Sequential Monte Carlo with transformations.

This paper examines methodology for performing Bayesian inference sequentially on a sequence of posteriors on spaces of different dimensions. For this, we use sequential Monte Carlo samplers, introducing the innovation of using deterministic transformations to move particles effectively between target distributions with different dimensions. This approach, combined with adaptive methods, yields an extremely flexible and general algorithm for Bayesian model comparison that is suitable for use in applications where the acceptance rate in reversible jump Markov chain Monte Carlo is low. We use this approach on model comparison for mixture models, and for inferring coalescent trees sequentially, as data arrives.

Overreliance on Cost Reduction as a Featured Element of Sensor Design.

In this Perspective, we examine the role of cost in sensor design, its meaning within the context of converting academic prototypes into commercial products, and the importance of these issues to clear scientific communication. The possible motivations to consider the cost of a technology, sensor, or assay are both numerous and apparent. However, the idea that the cost of reagents and materials at the laboratory scale will directly translate to the purchase price for a user is inaccurate. While calculating the bill of materials is easy, there are many business considerations that make commercial products entirely different from academic prototypes. With these critical aspects of commercialization considered, academics are often not equipped to predict what the final price of an assay, sensor, or instrument will be to the end user. When used without proper context and accuracy, an overreliance on the phrase "low cost" in the absence of a sufficient discussion of cost weakens the meaning of this popular term and precludes practical scientific advancements. To demonstrate how the relationship between a bill of materials and "expected purchase price" breaks down when considering academic innovations, we discuss pregnancy tests as a case study where an academic bill of materials can lead to both overestimations and underestimations of pricing.

Bayesian inference of ancestral dates on bacterial phylogenetic trees.

The sequencing and comparative analysis of a collection of bacterial genomes from a single species or lineage of interest can lead to key insights into its evolution, ecology or epidemiology. The tool of choice for such a study is often to build a phylogenetic tree, and more specifically when possible a dated phylogeny, in which the dates of all common ancestors are estimated. Here, we propose a new Bayesian methodology to construct dated phylogenies which is specifically designed for bacterial genomics. Unlike previous Bayesian methods aimed at building dated phylogenies, we consider that the phylogenetic relationships between the genomes have been previously evaluated using a standard phylogenetic method, which makes our methodology much faster and scalable. This two-step approach also allows us to directly exploit existing phylogenetic methods that detect bacterial recombination, and therefore to account for the effect of recombination in the construction of a dated phylogeny. We analysed many simulated datasets in order to benchmark the performance of our approach in a wide range of situations. Furthermore, we present applications to three different real datasets from recent bacterial genomic studies. Our methodology is implemented in a R package called BactDating which is freely available for download at https://github.com/xavierdidelot/BactDating.

Reconfigurable Pipet for Customized, Cost-Effective Liquid Handling.

We have developed a multichannel air displacement pipet with reconfigurable channels for nonstandard liquid handling applications. While linear multichannel pipets enable many established assays, they do not support analytical tools with customized liquid holding geometries, specifically paper-based microfluidic devices. Using our pipet, complex paper-based microfluidic devices can be fabricated without requiring multiple, time-consuming motions with a single-channel pipet or device designs limited to the configurations of traditional multichannel pipets. We created this tool by modifying a commercial 8-channel pipet using machined and 3D-printed components. We demonstrate the quantitative capabilities of our tool by comparing its performance to that of a calibrated, single-channel pipet in volume delivery experiments. Our reconfigurable pipet supports the advancement of custom analytical tools with nonstandard liquid handling requirements and provides an ergonomic alternative to commercial equipment for developers of paper-based devices.

The Bacterial Sequential Markov Coalescent.

Bacteria can exchange and acquire new genetic material from other organisms directly and via the environment. This process, known as bacterial recombination, has a strong impact on the evolution of bacteria, for example, leading to the spread of antibiotic resistance across clades and species, and to the avoidance of clonal interference. Recombination hinders phylogenetic and transmission inference because it creates patterns of substitutions (homoplasies) inconsistent with the hypothesis of a single evolutionary tree. Bacterial recombination is typically modeled as statistically akin to gene conversion in eukaryotes, i.e., using the coalescent with gene conversion (CGC). However, this model can be very computationally demanding as it needs to account for the correlations of evolutionary histories of even distant loci. So, with the increasing popularity of whole genome sequencing, the need has emerged for a faster approach to model and simulate bacterial genome evolution. We present a new model that approximates the coalescent with gene conversion: the bacterial sequential Markov coalescent (BSMC). Our approach is based on a similar idea to the sequential Markov coalescent (SMC)-an approximation of the coalescent with crossover recombination. However, bacterial recombination poses hurdles to a sequential Markov approximation, as it leads to strong correlations and linkage disequilibrium across very distant sites in the genome. Our BSMC overcomes these difficulties, and shows a considerable reduction in computational demand compared to the exact CGC, and very similar patterns in simulated data. We implemented our BSMC model within new simulation software FastSimBac. In addition to the decreased computational demand compared to previous bacterial genome evolution simulators, FastSimBac provides more general options for evolutionary scenarios, allowing population structure with migration, speciation, population size changes, and recombination hotspots. FastSimBac is available from https://bitbucket.org/nicofmay/fastsimbac, and is distributed as open source under the terms of the GNU General Public License. Lastly, we use the BSMC within an Approximate Bayesian Computation (ABC) inference scheme, and suggest that parameters simulated under the exact CGC can correctly be recovered, further showcasing the accuracy of the BSMC. With this ABC we infer recombination rate, mutation rate, and recombination tract length of Bacillus cereus from a whole genome alignment.

Comparing the Efficacy of Ophthalmic NSAIDs in Common Indications: A Literature Review to Support Cost-effective Prescribing.

OBJECTIVE: To review the commercially available ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs), identify opportunities for therapeutic substitutions within and outside of their Food and Drug Administration (FDA)-approved indications, and identify clinically superior drugs within the class for specific indications. DATA SOURCE: A PubMed search (1992 through January 2014) was performed on the terms diclofenac, ketorolac, flurbiprofen, bromfenac, and nepafenac. STUDY SELECTION AND DATA EXTRACTION: Clinical trials, meta-analyses, and review articles were evaluated if they were written in English and pertained to human subjects. Studies were excluded if they were in vitro studies, solely evaluated pharmacokinetic or pharmacodynamic properties, did not relate to the topical ophthalmic route, did not evaluate the FDA-approved indications of any available ophthalmic NSAID, or compared a reviewed drug with a nonreviewed drug (without placebo comparison). DATA SYNTHESIS: A total of 67 articles met the criteria for evaluation. Article quality, study design, and dosing of the medications were assessed to determine the clinical applicability of the results. The quality of the article was determined using the Oxford Centre for Evidence-based Medicine Levels of Evidence 1. CONCLUSIONS: Many formulations of the 5 reviewed NSAIDs have been studied across the 4 primary indications. These indications are (1) pain and inflammation associated with cataract surgery, (2) pain associated with corneal refractive surgery, (3) inhibition of intraoperative miosis, and (4) seasonal allergic conjunctivitis. Several studies have directly compared drugs within this class and have identified instances in which certain selections are therapeutically superior or equivalent to another. This information provides practitioners with guidance in selecting an optimal medication.

Basil O'Connor, the National Foundation for Infantile Paralysis and the Reorganization of Polio Research in the United States, 1935-41.

The costs associated with polio research in the late 1920s were high, while sources for research funding remained scarce. This began to change in the early 1930s with the creation of three private philanthropies that would form the basis of a system to fund polio research adequately: the International Committee for the Study of Infantile Paralysis (1928), The President's Birthday Ball Commission (1934), and the National Foundation for Infantile Paralysis (1938). This article explores how these three organizations shaped the process for directing funds to polio research. Beginning with the International Committee, all three philanthropies used medical advisory committees as vehicles for the review of proposals for research. The National Foundation adopted many of the policies and procedures of the earlier organizations, drawing on the experiences, misfortunes, and successes of its predecessors. The National Foundation also relied on some of the same personnel, although the microbiologist and writer Paul de Kruif, who was an influential figure in the early years, was gradually pushed out. This essay explores the establishment of the medical advisory committees of the National Foundation and reveals how by 1941 under leadership of Basil O'Connor and Dr. Thomas Rivers they developed a systematic and readily legitimated process for directing funding. By 1941, the NFIP had in place the fund-raising capacity to underwrite the scientific research that would ultimately produce two successful polio vaccines in the next twenty years.

Detection of mixed infection from bacterial whole genome sequence data allows assessment of its role in Clostridium difficile transmission.

Bacterial whole genome sequencing offers the prospect of rapid and high precision investigation of infectious disease outbreaks. Close genetic relationships between microorganisms isolated from different infected cases suggest transmission is a strong possibility, whereas transmission between cases with genetically distinct bacterial isolates can be excluded. However, undetected mixed infections-infection with ≥2 unrelated strains of the same species where only one is sequenced-potentially impairs exclusion of transmission with certainty, and may therefore limit the utility of this technique. We investigated the problem by developing a computationally efficient method for detecting mixed infection without the need for resource-intensive independent sequencing of multiple bacterial colonies. Given the relatively low density of single nucleotide polymorphisms within bacterial sequence data, direct reconstruction of mixed infection haplotypes from current short-read sequence data is not consistently possible. We therefore use a two-step maximum likelihood-based approach, assuming each sample contains up to two infecting strains. We jointly estimate the proportion of the infection arising from the dominant and minor strains, and the sequence divergence between these strains. In cases where mixed infection is confirmed, the dominant and minor haplotypes are then matched to a database of previously sequenced local isolates. We demonstrate the performance of our algorithm with in silico and in vitro mixed infection experiments, and apply it to transmission of an important healthcare-associated pathogen, Clostridium difficile. Using hospital ward movement data in a previously described stochastic transmission model, 15 pairs of cases enriched for likely transmission events associated with mixed infection were selected. Our method identified four previously undetected mixed infections, and a previously undetected transmission event, but no direct transmission between the pairs of cases under investigation. These results demonstrate that mixed infections can be detected without additional sequencing effort, and this will be important in assessing the extent of cryptic transmission in our hospitals.

Novel inhibitors of inosine monophosphate dehydrogenase in patent literature of the last decade.

Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed.

Transforming clinical microbiology with bacterial genome sequencing.

Whole-genome sequencing of bacteria has recently emerged as a cost-effective and convenient approach for addressing many microbiological questions. Here, we review the current status of clinical microbiology and how it has already begun to be transformed by using next-generation sequencing. We focus on three essential tasks: identifying the species of an isolate, testing its properties, such as resistance to antibiotics and virulence, and monitoring the emergence and spread of bacterial pathogens. We predict that the application of next-generation sequencing will soon be sufficiently fast, accurate and cheap to be used in routine clinical microbiology practice, where it could replace many complex current techniques with a single, more efficient workflow.

And they shall walk: ideal versus reality in polio rehabilitation in the United States.

This essay explores the significance that rehabilitation physicians and polio patients in the United States put on recovering the ability to walk. Polio often paralyzed or severely weakened the legs of those who contracted the disease. Regaining the ability to walk was thus a significant measure of recovery from the disease. However, walking meant more than the physical act itself. Regaining the ability to walk meant, in a symbolic sense, that one was no longer disabled, that one had again become normal. This attitude was shared by rehabilitation specialists and patients alike. This essay examines this attitude and the cultural values it embodied through a study of the efforts of selected polio survivors to learn to walk again and of the rehabilitation literature that held walking as an ideal. It also explores what happened when polio patients were unable to walk again because of the severity of their paralysis.

Campylobacter genotyping to determine the source of human infection.

BACKGROUND: Campylobacter species cause a high proportion of bacterial gastroenteritis cases and are a significant burden on health care systems and economies worldwide; however, the relative contributions of the various possible sources of infection in humans are unclear. METHODS: National-scale genotyping of Campylobacter species was used to quantify the relative importance of various possible sources of human infection. Multilocus sequence types were determined for 5674 isolates obtained from cases of human campylobacteriosis in Scotland from July 2005 through September 2006 and from 999 Campylobacter species isolates from 3417 contemporaneous samples from potential human infection sources. These data were supplemented with 2420 sequence types from other studies, representing isolates from a variety of sources. The clinical isolates were attributed to possible sources on the basis of their sequence types with use of 2 population genetic models, STRUCTURE and an asymmetric island model. RESULTS: The STRUCTURE and the asymmetric island models attributed most clinical isolates to chicken meat (58% and 78% of Campylobacter jejuni and 40% and 56% of Campylobacter coli isolates, respectively), identifying it as the principal source of Campylobacter infection in humans. Both models attributed the majority of the remaining isolates to ruminant sources, with relatively few isolates attributed to wild bird, environment, swine, and turkey sources. CONCLUSIONS: National-scale genotyping was a practical and efficient methodology for the quantification of the contributions of different sources to human Campylobacter infection. Combined with the knowledge that retail chicken is routinely contaminated with Campylobacter, these results are consistent with the view that the largest reductions in human campylobacteriosis in industrialized countries will come from interventions that focus on the poultry industry.

Focused atorvastatin therapy in managed-care patients with coronary heart disease and CKD.

BACKGROUND: This post hoc analysis of the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) Study investigates the effect of focused atorvastatin therapy versus usual care on cardiovascular outcomes in patients with coronary heart disease (CHD) with and without chronic kidney disease (CKD). STUDY DESIGN: Prospective randomized open-label; median follow-up, 54.3 months. SETTING & PARTICIPANTS: Managed care or Veterans Affairs facilities; 2,442 patients with CHD with dyslipidemia; mean age, 61.6 years. INTERVENTION: Focused atorvastatin therapy to a low-density lipoprotein cholesterol goal of less than 80 mg/dL or maximum dose of 80 mg/d versus usual care as deemed appropriate by patients' regular physicians. PREDICTOR: Baseline estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease Study equation of less than 60 mL/min/1.73 m(2) (patients with CKD) and 60 mL/min/1.73 m(2) or greater (patients without CKD). OUTCOMES & MEASUREMENTS: The primary end point was time to first cardiovascular event. Change from baseline eGFR was assessed in 1,768 patients with follow-up renal data. RESULTS: At baseline, 579 patients (23.7%) had CKD: 31.6% of these patients experienced a primary cardiovascular event during the study versus 23.6% of patients without CKD (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.18 to 1.68; P < 0.001). Compared with usual care, atorvastatin therapy reduced the relative risk of a primary outcome by 28% in patients with CKD (HR, 0.72; 95% CI, 0.54 to 0.97; P = 0.02) and 11% in patients without CKD (HR, 0.89; 95% CI, 0.74 to 1.07; P = 0.3) (P for treatment by CKD interaction = 0.2). There was no decrease in eGFR in atorvastatin-treated patients during the course of the study. LIMITATIONS: Follow-up of atorvastatin patients was restricted to every 6 months; interim data were unavailable for usual-care patients. CONCLUSIONS: Patients with CHD and CKD are at increased risk of cardiovascular events. Compared with usual care, focused atorvastatin treatment decreased cardiovascular risk for established patients in real-world settings, with no significant difference in treatment effects observed between patients with and without CKD.

Public perception and behavior change in relationship to hot weather and air pollution.

BACKGROUND: Changes in climate systems are increasing heat wave frequency and air stagnation, both conditions associated with exacerbating poor air quality and of considerable public health concern. OBJECTIVES: Heat and air pollution advisory systems are in place in many cities for early detection and response to reduce health consequences, or severity of adverse conditions. Whereas the ability to forecast heat waves and/or air pollution episodes has become increasingly sophisticated and accurate, little is known about the effectiveness of advisories in altering public behavior. METHODS: Air quality and meteorological conditions were measured during advisory and control days in Portland, OR and Houston, TX in 2005 and 2006 and 1962 subjects were interviewed by telephone about their perception and response to these conditions. RESULTS: Elevated ambient temperatures were accurately recognized regardless of air conditioning use; in Portland, respondents resorted to active cooling behavior (AC, fan, etc.), while in Houston no such change was observed. More heat-related symptoms were reported in Portland compared to Houston, probably due to low air conditioning use in the northwest. One-third of study participants were aware of air quality advisories but only approximately 10-15% claimed to have changed activities during such an episode. Not the advisory, however, drove their behavior change, but rather the perception of poor air quality, which was not related to PM(2.5) or ozone measurements. CONCLUSIONS: Messages are not reaching the public during potentially hazardous weather and air quality conditions. Climatic forecasts are increasingly predictive but public agencies fail to mount an appropriate outreach response.

Braces, wheelchairs, and iron lungs: the paralyzed body and the machinery of rehabilitation in the polio epidemics.

The successful fund raising appeals of the March of Dimes employed images of cute crippled children standing on braces and forearm crutches, sitting in wheelchairs, or confined to iron lungs. Those who had to use these devices as a result of polio, however, were often stigmatized as cripples. American cultural antipathy to these assistive devices meant that polio survivors often had to overcome an emotional and psychological resistance to using them. Whatever their fears, polio survivors quickly discovered the functionality of braces and wheelchairs. By confronting the cultural stigma associated with these devices and in some sense embracing these mechanical "friends," polio survivors compensated for their paralyzed bodies and became active in the wider world of home, school and work.

Partial weight-bearing gait retraining for persons following traumatic brain injury: preliminary report and proposed assessment scale.

The objectives of this investigation were to (1) document the recovery patterns of walking ability in two patients recovering from traumatic brain injury receiving partial weight-bearing gait retraining, and (2) introduce a new assessment scale of gait progress for patients receiving partial weight support therapy. The two patients were categorized as acute (< 6 months) and chronic (> 2 years) injury. Each patient received extensive in-patient rehabilitation, including physical therapy designed with twice-weekly partial body support gait training. The subjects made improvements in all measured indicators of gait ability (i.e. muscle strength, spasticity, standing balance). However, assessment of their improvement using standard assessment scales showed little progress. The newly devised Missouri Assisted Gait (MAG) scale, which includes developmental components of gait ability measured dramatic gains. This added precision of measurement was useful in communicating progress to both patients and providers.