52 research outputs found
Injunctive Relief in Patent Infringement Cases: Should Courts Apply a Rebuttable Presumption of Irreparable Harm After eBay Inc. v. Mercexchange, L.L.C.?
Implementing an innovative consent form: the PREDICT experience
<p>Abstract</p> <p>Background</p> <p>In the setting of coronary angiography, generic consent forms permit highly variable communication between patients and physicians. Even with the existence of multiple risk models, clinicians have been unable to readily access them and thus provide patients with vague estimations regarding risks of the procedure.</p> <p>Methods</p> <p>We created a web-based vehicle, PREDICT, for embedding patient-specific estimates of risk from validated multivariable models into individualized consent documents at the point-of-care. Beginning August 2006, outpatients undergoing coronary angiography at the Mid America Heart Institute received individualized consent documents generated by PREDICT. In February 2007 this approach was expanded to all patients undergoing coronary angiography within the four Kansas City hospitals of the Saint Luke's Health System. Qualitative research methods were used to identify the implementation challenges and successes with incorporating PREDICT-enhanced consent documents into routine clinical care from multiple perspectives: administration, information systems, nurses, physicians, and patients.</p> <p>Results</p> <p>Most clinicians found usefulness in the tool (providing clarity and educational value for patients) and satisfaction with the altered processes of care, although a few cardiologists cited delayed patient flow and excessive patient questions. The responses from administration and patients were uniformly positive. The key barrier was related to informatics.</p> <p>Conclusion</p> <p>This preliminary experience suggests that successful change in clinical processes and organizational culture can be accomplished through multidisciplinary collaboration. A randomized trial of PREDICT consent, leveraging the accumulated knowledge from this first experience, is needed to further evaluate its impact on medical decision-making, patient compliance, and clinical outcomes.</p
Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.
BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (â„18 years) with S aureus bacteraemia who had received â€96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment
Testing a global standard for quantifying species recovery and assessing conservation impact.
Recognizing the imperative to evaluate species recovery and conservation impact, in 2012 the International Union for Conservation of Nature (IUCN) called for development of a "Green List of Species" (now the IUCN Green Status of Species). A draft Green Status framework for assessing species' progress toward recovery, published in 2018, proposed 2 separate but interlinked components: a standardized method (i.e., measurement against benchmarks of species' viability, functionality, and preimpact distribution) to determine current species recovery status (herein species recovery score) and application of that method to estimate past and potential future impacts of conservation based on 4 metrics (conservation legacy, conservation dependence, conservation gain, and recovery potential). We tested the framework with 181 species representing diverse taxa, life histories, biomes, and IUCN Red List categories (extinction risk). Based on the observed distribution of species' recovery scores, we propose the following species recovery categories: fully recovered, slightly depleted, moderately depleted, largely depleted, critically depleted, extinct in the wild, and indeterminate. Fifty-nine percent of tested species were considered largely or critically depleted. Although there was a negative relationship between extinction risk and species recovery score, variation was considerable. Some species in lower risk categories were assessed as farther from recovery than those at higher risk. This emphasizes that species recovery is conceptually different from extinction risk and reinforces the utility of the IUCN Green Status of Species to more fully understand species conservation status. Although extinction risk did not predict conservation legacy, conservation dependence, or conservation gain, it was positively correlated with recovery potential. Only 1.7% of tested species were categorized as zero across all 4 of these conservation impact metrics, indicating that conservation has, or will, play a role in improving or maintaining species status for the vast majority of these species. Based on our results, we devised an updated assessment framework that introduces the option of using a dynamic baseline to assess future impacts of conservation over the short term to avoid misleading results which were generated in a small number of cases, and redefines short term as 10 years to better align with conservation planning. These changes are reflected in the IUCN Green Status of Species Standard
Injunctive Relief in Patent Infringement Cases: Should Courts Apply a Rebuttable Presumption of Irreparable Harm After eBay Inc. v. Mercexchange, L.L.C.?
A new high-prevalence LW antigen detected by an antibody in an Indigenous Australian homozygous for LW*A c.309C>A variant
Background and Objectives: The LW gene encodes the LW glycoprotein that carries the antigens of the LW blood group system. LW antigens are distinct from D antigen, however, they are phenotypically related and anti-LW antibodies are often mistaken as anti-D. An antibody was detected in an Australian patient of Aboriginal descent who consistently typed as LW(a+bâ). This study aimed to describe the antibody recognizing a high-prevalence antigen on the LW glycoprotein. Study Design and Methods: Samples from the patient and her four siblings were investigated. DNA was genotyped by single nucleotide polymorphism (SNP)-microarray and massively parallel sequencing (MPS) platforms. Red blood cells (RBCs) were phenotyped using standard haemagglutination techniques. Antibody investigations were performed using a panel of phenotyped RBCs from adults and cord blood cells. Results: SNP-microarray and MPS genotyped all family members as LW*A/A, (c.299A), predicting LW(a+bâ). In addition, a novel LW*A c.309C>A single nucleotide variant was detected in all family members. The patient and one of her siblings (M4) were LW c.309C>A homozygous. Antibody from the patient reacted positive to all reagent panel RBCs and cord blood cells but negative with RBCs from LW(aâbâ), Rhnull and sibling M4. Antibody failed to react with RBCs treated with dithiothreitol. Conclusion: Antibody detected in the patient recognized a novel high-prevalence antigen, LWEM, in the LW blood group system. LWEM-negative patients who developed anti-LWEM can be safely transfused with D+ RBCs, however, Dâ is preferred. Accurate antibody identification can help better manage allocation of blood products especially when Dâ RBCs are in short supply.</p
Niemann-Pick Type C1 I1061T Mutant Encodes a Functional Protein That Is Selected for Endoplasmic Reticulum-associated Degradation Due to Protein Misfolding*
Over 200 disease-causing mutations have been identified in the
NPC1 gene. The most prevalent mutation,
NPC1I1061T, is predicted to lie within the cysteine-rich
luminal domain and is associated with the classic juvenile-onset phenotype of
Niemann-Pick type C disease. To gain insight into the molecular mechanism by
which the NPC1I1061T mutation causes disease, we examined
expression of the mutant protein in human fibroblasts homozygous for the
NPC1I1061T mutation. Despite similar NPC1 mRNA
levels between wild type and NPC1I1061T fibroblasts, NPC1
protein levels are decreased by 85% in NPC1I1061T cells.
Metabolic labeling studies demonstrate that unlike wild type protein, which
undergoes a glycosylation pattern shift from Endo H-sensitive to Endo
H-resistant species, NPC1I1061T protein remains almost exclusively
Endo H-sensitive and exhibits a reduced half-life
(tœ 6.5 h) versus wild type Endo
H-resistant species (tœ 42 h). Treatment with
chemical chaperones, growth at permissive temperature, or inhibition of
proteasomal degradation increases NPC1I1061T protein levels,
indicating that the mutant protein is likely targeted for endoplasmic
reticulum-associated degradation (ERAD) due to protein misfolding.
Overexpression of NPC1I1061T in NPC1-deficient cells
results in late endosomal localization of the mutant protein and
complementation of the NPC mutant phenotype, likely due to a small
proportion of the nascent NPC1I1061T protein that is able to fold
correctly and escape the endoplasmic reticulum quality control checkpoints.
Our findings provide the first description of an endoplasmic reticulum
trafficking defect as a mechanism for human NPC disease, shedding light on the
mechanism by which the NPC1I1061T mutation causes disease
and suggesting novel approaches to treat NPC disease caused by the
NPC1I1061T mutation
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