Truncated Variational Sampling for "Black Box" Optimization of Generative Models

We investigate the optimization of two probabilistic generative models with binary latent variables using a novel variational EM approach. The approach distinguishes itself from previous variational approaches by using latent states as variational parameters. Here we use efficient and general purpose sampling procedures to vary the latent states, and investigate the "black box" applicability of the resulting optimization procedure. For general purpose applicability, samples are drawn from approximate marginal distributions of the considered generative model as well as from the model's prior distribution. As such, variational sampling is defined in a generic form, and is directly executable for a given model. As a proof of concept, we then apply the novel procedure (A) to Binary Sparse Coding (a model with continuous observables), and (B) to basic Sigmoid Belief Networks (which are models with binary observables). Numerical experiments verify that the investigated approach efficiently as well as effectively increases a variational free energy objective without requiring any additional analytical steps

Optimising use of electronic health records to describe the presentation of rheumatoid arthritis in primary care: a strategy for developing code lists

Background Research using electronic health records (EHRs) relies heavily on coded clinical data. Due to variation in coding practices, it can be difficult to aggregate the codes for a condition in order to define cases. This paper describes a methodology to develop ‘indicator markers’ found in patients with early rheumatoid arthritis (RA); these are a broader range of codes which may allow a probabilistic case definition to use in cases where no diagnostic code is yet recorded. Methods We examined EHRs of 5,843 patients in the General Practice Research Database, aged ≥30y, with a first coded diagnosis of RA between 2005 and 2008. Lists of indicator markers for RA were developed initially by panels of clinicians drawing up code-lists and then modified based on scrutiny of available data. The prevalence of indicator markers, and their temporal relationship to RA codes, was examined in patients from 3y before to 14d after recorded RA diagnosis. Findings Indicator markers were common throughout EHRs of RA patients, with 83.5% having 2 or more markers. 34% of patients received a disease-specific prescription before RA was coded; 42% had a referral to rheumatology, and 63% had a test for rheumatoid factor. 65% had at least one joint symptom or sign recorded and in 44% this was at least 6-months before recorded RA diagnosis. Conclusion Indicator markers of RA may be valuable for case definition in cases which do not yet have a diagnostic code. The clinical diagnosis of RA is likely to occur some months before it is coded, shown by markers frequently occurring ≥6 months before recorded diagnosis. It is difficult to differentiate delay in diagnosis from delay in recording. Information concealed in free text may be required for the accurate identification of patients and to assess the quality of care in general practice

Eicosapentaenoic Acid Modulates Trichomonas 1 vaginalis Activity

Trichomonas vaginalis is a sexually transmitted parasite and, while it is often asymptomatic in 50 males, the parasite is associated with disease in both sexes. Metronidazole is an effective 51 treatment for trichomoniasis, but resistant strains have evolved and, thus, it has become 52 necessary to investigate other possible therapies. In this study, we examined the effects of native 53 and oxidized forms of the sodium salts of eicosapentaenoic, docosahexaenoic and arachidonic 54 acids on T. vaginalis activity. Eicosapentaenoic acid was the most toxic with 190 μM and 380 55 μM causing approximately 90% cell death in Casu2 and ATCC 50142 strains, respectively. In 56 contrast, oxidized eicosapentaenoic acid was the least toxic, requiring \u3e3 mM to inhibit activity, 57 while low levels (10μM) were associated with increased parasite density. Mass spectrometric 58 analysis of oxidized eicosapentaenoic acid revealed C20 products containing one to six 59 additional oxygen atoms and various degrees of bond saturation. These results indicate that 60 eicosapentaenoic acid has different effects on T. vaginalis survival, depending on whether it is 61 present in the native or oxidized form. A better understanding of lipid metabolism in T. vaginalis 62 may facilitate the design of synthetic fatty acids that are effective for the treatment of 63 metronidazole-resistant T. vaginalis

Comparison of broad range 16S rDNA PCR and conventional blood culture for diagnosis of sepsis in the newborn: a case control study

<p>Abstract</p> <p>Background</p> <p>Early onset bacterial sepsis is a feared complication of the newborn. A large proportion of infants admitted to the Neonatal Intensive Care Unit (NICU) for suspected sepsis receive treatment with potent systemic antibiotics while a diagnostic workup is in progress. The gold standard for detecting bacterial sepsis is blood culture. However, as pathogens in blood cultures are only detected in approximately 25% of patients, the sensitivity of blood culture is suspected to be low. Therefore, the diagnosis of sepsis is often based on the development of clinical signs, in combination with laboratory tests such as a rise in C – reactive protein (CRP). Molecular assays for the detection of bacterial DNA in the blood represent possible new diagnostic tools for early identification of a bacterial cause.</p> <p>Methods</p> <p>A broad range 16S rDNA polymerase chain reaction (PCR) without preincubation was compared to conventional diagnostic work up for clinical sepsis, including BACTEC blood culture, for early determination of bacterial sepsis in the newborn. In addition, the relationship between known risk factors, clinical signs, and laboratory parameters considered in clinical sepsis in the newborn were explored.</p> <p>Results</p> <p>Forty-eight infants with suspected sepsis were included in this study. Thirty-one patients were diagnosed with sepsis, only 6 of these had a positive blood culture. 16S rDNA PCR analysis of blinded blood samples from the 48 infants revealed 10 samples positive for the presence of bacterial DNA. PCR failed to be positive in 2 samples from blood culture positive infants, and was positive in 1 sample where a diagnosis of a non-septic condition was established. Compared to blood culture the diagnosis of bacterial proven sepsis by PCR revealed a 66.7% sensitivity, 87.5% specificity, 95.4% positive and 75% negative predictive value. PCR combined with blood culture revealed bacteria in 35.1% of the patients diagnosed with sepsis. Irritability and feeding difficulties were the clinical signs most often observed in sepsis. CRP increased in the presence of bacterial infection.</p> <p>Conclusion</p> <p>There is a need for PCR as a method to quickly point out the infants with sepsis. However, uncertainty about a bacterial cause of sepsis was not reduced by the PCR result, reflecting that methodological improvements are required in order for DNA detection to replace or supplement traditional blood culture in diagnosis of bacterial sepsis.</p

Radar‐Sounding Characterization of the Subglacial Groundwater Table Beneath Hiawatha Glacier, Greenland

Radar-sounding surveys associated with the discovery of a large impact crater beneath Hiawatha Glacier, Greenland, revealed bright, flat subglacial reflections hypothesized to originate from a subglacial groundwater table. We test this hypothesis using radiometric and hydrologic analysis of those radar data. The dielectric loss between the reflection from the top of the basal layer and subglacial reflection and their reflectivity difference represent dual constraints upon the complex permittivity of the basal material. Either ice-cemented debris or fractured, well-drained bedrock explain the basal layer's radiometric properties. The subglacial reflector's geometry is parallel to isopotential hydraulic head contours, located 7.5–15.3 m below the interface, and 11 ± 7 dB brighter than the ice–basal layer reflection. We conclude that this subglacial reflection is a groundwater table and that its detection was enabled by the wide bandwidth of the radar system and unusual geologic setting, suggesting a path for future direct radar detection of subglacial groundwater elsewhere

Chest pain and shortness of breath in cardiovascular disease: a prospective cohort study in UK primary care.

OBJECTIVE: To determine characteristics associated with monthly chest pain and shortness of breath (SoB) during activity in cardiovascular disease (CVD) and trajectories of these symptoms over 10 months. STUDY DESIGN AND SETTING: Baseline questionnaire was sent to patients aged ≥40 years from 10 UK general practices. Responders were sent monthly questionnaires for 10 months. For patients with CVD (ischaemic heart disease and heart failure), the association of sociodemographic characteristics, pain elsewhere and anxiety and depression with monthly reports of chest pain and SoB during activity were determined using multilevel, multinomial logistic regression. Common symptom trajectories were determined using dual trajectory latent class growth analysis. RESULTS: 661 patients with CVD completed at least 5 monthly questionnaires. Multiple other pain sites (relative risk ratio: 4.03; 95% CI 1.64 to 9.91) and anxiety or depression (relative risk ratio: 3.31; 95% CI 1.89 to 5.79) were associated with reporting weekly chest pain. Anxiety or depression (relative risk ratio: 4.10; 95% CI 2.72 to 6.17), obesity (relative risk ratio: 2.53; 95% CI 1.49 to 4.30), older age (80+: relative risk ratio: 2.51; 95% CI 1.19 to 5.26), increasing number of pain sites (4+: relative risk ratio: 4.64; 95% CI 2.35 to 9.18) and female gender (relative risk ratio: 1.81; 95% CI 1.20 to 2.75) were associated with reporting weekly SoB. Eight symptom trajectories were identified, with SoB symptoms more common than chest pain. CONCLUSIONS: Potentially modifiable characteristics are associated with the experience of chest pain and SoB. Identified symptom trajectories may facilitate tailored care to improve outcomes in patients with CVD

Efficacy of bacterial ribosomal RNA-targeted reverse transcription-quantitative PCR for detecting neonatal sepsis: a case control study

<p>Abstract</p> <p>Background</p> <p>Neonatal sepsis is difficult to diagnose and pathogens cannot be detected from blood cultures in many cases. Development of a rapid and accurate method for detecting pathogens is thus essential. The main purpose of this study was to identify etiological agents in clinically diagnosed neonatal sepsis using bacterial ribosomal RNA-targeted reverse transcription-quantitative PCR (BrRNA-RT-qPCR) and to conduct comparisons with the results of conventional blood culture. Since BrRNA-RT-qPCR targets bacterial ribosomal RNA, detection rates using this approach may exceed those using conventional PCR.</p> <p>Methods</p> <p>Subjects comprised 36 patients with 39 episodes of suspected neonatal sepsis who underwent BrRNA-RT-qPCR and conventional blood culture to diagnose sepsis. Blood samples were collected aseptically for BrRNA-RT-qPCR and blood culture at the time of initial sepsis evaluation by arterial puncture. BrRNA-RT-qPCR and blood culture were undertaken using identical blood samples, and BrRNA-RT-qPCR was performed using 12 primer sets.</p> <p>Results</p> <p>Positive rate was significantly higher for BrRNA-RT-qPCR (15/39, 38.5%) than for blood culture (6/39, 15.4%; p = 0.0039). BrRNA-RT-qPCR was able to identify all pathogens detected by blood culture. Furthermore, this method detected pathogens from neonates with clinical sepsis in whom pathogens was not detected by culture methods.</p> <p>Conclusions</p> <p>This RT-PCR technique is useful for sensitive detection of pathogens causing neonatal sepsis, even in cases with negative results by blood culture.</p

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics

Life-Space Mobility and Aging in Place

Research on older adults explores the notion of “aging in place”—providing older adults the opportunity to continue to occupy familiar surroundings, to live in their own homes and communities. But oftentimes one’s ability to stay or leave, particularly in old age, depends on the built environment. Mobility is the ability to meet the basic needs to access goods, activities, services, and social interactions as they relate to quality of life. Thus, mobility is essential to older adults due to their limited, or gradually reducing, physical and cognitive abilities. In transportation research, mobility is often regarded in terms of travel behavior and it is measured by the number of outside-home travel. However, in other fields, including public health, it refers to the relative ease and freedom of movement in all of its forms. This study intends to broaden the understanding of the environmental factors on older adults’ mobility in different life spaces, from one’s bedroom to sidewalk, from home to a final destination via walking, public transit and/or driving. We document and examine 1) the ways in which older adults talk about, understand, and make meaning of their experiences and conditions related to life-space mobility and, 2) how these frames of reference guide their ability to be able to age in place. To achieve these aims, we developed a life-space mobility assessment tool and conduct semi-structured interviews with 25 older adults who have participated in home accessibility modification programs in the U.S. Western region. Given that interviewees already have engaged in some level of self-determination to improve their lives at home, we are interested in their life-space mobility and which opportunities they might see to improve their auto sufficiency. Our work provides both a basis and springboard for studying further geographies and discussion about policy initiatives to effectively and equitably address growing mobility disparities

Recommendations for exercise adherence measures in musculoskeletal settings : a systematic review and consensus meeting (protocol)

Background: Exercise programmes are frequently advocated for the management of musculoskeletal disorders; however, adherence is an important pre-requisite for their success. The assessment of exercise adherence requires the use of relevant and appropriate measures, but guidance for appropriate assessment does not exist. This research will identify and evaluate the quality and acceptability of all measures used to assess exercise adherence within a musculoskeletal setting, seeking to reach consensus for the most relevant and appropriate measures for application in research and/or clinical practice settings. Methods/design: There are two key stages to the proposed research. First, a systematic review of the quality and acceptability of measures used to assess exercise adherence in musculoskeletal disorders; second, a consensus meeting. The systematic review will be conducted in two phases and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a robust methodology. Phase one will identify all measures that have been used to assess exercise adherence in a musculoskeletal setting. Phase two will seek to identify published and unpublished evidence of the measurement and practical properties of identified measures. Study quality will be assessed against the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidelines. A shortlist of best quality measures will be produced for consideration during stage two: a meeting of relevant stakeholders in the United Kingdom during which consensus on the most relevant and appropriate measures of exercise adherence for application in research and/or clinical practice settings will be sought. Discussion: This study will benefit clinicians who seek to evaluate patients’ levels of exercise adherence and those intending to undertake research, service evaluation, or audit relating to exercise adherence in the musculoskeletal field. The findings will impact upon new research studies which aim to understand the factors that predict adherence with exercise and which test different adherence-enhancing interventions. PROSPERO reference: CRD4201300621