracycline-regulated agnoprotein. As control, the effects were compared with the ICP47 protein of Herpes simplex virus-1, which has been previously reported to effectively down-regulate HLA class I. Although both viral proteins share some similarities at the protein level, our results showed that BKPyV agnoprotein did not down-regulate HLA class I or class II molecules. Also, there was not inhibitory effect on the increase of HLA-class I or class-II surface expression following exposure to interferon-. By contrast, ICP47 reduced HLA class I surface expression, but not class II. We also evaluated effects of agnoprotein on virus epitope-specific T-cell killing by 51Chromium release assay, however no interference could be observed. We concluded that agnoprotein did not contribute to these types of HLA-dependent immune evasion processes. However, further investigations are needed to understand if agnoprotein could contribute to viral immune escape by other mechanisms.
In the second project, we aimed at better characterizing BKPyV-specific CD8 T cell immunity targeting epitopes encoded in the early viral gene region (EVGR). Selected coding sequences of the BKPyV EVGR were submitted to two web-based computer algorithms (SYFPEITHI, IEDB) in order to predict immunodominant 9mer epitopes presented by 14 frequent HLA-class I molecules. For an experimental confirmation, 97 different 9mer epitopes were chemically synthesized and tested in 42 healthy individuals. A total of 39 epitopes could be confirmed by interferon- ELISpot assay in at least 30% of healthy individuals. Interestingly, most of the 9mer epitopes appeared to cluster in short amino acid stretches, and some 9mer could be presented by more than one HLA class I allele as expected for immunodominant domains. HLA-specific presentation was demonstrated by 9mer- MHC-I streptamers for 21/39 (54%) epitopes. The 9mer dependent T-cell killing by 51Chromium release assay and the CD107a surface detection indicated that the 9mer epitopes could be recognized by cytotoxic T-cells. Moving to a clinically relevant situation, 13 9mer epitopes could be validated in 19 kidney transplant patients protected from, or recovering from, BKPyV viremia. The results suggest that, pending further corroboration in larger patient populations, novel 9mer epitopes can be identified, which are associated with CD8 T cell control of BKPyV replication. Thus the identified immunodominant 9mer T-cell epitopes could be further developed for clinical assays to better predict the risk and the recovery of BKPyV diseases, help guiding immunosuppression reduction, and to develop specific adoptive T-cell therapy or vaccine responses to prevent or treat BKPyV-associated disease
Can educational videos reduce opioid consumption in trauma inpatients? A cluster-randomized pilot study
No full textAdditional file 1: of Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge
No full textFigure S1. Characterization of microglial cultures, cell toxicity of DMF, and enriched astrocyte cultures. (PDF 134Â kb
A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury
No full textLos derechos de propiedad intelectual y la protección a la libre competencia. Una discusión sin superar: los patent thickets en el mercado farmacéutico
No full textThe exercise of Intellectual Property Rights, particularly the pharmaceutical industry market, has given rise to a discussion about its anti-competitive effects. This discussion has brought those who suggest that Intellectual Property and Antitrust rules are contradictory regimes together as well as those who consider it an illusory conflict. Although the prevailing view today is that this is an apparent conflict and, conversely share common purposes, patenting practices in the pharmaceutical industry keep the issue alive. One such alleged practice is the creation of patent thickets. This paper aims to address the vicissitudes of their definition, their relationship with other concepts such as strategic patenting and, finally, the case law on the subject, making visible the issues that this problem is raising.El ejercicio de derechos de propiedad intelectual, particularmente en industrias como la farmacéutica, ha suscitado una discusión sobre los efectos anticompetitivos que pueden derivarse de las prerrogativas otorgadas por las patentes. Esta discusión ha logrado reunir a quienes sugieren que las normas de propiedad intelectual y las de protección a la competencia son regímenes antinómicos, como a quienes estiman que se trata de un conflicto aparente. Aun cuando en la actualidad la postura preponderante es que se trata de un conflicto aparente y que, por el contrario, son regímenes que persiguen objetivos compatibles, las prácticas de patentamiento que se presentan en industrias como la farmacéutica mantienen vigente esta discusión. Una de estas prácticas presuntamente anticompetitiva a juicio de algunos son los patent thickets o marañas de patentes. El presente escrito pretende abordar las vicisitudes sobre su definición, su relación con otros conceptos, como el patentamiento estratégico, y los pronunciamientos jurisprudenciales al respecto, haciendo visibles las aristas que esta problemática plantea de cara a la compatibilidad o incompatibilidad de los regímenes de propiedad intelectual y protección a la libre competencia
