Researchers have increasingly turned to online convenience samples as sources of survey responses that are easy and inexpensive to collect. As reliance on these sources has grown, so too have ...concerns about the use of convenience samples in general and Amazon’s Mechanical Turk in particular. We distinguish between “external validity” and theoretical relevance, with the latter being the more important justification for any data collection strategy. We explore an alternative source of online convenience samples, the Lucid Fulcrum Exchange, and assess its suitability for online survey experimental research. Our point of departure is the 2012 study by Berinsky, Huber, and Lenz that compares Amazon’s Mechanical Turk to US national probability samples in terms of respondent characteristics and treatment effect estimates. We replicate these same analyses using a large sample of survey responses on the Lucid platform. Our results indicate that demographic and experimental findings on Lucid track well with US national benchmarks, with the exception of experimental treatments that aim to dispel the “death panel” rumor regarding the Affordable Care Act. We conclude that subjects recruited from the Lucid platform constitute a sample that is suitable for evaluating many social scientific theories, and can serve as a drop-in replacement for many scholars currently conducting research on Mechanical Turk or other similar platforms.
For decades, the management of patients with advanced prostate cancer has been hormonal therapy, known as androgen deprivation therapy, which is intended to lower testosterone levels. Further ...incremental progress in the treatment of men with metastatic hormone‐sensitive prostate cancer (mHSPC) has come from the addition of docetaxel or abiraterone acetate to androgen deprivation therapy for more aggressive upfront treatment regimens. Other combinatorial regimens testing the addition of novel therapies currently are in the late stages of development and are expected to further improve the clinical outcomes of these patients. The emergence of new positron emission tomography tracers specifically for prostate cancer, particularly prostate‐specific membrane antigen and fluciclovine, has increased the ability to detect metastatic disease earlier in the course of the disease and has helped to describe a new group of patients with mHSPC and oligometastatic disease. For this group of patients with mHSPC, the authors discuss the existing data with metastasis‐directed therapy and primary tumor‐directed therapy.
Progress in the treatment of men with metastatic hormone‐sensitive prostate cancer has come from the addition of docetaxel or abiraterone acetate to androgen deprivation therapy for more aggressive upfront treatment regimens. Other combinatorial regimens currently are in the late stages of development and are expected to further improve the clinical outcomes of these patients. The emergence of new positron emission tomography tracers has helped to diagnose metastatic hormone‐sensitive prostate cancer with oligometastases, for which the authors discuss the existing data with metastasis‐directed therapy and primary tumor‐directed therapy.
Summary Background Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to ...treat patients with C difficile infection in Europe, Canada, and the USA. Methods In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov , number NCT00468728. Findings Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI −4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI −4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 90·2% of 51) than with vancomycin (33 73·3% of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Interpretation Fidaxomicin could be an alternative treatment for infection with C difficile , with similar efficacy and safety to vancomycin. Funding Optimer Pharmaceuticals.
Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables ...assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital Sequencing™ is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test. Here we report the analytic and clinical validation of the gene panel. Analytic sensitivity down to 0.1% mutant allele fraction is demonstrated via serial dilution studies of known samples. Near-perfect analytic specificity (> 99.9999%) enables complete coverage of many genes without the false positives typically seen with traditional sequencing assays at mutant allele frequencies or fractions below 5%. We compared digital sequencing of plasma-derived cell-free DNA to tissue-based sequencing on 165 consecutive matched samples from five outside centers in patients with stage III-IV solid tumor cancers. Clinical sensitivity of plasma-derived NGS was 85.0%, comparable to 80.7% sensitivity for tissue. The assay success rate on 1,000 consecutive samples in clinical practice was 99.8%. Digital sequencing of plasma-derived DNA is indicated in advanced cancer patients to prevent repeated invasive biopsies when the initial biopsy is inadequate, unobtainable for genomic testing, or uninformative, or when the patient's cancer has progressed despite treatment. Its clinical utility is derived from reduction in the costs, complications and delays associated with invasive tissue biopsies for genomic testing.
Gastric cancer represents one of the leading causes of cancer deaths worldwide. Helicobacter pylori (H. pylori) infection is the strongest risk factor associated with gastric cancer. Due to new ...molecular techniques allowing greater identification of stomach microbes, investigators are beginning to examine the role that bacteria other than H. pylori play in gastric cancer development. Recently, researchers have investigated how the composition of the gastric microbiota varies among individuals with various stages of gastric disease. Specific microbes residing in the stomach have been preferentially associated with gastric cancer patients compared to individuals with a healthy gastric mucosa. Studies conducted on the insulin-gastrin (INS-GAS) transgenic mouse model have provided additional insight into the association between the gastric microbiota and gastric cancer. The purpose of this article is to review the current state of literature on the relationship between the gastric microbiota and gastric cancer based on clinical studies performed to date.
Multidimensional ultrafast spectroscopies are one of the premier tools to investigate condensed phase dynamics of biological, chemical and functional nanomaterial systems. As they reach maturity, the ...variety of frequency domains that can be explored has vastly increased, with experimental techniques capable of correlating excitation and emission frequencies from the terahertz through to the ultraviolet. Some of the most recent innovations also include extreme cross-peak spectroscopies that directly correlate the dynamics of electronic and vibrational states. This review article summarizes the key technological advances that have permitted these recent advances, and the insights gained from new multidimensional spectroscopic probes.
Endothelial cells (ECs), which line blood and lymphatic vessels, are generally described to come from the lateral plate mesoderm despite experimental evidence for a broader source of origin, ...including the paraxial mesoderm (PXM). Current dogma suggests that following specification from mesoderm, local environmental cues establish the distinct molecular and functional characteristics of ECs in different vascular beds. Here we present evidence to challenge this view, showing that lymphatic EC fate is imprinted during transition through the PXM lineage. We show that PXM-derived cells form the lymphatic endothelium of multiple organs and tissues, with a more restricted contribution to blood vessel endothelium. By deleting Prox1 specifically in PXM-derived cells, we show that this lineage is indispensable for lymphatic vessel development. Collectively, our data establish lineage history as a critical determinant of EC specialization, a finding with broad implications for our understanding of vascular development and heterogeneity.
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•Lineage history is a key determinant of endothelial cell specialization•Endothelial cells arising from paraxial mesoderm preferentially form lymphatic vessels•Paraxial-mesoderm-derived endothelial cells are essential for lymphatic development
Following specification from mesoderm, the prevailing view is that local environmental cues control the specialization of endothelial cells in different vessel beds. Stone and Stainier show that lymphatic endothelial cell fate is imprinted much earlier as cells transition through the paraxial mesoderm.
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in ...prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound ...global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.
Summary
Objectives
Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus ...disease 19 (COVID‐19) associated invasive aspergillosis at a single centre in Cologne, Germany.
Methods
A retrospective chart review of all patients with COVID‐19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany.
Results
COVID‐19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS.
Conclusion
Clinicians caring for patients with ARDS due to COVID‐19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co‐infection.
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