Delay from symptom onset to treatment start among tuberculosis patients in England, 2012-2015.

Improving access to tuberculosis (TB) care and ensuring early diagnosis are two major aims of the WHO End TB strategy and the Collaborative TB Strategy for England. This study describes risk factors associated with diagnostic delay among TB cases in England. We conducted a retrospective cohort study of TB cases notified to the Enhanced TB Surveillance System in England between 2012 and 2015. Diagnostic delay was defined as more than 4 months between symptom onset and treatment start date. Multivariable logistic regression was used to identify demographic and clinical factors associated with diagnostic delay. Between 2012 and 2015, 22 422 TB cases were notified in England and included in the study. A third (7612) of TB cases had a diagnostic delay of more than 4 months. Being female, aged 45 years and older, residing outside of London and having extra-pulmonary TB disease were significantly associated with a diagnostic delay in the multivariable model (aOR = 1.2, 1.2, 1.2, 1.3, 1.8, respectively). This study identifies demographic and clinical factors associated with diagnostic delay, which will inform targeted interventions to improve access to care and early diagnosis among these groups, with the ultimate aim of helping reduce transmission and improve treatment outcomes for TB cases in England.

Author Correction to: Dynamic Scheduling for Veterans Health Administration Patients Using Geospatial Dynamic Overbooking.

The original version of this article unfortunately contained a mistake. The name of Matthew Gerber was incorrectly spelled as Mathew Gerber. The correct spelling is now presented correctly in this correction article.

Dynamic Scheduling for Veterans Health Administration Patients using Geospatial Dynamic Overbooking.

The Veterans Health Administration (VHA) is plagued by abnormally high no-show and cancellation rates that reduce the productivity and efficiency of its medical outpatient clinics. We address this issue by developing a dynamic scheduling system that utilizes mobile computing via geo-location data to estimate the likelihood of a patient arriving on time for a scheduled appointment. These likelihoods are used to update the clinic's schedule in real time. When a patient's arrival probability falls below a given threshold, the patient's appointment is canceled. This appointment is immediately reassigned to another patient drawn from a pool of patients who are actively seeking an appointment. The replacement patients are prioritized using their arrival probability. Real-world data were not available for this study, so synthetic patient data were generated to test the feasibility of the design. The method for predicting the arrival probability was verified on a real set of taxicab data. This study demonstrates that dynamic scheduling using geo-location data can reduce the number of unused appointments with minimal risk of double booking resulting from incorrect predictions. We acknowledge that there could be privacy concerns with regards to government possession of one's location and offer strategies for alleviating these concerns in our conclusion.

A UK-based resource to support the monitoring and safe use of anti-TB drugs and second-line treatment of multidrug-resistant TB.

Using the best available evidence and expert consensus, this document provides guidance for adverse effect monitoring in multidrug-resistant TB (MDR-TB). It includes recommendations for baseline tests, routine drug and toxicity monitoring guides as well as individual drug monographs for all drugs currently available in the UK to treat TB. These recommendations provide a structure through which healthcare professionals can better manage the complex drug regimens required for the treatment of MDR-TB; minimising the risk of adverse incidents and helping to improve patients' tolerance, compliance and treatment completion.

Systematic review of randomised controlled trials of the effects of caffeine or caffeinated drinks on blood glucose concentrations and insulin sensitivity in people with diabetes mellitus.

BACKGROUND: Compounds other than macronutrients have been shown to influence blood glucose concentrations and insulin sensitivity in people with diabetes, with caffeine being one such substance. The present study systematically reviewed the evidence of the effects of caffeine on blood glucose concentrations and/or insulin sensitivity in people with diabetes. METHODS: Four databases, including MEDLINE and EMBASE, were searched up to 1 February 2012. Randomised controlled trials (RCTs) investigating the effects of caffeine on blood glucose and/or insulin sensitivity in humans, diagnosed with type I, type II or gestational diabetes mellitus (GDM), were included. Quality assessment and data extraction were conducted and agreed by both authors. RESULTS: Of 253 articles retrieved, nine trials (134 participants) were identified. Trials in people with type II diabetes demonstrated that the ingestion of caffeine (approximately 200-500 mg) significantly increased blood glucose concentrations by 16-28% of the area under the curve (AUC) and insulin concentrations by 19-48% of the AUC when taken prior to a glucose load, at the same time as decreasing insulin sensitivity by 14-37%. In type I diabetes, trials indicated enhanced recognition and a reduced duration of hypoglycaemic episodes following ingestion of 400-500 mg caffeine, without altering glycated haemoglobin. In GDM, a single trial demonstrated that approximately 200 mg of caffeine induced a decrease in insulin sensitivity by 18% and a subsequent increase in blood glucose concentrations by 19% of the AUC. CONCLUSIONS: Evidence indicates a negative effect of caffeine intake on blood glucose control in individuals with type II diabetes, as replicated in a single trial in GDM. Larger-scale RCTs of longer duration are needed to determine the effects of timing and dose. Early indications of a reduced duration and an improved awareness of hypoglycaemia in type I diabetes require further confirmation.

A preliminary study on the use of (10)Be in forensic radioecology of nuclear explosion sites.

Cosmogenic (10)Be, known for use in dating studies, unexpectedly is also produced in nuclear explosions with an atom yield almost comparable to (e.g.) (137)Cs. There are major production routes via (13)C(n, alpha)(10)Be, from carbon dioxide in the air and the organic explosives, possibly from other bomb components and to a minor extent from the direct fission reaction. Although the detailed bomb components are speculative, carbon was certainly present in the explosives and an order of magnitude calculation is possible. The (n, alpha) cross-section was determined by irradiating graphite in a nuclear reactor, and the resulting (10)Be estimated by Accelerator Mass Spectrometry (AMS) giving a cross-section of 34.5+/-0.7mb (6-9.3MeV), within error of previous work. (10)Be should have applications in forensic radioecology. Historical environmental samples from Hiroshima, and Semipalatinsk (Kazakhstan) showed two to threefold (10)Be excesses compared with the background cosmogenic levels. A sample from Lake Chagan (a Soviet nuclear cratering experiment) contained more (10)Be than previously reported soils. (10)Be may be useful for measuring the fast neutron dose near the Hiroshima bomb hypocenter at neutron energies double those previously available.

Systematics of radon at the Wairakei geothermal region, New Zealand.

222Rn and 220Rn in geothermal steam at Wairakei, NZ, range from 11 to 19, 500 Bq kg-1, and 25 to 16, 700 Bq kg-1, respectively, but do not cause toxic concentrations in air. The wide ranges are mainly due to differences in different physical conditions underground (e.g. thin silica diffusion barriers), not geochemical differences. Groundwater Rn from outside the area probably plays only a minor role. 210Po was found present in non-toxic levels in the steam. Historical records showed little change in Rn concentration over several decades, therefore potentially hazardous concentrations might be predicted from early exploration. 220Rn concentrations at Wairakei should decrease as the field becomes steam-dominated. Rock surfaces were variably leached or enriched with U, Th, Ra and 210Pb, providing a possible model for deposition in cooler regions near the field. Estimates of 222Rn permeability ranged from 2 to 77% of the maximum possible, with a median of 13%.

A framework for One Health research.

The need for multidisciplinary research to address today's complex health and environmental challenges has never been greater. The One Health (OH) approach to research ensures that human, animal, and environmental health questions are evaluated in an integrated and holistic manner to provide a more comprehensive understanding of the problem and potential solutions than would be possible with siloed approaches. However, the OH approach is complex, and there is limited guidance available for investigators regarding the practical design and implementation of OH research. In this paper we provide a framework to guide researchers through conceptualizing and planning an OH study. We discuss key steps in designing an OH study, including conceptualization of hypotheses and study aims, identification of collaborators for a multi-disciplinary research team, study design options, data sources and collection methods, and analytical methods. We illustrate these concepts through the presentation of a case study of health impacts associated with land application of biosolids. Finally, we discuss opportunities for applying an OH approach to identify solutions to current global health issues, and the need for cross-disciplinary funding sources to foster an OH approach to research.

Quorum-sensing in Gram-negative bacteria.

It has become increasingly and widely recognised that bacteria do not exist as solitary cells, but are colonial organisms that exploit elaborate systems of intercellular communication to facilitate their adaptation to changing environmental conditions. The languages by which bacteria communicate take the form of chemical signals, excreted from the cells, which can elicit profound physiological changes. Many types of signalling molecules, which regulate diverse phenotypes across distant genera, have been described. The most common signalling molecules found in Gram-negative bacteria are N-acyl derivatives of homoserine lactone (acyl HSLs). Modulation of the physiological processes controlled by acyl HSLs (and, indeed, many of the non-acyl HSL-mediated systems) occurs in a cell density- and growth phase-dependent manner. Therefore, the term 'quorum-sensing' has been coined to describe this ability of bacteria to monitor cell density before expressing a phenotype. In this paper, we review the current state of research concerning acyl HSL-mediated quorum-sensing. We also describe two non-acyl HSL-based systems utilised by the phytopathogens Ralstonia solanacearum and Xanthomonas campestris.

Novel quorum-sensing-controlled genes in Erwinia carotovora subsp. carotovora: identification of a fungal elicitor homologue in a soft-rotting bacterium.

Seven new genes controlled by the quorum-sensing signal molecule N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) have been identified in Erwinia carotovora subsp. carotovora. Using TnphoA as a mutagen, we enriched for mutants defective in proteins that could play a role in the interaction between E. carotovora subsp. carotovora and its plant hosts, and identified NipEcc and its counterpart in E. carotovora subsp. atroseptica. These are members of a growing family of proteins related to Nep1 from Fusarium oxysporum which can induce necrotic responses in a variety of dicotyledonous plants. NipEcc produced necrosis in tobacco, NipEca affected potato stem rot, and both affected virulence in potato tubers. In E. carotovora subsp. carotovora, nip was shown to be subject to weak repression by the LuxR family regulator, EccR, and may be regulated by the negative global regulator RsmA.

Quorum sensing as a population-density-dependent determinant of bacterial physiology.

The discovery that bacterial cells can communicate with each other has led to the realization that bacteria are capable of exhibiting much more complex patterns of co-operative behaviour than would be expected for simple unicellular microorganisms. Now generically termed 'quorum sensing', bacterial cell-to-cell communication enables a bacterial population to mount a unified response that is advantageous to its survival by improving access to complex nutrients or environmental niches, collective defence against other competitive microorganisms or eukaryotic host defence mechanisms and optimization of population survival by differentiation into morphological forms better adapted to combating environmental threats. The principle of quorum sensing encompasses the production and release of signal molecules by bacterial cells within a population. Such molecules are released into the environment and, as cell numbers increase, so does the extracellular level of signal molecule, until the bacteria sense that a threshold has been reached and gene activation, or in some cases depression or repression, occurs via the activity of sensor-regulator systems. In this review, we will describe the biochemistry and molecular biology of a number of well-characterized N-acylhomoserine lactone quorum sensing systems to illustrate how bacteria employ cell-to-cell signalling to adjust their physiology in accordance with the prevailing high-population-density environment.

Oral contraceptive hormones, folate metabolism, and the cervical epithelium.

The currently available evidence concerning disorders of folate metabolism in women taking oral contraceptives has been reviewed. A disturbance in folate balance serious enough to cause symptoms (i.e., megaloblastic anemia) occurs very rarely. In some series, but not in others, serum and/or red cell folate concentrations have been reduced in oral contraceptive users. It is doubtful whether sex steroids affect polyglutamate folate absorption. About 20 percent of women taking contraceptive hormones manifest mild megaloblastic changes on Papanicolaou smears of the cervicovaginal epithelium which disappear after folic acid therapy. The current evidence, however, would not indicate that any significant benefit would ensue from routine folate supplementation in women on oral contraceptives.

Rises in whole muscle passive tension of mammalian muscle after eccentric contractions at different lengths.

This is a report of experiments carried out on the medial gastrocnemius muscle of the anesthetized cat, investigating the effects of eccentric contractions carried out at different muscle lengths on the passive and active length-tension relationships. In one series of experiments, the motor supply to the muscle was divided into three approximately equal parts; in the other, whole muscles were used. Fifty eccentric contractions were carried out over different regions of the active length-tension curve for each partial or whole muscle. Active and passive length-tension curves were measured before and after the eccentric contractions. When eccentric contractions were carried out at longer lengths, there was a larger shift of the optimum length for active tension in the direction of longer muscle lengths and a larger fall in peak isometric tension. Passive tension was higher immediately after the eccentric contractions, and if the muscle was left undisturbed for 40 min, it increased further to higher values, particularly after contractions at longer lengths. A series of 20 passive stretches of the same speed and amplitude and covering the same length range as the active stretches, reduced the passive tension which redeveloped over a subsequent 40-min period. It is hypothesized that there are two factors influencing the level of passive tension in a muscle after a series of eccentric contractions. One is injury contractures in damaged muscle fibers tending to raise passive tension; the other is the presence of disrupted sarcomeres in series with still-functioning sarcomeres tending to reduce it.

Large-fiber mechanoreceptors contribute to muscle soreness after eccentric exercise.

Muscles subjected to eccentric exercise, in which the contracting muscle is forcibly lengthened, become sore the next day (delayed onset muscle soreness). In subjects who had their triceps surae of 1 leg exercised eccentrically by walking backwards on an inclined moving treadmill, mapping the muscle 48 hours later with a calibrated probe showed sensitive areas were localized but not restricted to the muscle-tendon junction. Injection of 5% sodium chloride into a sensitive site in the exercised leg did not produce more pain than injections into the unexercised leg, suggesting that nociceptor sensitization was not responsible. Applying controlled indentations to a sensitive area showed that the pain could be exacerbated by 20-Hz or 80-Hz vibration. In an unexercised muscle, vibration had the opposite effect; it reduced pain. Pain thresholds were measured before, during, and after a pressure block of the sciatic nerve. The block affected only large-diameter nerve fibers, as evidenced by disappearance of the H reflex and a weakened voluntary contraction, leaving painful heat and cold sensations unaltered. Pain thresholds increased significantly during the block. It is concluded that muscle mechanoreceptors, including muscle spindles, contribute to the soreness after eccentric exercise.

Correlates of experiencing life events just before or during pregnancy.

This study evaluates the prevalence of selected life events around the time of pregnancy, examining changes in the prevalence of these events, and identifying maternal characteristics associated with these events. We used data from the Pregnancy Risk Assessment Monitoring System (PRAMS) to examine 18 stressful life events among women who recently gave birth and to identify maternal characteristics associated with these events. PRAMS is a mail sample survey with telephone follow-up for non-respondents. Sixty-four percent of women experienced at least one event. The prevalence of specific events ranged from 0.4 to 30%. Women who experienced events differed from those who did not. Most notably, women of low socioeconomic status (SES) were much more likely to experience stressful life events. These events were also associated with other demographic and behavioral characteristics after controlling for SES. These results have implications for interpreting studies of stressful life events. The strong associations with SES highlight the importance of controlling for SES in studies of life events and health, and of considering differences in SES when interpreting these studies.

Application of a new method of searching for geochemical changes related to seismic activity.

222Rn in groundwater at three out of four New Zealand sites changed in a statistically significant way in response to increased monthly coseismic events M2.0-M5, 14-100 km away, particularly events normal to a nearby large faultline. delta 18O(H2O) at one site showed a coseismic negative relationship to seismicity the same day. Of other parameters at the four sites (CO2, CH4/N2, H2/N2, delta 18O(H2O), delta 13C(CO2), delta 13C(CH4), D/H, Ar/N2), only the latter showed some consistent sensitivity to seismicity, mainly as after-effects. There was no observable threshold strain value. The 9000 events studied gave considerable statistical power, but correlations useful for seismicity prediction were few and doubtful. The frequent negative relationships may indicate the closing of rock cracks by strain, hence reduced gas flow.

Evidence for a specific uptake and retention mechanism for 25-hydroxyvitamin D (25OHD) in skeletal muscle cells.

Little is known about the mechanism for the prolonged residence time of 25-hydroxyvitamin D (25OHD) in blood. Several lines of evidence led us to propose that skeletal muscle could function as the site of an extravascular pool of 25OHD. In vitro studies investigated the capacity of differentiated C2 murine muscle cells to take up and release 25OHD, in comparison with other cell types and the involvement of the membrane protein megalin in these mechanisms. When C2 cells are differentiated into myotubes, the time-dependent uptake of labeled 25OHD is 2-3 times higher than in undifferentiated myoblasts or nonmuscle osteoblastic MG63 cells (P < .001). During in vitro release experiments (after 25OHD uptake), myotubes released only 32% ± 6% stored 25OHD after 4 hours, whereas this figure was 60% ± 2% for osteoblasts (P < .01). Using immunofluorescence, C2 myotubes and primary rat muscle fibers were, for the first time, shown to express megalin and cubilin, endocytotic receptors for the vitamin D binding protein (DBP), which binds nearly all 25OHD in the blood. DBP has a high affinity for actin in skeletal muscle. A time-dependent uptake of Alexafluor-488-labeled DBP into mature muscle cells was observed by confocal microscopy. Incubation of C2 myotubes (for 24 hours) with receptor-associated protein, a megalin inhibitor, led to a 40% decrease in 25OHD uptake (P < .01). These data support the proposal that 25OHD, after uptake into mature muscle cells, is held there by DBP, which has been internalized via membrane megalin and is retained by binding to actin.