Lower Urinary Tract Infections: Management, Outcomes and Risk Factors for Antibiotic Re-prescription in Primary Care

Background: Urinary tract infections (UTIs) are major drivers of antibiotic prescribing in primary care. Inappropriate antibiotic prescribing for UTIs likely drives antibiotic resistance. We aimed to describe current investigation and antibiotic treatment to examine opportunities for improved antimicrobial stewardship. Methods: We identified a cohort of all patients with lower UTI diagnosis between 2011 and 2015 in the 390 primary care practices contributing data to ResearchOne in England. We examined investigation, antibiotic treatment and antibiotic re-prescription within 28 days according to guideline-defined patient groups. We assessed risk factors for re-prescription using mixed-effect logistic regression. Findings: In total, 494,675 UTIs were diagnosed in 300,354 patients. Median age was 54 years, and 83.3% were women. Same-day antibiotic was prescribed for 85.7% of UTIs; 56.8% were treated with trimethoprim, and urine sampling was undertaken in 25.0%. The antibiotic re-prescription rate was low (17,430, 4.1%) and increased slightly over time in men (from 5.2% in 2011 to 6.2% in 2015). Overall, 21.1% of pre-prescription were for the same antibiotic. The percentage of adults with recurrent UTIs ranged from 1.0% in 18–64 year-old men to 2.6% in women ≥65 years. The risk of antibiotic re-prescription increased with age, calendar year, recent antibiotic prescribing and treatment with antibiotic other than trimethoprim or nitrofurantoin. Interpretation: Most patients diagnosed with lower UTI in primary care receive same-day empirical antibiotics with little diversity in choice of agent. The antibiotic re-prescription rate is low. Microbiological investigation and re-prescription of the same antibiotic given for the initial episode happened in one quarter of UTIs. Funding: UK National Health Service Improvement

A Variational Method in Out of Equilibrium Physical Systems

A variational principle is further developed for out of equilibrium dynamical systems by using the concept of maximum entropy. With this new formulation it is obtained a set of two first-order differential equations, revealing the same formal symplectic structure shared by classical mechanics, fluid mechanics and thermodynamics. In particular, it is obtained an extended equation of motion for a rotating dynamical system, from where it emerges a kind of topological torsion current of the form $\epsilon_{ijk} A_j \omega_k$, with $A_j$ and $\omega_k$ denoting components of the vector potential (gravitational or/and electromagnetic) and $\omega$ is the angular velocity of the accelerated frame. In addition, it is derived a special form of Umov-Poynting's theorem for rotating gravito-electromagnetic systems, and obtained a general condition of equilibrium for a rotating plasma. The variational method is then applied to clarify the working mechanism of some particular devices, such as the Bennett pinch and vacuum arcs, to calculate the power extraction from an hurricane, and to discuss the effect of transport angular momentum on the radiactive heating of planetary atmospheres. This development is seen to be advantageous and opens options for systematic improvements.Comment: 22 pages, 1 figure, submitted to review, added one referenc

Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos

Background The aetiology of recurrent miscarriage (RM) remains largely unexplained. Women with RM have a shorter time to pregnancy interval than normally fertile women, which may be due to more frequent implantation of non-viable embryos. We hypothesized that human endometrial stromal cells (H-EnSCs) of women with RM discriminate less effectively between high-and low-quality human embryos and migrate more readily towards trophoblast spheroids than H-EnSCs of normally fertile women. Methodology/Principal Findings Monolayers of decidualized H-EnSCs were generated from endometrial biopsies of 6 women with RM and 6 fertile controls. Cell-free migration zones were created and the effect of the presence of a high-quality (day 5 blastocyst, n = 13), a low-quality (day 5 blastocyst with three pronuclei or underdeveloped embryo, n = 12) or AC-1M88 trophoblast cell line spheroid on H-ESC migratory activity was analyzed after 18 hours. In the absence of a spheroid or embryo, migration of H-EnSCs from fertile or RM women was similar. In the presence of a low-quality embryo in the zone, the migration of H-EnSCs of control women was inhibited compared to the basal migration in the absence of an embryo (P<0.05) and compared to the migration in the presence of high-quality embryo (p<0.01). Interestingly, the migratory response H-EnSCs of women with RM did not differ between high- and low-quality embryos. Furthermore, in the presence of a spheroid their migration was enhanced compared to the H-EnSCs of controls (p<0.001). Conclusions H-EnSCs of fertile women discriminate between high- and low-quality embryos whereas H-EnSCs of women with RM fail to do so. H-EnSCs of RM women have a higher migratory response to trophoblast spheroids. Future studies will focus on the mechanisms by which low-quality embryos inhibit the migration of H-EnSCs and how this is deregulated in women with RM

Comparison of two methods based on cross-sectional data for correcting corpus uterine cancer incidence and probabilities

BACKGROUND: Two methods are presented for obtaining hysterectomy prevalence corrected estimates of invasive cancer incidence rates and probabilities of the corpus uterine. METHODS: The first method involves cross-sectional hysterectomy data from the Utah Hospital Discharge Data Base and mortality data applied to life-table methods. The second involves hysterectomy prevalence estimates obtained directly from the Utah Behavior Risk Factor Surveillance System (BRFSS) survey. RESULTS: Hysterectomy prevalence estimates based on the first method are lower than those obtained from the second method through age 74, but higher in the remaining ages. Correction for hysterectomy prevalence is greatest among women ages 75–79. In this age group, the uncorrected rate is 125 (per 100,000) and the corrected rate based on the life-table method is 223 using 1995–97 data, 243 using 1992–94 data, and 228 from the survey method. The uncorrected lifetime probability of developing corpus uterine cancer is 2.6%; the corrected probability from the life-table method using 1995–97 data is 4.2%, using 1992–94 data is 4.5%; and based on prevalence data from the survey method is 4.6%. CONCLUSIONS: Both methods provide reasonable hysterectomy prevalence estimates for correcting corpus uterine cancer rates and probabilities. Because of declining trends in hysterectomy in recent decades, corrected estimates from the life-table method are less pronounced than those based on the survey method. These methods may be useful for obtaining corrected uterine cancer rates and probabilities in areas of the world that do not have sufficient years of hysterectomy data to directly compute prevalence

Stochastic population growth in spatially heterogeneous environments

Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study the following model for population abundances in $n$ patches: the conditional law of $X_{t+dt}$ given $X_t=x$ is such that when $dt$ is small the conditional mean of $X_{t+dt}^i-X_t^i$ is approximately $[x^i\mu_i+\sum_j(x^j D_{ji}-x^i D_{ij})]dt$, where $X_t^i$ and $\mu_i$ are the abundance and per capita growth rate in the $i$-th patch respectivly, and $D_{ij}$ is the dispersal rate from the $i$-th to the $j$-th patch, and the conditional covariance of $X_{t+dt}^i-X_t^i$ and $X_{t+dt}^j-X_t^j$ is approximately $x^i x^j \sigma_{ij}dt$. We show for such a spatially extended population that if $S_t=(X_t^1+...+X_t^n)$ is the total population abundance, then $Y_t=X_t/S_t$, the vector of patch proportions, converges in law to a random vector $Y_\infty$ as $t\to\infty$, and the stochastic growth rate $\lim_{t\to\infty}t^{-1}\log S_t$ equals the space-time average per-capita growth rate \sum_i\mu_i\E[Y_\infty^i] experienced by the population minus half of the space-time average temporal variation \E[\sum_{i,j}\sigma_{ij}Y_\infty^i Y_\infty^j] experienced by the population. We derive analytic results for the law of $Y_\infty$, find which choice of the dispersal mechanism $D$ produces an optimal stochastic growth rate for a freely dispersing population, and investigate the effect on the stochastic growth rate of constraints on dispersal rates. Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology.Comment: 47 pages, 4 figure

Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: an analysis of a total population perinatal database

BACKGROUND: The appropriateness of an individual's intra uterine growth is now considered an important determinant of both short and long term outcomes, yet currently used measures have several shortcomings. This study demonstrates a method of assessing appropriateness of intrauterine growth based on the estimation of each individual's optimal newborn dimensions from routinely available perinatal data. Appropriateness of growth can then be inferred from the ratio of the value of the observed dimension to that of the optimal dimension. METHODS: Fractional polynomial regression models including terms for non-pathological determinants of fetal size (gestational duration, fetal gender and maternal height, age and parity) were used to predict birth weight, birth length and head circumference from a population without any major risk factors for sub-optimal intra-uterine growth. This population was selected from a total population of all singleton, Caucasian births in Western Australia 1998–2002. Births were excluded if the pregnancy was exposed to factors known to influence fetal growth pathologically. The values predicted by these models were treated as the optimal values, given infant gender, gestational age, maternal height, parity, and age. RESULTS: The selected sample (N = 62,746) comprised 60.5% of the total Caucasian singleton birth cohort. Equations are presented that predict optimal birth weight, birth length and head circumference given gestational duration, fetal gender, maternal height, age and parity. The best fitting models explained 40.5% of variance for birth weight, 32.2% for birth length, and 25.2% for head circumference at birth. CONCLUSION: Proportion of optimal birth weight (length or head circumference) provides a method of assessing appropriateness of intrauterine growth that is less dependent on the health of the reference population or the quality of their morphometric data than is percentile position on a birth weight distribution

Computational investigation of the time-dependent contact behaviour of the human tibiofemoral joint under body weight

The knee joint is one of the most common sites for osteoarthritis, the onset and progression of which are believed to relate to the mechanical environment of cartilage. To understand this environment, it is necessary to take into account the complex biphasic contact interactions of the cartilage and menisci. In this study, the time-dependent contact behaviour of an intact and a meniscectomized human tibiofemoral joint was characterized under body weight using a computational model. Good agreement in the contact area and femoral displacement under static loads were found between model predictions of this study and published experimental measurements. The time-dependent results indicated that as loading time progressed, the contact area and femoral vertical displacement of both intact and meniscectomized joints increased. More load was transferred to the cartilage–cartilage interface over time. However, the portions of load borne by the lateral and medial compartments did not greatly vary with time. Additionally, during the whole simulation period, the maximum compressive stress in the meniscectomized joint was higher than that in the intact joint. The fluid pressure in the intact and meniscectomized joints remained remarkably high at the condyle centres, but the fluid pressure at the cartilage–meniscus interface decreased faster than that at the condyle centres as loading time progressed. The above findings provide further insights into the mechanical environment of the cartilage and meniscus within the human knee joint

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine