Effectiveness and cost-effectiveness of a physical activity loyalty scheme for behaviour change maintenance: a cluster randomised controlled trial.
Increasing physical activity in the workplace can provide employee physical and mental health benefits, and employer economic benefits through reduced absenteeism and increased productivity. The workplace is an opportune setting to encourage habitual activity. However, there is limited evidence on effective behaviour change interventions that lead to maintained physical activity. This study aims to address this gap and help build the necessary evidence base for effective, and cost-effective, workplace interventions. This cluster randomised control trial will recruit 776 office-based employees from public sector organisations in Belfast and Lisburn city centres, Northern Ireland. Participants will be randomly allocated by cluster to either the Intervention Group or Control Group (waiting list control). The 6-month intervention consists of rewards (retail vouchers, based on similar principles to high street loyalty cards), feedback and other evidence-based behaviour change techniques. Sensors situated in the vicinity of participating workplaces will promote and monitor minutes of physical activity undertaken by participants. Both groups will complete all outcome measures. The primary outcome is steps per day recorded using a pedometer (Yamax Digiwalker CW-701) for 7 consecutive days at baseline, 6, 12 and 18 months. Secondary outcomes include health, mental wellbeing, quality of life, work absenteeism and presenteeism, and use of healthcare resources. Process measures will assess intervention "dose", website usage, and intervention fidelity. An economic evaluation will be conducted from the National Health Service, employer and retailer perspective using both a cost-utility and cost-effectiveness framework. The inclusion of a discrete choice experiment will further generate values for a cost-benefit analysis. Participant focus groups will explore who the intervention worked for and why, and interviews with retailers will elucidate their views on the sustainability of a public health focused loyalty card scheme. The study is designed to maximise the potential for roll-out in similar settings, by engaging the public sector and business community in designing and delivering the intervention. We have developed a sustainable business model using a 'points' based loyalty platform, whereby local businesses 'sponsor' the incentive (retail vouchers) in return for increased footfall to their business. ISRCTN17975376 (Registered 19/09/2014).


Comparison of Head Elevation Protocols Following Femoral Artery Sheath Removal After Coronary Angiography.
To compare 2 standard protocols for head elevation following removal of a femoral artery sheath after coronary angiography and their effects on bleeding complications and reported levels of back pain. One protocol involved flat supine bed rest; the other allowed progressive head elevation. A prospective comparative study of 80 adult patients undergoing coronary angiography via the femoral approach. The Numeric Rating Scale was used as the measure of reported pain. No bleeding complications occurred in either group. Both groups had very low mean pain scores. Repeated-measures analysis demonstrated that the experience of pain differed significantly over time by location (F5,70 = 3.864, P = .004), with a notable decrease in pain scores more than 1 hour after sheath removal at the location that used the progressive head elevation protocol. Patients' satisfaction scores after discharge did not differ significantly between the 2 groups. Patients with a history of chronic back pain had consistently higher pain scores, but those pain scores did not differ significantly by location (or protocol). It appears that using a progressive head-elevation protocol within the first 3 hours after diagnostic angiography is not associated with an increased risk of bleeding complications at the access site and warrants further exploration in the mitigation of back pain associated with prolonged supine bed rest.


[Extrapulmonary tuberculosis in a patient with septic shock].
A 61-year-old woman who was negative for type 1 human immunodeficiency virus developed vertebral osteomyelitis and skin lesions due to sepsis by Staphylococcus aureus. Microscopic examination of the skin showed alcohol-resistant acid-fast bacilli. A polymerase chain reaction (PCR) assay for Mycobacterium tuberculosis was positive for skin and spinal samples, although the cultures were negative. The diagnosis of M. tuberculosis infection is difficult, particularly when the disease is extrapulmonary. Rapid diagnostic tests that use PCR identify the DNA of the bacillus with greater sensitivity than microscopic examination and can give results within 24 hours of receipt of a sample. We analyze the utility of PCR for diagnosing extrapulmonary tuberculosis.


Honey Bee Exposure to Pesticides: A Four-Year Nationwide Study.
Pollinators, including honey bees, are responsible for the successful reproduction of more than 87% of flowering plant species: they are thus vital to ecosystem health and agricultural services world-wide. To investigate honey bee exposure to pesticides, 168 pollen samples and 142 wax comb samples were collected from colonies within six stationary apiaries in six U.S. states. These samples were analyzed for evidence of pesticides. Samples were taken bi-weekly when each colony was active. Each apiary included thirty colonies, of which five randomly chosen colonies in each apiary were sampled for pollen. The pollen samples were separately pooled by apiary. There were a total of 714 detections in the collected pollen and 1008 detections in collected wax. A total of 91 different compounds were detected: of these, 79 different pesticides and metabolites were observed in the pollen and 56 were observed in the wax. In all years, insecticides were detected more frequently than were fungicides or herbicides: one third of the detected pesticides were found only in pollen. The mean (standard deviation (SD)) number of detections per pooled pollen sample varied by location from 1.1 (1.1) to 8.7 (2.1). Ten different modes of action were found across all four years and nine additional modes of action occurred in only one year. If synergy in toxicological response is a function of simultaneous occurrence of multiple distinct modes of action, then a high frequency of potential synergies was found in pollen and wax-comb samples. Because only pooled pollen samples were obtained from each apiary, and these from only five colonies per apiary per year, more data are needed to adequately evaluate the differences in pesticide exposure risk to honey bees among colonies in the same apiary and by year and location.


Metabonomic phenotyping reveals an embryotoxicity of deca-brominated diphenyl ether in mice.
Recent studies have demonstrated that polybrominated diphenyl ethers (PBDEs), a group of industrial chemicals, could disrupt thyroid hormone homeostasis and exhibit neurotoxicity, reproductive toxicity, and embryotoxicity. However, clear evidence of embryotoxicity and neurotoxicity of many of these congeners, such as deca-BDE, one of the least bioactive congeners of PBDEs, is still lacking. In the present study, we investigated deca-BDE embryotoxicity by quantitative analysis of two essential thyroid hormones (T4 and T3) and a variety of small-molecule metabolites in the serum of deca-BDE-dosed pregnant mice. Four groups of pregnant C57 mice were administrated with deca-BDE in 20% fat emulsion at a dose of 150, 750, 1,500, or 2,500 mg/kg body weight via gastric intubation on gestation days (g.d.s) 7 to 9, while a control group was given 20% fat emulsion. Maternal mice were euthanized on g.d. 16 and examined for external malformations of the fetus. Maternal serum samples were collected and analyzed by the enzyme linked immunosorbent assay (ELISA) and gas chromatography-time-of-flight mass spectrometry (GC-TOF MS). Using multivariate statistical analysis, we observed a significantly altered metabolic profile associated with deca-BDE embryotoxicity in maternal serum. Our results also demonstrated that deca-BDE at a dose of 2 500 mg/kg body weight induced significant disruption of thyroid hormone metabolism, the TCA cycle, and lipid metabolism in maternal mice, which subsequently led to a significant inhibition of fetal growth and development. We concluded that deca-BDE-induced embryotoxicity closely correlated with global metabolic disruption that can be characterized by thyroid hormone deficiency, disrupted lipid metabolism, and a depleted level of cholesterol in maternal mice.


Advanced methods for evaluating the impact of family planning communication programs: evidence from Tanzania and Nepal.
Evaluations of national family planning communication campaigns are often complicated by nonrandomized research designs and self-reported measures of exposure to media messages, both of which can bias estimates of campaign effectiveness if suitable analytical methods are not employed. This study uses three methods to address these problems: (1) single-equation multiple regression analysis; (2) propensity score matching (PSM); and (3) maximum-likelihood simultaneous equation models (SEM), namely bivariate probit. We use these methods to evaluate the impact of family planning health-communication campaigns on the use of modern family planning methods, focusing primarily on the radio drama Zinduka! in Tanzania and Ghanti Heri Haad Nilaun in Nepal. We find that these methods led to substantially different estimates of the magnitude of the impact of these communication campaigns. Specifically, we found that self-reported exposure to each radio program was exogenously related to family planning use and that PSM and multiple regression analysis gave similar estimates in those situations. An indicator of exposure to any type of family planning message was found to be endogenous, in which case bivariate probit and PSM gave different estimates of program impact. Researchers should, therefore, pay close attention to the results of tests for endogeneity and identification that guide the appropriate use of the different methods.


Theoretical investigation of the signal-to-noise ratio in fluorescence lifetime imaging.
We deduce the signal-to-noise ratio for fluorescence lifetime imaging when using frequency-domain methods. We assume mono-exponential decay and quantum-noise-limited performance. The results are compared with Monte Carlo simulations with good agreement. We also compare our results with previous investigations of time-domain methods for fluorescence lifetime imaging. For a given number of detected photons, we find that frequency-domain and time-domain methods are equally good. The correct choice of detection technique and its parameters is important for obtaining good results.


Opioid-free anaesthesia. Why and how? A contextual analysis.
If the use of natural opiates, such as opium, is more than millennial, the history of synthetic opioids begins after 1950, with the development of the so-called 'modern' anaesthetic techniques. In 1962, in Belgium, the use of fentanyl, the first synthetic opioid for use in anaesthesia, is described. Subsequently, the use of opioids at high doses during surgery became common. However, over the last twenty years, many studies have questioned this practice, highlighting the many unknowns as the side effects of these molecules. The so-called opioid-free anaesthesia (OFA) techniques were developed in parallel with a better understanding of perioperative pain. In this work, the following questions are addressed: Why is the human body producing endogenous opioids? Is the concept of pain valid during general anaesthesia? What are the effects of intraoperative opioids on postoperative pain? Is anaesthesia without opioids actually possible? With these questions, the reader can question the use of intraoperative opioids within an historical and evolutionary perspective. In the same time, if OFA is feasible, the research agenda still includes a formal testing of its added value over classical opioid-sparing techniques.


Associations between cancer and Parkinson's disease in U.S. elderly adults.
Several studies suggest that cancer is reduced before and after a Parkinson's disease (PD) diagnosis. However, determining relationships among diseases of ageing is challenging due to possible biases in ascertaining disease. This study evaluates the PD and cancer relationship, addressing potential biases. Using Surveillance, Epidemiology, and End Results-Medicare linked data (1992-2005) of adults ≥ 65 years, we assessed PD risk after cancer comparing PD in 743 779 cancer patients with PD in a non-cancer group (n = 419 432) in prospective cohort analyses. We also conducted a case-control study of 836 947 cancer cases and 142 869 controls to assess cancer following PD. We applied Cox proportional hazards models to estimate hazards ratios (HRs) for PD after cancer and unconditional logistic regression to estimate odds ratios (ORs) for PD preceding cancer, controlling for physician visits and other factors. To explore biases in ascertaining cancer, we examined relationships between cancer and automobile accident injuries, which we expected to be null. No association was observed between cancer and subsequent PD [HR = 0.97; 95% confidence interval (CI) = 0.92-1.01] nor between cancer and subsequent automobile injuries (HR = 1.03; 95% CI = 0.98-1.07). One site, lung cancer, was associated with subsequent reduced PD, which may reflect confounding by smoking. In the case-control analysis, PD was associated with reduced subsequent cancer, overall (OR = 0.77; 95% CI = 0.71-0.82) and for several cancer sites. However, the automobile injury/ subsequent cancer association was similar (OR = 0.83; 95% CI = 0.78-0.88), suggesting a cancer detection bias after serious health outcomes. In totality, our data do not support a biological relationship between PD and cancer.


Electrical coupling of fibroblasts and myocytes: relevance for cardiac propagation.
Myocytes, while giving rise to the bulk volume of normal cardiac muscle, form a "minority cell population" in the heart compared with nonmyocytes, chiefly fibroblasts. The heterogeneous cell types show very intimate spatial interrelation in situ, with virtually every myocyte in the mammalian heart bordering to 1 or more fibroblasts. Nonetheless, gap junction coupling in the heart is traditionally assumed to occur exclusively between myocytes. Yet, both freshly isolated cells and cell cultures have unambiguously shown functional heterogeneous myocyte-fibroblast coupling (mainly via connexin 43). Such coupling is sufficient, in vitro, to synchronize spontaneous beating in distant myocytes, connected over distances of up to 300 microm by fibroblasts only. More recently, functional myocyte-fibroblast coupling (via connexin 45) has been demonstrated in situ for sinoatrial node pacemaker tissue, and preliminary immunohistochemical data suggest that myocyte-fibroblast coupling may be present in postinfarct scar tissue. The functional relevance of such heterogeneous coupling for cardiac electrophysiology is only starting to emerge and has thus far mainly been assessed in theoretical studies. According to this research, fibroblasts may affect the origin and spread of excitation in several ways above and beyond formation of "passive" barriers that obstruct electrical conduction. Thus, fibroblasts may act as current sinks, contributing to the formation of unidirectional block or to the delay in atrioventricular conduction. Via short-range interaction, fibroblasts may help to smooth out propagating wave fronts, in particular in the sinoatrial node and in the cross-sheet direction of healthy ventricular myocardium, 2 tissues that might otherwise be expected to show fragmented conduction patterns. As long-distance communication lines, fibroblasts may bridge posttransplantation or ischemic scar tissue, with beneficial or detrimental effects on organ function (depending on the relation to normal conduction patterns), and explain the recruitment of myocyte islands embedded in fibrotic scar tissue. The inherent mechanosensitivity of cardiac fibroblasts could, furthermore, allow them to play a sensory role and to affect cardiac electrophysiology via mechanoelectric feedback. This article reviews the currently available experimental and theoretical evidence on the previous scenarios, and highlights areas for further research.


Learning Curve and Associated Morbidity of Minimally Invasive Esophagectomy: A Retrospective Multicenter Study.
To investigate the morbidity that is associated with the learning curve of minimally invasive esophagectomy. Although learning curves have been described, it is currently unknown how much extra morbidity is associated with the learning curve of technically challenging surgical procedures. Prospectively collected data were retrospectively analyzed of all consecutive patients undergoing minimally invasive Ivor Lewis esophagectomy in 4 European expert centers. The primary outcome parameter was anastomotic leakage. Secondary outcome parameters were operative time and textbook outcome ("optimal outcome"). Learning curves were plotted using weighted moving average and CUSUM analysis was used to determine after how many cases the plateau was reached. Learning associated morbidity was calculated with area under the curve analysis. This study included 646 patients. Three of the 4 hospitals reached the plateau of 8% anastomotic leakage. The length of the learning curve was 119 cases. The mean incidence of anastomotic leakage decreased from 18.8% during the learning phase to 4.5% after the plateau had been reached (P < 0.001). Thirty-six extra patients (10.1% of all patients operated on during the learning curve) experienced learning associated anastomotic leakage, that could have been avoided if patients were operated by surgeons who had completed the learning curve. The incidence of textbook outcome increased from 28% to 53% and the mean operative time decreased from 344 minutes to 270 minutes. A considerable number of 36 extra patients (10.1%) experienced learning associated anastomotic leakage. More research is urgently needed to investigate how learning associated morbidity can be reduced to increase patient safety during learning curves.


Case series: amantadine open-label treatment of impulsive and aggressive behavior in hospitalized children with developmental disabilities.
A growing body of literature implicates interactions between glutamatergic and neostriatal dopaminergic neurotransmitter systems in the development and expression of impulsivity, hyperactivity, and stereotypy. Amantadine hydrochloride, a drug used in young children for influenza prophylaxis, acts both as an indirect dopamine agonist as well as an N-methyl-D-aspartate (NMDA) receptor antagonist. Thus an open clinical trial of this medication for the treatment of symptoms of impulse control disorders in children was performed. A total of eight children (seven with neurodevelopmental disorders and all inpatients) with target behaviors refractory to other treatments were selected after parental informed consent. All patients were male and ranged in age from 4 to 12 years. Outcome was based on subjective consensus clinical ratings by the multidisciplinary treatment team. For four of the children, amantadine was associated with marked clinical improvement. In the remainder, improvement was also observed. Amantadine was well tolerated. On the basis of this experience, it appears that amantadine hydrochloride or related NMDA antagonists may warrant additional study in this and related populations.


Bertioga (Guama group) and Anhembi (Bunyamwera group), two new arboviruses isolated in São Paulo, Brazil.
Bertioga and Anhembi are two newly recognized arboviruses that were isolated in Saõ Paulo, Brazil. Bertioga was isolated from sentinel mice exposed in a forest of that name, and was shown to belong serologically to the Guama group of arboviruses. Anhembi, the second virus described, was isolated from pools of mosquitoes (Phoniomyia pilicauda and trichoprosopon pallidiventer), and from a spiny rat (Proechimys iheringi), and was shown to be a new member of the Bunyamwera group. The viruses are sensitive to sodium desoxycholate and are filterable through a millipore membrane of 450 mum pore size. Both are pathogenic for suckling mice and grow well in Vero cells, producing clear cytopathic effects. Detailed antigenic comparisons of Anhembi virus with other members of the Bunyamwera group isolated in the Americas, and of Bertioga virus with the members of the Guama group are presented. Both are believed to be new arboviruses in their groups.


On the origin and timing of Zika virus introduction in Brazil.
The timing and origin of Zika virus (ZIKV) introduction in Brazil has been the subject of controversy. Initially, it was assumed that the virus was introduced during the FIFA World Cup in June-July 2014. Then, it was speculated that ZIKV may have been introduced by athletes from French Polynesia (FP) who competed in a canoe race in Rio de Janeiro in August 2014. We attempted to apply mathematical models to determine the most likely time window of ZIKV introduction in Brazil. Given that the timing and origin of ZIKV introduction in Brazil may be a politically sensitive issue, its determination (or the provision of a plausible hypothesis) may help to prevent undeserved blame. We used a simple mathematical model to estimate the force of infection and the corresponding individual probability of being infected with ZIKV in FP. Taking into account the air travel volume from FP to Brazil between October 2013 and March 2014, we estimated the expected number of infected travellers arriving at Brazilian airports during that period. During the period between December 2013 and February 2014, 51 individuals travelled from FP airports to 11 Brazilian cities. Basing on the calculated force of ZIKV infection (the per capita rate of new infections per time unit) and risk of infection (probability of at least one new infection), we estimated that 18 (95% CI 12-22) individuals who arrived in seven of the evaluated cities were infected. When basic ZIKV reproduction numbers greater than one were assumed in the seven evaluated cities, ZIKV could have been introduced in any one of the cities. Based on the force of infection in FP, basic reproduction ZIKV number in selected Brazilian cities, and estimated travel volume, we concluded that ZIKV was most likely introduced and established in Brazil by infected travellers arriving from FP in the period between October 2013 and March 2014, which was prior to the two aforementioned sporting events.


Antimicrobial resistance in Salmonella enterica subsp. enterica serovar typhimurium from humans and production animals.
We have studied the frequency of antimicrobial resistance and epidemiological relatedness among 473 isolates of Salmonella enterica subsp. enterica serovar typhimurium (S. typhimurium) from human and veterinary sources. The human strains were clinical isolates from patients with diarrhoea sent to the State Serum Institute during August 1993 (228 isolates). The animal strains were isolated from clinical or subclinical infections in cattle (48 isolates), pigs (99 isolates) or poultry (98 isolates), all from 1993. All strains were tested against 22 different antimicrobial agents used in both human and veterinary medicine with the tablet diffusion method. Strains were also phage-typed and the plasmid content determined in all resistant strains. Ribotyping was performed on selected strains. Of 228 human isolates tested, 19.3% of the strains were resistant to one or more antimicrobial agent compared with 10.4% of strains from cattle, 11.1% of strains from pigs and 9.2% of strains from poultry. Multiple resistance, i.e. resistance against at least four antimicrobial agents, was found in 9.2% of the human strains, but in only two of the cattle isolates. The majority of the multi-resistant strains in humans were from infections contracted outside Denmark, most often in southern Europe or south-east Asia. Resistance in human strains was most common against tetracycline (13%), ampicillin (12%), sulphonamide (12%), streptomycin (10%) and chloramphenicol (8%). The resistance pattern differed somewhat in animal isolates: Poultry strains were usually resistant only to ampicillin, while pig and cattle isolates were most often resistant to sulphonamide, tetracycline and streptomycin. Typing of the strains showed that some animal strains and human strains were indistinguishable. In conclusion, while antimicrobial resistance was present in S. typhimurium isolated from humans and animals in Denmark, multiple resistance was most often acquired outside Denmark.


A systematic comparison of genome-scale clustering algorithms.
A wealth of clustering algorithms has been applied to gene co-expression experiments. These algorithms cover a broad range of approaches, from conventional techniques such as k-means and hierarchical clustering, to graphical approaches such as k-clique communities, weighted gene co-expression networks (WGCNA) and paraclique. Comparison of these methods to evaluate their relative effectiveness provides guidance to algorithm selection, development and implementation. Most prior work on comparative clustering evaluation has focused on parametric methods. Graph theoretical methods are recent additions to the tool set for the global analysis and decomposition of microarray co-expression matrices that have not generally been included in earlier methodological comparisons. In the present study, a variety of parametric and graph theoretical clustering algorithms are compared using well-characterized transcriptomic data at a genome scale from Saccharomyces cerevisiae. For each clustering method under study, a variety of parameters were tested. Jaccard similarity was used to measure each cluster's agreement with every GO and KEGG annotation set, and the highest Jaccard score was assigned to the cluster. Clusters were grouped into small, medium, and large bins, and the Jaccard score of the top five scoring clusters in each bin were averaged and reported as the best average top 5 (BAT5) score for the particular method. Clusters produced by each method were evaluated based upon the positive match to known pathways. This produces a readily interpretable ranking of the relative effectiveness of clustering on the genes. Methods were also tested to determine whether they were able to identify clusters consistent with those identified by other clustering methods. Validation of clusters against known gene classifications demonstrate that for this data, graph-based techniques outperform conventional clustering approaches, suggesting that further development and application of combinatorial strategies is warranted.


Analyzing large-scale conservation interventions with Bayesian hierarchical models: a case study of supplementing threatened Pacific salmon.
Myriad human activities increasingly threaten the existence of many species. A variety of conservation interventions such as habitat restoration, protected areas, and captive breeding have been used to prevent extinctions. Evaluating the effectiveness of these interventions requires appropriate statistical methods, given the quantity and quality of available data. Historically, analysis of variance has been used with some form of predetermined before-after control-impact design to estimate the effects of large-scale experiments or conservation interventions. However, ad hoc retrospective study designs or the presence of random effects at multiple scales may preclude the use of these tools. We evaluated the effects of a large-scale supplementation program on the density of adult Chinook salmon Oncorhynchus tshawytscha from the Snake River basin in the northwestern United States currently listed under the U.S. Endangered Species Act. We analyzed 43 years of data from 22 populations, accounting for random effects across time and space using a form of Bayesian hierarchical time-series model common in analyses of financial markets. We found that varying degrees of supplementation over a period of 25 years increased the density of natural-origin adults, on average, by 0-8% relative to nonsupplementation years. Thirty-nine of the 43 year effects were at least two times larger in magnitude than the mean supplementation effect, suggesting common environmental variables play a more important role in driving interannual variability in adult density. Additional residual variation in density varied considerably across the region, but there was no systematic difference between supplemented and reference populations. Our results demonstrate the power of hierarchical Bayesian models to detect the diffuse effects of management interventions and to quantitatively describe the variability of intervention success. Nevertheless, our study could not address whether ecological factors (e.g., competition) were more important than genetic considerations (e.g., inbreeding depression) in determining the response to supplementation.


Tumor proteomic profiling predicts the susceptibility of breast cancer to chemotherapy.
Chemotherapy is often used for breast cancer treatment, but individual outcome varies widely. We hypothesized that tumor proteomic profiles obtained prior to chemotherapy may predict the individual tumor response to treatment. The goal of our study was to explore feasibility of using proteomic profiling to preselect patients for an effective chemotherapeutic regimen. Tumors from 52 patients with T2-T4 breast cancer were prospectively collected before neoadjuvant chemotherapy, and were analyzed using surface-enhanced laser desorption ionization/time of flight (SELDI) mass spectrometry. Mass spectral profiles were obtained from tumors with various sensitivities to chemotherapy. Both non-supervised hierarchical clustering and supervised neural network-based classification approaches were employed to compare the profiles. The first two thirds of the enrolled cases (35) were allocated to a training set to select peaks characteristic of resistant tumors. The candidate peaks were used to develop a predicting rule to evaluate the remaining 17 specimens in the validation set. In the training set, the most prominent differences were found between drug resistant and drug susceptible tumors by non-supervised hierarchical clustering. In the validation set, the supervised classification with the K nearest neighbor (KNN) model correctly classified most tumor responses with an accuracy rate of 92.3% [100% of resistant tumors (4/4), and 84.6% of the tumors with favorable response (11/13)]. In the entire group, a single peak at m/z 16,906 correctly separated 88.9% of the tumors with pathologically complete response, and 91.7% of the resistant tumors. The data suggest that breast cancer protein biomarkers may be used to pre-select patients for optimal chemotherapeutic treatment.


NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation.
Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n = 38) and from FGR (n = 40) and age-matched controls (n = 32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies. KEY MESSAGES: NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.


Mapping EST-derived SSRs and ESTs involved in resistance to bacterial blight in Manihot esculenta.
Cassava (Manihot esculenta Crantz) is a major root crop widely grown in the tropics. Cassava bacterial blight, caused by Xanthomonas axonopodis pv. manihotis (Xam), is an important disease in Latin America and Africa resulting in significant losses. The preferred control method is the use of resistant genotypes. Mapping expressed sequence tags (ESTs) and determining their co-localization with quantitative trait loci (QTLs) may give additional evidence of the role of the corresponding genes in resistance or defense. Twenty-one EST-derived simple sequence repeats (SSRs) were mapped in 16 linkage groups. ESTs showing similarities with candidate resistance genes or defense genes were also mapped using strategies such as restriction fragment length polymorphisms, cleaved amplified polymorphic sequences, and allele-specific primers. In total, 10 defense-related genes and 2 bacterial artificial chromosomes (BACs) containing resistance gene candidates (RGCs) were mapped in 11 linkage groups. Two new QTLs associated with resistance to Xam strains CIO121 and CIO151 were detected in linkage groups A and U, respectively. The QTL in linkage group U explained 61.6% of the phenotypic variance and was associated with an RGC-containing BAC. No correlation was found between the new EST-derived SSRs or other mapped ESTs and the new or previously reported QTLs.


Normal Gaze Cueing in Children with Autism Is Disrupted by Simultaneous Speech Utterances in "Live" Face-to-Face Interactions.
Gaze cueing was assessed in children with autism and in typically developing children, using a computer-controlled "live" face-to-face procedure. Sensitivity to gaze direction was assessed using a Posner cuing paradigm. Both static and dynamic directional gaze cues were used. Consistent with many previous studies, using photographic and cartoon faces, gaze cueing was present in children with autism and was not developmentally delayed. However, in the same children, gaze cueing was abolished when a mouth movement occurred at the same time as the gaze cue. In contrast, typical children were able to use gaze cues in all conditions. The findings indicate that gaze cueing develops successfully in some children with autism but that their attention is disrupted by speech utterances. Their ability to learn to read nonverbal emotional and intentional signals provided by the eyes may therefore be significantly impaired. This may indicate a problem with cross-modal attention control or an abnormal sensitivity to peripheral motion in general or the mouth region in particular.


Acute cardiorespiratory, perceptual and enjoyment responses to high-intensity interval exercise in adolescents.
This study aimed to examine adolescents' acute cardiorespiratory and perceptual responses during high-intensity interval exercise (HIIE) and enjoyment responses following HIIE and work-matched continuous moderate intensity exercise (CMIE). Fifty-four 12- to 15-year olds (27 boys) completed 8 × 1-min cycling at 90% peak power with 75-s recovery (HIIE) and at 90% of the gas exchange threshold (CMIE). Absolute oxygen uptake ([Formula: see text]), percentage of maximal [Formula: see text] (%[Formula: see text]), heart rate (HR), percentage of maximal HR (%HRmax) and ratings of perceived exertion (RPE) were collected during HIIE. Enjoyment was measured using the physical activity enjoyment scale (PACES) following HIIE and CMIE. Boys elicited higher absolute [Formula: see text] during HIIE work (p < .01, effect size (ES) > 1.22) and recovery (p < .02, ES > 0.51) intervals but lower %[Formula: see text] during HIIE recovery intervals compared to girls (p < .01, ES > 0.67). No sex differences in HR and %HRmax were evident during HIIE and 48 participants attained ≥90% HRmax. Boys produced higher RPE at intervals 6 (p = .004, ES = 1.00) and 8 (p = .003, ES = 1.00) during HIIE. PACES was higher after HIIE compared with CMIE (p = .003, ES = 0.58). Items from PACES "I got something out of it", "It's very exciting" and "It gives me a strong feeling of success" were higher after HIIE (all p < .01, ES > 0.32). The items "I feel bored" and "It's not at all interesting" were higher after CMIE (all p < .01, ES > 0.46). HIIE elicits a maximal cardiorespiratory response in most adolescents. Greater enjoyment after HIIE was due to elevated feelings of reward, excitement and success and may serve as a strategy to promote health in youth.


Life Span Studies of ADHD-Conceptual Challenges and Predictors of Persistence and Outcome.
There is a renewed interest in better conceptualizing trajectories of attention-deficit/hyperactivity disorder (ADHD) from childhood to adulthood, driven by an increased recognition of long-term impairment and potential persistence beyond childhood and adolescence. This review addresses the following major issues relevant to the course of ADHD in light of current evidence from longitudinal studies: (1) conceptual and methodological issues related to measurement of persistence of ADHD, (2) estimates of persistence rate from childhood to adulthood and its predictors, (3) long-term negative outcomes of childhood ADHD and their early predictors, and (4) the recently proposed new adult-onset ADHD. Estimates of persistence vary widely in the literature, and diagnostic criteria, sample characteristics, and information source are the most important factors explaining variability among studies. Evidence indicates that ADHD severity, comorbid conduct disorder and major depressive disorder, and treatment for ADHD are the main predictors of ADHD persistence from childhood to adulthood. Comorbid conduct disorder and ADHD severity in childhood are the most important predictors of adverse outcomes in adulthood among children with ADHD. Three recent population studies suggested the existence of a significant proportion of individuals who report onset of ADHD symptoms and impairments after childhood. Finally, we highlight areas for improvement to increase our understanding of ADHD across the life span.


Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease.
Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease.


Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial.
Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.


Avian circannual clocks: adaptive significance and possible involvement of energy turnover in their proximate control.
Endogenous circannual clocks are found in many long-lived organisms, but are best studied in mammal and bird species. Circannual clocks are synchronized with the environment by changes in photoperiod, light intensity and possibly temperature and seasonal rainfall patterns. Annual timing mechanisms are presumed to have important ultimate functions in seasonally regulating reproduction, moult, hibernation, migration, body weight and fat deposition/stores. Birds that live in habitats where environmental cues such as photoperiod are poor predictors of seasons (e.g. equatorial residents, migrants to equatorial/tropical latitudes) rely more on their endogenous clocks than birds living in environments that show a tight correlation between photoperiod and seasonal events. Such population-specific/interspecific variation in reliance on endogenous clocks may indicate that annual timing mechanisms are adaptive. However, despite the apparent adaptive importance of circannual clocks, (i) what specific adaptive value they have in the wild and (ii) how they function are still largely untested. Whereas circadian clocks are hypothesized to be generated by molecular feedback loops, it has been suggested that circannual clocks are either based upon (i) a de-multiplication ('counting') of circadian days, (ii) a sequence of interdependent physiological states, or (iii) one or more endogenous oscillators, similar to circadian rhythms. We tested the de-multiplication of days (i) versus endogenous regulation hypotheses (ii) and (iii) in captive male and female house sparrows (Passer domesticus). We assessed the period of reproductive (testicular and follicular) cycles in four groups of birds kept either under photoperiods of LD 12L:12D (period length: 24h), 13.5L:13.5D (27 h), 10.5L:10.5D (23 h) or 12D:8L:3D:1L (24-h skeleton photoperiod), respectively, for 15 months. Contrary to predictions from the de-multiplication hypothesis, individuals experiencing 27-h days did not differ (i.e. did not have longer) annual reproductive rhythms than individuals from the 21- or 24-h day groups. However, in line with predictions from endogenous regulation, birds in the skeleton group had significantly longer circannual period lengths than all other groups. Birds exposed to skeleton photoperiods experienced fewer light hours per year than all other groups (3285 versus 4380) and had a lower daily energy expenditure, as tested during one point of the annual cycle using respirometry. Although our results are tantalizing, they are still preliminary as birds were only studied over a period of 15 months. Nevertheless, the present data fail to support a 'counting of circadian days' and instead support hypotheses proposing whole-organism processes as the mechanistic basis for circannual rhythms. We propose a novel energy turnover hypothesis which predicts a dependence of the speed of the circannual clock on the overall energy expenditure of an organism.


Gold nanowire based electrical DNA detection using rolling circle amplification.
We present an electrical sensor that uses rolling circle amplification (RCA) of DNA to stretch across the gap between two electrodes, interact with metal nanoparticle seeds to generate an electrically conductive nanowire, and produce electrical signals upon detection of specific target DNA sequences. RCA is a highly specific molecular detection mechanism based on DNA probe circularization. With this technique, long single-stranded DNA with simple repetitive sequences are produced. Here we show that stretched RCA products can be metalized using silver or gold solutions to form metal wires. Upon metallization, the resistance drops from TΩ to kΩ for silver and to Ω for gold. Metallization is seeded by gold nanoparticles aligned along the single-stranded DNA product through hybridization of functionalized oligonucleotides. We show that combining RCA with electrical DNA detection produces results in readout with very high signal-to-noise ratio, an essential feature for sensitive and specific detection assays. Finally, we demonstrate detection of 10 ng of Escherichia coli genomic DNA using the sensor concept.


Tailoring pharmacotherapy to specific eating behaviours in obesity: Can recommendations for personalised therapy be made from the current data?
Pharmacotherapy provides an adjunct to behaviour modification in the management of obesity. There are a number of new drug therapies purportedly targeting appetite; liraglutide, and bupropion/naltrexone, which are European Medicines Agency and US Food and Drug Administration (FDA) approved, and lorcaserin and phentermine/topiramate, which have FDA approval only. Each of the six drugs, used singly or in combination, has distinct pharmacological, and presumably distinct behavioural, mechanisms of action, thus the potential to provide defined therapeutic options to personalise the management of obesity. Yet, with regard to pharmacotherapy for obesity, we are far from true personalised medicine. We review the limited mechanistic data with four mono and combination pharmacotherapies, to assess the potential for tailoring their use to target specific obesogenic behaviours. Potential treatment options are considered, but in the absence of adequate research in respect to effects of these drugs on eating behaviour, neural activity and psychological substrates that underlie poorly controlled eating, we are far from definitive therapeutic recommendations. Specific mechanistic studies and broader behavioural phenotyping, possibly in conjunction with pharmacogenetic research, are required to characterise responders for distinct pharmacotherapeutic options.


A Histopathologic Scoring System for Perineural Invasion Correlates With Adverse Outcomes in Patients With Cutaneous Squamous Cell Carcinoma.
Perineural invasion (PNI) is a known risk factor for recurrence, metastasis, and death in cutaneous squamous cell carcinoma (cSCC). Current staging systems include PNI, but none define its extent or severity. To identify histopathologic features of cSCC with PNI that may be associated with adverse outcomes. This is a retrospective cohort study that included 45 patients with cSCC and PNI treated with surgical excision. Histopathologic slides were analyzed for 5 features of PNI: largest affected nerve diameter, number of nerves affected, depth of nerve involvement, intra- versus extratumoral PNI, and focal versus circumferential PNI. The median largest affected nerve diameter was 0.13 mm, and the median number of nerve structures involved was 4. After a median follow-up time of 24 months, 6 patients developed adverse outcomes, including 2 local recurrences, 4 metastases, and 2 tumor-related deaths. Univariate logistic regression analysis revealed that nerve diameter and number of affected nerves were significantly associated with adverse outcome. A composite PNI score, calculated from 5 histopathologic features, was the strongest predictor of adverse outcome (p = .020). Histopathologic features of PNI can be quantified with a composite PNI score that is significantly associated with adverse outcomes in cSCC.


Relative lack of conditional survival improvement in young adults with cancer.
Cancer prognosis is usually reported in terms of survival from time of diagnosis. For patients surviving a period of time after diagnosis, conditional survival (CS) accounts for changing risk over time. This report provides information on how CS in cancer patients changes as a function of age at diagnosis. Using data from the US Surveillance, Epidemiology and End Results database, we examined survival for patients diagnosed between 1973 and 2002. The average annual percent change (AAPC) in CS during the first 5 years after diagnosis was evaluated for the 14 most common cancers occurring in young adults, defined as 15- to 39-year-olds, and how they compared with cancers that are more common in older and younger patients. For all cancers, young adult patients had less CS improvement over time than younger or older patients, and this difference was most pronounced in those aged 20 to 29 years (45% below the mean). Eleven of the 14 most common cancers in 15- to 39-year-olds either had a lower CS improvement after diagnosis than either younger or older patients, or than just the older patients. Young adults with leukemia had the greatest improvement in CS over time. In conclusion, young adults with cancer have not enjoyed the same improvement in CS over time compared with other age groups. Explanations for this deficit include the biologic nature of the type of cancers in young adults and less effective therapies for patients in the age group. Regardless of the reasons, the deficit is yet another challenge faced by young adult patients that merits further study.


Model-based global analysis of heterogeneous experimental data using gfit.
Regression analysis is indispensible for quantitative understanding of biological systems and for developing accurate computational models. By applying regression analysis, one can validate models and quantify components of the system, including ones that cannot be observed directly. Global (simultaneous) analysis of all experimental data available for the system produces the most informative results. To quantify components of a complex system, the dataset needs to contain experiments of different types performed under a broad range of conditions. However, heterogeneity of such datasets complicates implementation of the global analysis. Computational models continuously evolve to include new knowledge and to account for novel experimental data, creating the demand for flexible and efficient analysis procedures. To address these problems, we have developed gfit software to globally analyze many types of experiments, to validate computational models, and to extract maximum information from the available experimental data.


Impact of distance and facility of initial diagnosis on depression treatment.
To assess whether distance to services or diagnosis at a hospital-based medical center compared with a community clinic influences the receipt of psychotherapy versus pharmacotherapy for depression. Veterans Affairs (VA) administrative data for 132,329 depressed veterans between October 2003 and September 2004. Multivariable logistic and multinomial regression models were used to examine the relationship between distance to the nearest mental health facility and the facility of initial depression diagnosis on receipt of any and adequate psychotherapy and/or pharmacotherapy, adjusted for patient characteristics. Compared with those living within 30 miles of the nearest mental health treatment facility, depressed patients living between 30 and 60 miles away had a decreased likelihood of receiving psychotherapy (OR=0.71; 95 percent CI: 0.66, 0.76) and a greater likelihood of receiving antidepressant treatment (OR=1.27; 95 percent CI: 1.22, 1.33). Initial diagnosis at a small community clinic compared with a VA medical center was not associated with a difference in receipt of any psychotherapy (OR=0.95; 95 percent CI: 0.83, 1.09), but it was associated with decreased likelihood of receiving eight or more psychotherapy visits (OR=0.46; 95 percent CI: 0.35, 0.61) or any antidepressant treatment (OR=0.69; 95 percent CI: 0.63, 0.75). The VA and similar health systems should make efforts to insure adequate psychotherapy is provided to patients who initiate treatment at small community clinics and provide psychotherapy alternatives that may be less sensitive to travel barriers for patients living remote distances from mental health treatment. Extending services to small community clinics that support antidepressant treatment should also be considered.


Macrophage secretory IL-1β promotes docetaxel resistance in head and neck squamous carcinoma via SOD2/CAT-ICAM1 signaling.
Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the development of acquired resistance remains a major obstacle to treatment response. Tumor-associated macrophages are associated with chemotherapeutic resistance. In the present study, increased infiltration of macrophages into the tumor microenvironment (TME) was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX, in patients with HNSCC. Macrophage coculture induced expression of intercellular adhesion molecule 1 (ICAM1), which promotes stemness and the formation of polyploid giant cancer cells, thereby reducing the efficacy of DTX. Both genetic silencing and pharmacological inhibition of ICAM1 sensitized HNSCC to DTX. Macrophage secretion of IL-1β was found to induce tumor expression of ICAM1. IL-1β neutralization and IL-1 receptor blockade reversed DTX resistance induced by macrophage coculture. IL-1β activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of ROS and inducing ICAM1 expression. Arsenic trioxide (ATO) reduced macrophage infiltration into the TME and impaired IL-1β secretion by macrophages. The combinatorial use of ATO enhanced the in vivo efficacy of DTX in a mouse model, which may provide a revolutionary approach to overcoming acquired therapeutic resistance in HNSCC.


Rapid wavelength-swept spectrally encoded confocal microscopy.
Spectrally encoded confocal microscopy (SECM) is a technique that allows confocal microscopy to be performed through the confines of a narrow diameter optical fiber probe. We present a novel scheme for performing SECM in which a rapid wavelength swept source is used. The system allows large field of view images to be acquired at rates up to 30 frames/second. Images of resolution targets and tissue specimens acquired ex vivo demonstrate high lateral (1.4 mum) and axial (6 mum) resolution. Imaging of human skin was performed in vivo at depths of up to 350 mum, allowing cellular and sub-cellular details to be visualized in real time.


Career plans and views of trainees in the Academic Clinical Fellowship Programme in England.
The Academic Clinical Fellowship (ACF) programme in England was introduced in 2007 to support the training of clinical academics. To report on career plans and views of ACF trainees. Questionnaire survey of trainees appointed in 2008. Of 102 responders, 63% expected to work eventually wholly in clinical academic posts, 34% in clinical service posts with some teaching and research, and none in clinical service posts with no teaching or research. Of factors that had influenced the choice of an academic career 'a great deal', 83% of responders cited having a 'varied and stimulating career', 79% the 'intellectual environment' of academic departments, 78% the 'challenge of research' and 62% the 'stimulation of teaching'. The most important factors that might dissuade them from eventually pursuing an academic career were 'difficulty obtaining research grants' (specified by 42%), followed by 'competing pressures in the three areas of research, clinical work and teaching', lack of 'pay parity with NHS colleagues', and concerns about adequate availability of academic posts at senior levels. The responders were highly motivated by the challenges of academic work. However, policymakers need to consider what, if anything, might realistically be done about potentially demotivating factors.


Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
Apoptosis in vivo is followed almost inevitably by rapid uptake into adjacent phagocytic cells, a critical process in tissue remodeling, regulation of the immune response, or resolution of inflammation. Phagocytosis of apoptotic cells by macrophages has been suggested to be a quiet process that does not lead to production of inflammatory mediators. Here we show that phagocytosis of apoptotic neutrophils (in contrast to immunoglobulin G-opsonized apoptotic cells) actively inhibited the production of interleukin (IL)-1beta, IL-8, IL-10, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-alpha, as well as leukotriene C4 and thromboxane B2, by human monocyte-derived macrophages. In contrast, production of transforming growth factor (TGF)-beta1, prostaglandin E2, and platelet-activating factor (PAF) was increased. The latter appeared to be involved in the inhibition of proinflammatory cytokine production because addition of exogenous TGF-beta1, prostaglandin E2, or PAF resulted in inhibition of lipopolysaccharide-stimulated cytokine production. Furthermore, anti-TGF-beta antibody, indomethacin, or PAF receptor antagonists restored cytokine production in lipopolysaccharide-stimulated macrophages that had phagocytosed apoptotic cells. These results suggest that binding and/or phagocytosis of apoptotic cells induces active antiinflammatory or suppressive properties in human macrophages. Therefore, it is likely that resolution of inflammation depends not only on the removal of apoptotic cells but on active suppression of inflammatory mediator production. Disorders in either could result in chronic inflammatory diseases.


Depth-resolved low-coherence enhanced backscattering.
The phenomenon of enhanced backscattering (also known as coherent backscattering), an object of substantial scientific interest, has awaited application to tissue optics for the past two decades. Here we demonstrate, for the first time to our knowledge, depth-resolved spectroscopic elastic light scattering measurements in tissue by use of low-coherence enhanced backscattering (LEBS). We achieve the depth resolution by exploiting the nature of the LEBS peak that contains information about a wide range of tissue depths. We further demonstrate that depth-resolved LEBS spectroscopy has the potential to identify the origin of precancerous transformations in the colon at an early, previously undetectable stage.


Treatment outcomes of childhood tuberculosis in Addis Ababa: a five-year retrospective analysis.
Tuberculosis (TB) kills one child every 5 min. Childhood TB is given low priority in most national health programmes particularly in TB-endemic areas. TB among children is an indicator of a recent transmission of the disease in the community. Treatment outcome results serve as a proxy of the quality of treatment provided by a health care system. In Ethiopia, data on treatment outcomes of childhood TB are limited. The aim of the study was to determine the treatment outcomes of childhood TB in a hospital setting in Addis Ababa. The study was conducted during June to August 2014. The data of 491 children treated for TB in Zewditu Memorial Hospital during a 5 year (2009-2013) was analysed. TB was diagnosed using standard methods. Demographic and clinical data including type of TB, TB-HIV co-infection and treatment outcomes were collected from registry of the TB clinic. Treatment outcome definitions are used according to the World Health Organization. Of the 491 children, 272(55.4 %) were females, 107(21.8 %) were under 5 year old, 454(92.5 %) of them were new cases. The types of TB were extra-pulmonary tuberculosis (EPTB) 243(49.5 %) and 248(50.5 %) pulmonary tuberculosis (PTB). Of the PTB cases, 42(16.9 %) were sputum smear positive. Of the 291 children tested for HIV, 82(28.2 %) were positive. The overall treatment success rate was 420(85.5 %) and the poor treatment outcome was 71(14.5 %). Of the children with poor treatment outcome, 9(1.8 %) died, 3(0.6 %) defaulted from treatment, 2(0.4 %) were treatment failure and 55(11.2 %) were transferred out. Males and females had similar treatment success rates of 85.8 % and 85.3 %, respectively. Infants under one year had significantly lower treatment success rate of 72.7 % compared to those above 1 years of age of 86.5 % (P < 0.001). Treatment success rate ranged from 78.0 to 92.6 % during the study period. Associated factors for treatment outcome were age above 5 years (AOR = 0.59, 95 % CI: 0.62-0.97) and seropositive for HIV infection (AOR = 6.66, 95 % CI: 3.07-14.47). The treatment success rate in this study is 85.5 %. The outcome of treatment varied with age, and presence of HIV infection. In order to the further improve of treatment success rate, continuous follow up with frequent support of patients during treatment course and strengthen the recording system are strongly recommend.


The Complete Genome Sequence of the Fish Pathogen Tenacibaculum maritimum Provides Insights into Virulence Mechanisms.
Tenacibaculum maritimum is a devastating bacterial pathogen of wild and farmed marine fish with a broad host range and a worldwide distribution. We report here the complete genome sequence of the T. maritimum type strain NCIMB 2154T. The genome consists of a 3,435,971-base pair circular chromosome with 2,866 predicted protein-coding genes. Genes encoding the biosynthesis of exopolysaccharides, the type IX secretion system, iron uptake systems, adhesins, hemolysins, proteases, and glycoside hydrolases were identified. They are likely involved in the virulence process including immune escape, invasion, colonization, destruction of host tissues, and nutrient scavenging. Among the predicted virulence factors, type IX secretion-mediated and cell-surface exposed proteins were identified including an atypical sialidase, a sphingomyelinase and a chondroitin AC lyase which activities were demonstrated in vitro.


Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable.
Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation (AF) but increases hemorrhage. To quantify the net benefit of adding clopidogrel to aspirin therapy, accounting for differences in clinical significance between ischemic and hemorrhagic events. Observational cohort study to assign the relative weighting of events and post hoc analysis of randomized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) clinical trials. Global randomized clinical trial. 10,041 patients with AF, 7554 of whom were not candidates for warfarin therapy. Ischemic events (ischemic stroke or myocardial infarction) and hemorrhagic events (hemorrhagic stroke or subdural or extracranial bleeding), weighted by the hazard ratio for death (or death or disability) after an event relative to death (or death or disability) after ischemic stroke. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patients years. Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent (95% CI, -0.12 to 1.24) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent (CI, -0.03 to 1.18) when weighted by death or disability after ischemia or hemorrhage. No attempt was made to relate deaths used for weighting to events; disability data were missing for more than one half of patients. Adding clopidogrel to aspirin therapy resulted in a modest net benefit among patients with AF for whom warfarin was unsuitable. The benefit would probably be clinically relevant for some patients, but estimates could not exclude the possibility of either no benefit or very small harm in this population. Bristol-Myers Squibb and sanofi-aventis.


The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy.
TNF superfamily member 13 (TNFSF13) has been identified as a susceptibility gene for IgA nephropathy in recent genetic studies. However, the role of TNFSF13 in the progression of IgA nephropathy remains unresolved. We evaluated two genetic polymorphisms (rs11552708 and rs3803800) and plasma levels of TNFSF13 in 637 patients with IgA nephropathy, and determined the risk of ESRD according to theses variable. Neither of the examined genetic polymorphisms associated with a clinical outcome of IgA nephropathy. However, high plasma levels of TNFSF13 increased the risk of ESRD. To explore the causal relationship and underlying mechanism, we treated B cells from patients (n=21) with or without recombinant human TNFSF13 (rhTNFSF13) and measured the expression of IgA and galactose-deficient IgA (GdIgA) using ELISA and flow cytometry. Treatment with rhTNFSF13 significantly increased the total IgA level among B cells, and TNFSF13 receptor blockade abrogated this increase. Furthermore, the absolute levels of GdIgA increased with rhTNFSF13 treatment, but the total IgA-normalized levels did not change. Both RNA sequencing and quantitative PCR results showed that rhTNFSF13 did not alter the expression of glycosyltransferase enzymes. These results suggest that high plasma TNFSF13 levels associate with a worse prognosis of IgA nephropathy through the relative increase in GdIgA levels.


Identification and genetic mapping of a new polycystic kidney disease on mouse chromosome 8.
We report here a new mouse mutation, kat, that causes pleiotropic effects including facial dysmorphism, dwarfing, male sterility, anemia, and progressive polycystic kidney disease. kat (kidney anemia and testis) and a second allele, kat2J, that occurred on C57BL/ 6J were mapped to mouse chromosome (Chr) 8 using intra- and intersubspecific intercrosses. A high-resolution map for kat2J on Chr 8 was constructed using the F2 progeny from a cross between C57BL/6J-kat2J/+ and an inbred strain of Mus musculus castaneus (CAST/Ei). The kat2J mutation was localized between D8Mit129 and D8Mit128 with the gene order centromere-D8Mit100-(1.2 +/- 0.26 cM)-D8Mit231-(0.17 +/- 0.09 cM)-D8Mit129-(0.28 +/- 0.12 cM)-D8Mit128-(0.98 +/- 0.23 cM)-D8Mit25/D8Mit8. This segment is homologous to human Chr 19p. The two mutations at this locus that have occurred at The Jackson Laboratory will be invaluable for positional cloning and subsequent functional analysis of the mutated gene.


Do generic utility measures capture what is important to the quality of life of people with multiple sclerosis?
The three most widely used utility measures are the Health Utilities Index Mark 2 and 3 (HUI2 and HUI3), the EuroQol-5D (EQ-5D) and the Short-Form-6D (SF-6D). In line with guidelines for economic evaluation from agencies such as the National Institute for Health and Clinical Excellence (NICE) and the Canadian Agency for Drugs and Technologies in Health (CADTH), these measures are currently being used to evaluate the cost-effectiveness of different interventions in MS. However, the challenge of using such measures in people with a specific health condition, such as MS, is that they may not capture all of the domains that are impacted upon by the condition. If important domains are missing from the generic measures, the value derived will be higher than the real impact creating invalid comparisons across interventions and populations. Therefore, the objective of this study is to estimate the extent to which generic utility measures capture important domains that are affected by MS. The available study population consisted of men and women who had been registered after 1994 in three participating MS clinics in Greater Montreal, Quebec, Canada. Subjects were first interviewed on an individualized measure of quality of life (QOL) called the Patient Generated Index (PGI). The domains identified with the PGI were then classified and grouped together using the World Health Organization's International Classification of Functioning, Disability and Health (ICF), and mapped onto the HUI2, HUI3, EQ-5D and SF-6D. A total of 185 persons with MS were interviewed on the PGI. The sample was relatively young (mean age 43) and predominantly female. Both men and women had mild disability with a median Expanded Disability Status Scale (EDSS) score of 2. The top 10 domains that patients identified to be the most affected by their MS were, work (62%), fatigue (48%), sports (39%), social life (28%), relationships (23%), walking/mobility (22%), cognition (21%), balance (14%), housework (12%) and mood (11%). The SF-6D included the most number of domains (6 domains) important to people with MS, followed by the EQ-5D (4 domains) and the HUI2 (4 domains) and then the HUI3 (3 domains). The mean and standard deviation (SD) for the PGI, EQ-5D and the SF-6D were 0.50 (SD 0.25), 0.69 (0.18) and 0.69 (0.13), respectively. The magnitude of difference between the PGI and the generic utility measures was large and statistically significant. Although the generic utility measures included certain items that were important to people with MS, there were several that were missing. An important consequence of this mismatch was that values of QOL derived from the PGI were importantly and significantly lower than those estimated using any of the generic utility measures. This could have a substantial impact in evaluating the effect of interventions for people with MS.


Proton magnetic resonance spectroscopy findings of a sacrococcygeal schwannoma.
Schwannoma is tumor of peripheral nerves, originating from Schwann cells. It is a rare nerve sheath tumor, which frequently occurs in the intracranial acoustic nerve and spinal nerves. We report on a 28-year-old woman who suffered from a large pelvic mass that was diagnosed to be sacrococcygeal schwannoma. The features of proton magnetic resonance spectroscopy (MRS) study are discussed. The magnetic resonance imaging instrument was a 1.5 T, Gyroscan Intera with a body coil as a radiofrequency transmitter and a signal receiver. T2-weighted images were obtained under the following conditions-turbo spin echo (TSE) T2: turbo spin echo repeat time (TR) = 4500 msec, echo time (TE) = 96 msec. Single voxel MRS was performed by the point-resolved spectroscopy technique with a long TE (136 msec). MRS measurement was performed on two different parts of the tumor. As well as strongly elevated choline and lipid signals, the tumor spectrum showed increased N-acetylaspartate resonances. MRS can be used effectively in the preoperative diagnosis of retroperitoneal and pelvic masses, which demonstrate unusual clinical features.


Nutritional differences in neurologically impaired children.
To determine whether the recommended nutritional intake of moderately to severely neurologically impaired children is congruent with current growth parameter expectations. Observational cross-sectional study at a children's hospice and a tertiary care children's hospital. Medically stable enterally fed children followed by the palliative care team underwent anthropometric assessment and chart review for diagnosis, intake and medications. Intakes, guidelines and recommendations were compared. Intakes were less than recommended. All children were <50th percentile weight-for-age, with many <3rd percentile. Fourteen of 15 were in higher percentiles for absolute and relative body fat. Recommended dietary intakes were not achieved by these children. Despite this, measures of body fat indicate adequate intake. Low weight values may reflect diagnosis-related growth stunting or decreased muscle mass and bone density from immobility. The Centers for Disease Control and Prevention (Georgia, USA) weight-for-age and body mass index are not suitable measures of adequate intake in this group of children.


Synthesis from hyperproperties.
We study the reactive synthesis problem for hyperproperties given as formulas of the temporal logic HyperLTL. Hyperproperties generalize trace properties, i.e., sets of traces, to sets of sets of traces. Typical examples are information-flow policies like noninterference, which stipulate that no sensitive data must leak into the public domain. Such properties cannot be expressed in standard linear or branching-time temporal logics like LTL, CTL, or CTL ∗ . Furthermore, HyperLTL subsumes many classical extensions of the LTL realizability problem, including realizability under incomplete information, distributed synthesis, and fault-tolerant synthesis. We show that, while the synthesis problem is undecidable for full HyperLTL, it remains decidable for the ∃ ∗ , ∃ ∗ ∀ 1 , and the linear ∀ ∗ fragments. Beyond these fragments, the synthesis problem immediately becomes undecidable. For universal HyperLTL, we present a semi-decision procedure that constructs implementations and counterexamples up to a given bound. We report encouraging experimental results obtained with a prototype implementation on example specifications with hyperproperties like symmetric responses, secrecy, and information flow.


Counting cytokinesis proteins globally and locally in fission yeast.
We used fluorescence microscopy to measure global and local concentrations of 28 cytoskeletal and signaling proteins fused to yellow fluorescent protein (YFP) in the fission yeast Schizosaccharomyces pombe. Native promoters controlled the expression of these functional YFP fusion proteins. Fluorescence measured by microscopy or flow cytometry was directly proportional to protein concentration measured by quantitative immunoblotting. Global cytoplasmic concentrations ranged from 0.04 (formin Cdc12p) to 63 micromolar (actin). Proteins concentrated up to 100 times in contractile rings and 7500 times in spindle pole bodies at certain times in the cell cycle. This approach can be used to measure the global and local concentrations of any fusion protein.


Role of IGF-I, IGF-II and IGFBP-3 in lung function of males: the Caerphilly Prospective Study.
Insulin-like growth factors are peptide hormones that have an endocrine role in the development, growth and repair of human tissues including the respiratory tract. To date, only one population study exists which found positive cross-sectional associations with IGF-I and higher lung volumes. We hypothesised that higher IGF-I, IGF-II, IGFBP-3 and IGF molar ratio would be associated with better cross-sectional and longitudinal lung function. We examined cross-sectional (n=843) and prospective associations (n=717) between IGF-I, IGF-II, IGFBP-3 and IGF molar ratio with lung function in the Caerphilly Prospective Study (CaPS) from blood samples obtained around 1986, with spirometry (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)) performed in the same year and around 2003. Higher IGF molar ratio was associated with improved FEV1/FEV ratio cross-sectionally in both simple (0.007, 95% CI 0.001-0.013, P=0.02) and fully adjusted (0.001, 95% CI 0.001-0.012, P=0.03) models. With the exception of IGFBP-3 and FEV1/FVC in the simple model (0.009, 95% CI 0.001-0.018, P=0.04) all prospective associations between IGF and spirometric measures were consistent with chance. In this study of men, higher IGF molar ratio was associated with improved cross-sectional lung function, although these findings were not replicated prospectively. Further work is required with repeat IGF sampling during follow up to see if IGF levels play any role in predicting future lung function through the life course.


Cancer risk from professional exposure in staff working in cardiac catheterization laboratory: insights from the National Research Council's Biological Effects of Ionizing Radiation VII Report.
Occupational doses from fluoroscopy-guided interventional procedures are the highest ones registered among medical staff using x-rays. The aim of the present study was to evaluate the order of magnitude of cancer risk caused by professional radiation exposure in modern invasive cardiology practice. From the dosimetric Tuscany Health Physics data bank of 2006, we selected dosimetric data of the 26 (7 women, 19 men; age 46 +/- 9 years) workers of the cardiovascular catheterization laboratory with effective dose >2 mSv. Effective dose (E) was expressed in milliSievert, calculated from personal dose equivalent registered by the thermoluminescent dosimeter, at waist or chest, under the apron, according to the recommendations of National Council of Radiation Protection. Lifetime attributable risk of cancer was estimated using the approach of Biological Effects of Ionizing Radiation 2006 report VII. Cardiac catheterization laboratory staff represented 67% of the 6 workers with yearly exposure >6 mSv. Of the 26 workers with 2006 exposure >2 mSv, 15 of them had complete records of at least 10 (up to 25) consecutive years. For these 15 subjects having a more complete lifetime dosimetric history, the median individual effective dose was 46 mSv (interquartile range = 24-64). The median risk of (fatal and nonfatal) cancer (Biological Effects of Ionizing Radiation 2006) was 1 in 192 (interquartile range = 1 in 137-1 in 370). Cumulative professional radiological exposure is associated with a non-negligible Lifetime attributable risk of cancer for the most exposed contemporary cardiac catheterization laboratory staff.


Brief Report: What Happens After School? Exploring Post-school Outcomes for a Group of Autistic and Non-autistic Australian Youth.
Young autistic Australians are less likely to attend higher education and have lower employment rates than non-autistic Australians (in: Australian Bureau of Statistics, Survey of disability, ageing and carers Australia: Summary of Findings 2018. Australian Bureau of Statistics, Canberra, 2019a). Few studies have examined post-school outcomes among this population. Using data from the first phase of a national longitudinal study including autistic (n = 79) and non-autistic (n = 107) 17-25-year olds, we found young autistic adults were (a) less likely to be employed, (b) more likely to attend technical and further education (TAFE) than university, (c) more likely to enrol in higher education on a part-time basis and (d) less likely to be engaged in both higher education and employment, than their non-autistic peers. Findings highlight a need to understand post-school trajectories of young autistic adults.


Plexina1 autoinhibition by the plexin sema domain.
Semaphorin 3A (Sema3A) binds to neuropilin-1 (NP1) and activates the transmembrane Plexin to transduce a repulsive axon guidance signal. Here, we show that Sema3 signals are transduced equally effectively by PlexinA1 or PlexinA2, but not by PlexinA3. Deletion analysis of the PlexinA1 ectodomain demonstrates that the sema domain prevents PlexinA1 activation in the basal state. Sema-deleted PlexinA1 is constitutively active, producing cell contraction, growth cone collapse, and inhibition of neurite outgrowth. The sema domain of PlexinA1 physically associates with the remainder of the PlexinA1 ectodomain and can reverse constitutive activation. Both the sema portion and the remainder of the ectodomain of PlexinA1 associate with NP1 in a Sema3A-independent fashion. Plexin A1 is autoinhibited by its sema domain, and Sema3A/NP1 releases this inhibition.


Signals from the Metastatic Niche Regulate Early and Advanced Ovarian Cancer Metastasis through miR-4454 Downregulation.
Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. IMPLICATIONS: This study identifies a miRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced ovarian cancer metastasis through its effects on FAK activation, mutant p53 stabilization, and apoptosis inhibition.


Methane Emission Reductions from the Alternate Wetting and Drying of Rice Fields Detected Using the Eddy Covariance Method.
Rice cultivation contributes 11% of the global 308 Tg CH4 anthropogenic emissions. The alternate wetting and drying (AWD) irrigation practice can conserve water while reducing CH4 emissions through the deliberate, periodic introduction of aerobic soil conditions. This paper is the first to measure the impact of AWD on rice field CH4 emissions using the eddy covariance (EC) method. This method provides continuous, direct observations over a larger footprint than in previous chamber-based approaches. Seasonal CH4 emissions from a pair of adjacent, production-sized rice fields under delayed flood (DF) and AWD irrigation were compared from 2015 to 2017. Across the 2 fields and 3 years, cumulative CH4 emissions in the production season were in the range of 7.1 to 31.7 kg CH4-C ha-1 for the AWD treatment and in the range of 75.7-141.6 kg CH4-C ha-1 for the DF treatments. Correcting for field-to-field differences in CH4 production, the AWD practice reduced seasonal CH4 emissions by 64.5 ± 2.5%. The AWD practice is increasingly implemented for water conservation in the mid-south region of the United States; however, based on this study, it also has great potential for reducing CH4 emissions.


Facilitating successful implementation of a person-centred intervention to support family carers within palliative care: a qualitative study of the Carer Support Needs Assessment Tool (CSNAT) intervention.
An understanding of how to implement person-centred interventions in palliative and end of life care is lacking, particularly for supporting family carers. To address this gap, we investigated components related to successful implementation of the Carer Support Needs Assessment Tool (CSNAT) intervention, a person-centred process of carer assessment and support, using Promoting Action on Research Implementation in Health Services (PARIHS) as a theoretical framework. This study identifies how the PARIHS component of 'facilitation' and its interplay with the components of 'context' and 'evidence' affect implementation success. MRC Framework Phase IV study to evaluate implementation of the CSNAT intervention at scale, over six months, in 36 UK palliative care services. 38 practitioners acting as internal facilitators in 35/36 services were interviewed. Field notes were collected during teleconference support sessions between the external and internal facilitators. Successful implementation was associated with internal facilitators' 'leverage' including their positioning within services, authority to change practice, and having a team of supportive co-facilitators. Effective facilitation processes included a collaborative approach, ongoing communication, and proactive problem solving to address implementation barriers. Facilitators needed to communicate the evidence and provide legitimacy for changing practice. Contextual constraints on facilitation included having to adjust recording systems to support implementation, organisational changes, a patient-focused culture and lack of managerial support. The CSNAT intervention requires attention to both facilitation processes and conducive organisational structures for successful implementation. These findings are likely to be applicable to any person-centred process of assessment and support within palliative care.


Scrub typhus and spotted fever among hospitalised children in South India: Clinical profile and serological epidemiology.
Rickettsial infections are re-emerging. In India, they are now being reported from several areas where they were previously unknown. The objective of this study was to describe the epidemiology, clinical profile and outcome of serologically-confirmed scrub typhus and spotted fever among children in a tertiary care hospital in Bengaluru. Hospitalised children aged <18 years, with clinical features suggestive of rickettsial disease admitted between January 2010 and October 2012 were included prospectively. Diagnosis was based on scrub typhus and spotted fever-specific IgM and IgG by enzyme-linked immunosorbent assay (ELISA). Of 103 children with clinical features suggestive of rickettsial illness, ELISA test confirmed 53 cases for scrub typhus, 23 cases for spotted fever group and 14 with mixed infection. The average age was 7.3 (±3.9) years and 44 (71.0%) children were male. Majority of cases were from Karnataka (50%), Andhra Pradesh (32.3%) and Tamil Nadu (17.7%). Common clinical features included fever (100%, average duration 11 days), nausea and vomiting (44%), rash (36%); eschar was rare. Compared to the ELISA test, Weil-Felix test (OX-K titre of 1:80) had a sensitivity and specificity of 88.7% and 43.9%, respectively. Treatment with chloramphenicol or doxycycline was given to the majority of the children. Complications included meningoencephalitis (28%), shock (10%), retinal vasculitis (10%) and purpura fulminans (7%). These findings suggest that the burden of rickettsial infection among children in India is high, with a substantially high complication rate. Rickettsial-specific ELISA tests can help in early diagnosis and early institution of appropriate treatment that may prevent life-threatening complications.


N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease.
This study assessed the biological and clinical effects in patients with Parkinson's disease (PD) of N-acetyl-cysteine (NAC), the prodrug to l-cysteine, a precursor to the natural biological antioxidant glutathione. Forty-two patients with PD were randomized to either weekly intravenous infusions of NAC (50 mg/kg) plus oral doses (500 mg twice per day) for 3 months or standard of care only. Participants received prebrain and postbrain imaging with ioflupane (DaTscan) to measure dopamine transporter (DAT) binding. In the NAC group, significantly increased DAT binding was found in the caudate and putamen (mean increase from 3.4% to 8.3%) compared with controls (P < 0.05), along with significantly improved PD symptoms (P < 0.0001). The results suggest NAC may positively affect the dopaminergic system in patients with PD, with corresponding positive clinical effects. Larger scale studies are warranted.


Utility and drawbacks of continuous use of a copper T IUD for 20 years.
This article examines interrelated questions concerning the extent of need for contraception in women 40 years and older and the degree to which that need can be served when use of collared T IUDs is initiated in women aged 25-35 years. Differentials in the impacts of intrauterine device (IUD) use on health issues in the second decade of contraception are also addressed. Although fertility of all women aged 40-44 years is below 100 per 1000 in all regions of the world today, the risk of pregnancy among married or cohabiting women who do not use contraception is estimated at 270-300 per 1000 or 27-30% per year. At ages 45-49 years, the annual risk of pregnancy to women in union who do not use contraception lies at or above 10% per year. Data from three studies show that users of collared copper IUDs who continued using the same device beyond the completion of 10 years experienced no pregnancies through the end of 15 years. A small number of women continued with the same IUD through 20 years and still experienced no pregnancies. Use of collared copper T IUDs beyond 10 years was not associated with intensification of side effects nor with an increase in the relative frequency of those effects, with the exception of the experience of perimenopausal symptoms and problems. Neither increased bleeding nor increased severity of pelvic disease was manifest in the second decade of continuous use of the same IUD, as compared with the first decade of such use. Under our current understanding of the duration of IUD effectiveness, only a small percentage of women complete 10 years of use. Even with revised understanding of the duration of effectiveness of long-acting copper devices, average annual continuation rates must be quite high in order that 20% of women aged 25-35 years initiate a second decade of continuous IUD use. Those who do so would find considerable protection against pregnancy and reasonable economic benefits in continuing to use the same device.


Prevention of phosphate--in-duced mitochondrial swelling.
The prevention of phosphate-induced mitochondrial swelling in the whole retina of the rabbit was studied with the electron microscope. It was found that a mixture of ATP, Mg(++), and bovine serum albumin protected the mitochondria in vitro. This finding confirmed the results obtained spectrophotometrically with isolated rat liver mitochondria by Lehninger.


Which Patients Require More Care after Hospital Discharge? An Analysis of Post-Acute Care Use among Elderly Patients Undergoing Elective Surgery.
The use of post-acute care is common among the elderly and accounts for $62 billion in annual Medicare expenditures. However, little is known about post-acute care use after surgery. Data were merged between the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and Medicare claims for 2005 to 2008. Post-acute care use, including skilled nursing facilities (SNF), inpatient rehabilitation facilities (IRF), and home health care (HHC) were analyzed for 3 operations: colectomy, pancreatectomy, and open abdominal aortic aneurysm repair. Controlling for both preoperative risk factors and the occurrence of postoperative complications, we used multinomial logistic regression to estimate the odds of use for each type of post-acute care after elective surgery compared with home discharge. Post-acute care was used frequently for patients undergoing colectomy (40.0%; total n=10,932), pancreatectomy (46.0%; total n=2,144), and open abdominal aortic aneurysm (AAA) repair (44.9%; total n=1,736). Home health was the most frequently reported post-acute care service for each operation (range 23.2% to 31.5%) followed by SNF (range 12.0% to 15.0%), and then by IRF (range 2.5% to 5.4%). The majority of patients with at least 1 inpatient complication were discharged to post-acute care (range 58.6% for open AAA repair to 64.4% for colectomy). In multivariable analysis, specific preoperative risk factors, including advanced age, poor functional status, and inpatient complications were significantly associated with increased risk-adjusted odds of discharge to post-acute care for each operation studied. Among elderly patients, post-acute care use is frequent after surgery and is significantly associated with several preoperative risk factors and postoperative inpatient complications. Further work is needed to ensure that post-acute care services are used appropriately and cost-effectively.


The effect of lichen-dominated biological soil crusts on growth and physiological characteristics of three plant species in a temperate desert of northwest China.
Biocrusts (biological soil crusts) cover open spaces between vascular plants in most arid and semi-arid areas. Information on effects of biocrusts on seedling growth is controversial, and there is little information on their effects on plant growth and physiology. We examined impacts of biocrusts on growth and physiological characteristics of three habitat-typical plants, Erodium oxyrhynchum, Alyssum linifolium and Hyalea pulchella, growing in the Gurbantunggut Desert, northwest China. The influence of biocrusts on plant biomass, leaf area, leaf relative water content, photosynthesis, maximum quantum efficiency of PSII (F(v)/F(m)), chlorophyll, osmotic solutes (soluble sugars, protein, proline) and antioxidant enzymes (superoxide dismutase, catalase, peroxidase) was investigated on sites with or without biocrust cover. Biomass, leaf area, leaf water content, photosynthesis, F(v)/F(m) and chlorophyll content in crusted soils were higher than in uncrusted soils during early growth and lower later in the growth period. Soluble sugars, proline and antioxidant enzyme activity were always higher in crusted than in uncrusted soils, while soluble protein content was always lower. These findings indicate that biocrusts have different effects on these three ephemeral species during growth in this desert, primarily via effects on soil moisture, and possibly on soil nutrients. The influence of biocrusts changes during plant development: in early plant growth, biocrusts had either positive or no effect on growth and physiological parameters. However, biocrusts tended to negatively influence plants during later growth. Our results provide insights to explain why previous studies have found different effects of biocrusts on vascular plant growth.


Anticholinergic drugs versus other medications for overactive bladder syndrome in adults.
Overactive bladder syndrome is defined as "urgency with or without urge incontinence, usually with frequency and nocturia". It is a common condition with significant economic and quality of life implications. While the condition's pathophysiology remains to be fully elucidated, pharmacotherapy is the main treatment option. Despite uncertainty as to drug treatment of choice, anticholinergics are increasingly being used in primary and secondary care settings. This review compares anticholinergic drugs with other types or classes of drugs for treating overactive bladder syndromes. To compare anticholinergic drugs with other types or classes of drugs for treating overactive bladder symptoms. We searched the Cochrane Incontinence Group Specialised Trials Register (searched 20 December 2006) and the reference lists of relevant articles. No language or other limits were imposed. All randomised and quasi-randomised controlled trials comparing anticholinergic drugs with other drugs for the treatment of overactive bladder symptoms. At least one arm of the study used an anticholinergic drug and at least one other arm used a non-anticholinergic drug. Two reviewers assessed the identified studies for eligibility and methodological quality and independently extracted data from the included studies. Data analysis was performed using RevMan software (version 4.2.8). Twelve trials were included in the review. There were seven crossover trials and five parallel group studies. For the comparisons between anticholinergic drugs with tricyclic antidepressants, alpha adrenergic agonists, afferent nerve inhibitors, and calcium channel blocker a single trial was identified for each. Nine trials compared flavoxate with anticholinergics. There was no evidence of a difference in cure rates between anticholinergics and flavoxate. Adverse effects were more frequent in anticholinergic groups versus flavoxate groups (RR 2.28 95% CI 1.45 to 3.56). There was no strong evidence to favour either anticholinergic drugs or the comparators. Many of the drugs considered in trials in this review are no longer used in clinical practice (and this includes the most commonly tested - flavoxate). There is inadequate evidence as to determine whether any of the available drugs are better or worse than anticholinergic medications. Larger randomised controlled trials in clinical settings are required to further establish the role of these medications in the management of overactive bladder syndrome.