Dehydroepiandrosterone (DHEA) for Depression: A Systematic Review and Meta-Analysis.
Depression is a mental disorder that affects a large part of the world's population. DHEA is a hormone that has long been attributed to the ability to improve depressive symptoms. However, few studies were conducted with depression individuals not resulting from other medical conditions. To investigate whether DHEA is more effective than placebo in the treatment of depressive symptoms in subjects with depression not resulting from other psychiatric or medical comorbidities. An electronic search was carried out using the keywords Dehydroepiandrosterone (Mesh) AND Depression (Mesh) in the following databases: Medical Literature databases Analysis and Retrieval System Online (Medline), Excerpta Medical Database (EMBASE), Latin American and Caribbean Health Sciences (LILACS) and the Cochrane Library through their website for relevant publications until June 2018. Only randomized clinical trials were included. The critical appraisal of the articles was performed using the Risk of Bias Tool from Cochrane Collaboration. The meta-analysis applied in this review pointed to a significant effect in favor of treatment with DHEA compared to placebo. DHEA may be one more effective alternative between the drugs used in the treatment of depression.


Metastasis as a therapeutic target in prostate cancer: a conceptual framework.
Metastasis is the main cause of prostate cancer-associated deaths. While significant progerss has been made in the treatment of primary tumors, efficent therapies that target the metastatic spread of prostate cancer are far from clinical reality. To efficiently treat cancer we need be able to impede its spread. Unfortunately, the majority of current therapeutics approved to treat metastatic cancer were originally selected based on their ability to inhibit primary tumor growth. This inherent flaw precluded these therapies from efficiently targeting the development of secondary metastatic lesions, a process that is distinct from that of primary tumor progression. In this review we will summarize the conceptual, cellular and molecular targets that should be considered to design effective anti-metastatic therapies.


Gender-based differences in mortality in response to high product ratio massive transfusion.
Recent data suggest that patients undergoing massive transfusion have lower mortality rates when ratios of plasma and platelets to red blood cells (RBCs) of ≥ 1:2 are used. This has not been examined independently in women and men. A gender dichotomy in outcome after severe injury is known to exist. This study examined gender-related differences in mortality after high product ratio massive transfusion. A retrospective study was conducted using a database containing massively transfused trauma patients from 23 Level I trauma centers. Baseline demographic, physiologic, and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (≥ 1:2) or low (<1:2) ratios of plasma or platelets to RBCs was compared in women and men independently. Seven hundred four patients were analyzed. In males, mortality was lower for patients receiving a high plasma:RBC ratio at 24 hours (20.6% vs. 33.0% for low ratio, p = 0.005) and at 30 days (34.9% vs. 42.8%, p = 0.032). Males receiving a high platelet:RBC ratio also had lower 24-hour mortality (17.6% vs. 31.5%, p = 0.004) and 30-day mortality (32.1% vs. 42.2%, p = 0.045). Females receiving high ratios of plasma or platelets to RBCs had no improvement in 24-hour mortality (p = 0.119 and 0.329, respectively) or 30-day mortality (p = 0.199 and 0.911, respectively). Use of high product ratio transfusions did not affect 24-hour RBC requirements in males or females. Use of high plasma:RBC or platelet:RBC ratios in massive transfusion may benefit men more than women. This may be due to gender-related differences in coagulability. Further study is needed to determine whether separate protocols for women and men should be established.


Shorter telomere lengths in patients with severe COVID-19 disease.
The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.


Site-specific analysis of the SARS-CoV-2 glycan shield.
The emergence of the betacoronavirus, SARS-CoV-2 that causes COVID-19, represents a significant threat to global human health. Vaccine development is focused on the principal target of the humoral immune response, the spike (S) glycoprotein, that mediates cell entry and membrane fusion. SARS-CoV-2 S gene encodes 22 N-linked glycan sequons per protomer, which likely play a role in immune evasion and occluding immunogenic protein epitopes. Here, using a site-specific mass spectrometric approach, we reveal the glycan structures on a recombinant SARS-CoV-2 S immunogen. This analysis enables mapping of the glycan-processing states across the trimeric viral spike. We show how SARS-CoV-2 S glycans differ from typical host glycan processing, which may have implications in viral pathobiology and vaccine design.


Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial.
Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12,092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months). Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes. ClinicalTrials.gov Identifier NCT00064428.


Pancreatic enzyme replacement therapy in post-pancreatectomy patients.
The occurrence of malnutrition and maldigestion was studied in nine patients who underwent pancreatoduodenectomy and sclerosis of the residual pancreatic stump with neoprene. The operation causes a complete loss of exocrine pancreatic function, but spares islet cell function. Upon discharge from the hospital, patients received pancreatin powder as a dietary enzyme supplement (18,000 lipase U/meal). Patients were again hospitalized 2 y after surgery for evaluation of nutritional status and digestive function (hospital checkup). Nutritional status was evaluated by measuring serum albumin, total iron binding capacity, and total lymphocytes. Digestive function was assessed by the D-xylose tolerance test and determination of fecal fat excretion. Patients were then discharged with pancrelipase enteric-coated microspheres (ECM) as a dietary enzyme supplement (16,050 lipase U/meal). Malnutrition, defined as the occurrence of at least two abnormal nutritional parameters, was observed in three patients at the time of the hospital checkup. Upon reevaluation of nutritional status after 6 mo on pancrelipase ECM, all patients were well nourished. The mean body weight, which had been 52.8 Kg immediately after surgery, increased to 54.9 Kg at the time of the hospital checkup (p less than 0.01) and to 58.0 Kg after six months of pancrelipase ECM therapy (p less than 0.05). At the hospital checkup, the D-xylose test was normal in all patients and steatorrhea had decreased from a mean of 32.8 g/d without enzyme supplementation to 16.7 g/d with pancrelipase therapy (16,050 lipase U/meal). The complete loss of exocrine pancreatic function following surgery was well tolerated. In fact, when patients were on pancrelipase therapy, much of the original body weight was recovered and the biochemical indices of malnutrition were normalized.


Stopping-time resampling and population genetic inference under coalescent models.
To extract full information from samples of DNA sequence data, it is necessary to use sophisticated model-based techniques such as importance sampling under the coalescent. However, these are limited in the size of datasets they can handle efficiently. Chen and Liu (2000) introduced the idea of stopping-time resampling and showed that it can dramatically improve the efficiency of importance sampling methods under a finite-alleles coalescent model. In this paper, a new framework is developed for designing stopping-time resampling schemes under more general models. It is implemented on data both from infinite sites and stepwise models of mutation, and extended to incorporate crossover recombination. A simulation study shows that this new framework offers a substantial improvement in the accuracy of likelihood estimation over a range of parameters, while a direct application of the scheme of Chen and Liu (2000) can actually diminish the estimate. The method imposes no additional computational burden and is robust to the choice of parameters.


Effect of varying electric potential on surface-plasmon resonance sensing.
The high sensitivity of surface-plasmon resonance (SPR) sensors allows measurements of small variations in surface potentials to be made. We studied the changes of the SPR angle when an oscillating electric potential was applied to a gold film on which surface plasmons were excited. The shifts of the SPR resonance angle were observed for various aqueous solutions as an adjacent medium. A model that takes into account the redistribution of charges at the double layer near the metal-liquid interface as well as the oxidation of the gold film was developed. It was found that a change in the electronic density at voltages below the oxidation potential and, in addition, the oxidation of the gold surface above this potential are the main mechanisms that account for the observed dependences. It was shown that relatively slow oxidation-reduction processes can explain the observed hysteresis effect. Application of these techniques to studies of dielectric properties and conformational changes of polar biomolecules, such as tubulin, are discussed.


Early transcriptional control of ENaC (de)ubiquitylation by aldosterone.
Aldosterone increases sodium reabsorption across kidney target tubules already before it increases the number of transport proteins, indicating that the early functional response to aldosterone depends on the activation of preexisting channels and pumps. A central mediator of this action is the early aldosterone-induced kinase Sgk1 that de-represses the surface expression and activity of the epithelial sodium channel (ENaC). A main mechanism by which Sgk1 exerts this de-repression is the phosphorylation of the ubiquitin ligase Nedd4-2 that is thereby prevented from ubiquitylating ENaC. Among a series of new early aldosterone-induced gene products recently identified in kidney target tubules, an additional regulator of ENaC ubiquitylation, the deubiquitylating enzyme Usp2-45, was identified. Coexpression of Usp2-45 was shown to increase ENaC surface expression and activity, and to decrease its ubiquitylation in expression systems, whereas other Usps such as the splice variant Usp2-69 had no effect. Since both Sgk1 and Usp2-45 are similarly induced in distal colon as well, in contrast to other gene products strongly induced in kidney that are not regulated in colon, we suggest that (de)ubiquitylation is the major ENaC regulatory mechanism targeted by aldosterone in the short-term via transcriptional regulation.


Evaluation of cultural techniques for isolating Campylobacter pyloridis from endoscopic biopsies of gastric mucosa.
One hundred and three gastroscopic biopsies from 80 patients were cultured for Campylobacter pyloridis and studied histologically. Active chronic gastritis, as shown by the presence of polymorphonuclear leucocytes, was diagnosed in 51 biopsies and C pyloridis was found in 47. Sixteen gastric biopsies showed normal histology (no inflammation); C pyloridis was detected in only one of these, and a second biopsy taken from this patient at the same time showed active gastritis. Biopsies could be kept at 4 degrees C for five hours without loss of viability of C pyloridis. An inoculum made by grinding the biopsy in a ground glass grinder consistently gave a much heavier growth of C pyloridis than one made by mincing the specimen. The campylobacter supplement ferrous sulphate, sodium metabisulphite, sodium pyruvate (FBP) (Oxoid) was inhibitory for some isolates; the inhibitory component was found to be sodium metabisulphite. Contaminants, but not C pyloridis, were inhibited by the incorporation of vancomycin 6 mg/l, nalidixic acid 20 mg/l, and amphotericin 2 mg/l, but higher concentrations inhibited C pyloridis. Undried plates kept in a plastic container at room temperature for up to two weeks were as satisfactory as freshly poured plates for the isolation of C pyloridis.


Comparative evolutionary diversity and phylogenetic structure across multiple forest dynamics plots: a mega-phylogeny approach.
Forest dynamics plots, which now span longitudes, latitudes, and habitat types across the globe, offer unparalleled insights into the ecological and evolutionary processes that determine how species are assembled into communities. Understanding phylogenetic relationships among species in a community has become an important component of assessing assembly processes. However, the application of evolutionary information to questions in community ecology has been limited in large part by the lack of accurate estimates of phylogenetic relationships among individual species found within communities, and is particularly limiting in comparisons between communities. Therefore, streamlining and maximizing the information content of these community phylogenies is a priority. To test the viability and advantage of a multi-community phylogeny, we constructed a multi-plot mega-phylogeny of 1347 species of trees across 15 forest dynamics plots in the ForestGEO network using DNA barcode sequence data (rbcL, matK, and psbA-trnH) and compared community phylogenies for each individual plot with respect to support for topology and branch lengths, which affect evolutionary inference of community processes. The levels of taxonomic differentiation across the phylogeny were examined by quantifying the frequency of resolved nodes throughout. In addition, three phylogenetic distance (PD) metrics that are commonly used to infer assembly processes were estimated for each plot [PD, Mean Phylogenetic Distance (MPD), and Mean Nearest Taxon Distance (MNTD)]. Lastly, we examine the partitioning of phylogenetic diversity among community plots through quantification of inter-community MPD and MNTD. Overall, evolutionary relationships were highly resolved across the DNA barcode-based mega-phylogeny, and phylogenetic resolution for each community plot was improved when estimated within the context of the mega-phylogeny. Likewise, when compared with phylogenies for individual plots, estimates of phylogenetic diversity in the mega-phylogeny were more consistent, thereby removing a potential source of bias at the plot-level, and demonstrating the value of assessing phylogenetic relationships simultaneously within a mega-phylogeny. An unexpected result of the comparisons among plots based on the mega-phylogeny was that the communities in the ForestGEO plots in general appear to be assemblages of more closely related species than expected by chance, and that differentiation among communities is very low, suggesting deep floristic connections among communities and new avenues for future analyses in community ecology.


Purines inhibit poly(ADP-ribose) polymerase activation and modulate oxidant-induced cell death.
Purines such as adenosine, inosine, and hypoxanthine are known to have potent antiinflammatory effects. These effects generally are believed to be mediated by cell surface adenosine receptors. Here we provide evidence that purines protect against oxidant-induced cell injury by inhibiting the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Upon binding to broken DNA, PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins such as histones and PARP itself. Overactivation of PARP depletes cellular NAD+ and ATP stores and causes necrotic cell death. We have identified some purines (hypoxanthine, inosine, and adenosine) as potential endogenous PARP inhibitors. We have found that purines (hypoxanthine > inosine > adenosine) dose-dependently inhibited PARP activation in peroxynitrite-treated macrophages and also inhibited the activity of the purified PARP enzyme. Consistently with their PARP inhibitory effects, the purines also protected interferon gamma + endotoxin (IFN/LPS) -stimulated RAW macrophages from the inhibition of mitochondrial respiration and inhibited nitrite production from IFN/LPS-stimulated macrophages. We have selected hypoxanthine as the most potent cytoprotective agent and PARP inhibitor among the three purine compounds, and investigated the mechanism of its cytoprotective effect. We have found that hypoxanthine protects thymocytes from death induced by the cytotoxic oxidant peroxynitrite. In line with the PARP inhibitory effect of purines, hypoxanthine has prevented necrotic cell death while increasing caspase activity and DNA fragmentation. As previously shown with other PARP inhibitors, hypoxanthine acted proximal to mitochondrial alterations as hypoxanthine inhibited the peroxynitrite-induced mitochondrial depolarization and secondary superoxide production. Our data imply that purines may serve as endogenous PARP inhibitors. We propose that, by affecting PARP activation, purines may modulate the pattern of cell death during shock, inflammation, and reperfusion injury.


Surgical Diabetic Foot Infections: Is Osteomyelitis Associated With a Worse Prognosis?
It has been reported that patients with diabetes and foot ulcers complicated with osteomyelitis (OM) have a worse prognosis than those complicated with soft tissue infections (STI). Our study aimed to determine whether OM is associated with a worse prognosis in cases of moderate and severe diabetic foot infections requiring surgery. A retrospective series consisted of 150 patients who underwent surgery for diabetic foot infections. We studied the differences between OM versus STI. Furthermore, diabetic foot infections were reclassified into four groups: moderate STI (M-STI), moderate OM (M-OM), severe STI (S-STI), and severe OM (S-OM). The variables associated with prognosis were limb loss, length of hospital stay, duration of antibiotic treatment, recurrence of the infection, and time to healing (both the initial ulcer and the postoperative wound). No differences in limb salvage, hospital stay, duration of antibiotic treatment, recurrence of the infection, and time to healing were found when comparing OM with STI. Patients with M-O had a higher rate of recurrences after initial treatment and a longer time to healing when comparing with M-STI. We didn't find any differences between severe infections with or without OM. In conclusion, we have found in our surgical series of diabetic foot infections that OM is not associated with worse prognosis when comparing with STI regarding limb loss rate, length of hospital stays, duration of antibiotic treatment, recurrence of the infection, and time to healing. The results of the present series should further be confirmed by other authors.


Developmental regulation of spine motility in the mammalian central nervous system.
The function of dendritic spines, postsynaptic sites of excitatory input in the mammalian central nervous system (CNS), is still not well understood. Although changes in spine morphology may mediate synaptic plasticity, the extent of basal spine motility and its regulation and function remains controversial. We investigated spine motility in three principal neurons of the mouse CNS: cerebellar Purkinje cells, and cortical and hippocampal pyramidal neurons. Motility was assayed with time-lapse imaging by using two-photon microscopy of green fluorescent protein-labeled neurons in acute and cultured slices. In all three cell types, dendritic protrusions (filopodia and spines) were highly dynamic, exhibiting a diversity of morphological rearrangements over short (<1-min) time courses. The incidence of spine motility declined during postnatal maturation, but dynamic changes were still apparent in many spines in late-postnatal neurons. Although blockade or induction of neuronal activity did not affect spine motility, disruption of actin polymerization did. We hypothesize that this basal motility of dendritic protrusions is intrinsic to the neuron and underlies the heightened plasticity found in developing CNS.


A tunable coupler for superconducting microwave resonators using a nonlinear kinetic inductance transmission line.
We present a tunable coupler scheme that allows us to tune the coupling strength between a feedline and a superconducting resonator in situ over a wide range. In this scheme, we shunt the feedline with a 50-Ω lumped-element nonlinear transmission line made from a 20 nm NbTiN film. By injecting a DC current, the nonlinear kinetic inductance changes and the effective impedance shunting the resonator periodically varies from a short to an open, which tunes the coupling strength and coupling quality factor Qc . We have demonstrated Qc tuning over a factor of 40, between Qc ~ 5.5 × 104 and Qc ~ 2.3 × 106, for a 4.5 GHz resonator by applying a DC current less than 3.3 mA. Our tunable coupler scheme is easy to implement and may find broad applications in superconducting detector and quantum computing/information experiments.


Discovery pipelines for marine resources: an ocean of opportunity for biotechnology?
Marine microbial diversity offers enormous potential for discovery of compounds of crucial importance in healthcare, food security and bioindustry. However, access to it has been hampered by the difficulty of accessing and growing the organisms for study. The discovery and exploitation of marine bioproducts for research and commercial development requires state-of-the-art technologies and innovative approaches. Technologies and approaches are advancing rapidly and keeping pace is expensive and time consuming. There is a pressing need for clear guidance that will allow researchers to operate in a way that enables the optimal return on their efforts whilst being fully compliant with the current regulatory framework. One major initiative launched to achieve this, has been the advent of European Research Infrastructures. Research Infrastructures (RI) and associated centres of excellence currently build harmonized multidisciplinary workflows that support academic and private sector users. The European Marine Biological Research Infrastructure Cluster (EMBRIC) has brought together six such RIs in a European project to promote the blue bio-economy. The overarching objective is to develop coherent chains of high-quality services for access to biological, analytical and data resources providing improvements in the throughput and efficiency of workflows for discovery of novel marine products. In order to test the efficiency of this prototype pipeline for discovery, 248 rarely-grown organisms were isolated and analysed, some extracts demonstrated interesting biochemical properties and are currently undergoing further analysis. EMBRIC has established an overarching and operational structure to facilitate the integration of the multidisciplinary value chains of services to access such resources whilst enabling critical mass to focus on problem resolution.


Methenamine hippurate for preventing urinary tract infections.
Methenamine salts are often used as an alternative to antibiotics for the prevention of urinary tract infection (UTI). This review was first published in Issue 1, 2002 and updated in Issue 4, 2007. To assess the benefits and harms of methenamine hippurate in preventing UTI. We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), MEDLINE (from 1950), EMBASE (from 1980), reference lists of articles and abstracts from conference proceedings without language restriction. Manufacturers' of methenamine salts were contacted for unpublished studies and contact was made with known investigators.Date of last search: June 2012 Randomised controlled trials (RCT) and quasi-RCTs of methenamine hippurate used for the prevention of UTIs in all population groups were eligible. A comparison with a control/no treatment group was a prerequisite for selection. Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as risk ratio (RR) for dichotomous outcomes with 95% confidence intervals (CI). An exploration of heterogeneity and a detailed description of results, grouped by population, was undertaken. Thirteen studies (2032 participants) were included. Six studies (654 patients) reported symptomatic UTI and eight studies (796 patients) reported bacteriuria. Overall, study quality was mixed. The overall pooled estimates for the major outcome measures were not interpretable because of underlying heterogeneity. Subgroup analyses suggested that methenamine hippurate may have some benefit in patients without renal tract abnormalities (symptomatic UTI: RR 0.24, 95% CI 0.07 to 0.89; bacteriuria: RR 0.56, 95% CI 0.37 to 0.83), but not in patients with known renal tract abnormalities (symptomatic UTI: RR 1.54, 95% CI 0.38 to 6.20; bacteriuria: RR 1.29, 95% CI 0.54 to 3.07). For short-term treatment duration (1 week or less) there was a significant reduction in symptomatic UTI in those without renal tract abnormalities (RR 0.14, 95% CI 0.05 to 0.38). The rate of adverse events was low. Methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, particularly when used for short-term prophylaxis. It does not appear to work in patients with neuropathic bladder or in patients who have renal tract abnormalities. The rate of adverse events was low, but poorly described.There is a need for further large well-conducted RCTs to clarify this question, particularly for longer term use for people without neuropathic bladder.


Putting sexuality (back) into HIV/AIDS: issues, theory and practice.
After more than twenty years of programming and activism aimed at stemming the sexual transmission of HIV (and addressing the needs of those most vulnerable to infection) the HIV/AIDS epidemic continues to grow worldwide. Taking up this concern, this paper argues that one of the reasons why HIV prevention has had limited success is because of inadequate conceptualization of human sexuality in such work. Giving sexuality a more prominent position in responses to the epidemic raises a range of issues, including theorization of gender, understanding of sexual subjectivity, the significance of pleasure (or lack of pleasure) in sexual decision-making, and conceptualization of sexual behaviour and culture. Taking these themes forward entails asking significant questions about the underlying paradigmatic and methodological commitments of mainstream HIV/AIDS research, especially the tendency to reproduce accounts of human sexuality as if it were a measurable form of conduct only. Advocating new approaches that take the meaning and symbolic value of sexualities into account complicates established orthodoxies in the field whilst offering potential for more effective HIV prevention strategies.


Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.
Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.


Phytophthora infestans Mating Types on Tomato (Solanum lycopersicum) in Southern Spain.
During 2004, an unusual spread of Phytophthora infestans on tomato plants in greenhouses located in Almería and Granada provinces, southern Spain, was observed. Infected plants had water-soaked, brown spots on leaves and stems and necrotic areas with white mold on the surface of fruits. Three isolates were obtained by plating diseased tissue on V8 juice agar medium and maintained on rye agar at 18°C. These isolates were analyzed for the mating type. Crosses were carried out using V8 juice agar and rye agar. The two parental isolates US1 (A1) and US8 (A2) were both provided by W. E. Fry, Cornell University, Ithaca, NY. Two of the Spanish isolates were homothallic and the other isolate belonged to the uncommon mating type A1A2. To confirm the occurrence of the two mating types, 43 single-sporangium progeny were produced and analyzed from the A1A2 mating type. Thirty eight isolates were A1, two were A2, one was A1A2 mating type, and two were sterile. Assessment of five single-sporangium progeny from the homothallic type resulted in two A1, two homothallic, and one sterile isolate. A1A2 isolates produced oospores when crossed with either A1 or A2, but not when self-crossed. Previously, the A1A2 mating type has been found in Israel in the field and was obtained from oospores produced on tomato seeds (2,3). Since 2003, mating types of P. infestans isolates recovered from potato (60) and tomato (8) in southern Spain have been characterized. Seventy-five percent of the isolates recovered from potato were A1 and 25% were A2 mating types. Isolates recovered from tomato were 50% A1 and 50% A2 (1). To our knowledge, this is the first report of the occurrence of the A1A2 mating type and homothallic P. infestans isolates on tomato in Spain. References: (1) E. Andujar et al. Congr. Sociedad Española de Fitopatol. 12:244, 2004. (2) E. Rubin and Y. Cohen. Phytoparasitica 32:237, 2004. (3) E. Rubin and Y. Cohen. Plant Dis. 90:741, 2006.


A study in vitro to compare home and surgery vital bleaching techniques.
The aim of this study was to compare the effectiveness of three different types of commonly used bleaching techniques using an in-vitro model. Five groups of 10 tooth specimens were prepared and allocated randomly to treatment groups. The four treatment groups tested were a home tray bleaching product, an 'in surgery' tray bleaching product and an 'in surgery power bleaching' product for use with an activating light. The bleaching agent in the latter group was also tested without light activation to assess the additional benefit of the bleaching lamp. A placebo group treated with water was also included. Colour change was assessed using a Vita shade guide and an electronic chromometer. The mean change in shade guide units ranged from 10.9 to 13.2 units, with the 'in surgery' tray bleaching system producing the largest change. For the chromometer readings the mean change in tooth colour ranged from 3.6 to 25.6 units, with the night guard vital bleaching product producing the largest change. This study has demonstrated in vitro that all the different bleaching systems tested produced comparable changes in tooth colour.


Closing the gap - inclusion of ultrashort-chain perfluoroalkyl carboxylic acids in the total oxidizable precursor (TOP) assay protocol.
An improved protocol of the total oxidizable precursor (TOP) assay was developed for precursors to C2-C14 perfluoroalkyl carboxylic acids (PFCAs) and C4-C8 and C10 perfluoroalkyl sulfonic acids (PFSAs). The proposed protocol was tested and validated for contaminated soil samples. The perfluoroalkyl acids (PFAAs) present in the soil extract solutions after oxidation with persulfate were separated from the inorganic salts by vacuum-assisted drying of the digestion solution followed by solid-liquid extraction of the PFAAs with acetonitrile from the dry residue. Ion chromatography (for C2-C4 PFCAs) and reversed phase liquid chromatography (for all other PFASs), both coupled to tandem mass spectrometry, were used for quantification. High procedural recoveries of PFAAs between 68% and 123% with RSDs between 0.2% and 25% (n = 3) were achieved. The method was validated using selected polyfluoroalkyl phosphoric acid esters (PAPs) and bis-[2-(N-ethyl perfluorooctane-1-sulfonamido)ethyl] phosphoric acid ester (diSAmPAP) as model precursors in pure solutions and in the presence of soil matrix. The oxidation led to characteristic and reproducible PFCA patterns (in the case of PAPs) or PFOA (in the case of diSAmPAP) with total reaction yields between 92 ± 4% and 123 ± 13% (n = 3). The impact of the soil matrix on transformation yields was negligible. In a soil core from a PFAS-polluted agricultural site, precursors were concentrated in the upper 40 cm with long-chain precursors being prevalent. After oxidative digestion, the total molar PFAA-concentrations increased by factors of 1.6 to 5.0. More than 40 cm below ground precursors of TFAA, PFPrA and PFBA accounted for ∼50% of the reaction products, underlining the importance of their inclusion in mass balances based on the TOP assay.


Complex couplings between joints, muscles and performance: the role of the wrist in grasping.
The relationship between posture, muscle length properties and performance remains unclear, because of a lack of quantitative data. Studies on grasping tasks suggested that wrist position could favour the extrinsic finger flexor in regards to their length to maximise grip force performance. The present study aimed at providing quantitative evidence of the links between wrist posture, muscle capacities and grip capabilities. It combines experimental measurements and a musculoskeletal model including the force-length relationship of the four prime muscles used in grasping. Participants exerted their maximum grip force on a cylindrical dynamometer in four different wrist postures, including one freely chosen by participants (spontaneous). A musculoskeletal model computed the muscle force level and length from motion capture and muscle activation. Results revealed that participants exerted maximum grip force spontaneously, with a loss of force when using other postures. At muscle force and length level, grip force variation seems to be associated with all the muscles under study. This observation led to a first quantitative link between power grip, posture and muscle properties, which could provide more insight into neuromechanical interaction involved when grasping. The design of ergonomic devices could also benefit from this quantification of the relationship between wrist angle and muscle length properties.


Modulation of the human gut microflora towards improved health using prebiotics--assessment of efficacy.
There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An "optimal" gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.


Evaluation of aging in place model with home care services and registered nurse care coordination in senior housing.
A state-sponsored evaluation of aging in place (AIP) as an alternative to assisted living and nursing home has been underway in Missouri. Cost, physical, and mental health assessment data reveal the cost-effectiveness and positive health measures of AIP. Findings of the first four years of the AIP evaluation of two long-term care settings in Missouri with registered nurse care coordination are compared with national data for traditional long-term care. The combined care and housing cost for any resident who received care services beyond base services of AIP and who qualified for nursing home care has never approached or exceeded the cost of nursing home care at either location. Both mental health and physical health measures indicate the health restoration and independence effectiveness of the AIP model for long-term care.


Time-dependent performance of soil mix technology stabilized/solidified contaminated site soils.
This paper presents the strength and leaching performance of stabilized/solidified organic and inorganic contaminated site soil as a function of time and the effectiveness of modified clays applied in this project. Field trials of deep soil mixing application of stabilization/solidification (S/S) were performed at a site in Castleford in 2011. A number of binders and addictives were applied in this project including Portland cement (PC), ground granulated blastfurnace slag (GGBS), pulverised fuel ash (PFA), MgO and modified clays. Field trial samples were subjected to unconfined compressive strength (UCS), BS CN 12457 batch leaching test and the extraction of total organics at 28 days and 1.5 years after treatment. The results of UCS test show that the average strength values of mixes increased from 0-3250 kPa at 28 days to 250-4250 kPa at 1.5 years curing time. The BS EN 12457 leachate concentrations of all metals were well below their drinking water standard, except Ni in some mixes exceed its drinking water standard at 0.02 mg/l, suggesting that due to varied nature of binders, not all of them have the same efficiency in treating contaminated soil. The average leachate concentrations of total organics were in the range of 20-160 mg/l at 28 days after treatment and reduced to 18-140 mg/l at 1.5 years. In addition, organo clay (OC)/inorgano-organo clay (IOC) slurries used in this field trial were found to have a negative effect on the strength development, but were very effective in immobilizing heavy metals. The study also illustrates that the surfactants used to modify bentonite in this field trail were not suitable for the major organic pollutants exist in the site soil in this project.


Response inhibition in psychopathy: the frontal N2 and P3.
Psychopathy has been associated with atypical function of the anterior cingulate cortex (ACC) and adjacent brain regions and with abnormalities in performance monitoring, which is thought to rely on these structures. The ACC and adjacent regions are also involved in the generation of two characteristic components of the event-related potential: the frontal N2 and P3. Both components are enhanced when a response is withheld (NoGo trial) within a series of positive-responses (Go trials) and are considered an index of response inhibition. We recorded event-related potentials while violent offenders who varied on the dimension of psychopathy and non-offender controls performed a Go/NoGo task. The offenders made more errors of commission on NoGo trials but this effect was unrelated to level of psychopathy within the group and, inconsistent with a previous report, they produced the enhanced frontal N2 and P3 effect in response to NoGo relative to Go conditions. We conclude that the neural processes involved in response inhibition are not abnormal in psychopaths when both stimuli and context are affectively neutral and suggest that a more nuanced perspective regarding impulsivity in this population be considered.


A cohort study of subjective global assessment and mortality in Taiwanese hemodialysis patients.
Many patients with end-stage renal disease are malnourished, and cross-sectional studies have shown that markers of malnutrition may predict death. In this study, we investigated the possible association of Subjective Global Assessment and mortality in a small cohort of Taiwanese hemodialysis patients. Fifty hemodialysis patients at a hemodialysis center in eastern Taiwan were enrolled in June 2002. Height and weight were used to determine the body mass index. Bioelectrical impedance analysis of body fat mass was performed before and after a mid-week dialysis session. Biochemical indexes of the nutritional status included serum albumin, creatinine, transferrin, cholesterol, and the normalized protein catabolic rate. Mortality data during 42 months after enrollment were obtained. Twenty-six hemodialysis patients were classified as well-nourished and twenty-four as malnourished based on Subjective Global Assessment. Decreased body mass index (p = 0.006), increased body fat mass (p = 0.019 before hemodialysis; p = 0.007 after hemodialysis), decreased serum albumin (p = 0.011), and decreased serum creatinine (p = 0.006) were significantly higher in the malnourished group. Older age (p = 0.042), decreased serum albumin (p = 0.028), decreased serum transferrin (p = 0.041), and malnourishment (p = 0.004) were significantly higher in the mortality group. Multivariate forward stepwise linear regression analysis of mortality and nutrition profiles show that Subjective Global Assessment is the independent predictor of mortality (R(2) = 0.20). Malnourished hemodialysis patients had a higher mortality rate than well-nourished hemodialysis patients in Taiwan. Subjective Global Assessment of the nutritional status appears to be a simple tool for assessing the nutritional status of hemodialysis patients in long-term care. This assessment tool is also beneficial for hemodialysis patients who are at a greater risk of nutritional-associated mortality.


Comparison of the treatment performance of bio-substrate based and meadow brown soil based subsurface infiltration systems for domestic wastewater treatment.
To foster the practical development of subsurface wastewater infiltration (SWI) systems in China, two systems were implemented on the campus of Shenyang University. The bio-substrate filled SWI (BSWI) and meadow brown soil filled SWI (MSWI) system operated under the same operation mode. According to the 12-month experimental results, the bio-substrate had much higher potential to be a good substrate as compared to the meadow brown soil. The maximum adsorbing capability for NH(4)(+)-N of the bio-substrate was 0.724 mg/g, while for the meadow brown soil, the maximum value was 0.471 mg/g. The amounts of nitrifying and denitrifying bacteria of the BSWI were one order of magnitude higher than that for the MSWI. Ammonia, nitrite and nitrate nitrogen concentrations implied nitrification-denitrification process went well in the BSWI. Moreover, the BSWI system maintained efficient pollutants removal, the mean removal efficiencies were 92.3 ± 1.5%, 96.5 ± 3.1%, 90.0 ± 2.1%, 78.6 ± 1.2%, 91.2 ± 1.1% and 99.7 ± 1.0% for COD, BOD(5), NH(4)(+)-N, TN, TP and SS, respectively. As compared with the MSWI system, pollutant removal efficiencies improved by 26.8 ± 2.3% for NH(4)(+)-N, 33.8 ± 1.7% for TN, 22.4 ± 1.4% for COD, 26.0 ± 3.5% for BOD(5) and 14.7 ± 2.9% for TP, respectively.


Health behaviors of adults: United States, 2005-2007.
This report presents selected prevalence estimates for key indicators of alcohol use, cigarette smoking, leisure-time physical activity, body weight status, and sleep among U.S. adults, using data from the 2005-2007 National Health Interview Survey (NHIS). The NHIS is conducted annually by the Centers for Disease Control and Prevention's National Center for Health Statistics. Estimates are shown for several sociodemographic subgroups for both sexes combined and for men and women separately. The subgroups are compared in terms of their prevalence of "healthy" and "unhealthy" behaviors. Data for the U.S. civilian noninstitutionalized population were collected by the NHIS using computer-assisted personal interviews (CAPI). Questions on health behaviors were asked of one randomly selected adult per family in the Sample Adult component of the basic core questionnaire. This report is based on a total of 79,096 completed interviews with sample adults aged 18 years and over, representing an overall sample adult response rate of 69.2% for the 3 years combined. Statistics shown in this report were age adjusted to the 2000 U.S. standard population. Overall, 6 in 10 (61.2%) U.S. adults were current drinkers in 2005-2007; about 1 in 4 adults (24.6%) were lifetime abstainers. About 1 in 5 adults (20.4%) were current smokers and over one-half of adults (58.5%) had never smoked cigarettes. About 4 in 10 (42.5%) current smokers tried to quit smoking in the past year. About 6 in 10 adults engaged in at least some leisure-time physical activity with about 3 in 10 regularly engaging in such activities. About 6 in 10 adults were overweight or obese (BMI > 25), with about 4 in 10 adults being of healthy weight. About 6 in 10 adults usually slept 7 to 8 hours in a 24-hour period.


H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK.
Regions of hypoxia occur in most solid tumors, and they are associated with a poor prognostic outcome. Despite the absence of detectable DNA damage, severe hypoxia (<0.1% O2) induces a DNA damage response, including the activation of p53 and subsequent induction of p53-dependent apoptosis. Factors affecting hypoxia-induced p53-dependent apoptosis are unclear. Here we asked whether H3K9me3, through mediating gene repression, could regulate hypoxia-induced p53-dependent apoptosis. Under hypoxic conditions, increases in H3K9me3 occur in an oxygen-dependent but HIF-1-independent manner. We demonstrate that under hypoxic conditions, which induce p53 activity, the negative regulator of p53, APAK, is repressed by increases in H3K9me3 along the APAK loci. APAK repression in hypoxia is mediated by the methyltransferase SETDB1 but not Suv39h1 or G9a. Interestingly, increasing hypoxia-induced H3K9me3 through pharmacological inhibition of JMJD2 family members leads to an increase in apoptosis and decreased clonogenic survival and again correlates with APAK expression. The relevance of understanding the mechanisms of APAK expression regulation to human disease was suggested by analysis of patients with colorectal cancer, which demonstrates that high APAK expression correlates with poor prognosis. Together, these data demonstrate the functional importance of H3K9me3 in hypoxia, and they provide a novel mechanistic link between H3K9me3, p53 and apoptosis in physiologically relevant conditions of hypoxia.


Identification of the catalytic motif of the microbial ribosome inactivating cytotoxin colicin E3.
Colicin E3 is a cytotoxic ribonuclease that specifically cleaves 16S rRNA at the ribosomal A-site to abolish protein synthesis in sensitive Escherichia coli cells. We have performed extensive mutagenesis of the 96-residue colicin E3 cytotoxic domain (E3 rRNase), assayed mutant colicins for in vivo cytotoxicity, and tested the corresponding E3 rRNase domains for their ability to inactivate ribosome function in vitro. From 21 alanine mutants, we identified five positions where mutation resulted in a colicin with no measurable cytotoxicity (Y52, D55, H58, E62, and Y64) and four positions (R40, R42, E60, and R90) where mutation caused a significant reduction in cytotoxicity. Mutations that were found to have large in vivo and in vitro effects were tested for structural integrity through circular dichroism and fluorescence spectroscopy using purified rRNase domains. Our data indicate that H58 and E62 likely act as the acid-base pair during catalysis with other residues likely involved in transition state stabilization. Both the Y52 and Y64 mutants were found to be highly destabilized and this is the likely origin of the loss of their cytotoxicity. The identification of important active site residues and sequence alignments of known rRNase homologs has allowed us to identify other proteins containing the putative rRNase active site motif. Proteins that contained this active site motif included three hemagglutinin-type adhesins and we speculate that these have evolved to deliver a cytotoxic rRNase into eukaryotic cells during pathogenesis.


Gonads or body? Differences in gonadal and somatic photoperiodic growth response in two vole species.
To optimally time reproduction, seasonal mammals use a photoperiodic neuroendocrine system (PNES) that measures photoperiod and subsequently drives reproduction. To adapt to late spring arrival at northern latitudes, a lower photoperiodic sensitivity and therefore a higher critical photoperiod for reproductive onset is necessary in northern species to arrest reproductive development until spring onset. Temperature-photoperiod relationships, and hence food availability-photoperiod relationships, are highly latitude dependent. Therefore, we predict PNES sensitivity characteristics to be latitude dependent. Here, we investigated photoperiodic responses at different times during development in northern (tundra or root vole, Microtus oeconomus) and southern vole species (common vole, Microtus arvalis) exposed to constant short (SP) or long photoperiod (LP). Although the tundra vole grows faster under LP, no photoperiodic effect on somatic growth is observed in the common vole. In contrast, gonadal growth is more sensitive to photoperiod in the common vole, suggesting that photoperiodic responses in somatic and gonadal growth can be plastic, and might be regulated through different mechanisms. In both species, thyroid-stimulating hormone β-subunit (Tshβ) and iodothyronine deiodinase 2 (Dio2) expression is highly increased under LP, whereas Tshr and Dio3 decrease under LP. High Tshr levels in voles raised under SP may lead to increased sensitivity to increasing photoperiods later in life. The higher photoperiodic-induced Tshr response in tundra voles suggests that the northern vole species might be more sensitive to thyroid-stimulating hormone when raised under SP. In conclusion, species differences in developmental programming of the PNES, which is dependent on photoperiod early in development, may form different breeding strategies as part of latitudinal adaptation.


Epigenetic inactivation of laminin-5-encoding genes in lung cancers.
We investigated the loss of expression of three laminin-5 (LN5)-encoding genes in lung cancer cell lines and elucidated the mechanism of inactivation of the genes in lung cancer cell lines and tumors. We examined the expression of LN5-encoding genes by reverse transcription-PCR in 49 lung cancer cell lines. To elucidate the mechanism of gene silencing, we treated expression-negative cell lines (two for each gene) with a demethylating agent and examined the restoration of expression by reverse transcription-PCR. We dissected out the methylation patterns of CpG sites unique to the promoter regions of LN5-encoding genes by bisulfite genomic sequencing of expression-negative cell lines. We designed methylation-specific primers and validated the methylation status of the promoter regions in lung cancer cell lines using methylation-specific PCR. We further studied the methylation patterns of primary non-small cell lung cancer [NSCLC (n = 36)], small cell lung cancer [SCLC (n = 26)], and carcinoids (n = 24) tumors. We observed frequent losses of expression in NSCLC (20-60%) and SCLC (65-86%) cell lines. Expression of one or more genes was lost in 90% of SCLC cell lines and 65% of NSCLC cell lines. Treatment of expression-negative cell lines with demethylating agent restored expression in all of the cases. Methylation of LN5-encoding genes was present more frequently in SCLC cell lines (60-80%) than in NSCLC cell lines (15-60%), and at least one gene was methylated in 95% of SCLC and 60% of NSCLC cell lines. The concordances between loss of expression and methylation in 40 lung cancer cell lines for the three genes (90-95%) were statistically significant. Methylation was more frequent in SCLC tumors (58-77%) than in NSCLC tumors (22-42%) and carcinoids (13-33%), and at least one gene was methylated in 92% of SCLC tumors, 47% of NSCLC tumors, and 33% of carcinoids. Our results demonstrate frequent epigenetic inactivation of LN5-encoding genes in lung cancers, and these findings are of biological interest and are potentially of clinical importance.


Donation after circulatory death in lung transplantation-five-year follow-up from ISHLT Registry.
This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality.


MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development.
Alternative pre-mRNA splicing determines many changes in gene expression during development. Two regulators known to control splicing patterns during neuron and muscle differentiation are the polypyrimidine tract-binding protein (PTB) and its neuronal homolog nPTB. These proteins repress certain exons in early myoblasts, but upon differentiation of mature myotubes PTB/nPTB expression is reduced, leading to increased inclusion of their target exons. We show here that the repression of nPTB expression during myoblast differentiation results from its targeting by the muscle-restricted microRNA miR-133. During differentiation of C2C12 myoblasts, nPTB protein but not mRNA expression is strongly reduced, concurrent with the up-regulation of miR-133 and the induction of splicing for several PTB-repressed exons. Introduction of synthetic miR-133 into undifferentiated C2C12 cells leads to a decrease in endogenous nPTB expression. Both the miR-133 and the coexpressed miR-1/206 microRNAs are extremely conserved across animal species, and PTB proteins are predicted targets for these miRNAs in Drosophila, mice, and humans. There are two potential miR-133-responsive elements (MRE) within the nPTB 3' untranslated region (UTR), and a luciferase reporter carrying this 3' UTR is repressed by miR-133 in an MRE-dependent manner. Transfection of locked nucleic acid (LNA) oligonucleotides designed to block the function of miR-133 and miR-1/206 increases expression of nPTB and decreases the inclusion of PTB dependent exons. These results indicate that miR-133 directly down-regulates a key splicing factor during muscle development and establishes a role for microRNAs in the control of a developmentally dynamic splicing program.


[Diagnosing and treating rheumatoid arthritis].
Rheumatoid arthritis (RA) is a chronic, autoimmune joint disease associated with increased risk of multiorgan involvement and comorbidities such as osteoporosis, cardiovascular disease, and infections. Therefore, doctors in other specialities should have knowledge of RA. No diagnostic criteria are available, but the classification criteria are often used as a diagnostic tool. Early initiation of effective immunosuppressive treatment is essential to improve outcome. The cornerstone of treatment is intra-articular administration of glucocorticoids in combination with methotrexate.


Irrigation versus suction alone during laparoscopic appendectomy for perforated appendicitis: a prospective randomized trial.
The efficacy of irrigating the peritoneal cavity during appendectomy for perforated appendicitis has been debated extensively. To date, prospective comparative data are lacking. Therefore, we conducted a prospective, randomized trial comparing peritoneal irrigation to suction alone during laparoscopic appendectomy in children. Children younger than 18 years with perforated appendicitis were randomized to peritoneal irrigation with a minimum of 500 mL normal saline, or suction only during laparoscopic appendectomy. Perforation was defined as a hole in the appendix or fecalith in the abdomen. The primary outcome variable was postoperative abscess. Using a power of 0.8 and alpha of 0.05, a sample size of 220 patients was calculated. A battery-powered laparoscopic suction/irrigator was used in all cases. Pre- and postoperative management was controlled. Data were analyzed on an intention-to-treat basis. A total of 220 patients were enrolled between December 2008 and July 2011. There were no differences in patient characteristics at presentation. There was no difference in abscess rate, which was 19.1% with suction only and 18.3% with irrigation (P = 1.0). Duration of hospitalization was 5.5 ± 3.0 with suction only and 5.4 ± 2.7 days with group (P = 0.93). Mean hospital charges was $48.1K in both groups (P = 0.97). Mean operative time was 38.7 ± 14.9 minutes with suction only and 42.8 ± 16.7 minutes with irrigation (P = 0.056). Irrigation was felt to be necessary in one case (0.9%) randomized to suction only. In the patients who developed an abscess, there was no difference in duration of hospitalization, days of intravenous antibiotics, duration of home health care, or abscess-related charges. There is no advantage to irrigation of the peritoneal cavity over suction alone during laparoscopic appendectomy for perforated appendicitis. The study was registered with clinicaltrials.gov at the inception of enrollment (NCT00981136).


Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation.
A double transgenic mouse expressing the amyloid precursor protein, bearing the Swedish mutations, and expressing tau protein containing three of the mutations present in frontotemporal dementia linked to chromosome 17 (FTDP-17), has been characterized. In the double transgenic mouse an increase in tau phosphorylation at serine S262 and S422 was observed compared with that found in simple transgenic mice. The phosphorylation at S262 was also found, in a much lower level, in the single transgenic mouse expressing amyloid precursor protein (APP), and it was absent in that overexpressing tau variant. Additionally, in the double transgenic mouse a slight increase in the amount of sarkosyl insoluble tau polymers was observed in comparison with that found in single transgenic tau mouse. Also, wider tau filaments were found in the double transgenic mouse compared with those found in the single transgenic mouse. Our results suggest that beta-amyloid peptide could facilitate the phosphorylation of tau at a site not directed by proline, such as serine 262, and that modification could facilitate tau aberrant aggregation. Also, they suggest that different types of tau filamentous polymers can occur in different mouse models for tauopathies, like those used for Alzheimer's disease or FTDP-17.


The Trump Effect: Postinauguration Changes in Marketplace Enrollment.
On January 20, 2017, President Donald Trump penned his first executive order, which aimed to "minimiz[e] the economic burden" of the Affordable Care Act, signaling his intent to make good on promises to repeal and replace the law. This executive order, along with concurrent changes in political messaging associated with the transition in power and reductions in HealthCare.gov advertising, lowered Health Insurance Marketplace enrollment at the end of the 2017 open enrollment period. The authors used difference-in-differences and event-study models with weekly county-level Marketplace application data from 1,476 counties in 37 states to estimate the incremental enrollment loss in the postinauguration period. Estimates indicate a population-weighted decline of over 700 applications per county-week during the final 2 weeks of the 2017 open enrollment period relative to 2016, corresponding to a nearly 30% decline in applications submitted. A more flexible event-study approach that better accounts for time shifting of enrollment across open enrollment periods found a similar decline of approximately 660 applications per county-week associated with the postinauguration period (-24%). The lack of political support for the law by the incoming administration seemingly had an immediate and significant downward effect on Marketplace enrollment nationwide.


α-Tocopherol-based cationic amphiphiles with a novel pH sensitive hybrid linker for gene delivery.
Endosomal escape is one of the barriers for the efficient liposomal gene delivery. To address this and based on earlier encouraging results using tocopherol cationic lipids, we elaborated chemical modifications on tocopherol cationic lipids by introducing a novel hybrid pH sensitive linker "ether-β-hydroxy-triazole" between tocopherol, the anchoring moiety and the basic tris(2-hydroxy ethyl)quaternary ammonium head group (Lp2). As control lipids we designed two lipids (Lp1 and Lp3), one is with only the ether-β-hydroxy linker in between α-tocopherol and quaternary tris(2-hydroxyethyl)ammonium (Lp1) and the other is with the same novel hybrid linker i.e. "ether-β-hydroxy-triazole" between the α-tocopherol linked and quaternary tris-ethyl ammonium head group (Lp3). Liposomes were formulated with a combination of a well-known co-lipid, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and biophysical characteristics such as DNA binding, hydrodynamic diameters and global surface charges for liposomes and lipoplexes of respective lipids were evaluated. Cell viability assay and in vitro transfection studies were carried out in NIH3 T3, B16F10, HEK-293, and HepG2 cell lines. In vitro transfection data for the liposomes of lipids (Lp1, Lp2 and Lp3) revealed that the Lp2 lipid with a novel hybrid pH sensitive linker showed superior transfection efficiency when compared with the remaining two analogues. More importantly, Lp2 has shown a similar pattern of transfection efficiency in HepG2 and HEK-293 cell lines when compared with commercially available Lipofectamine 3000.


Twinship and risk of postmenopausal breast cancer.
Intrauterine exposure to high levels of endogenous estrogens has been hypothesized to increase the risk of breast cancer. Because estrogens and other pregnancy hormones are substantially elevated in twin pregnancies, and possibly more so in dizygotic twin pregnancies, we evaluated the association between aspects of twin membership (i.e., belonging to a twin pair) and the risk of breast cancer. In a cohort of 29 197 postmenopausal Iowa women with no prior diagnosis of cancer (except for nonmelanoma skin cancer), breast cancer risk factors were determined by use of a mailed questionnaire in 1986 (baseline); twin membership, sex of the twin, and zygosity were determined by use of a follow-up questionnaire in 1992. Within the cohort, 1.8% (n = 538) of the women reported being a twin; of these, 24% (n = 130) were monozygotic twins, 63% (n = 337) were dizygotic twins, and 13% (n = 71) did not know their zygosity. From 1986 through 1996, 1230 breast cancers in the cohort were ascertained by linkage to the Iowa Cancer Registry. Compared with singletons, women who belonged to a twin pair were at elevated risk of breast cancer (multivariate-adjusted risk ratio [RR] = 1.72; 95% confidence interval [CI] = 1.22-2.42), with adjustment for educational level, family history of breast cancer, height, body mass index, body fat distribution, age at menarche, age at first live birth, use of hormone replacement therapy, and alcohol use. Multivariate-adjusted risk was elevated (in comparison with singletons) if the sex of the other twin was female (RR = 1.82; 95% CI = 1.20-2.75); however, this risk was limited to female dizygotic twins (RR = 2.14; 95% CI = 1. 21-3.79), since no excess risk was evident for monozygotic twins (RR = 1.04; 95% CI = 0.43-2.50). The risk to women with a male twin was also elevated (RR = 1.49; 95% CI = 0.80-2.78) in comparison with singletons, but this estimate was not statistically significant. This cohort study lends further support to the theory that there are important intrauterine influences on carcinogenesis of the breast.


Fabrication of Fe-Al nanoparticles by selective oxidation of Fe-Al thin films.
The possibility of a new technique for fabricating nanoparticles from thin films using selective oxidation in an atmosphere mixture of water vapor and hydrogen was investigated. Fe-5wt.%Al films were RF-sputtered and annealed in the atmosphere mixture at 900°C for up to 200 min, in order to oxidize aluminum selectively. Thermodynamics simulation showed that temperatures exceeding 800°C are necessary to prevent iron from being oxidized, as confirmed by the depth profile of XPS. As the annealing time increased, the morphology of the 200-nm Fe-Al films changed from the continuous to the discontinuous type; thus, particulate Fe-Al films formed after 100 min. The particulate 10- to 100-nm Fe-Al films showed super-paramagnetic behavior after the oxidation. Thus, a new technique for fabricating nanoparticles was successfully introduced using selective oxidation.


Relationship between quantitative CT metrics and health status and BODE in chronic obstructive pulmonary disease.
The value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St George's Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE). 1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a -950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10 mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE. In separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p<0.001; for WA%, 1.20-fold increase, p<0.001; for pi10, 1.16-fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26-fold increase, p<0.001). Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.


Using Odds Ratios to Detect Differential Item Functioning.
Differential item functioning (DIF) makes test scores incomparable and substantially threatens test validity. Although conventional approaches, such as the logistic regression (LR) and the Mantel-Haenszel (MH) methods, have worked well, they are vulnerable to high percentages of DIF items in a test and missing data. This study developed a simple but effective method to detect DIF using the odds ratio (OR) of two groups' responses to a studied item. The OR method uses all available information from examinees' responses, and it can eliminate the potential influence of bias in the total scores. Through a series of simulation studies in which the DIF pattern, impact, sample size (equal/unequal), purification procedure (with/without), percentages of DIF items, and proportions of missing data were manipulated, the performance of the OR method was evaluated and compared with the LR and MH methods. The results showed that the OR method without a purification procedure outperformed the LR and MH methods in controlling false positive rates and yielding high true positive rates when tests had a high percentage of DIF items favoring the same group. In addition, only the OR method was feasible when tests adopted the item matrix sampling design. The effectiveness of the OR method with an empirical example was illustrated.


Socioeconomic disparities in infant mortality after nonaccidental trauma: a multicenter study.
While disparities in abuse-related mortality between minority and white infants have been reported, the influence of socioeconomic status on outcome has not been evaluated. The goal of this study was to determine the impact of socioeconomic status and race on outcomes for abused infants using multiinstitutional data. Data on infants (<12 months old) with abusive injuries over a 5-year period were obtained from nine U.S. pediatric trauma centers. Demographics, insurance status, Injury Severity Scores, Glasgow Coma Scale scores, median household income and outcomes were recorded. Logistic regression was used to evaluate the impact of race, income and insurance status on mortality. There were 867 patients identified with a mortality of 8.8%. Patients without private insurance had a 3.8 times greater odds (give 95% confidence interval) of dying. Those in the lower three quartiles of income also had a higher odds of death even after controlling for race, injury severity, and Glasgow Coma Scale. Although African American infants had a higher overall mortality than whites (11.2% vs. 7.8%, p = 0.14), race was not an independent predictor of mortality (p = 0.98). There are significant differences in mortality among abused infants associated with insurance status and income even after controlling for injury severity. These associations show a need to better understand and address socioeconomic variations in outcome.


Anticipation of monetary gain but not loss in healthy older adults.
Although global declines in structure have been documented in the aging human brain, little is known about the functional integrity of the striatum and prefrontal cortex in older adults during incentive processing. We used event-related functional magnetic resonance imaging to determine whether younger and older adults differed in both self-reported and neural responsiveness to anticipated monetary gains and losses. The present study provides evidence for intact striatal and insular activation during gain anticipation with age, but shows a relative reduction in activation during loss anticipation. These findings suggest that there is an asymmetry in the processing of gains and losses in older adults that may have implications for decision-making.


Transduction of staphylococcal cassette chromosome mec elements between strains of Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known public health concern. However, the means by which methicillin resistance genes are transferred among staphylococci in nature remains unknown. Older scientific literature suggests transduction as a means of mecA transfer, but the optimal conditions are reported to require plasmids and potentially a lysogenic phage. These reports preceded discovery of the staphylococcal cassette chromosome mec (SCCmec) elements. We undertook studies to confirm and clarify the conditions promoting transduction of SCCmec in S. aureus populations using well-characterized donor and recipient strains primarily of the USA300 lineage. Both bacteriophages 80α and 29 were capable of transducing SCCmec type IV and SCCmec type I to recipient strains of S. aureus. Pulsed-field gel electrophoresis and mec-associated dru typing were used to confirm the identity of the transductants. Transfer of mecA via transduction occurred at low frequency and required extended selection times for mecA gene expression and the presence of a penicillinase plasmid in the recipient. However, interference with the process by clavulanic acid and the necessity of lysogeny with 11 in the recipient or the presence of a small (4-kb) tetracycline resistance plasmid, as previously reported, were not confirmed. SCCmec transduction was occasionally associated with substantial deletions or truncation of SCCmec and the arginine catabolic metabolic element in USA300 recipients. Overall, these data clarify the conditions required for SCCmec transduction and document that rearrangements may occur during the process.


Aerobic co-treatment of landfill leachate and domestic wastewater - are slowly biodegradable organics removed or simply diluted?
This study investigated the co-treatment of landfill leachate/domestic wastewater in bench-scale activated sludge (AS) reactors to determine whether the slowly biodegradable organic matter (SBOM) was removed rather than diluted. The AS reactors were loaded with mixtures of raw leachate and leachate that was pretreated by air stripping. The tested volumetric ratios were 0%, 0.2%, 2% and 5%. For all of the tested conditions, the reactors performed better when pretreated leachate was used rather than raw leachate, and the best volumetric ratio was 2%. The following removals were obtained: 97% for the biochemical oxygen demand (BOD5,20), 79% for total suspended solids, 77% for dissolved organic carbon and 84% for soluble chemical oxygen demand. Most of the pretreated leachate SBOM (65%) was removed rather than diluted or adsorbed into the sludge, as confirmed by Fourier transform infrared (FTIR) spectroscopy analyses.


Patients with Ventromedial Prefrontal Lesions Show an Implicit Approach Bias to Angry Faces.
Damage to the ventromedial PFC (VMPFC) can cause maladaptive social behavior, but the cognitive processes underlying these behavioral changes are still uncertain. Here, we tested whether patients with acquired VMPFC lesions show altered approach-avoidance tendencies to emotional facial expressions. Thirteen patients with focal VMPFC lesions and 31 age- and gender-matched healthy controls performed an implicit approach-avoidance task in which they either pushed or pulled a joystick depending on stimulus color. Whereas controls avoided angry faces, VMPFC patients displayed an incongruent response pattern characterized by both increased approach and reduced avoidance of angry facial expressions. The approach bias was stronger in patients with higher self-reported impulsivity and disinhibition and in those with larger lesions. We further used linear ballistic accumulator modeling to investigate latent parameters underlying approach-avoidance decisions. Controls displayed negative drift rates when approaching angry faces, whereas VMPFC lesions abolished this pattern. In addition, VMPFC patients had weaker response drifts than controls during avoidance. Finally, patients showed reduced drift rate variability and shorter nondecision times, indicating impulsive and rigid decision-making. Our findings thus suggest that VMPFC damage alters the pace of evidence accumulation in response to social signals, eliminating a default, protective avoidant bias and facilitating a dysfunctional approach behavior.


Combining machine learning with Cox models to identify predictors for incident post-menopausal breast cancer in the UK Biobank.
We aimed to identify potential novel predictors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction. We utilised an analysis pipeline where machine learning was used for feature selection, prior to risk prediction by classical statistical models. An "extreme gradient boosting" (XGBoost) machine with Shapley feature-importance measures were used for feature selection among [Formula: see text] 1.7 k features in 104,313 post-menopausal women from the UK Biobank. We constructed and compared the "augmented" Cox model (incorporating the two PRS, known and novel predictors) with a "baseline" Cox model (incorporating the two PRS and known predictors) for risk prediction. Both of the two PRS were significant in the augmented Cox model ([Formula: see text]). XGBoost identified 10 novel features, among which five showed significant associations with post-menopausal breast cancer: plasma urea (HR = 0.95, 95% CI 0.92-0.98, [Formula: see text]), plasma phosphate (HR = 0.68, 95% CI 0.53-0.88, [Formula: see text]), basal metabolic rate (HR = 1.17, 95% CI 1.11-1.24, [Formula: see text]), red blood cell count (HR = 1.21, 95% CI 1.08-1.35, [Formula: see text]), and creatinine in urine (HR = 1.05, 95% CI 1.01-1.09, [Formula: see text]). Risk discrimination was maintained in the augmented Cox model, yielding C-index 0.673 vs 0.667 (baseline Cox model) with the training data and 0.665 vs 0.664 with the test data. We identified blood/urine biomarkers as potential novel predictors for post-menopausal breast cancer. Our findings provide new insights to breast cancer risk. Future research should validate novel predictors, investigate using multiple PRS and more precise anthropometry measures for better breast cancer risk prediction.


Monitoring intracellular proteins using fluorescence techniques: from protein synthesis and localization to activity.
The recent breakthroughs in genomics and proteomics and improvements of optical methods have made it possible to obtain localized, real-time information on intracellular proteins dynamics, through dynamic three-dimensional (3D) maps of the living cell with nanometric resolution of individual molecules. On one side, brighter variants of the Green Fluorescence Protein (GFP) have been engineered that have different excitation and/or emission spectra that better match available light sources. Like their parent molecule, these variants retain their fluorescence when fused to heterologous proteins on the N- and C- terminals, and this binding generally does not affect the functionality of the tagged protein leading the way to their use as an intracellular reporter. On the other side, optical methods have been improved to allow reaching the level of single-molecule detection inside living cells. Nevertheless some limitations exist for the use of GFP variants for probing 3D conformational changes of proteins. First, these variants are fused to the N and/or C terminals of the studied protein, which are generally not the best location to detect conformational changes resulting from the binding to other proteins or enzyme substrates. Then their own relatively large size makes them unusable for tagging small proteins. These limitations suggest that new tagging processes, permitting the location of the right fluorescent markers at the right places, must be found to built up inter- and/or intra-molecular rulers allowing one to monitor conformational changes resulting from intracellular protein-protein, protein-membrane, and enzyme-substrate binding. These specific locations can be obtained from in vitro studies of 3D conformational changes that occur during protein docking.


Comparison of Coronary Atherosclerotic Plaque Burden and Composition of Culprit Lesions Between Cigarette Smokers and Non-Smokers by In Vivo Virtual Histology Intravascular Ultrasound.
Cigarette smoking is a major risk factor in the progression of atherosclerosis and has been shown to cause endothelial dysfunction, inflammation, and modification of lipid profile. However, its role in the pathogenesis of vulnerable coronary plaque remains unknown. We investigated the relationship between cigarette smoking and the development of vulnerable coronary artery plaque using virtual histology intravascular ultrasound (VH-IVUS). Data from consecutive patients who underwent VH-IVUS assessment of native coronary artery stenosis during clinically indicated cardiac catheterization at our institution over a 2-year period were analyzed. Baseline demographic and study characteristics were collected on all patients. Coronary plaque compositions of the culprit lesion were compared on bivariate and multivariate analysis. We analyzed data on 160 patients with a mean age of 60 ± 11 years. Sixty-nine percent of these patients were admitted for acute coronary syndrome, 31% were smokers, and the mean plaque burden was 66%. On average, 58% of these plaques were fibrous, 19% were fibro-fatty, 18.3% had a necrotic core, and 5.4% were composed of dense calcium. Cigarette smokers had a higher burden of necrotic core (20.7% vs 17.2%; P=.04). On multivariate analysis, cigarette smoking was independently associated with a 4.54% increase in the burden of necrotic core (P=.01). Older age (>80 years) was also a predictor of higher necrotic core burden (P=.02). In conclusion, cigarette smoking is associated with a higher burden of necrotic core in coronary atherosclerotic plaques. This may represent one of the mechanisms for increased cardiovascular events.


Rhesus monkeys (Macaca mulatta) discriminate between knowing and not knowing and collect information as needed before acting.
Humans use memory awareness to determine whether relevant knowledge is available before acting, as when we determine whether we know a phone number before dialing. Such metacognition, or thinking about thinking, can improve selection of appropriate behavior. We investigated whether rhesus monkeys ( Macaca mulatta) are capable of a simple form of metacognitive access to the contents of short-term memory. Monkeys chose among four opaque tubes, one of which concealed food. The tube containing the reward varied randomly from trial to trial. On half the trials the monkeys observed the experimenter baiting the tube, whereas on the remaining trials their view of the baiting was blocked. On each trial, monkeys were allowed a single chance to select the tube containing the reward. During the choice period the monkeys had the opportunity to look down the length of each tube, to determine if it contained food. When they knew the location of the reward, most monkeys chose without looking. In contrast, when ignorant, monkeys often made the effort required to look, thereby learning the location of the reward before choosing. Looking improved accuracy on trials on which monkeys had not observed the baiting. The difference in looking behavior between trials on which the monkeys knew, and trials on which they were ignorant, suggests that rhesus monkeys discriminate between knowing and not knowing. This result extends similar observations made of children and apes to a species of Old World monkey, suggesting that the underlying cognitive capacities may be widely distributed among primates.


Investigating and managing the rapid emergence of white-nose syndrome, a novel, fatal, infectious disease of hibernating bats.
White-nose syndrome (WNS) is a fatal disease of bats that hibernate. The etiologic agent of WNS is the fungus Geomyces destructans, which infects the skin and wing membranes. Over 1 million bats in six species in eastern North America have died from WNS since 2006, and as a result several species of bats may become endangered or extinct. Information is lacking on the pathogenesis of G. destructans and WNS, WNS transmission and maintenance, individual and site factors that contribute to the probability of an outbreak of WNS, and spatial dynamics of WNS spread in North America. We considered how descriptive and analytical epidemiology could be used to fill these information gaps, including a four-step (modified) outbreak investigation, application of a set of criteria (Hill's) for assessing causation, compartment models of disease dynamics, and spatial modeling. We cataloged and critiqued adaptive-management options that have been either previously proposed for WNS or were helpful in addressing other emerging diseases of wild animals. These include an ongoing program of prospective surveillance of bats and hibernacula for WNS, treatment of individual bats, increasing population resistance to WNS (through vaccines, immunomodulators, or other methods), improving probability of survival from starvation and dehydration associated with WNS, modifying hibernacula environments to eliminate G. destructans, culling individuals or populations, controlling anthropogenic spread of WNS, conserving genetic diversity of bats, and educating the public about bats and bat conservation issues associated with WNS.


Germinal centres in diagnostic labial gland biopsies of patients with primary Sjögren's syndrome are not predictive for parotid MALT lymphoma development.
Patients with primary Sjögren's syndrome (pSS) have an increased risk of developing non-Hodgkin's lymphoma (NHL), particularly parotid gland mucosa-associated lymphoid tissue (MALT) lymphomas. Presence of germinal centres (GCs) in labial gland biopsies has been suggested as predictive factor for NHL. We assessed whether presence of GCs is increased in labial gland biopsies from patients with pSS who developed parotid MALT lymphoma, the dominant NHL-subtype in pSS, compared with patients with pSS who did not develop lymphoma. Eleven labial gland biopsies from patients with pSS that were taken prior to parotid MALT lymphoma development were compared with biopsies of 22 matched pSS controls (1:2) who did not develop lymphoma. Biopsies were evaluated for GCs (H&E and Bcl6). Labial gland biopsies of pSS MALT lymphoma patients, revealed GCs in 2/11 (18%) H&E sections and 3/11 (27%) Bcl6 stained sections. In controls, GCs were present in 4/22 (18%) of H&E sections and 5/22 (23%) of Bcl6 stained sections. Presence of GCs in labial gland biopsies does not differ between patients with pSS that develop parotid MALT lymphoma and patients with pSS who do not develop lymphoma. The presence of GCs in labial gland biopsies is therefore not a predictive factor for pSS-associated parotid MALT lymphomas.


Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials.
To evaluate the effect of aerobic exercise on cognitive function in people with mild cognitive impairment (MCI). Systematic review and meta-analysis of aerobic exercise intervention for cognitive function in older adults with MCI. PubMed, EMBASE, SinoMed, China National Knowledge Infrastructure (CNKI), Wanfang and Chinese Science and Technology Periodical (VIP) databases from their inception to 31 January 2015, the Cochrane Central Register of Controlled Trials (Cochrane Library, 2015, Issue 3) and the reference lists of all retrieved articles. Randomised controlled trials, older adults with MCI, aerobic exercises compared with no specific exercise intervention for global cognitive ability and any specific domains of cognition. Meta-analysis was conducted with RevMan V.5.3 software using the fixed-effect model for the available data without significant heterogeneity, or the random-effect model was used if appropriate. 11 studies were identified involving 1497 participants. Meta-analysis showed that aerobic exercise significantly improved global cognitive ability (Mini-Mental State Examination (MMSE) scores: MD=0.98, 95% CI 0.5 to 1.45, p<0.0001; Montreal Cognitive Assessment (MoCA) scores: MD=2.7, 95% CI 1.11 to 4.29, p=0.0009); weakly, positively improve memory (immediately recall: SMD=0.29, 95% CI 0.13 to 0.46, p=0.0005; delay recall: SMD=0.22, 95% CI 0.09 to 0.34, p=0.0005). No significant improvement was found in other domains of cognition. Aerobic exercise led to an improvement in global cognitive ability and had a positive effect with a small effect size on memory in people with MCI. However, owing to the limitations of the included studies, these findings should be interpreted cautiously.


Comparison of accelerometer-measured sedentary behavior, and light- and moderate-to-vigorous-intensity physical activity in white- and blue-collar workers in a Japanese manufacturing plant.
The times spent in sedentary behavior (SB) and moderate-to-vigorous physical activity (MVPA) are independently associated with health outcomes; however, objective data on physical activity levels including SB among different occupations is limited. We compared accelerometer-measured times spent in SB, light-intensity physical activity (LPA), and MVPA, and the patterns associated with prolonged bouts of SB between white- and blue-collar workers. The study population consisted of 102 full-time plant workers (54 white-collar and 48 blue-collar) who wore a triaxial accelerometer during waking hours for 5 working days. Accelerometer-measured activity levels were categorized as SB (≤1.5 metabolic equivalents (METs)), LPA (1.6-2.9 METs), and MVPA (≥3.0 METs). A sedentary bout was defined as consecutive minutes during which the accelerometer registered less than ≤1.5 METs. Accelerometer variables were compared between white- and blue-collar workers through analysis of covariance. During working hours, white-collar workers spent significantly more time in SB and less time in LPA than blue-collar workers (SB: 6.4 h vs. 4.8 h, 73% vs. 55% of total work time; LPA: 1.9 h vs. 3.5 h, 22% vs. 40% of total work time, p<.001), whereas the MVPA time was similar between the groups. White-collar workers spent significantly more SB time in prolonged sedentary bouts (≥30 min) compared to blue-collar workers. During leisure time, the SB, LPA, and MVPA times were similar between the groups. White-collar workers have significantly longer SB times than blue-collar workers during work hours, and do not compensate for their excess SB during work by reducing SB during leisure time.


Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States.
Aims: To evaluate the cost-effectiveness of adjuvant pembrolizumab relative to observation alone following complete resection of high-risk stage III melanoma with lymph node involvement, from a US health system perspective. Materials and methods: A Markov cohort model with four health states (recurrence-free, locoregional recurrence, distant metastases, and death) was developed to estimate costs, life-years, and quality-adjusted life-years (QALYs) associated with pembrolizumab vs observation over a lifetime (46-year) horizon. Using a parametric multi-state modeling approach, transition probabilities starting from recurrence-free were estimated based on patient-level data from KEYNOTE-054 (NCT02362594), a direct head-to-head phase 3 trial. Post-recurrence transition probabilities were informed by real-world retrospective data and clinical trials in advanced melanoma. Health state utilities and adverse event-related disutility were derived from KEYNOTE-054 trial data and published literature. Costs of drug acquisition and administration, adverse events, disease management, and terminal care were estimated in 2018 US dollars. Deterministic and probabilistic sensitivity analyses were conducted to assess robustness. Results: Over a lifetime horizon, adjuvant pembrolizumab and observation were associated with total QALYs of 9.24 and 5.95, total life-years of 10.54 and 7.15, and total costs of $489,820 and $440,431, respectively. The resulting incremental cost-effectiveness ratios (ICERs) for pembrolizumab vs observation were $15,009/QALY and $14,550/life-year. Across the range of input values and assumptions tested in deterministic sensitivity analyses, pembrolizumab ranged from being a dominant strategy to having an ICER of $57,449/QALY vs observation. The ICER was below a willingness-to-pay threshold of $100,000/QALY in 90.2% of probabilistic simulations. Limitations: Long-term extrapolation of outcomes was based on interim results from KEYNOTE-054, with a median follow-up of 15 months. Conclusions: Based on common willingness-to-pay benchmarks, pembrolizumab is highly cost-effective compared with observation alone for the adjuvant treatment of completely resected stage III melanoma in the US.


Automatic and Accurate Shadow Detection Using Near-Infrared Information.
We present a method to automatically detect shadows in a fast and accurate manner by taking advantage of the inherent sensitivity of digital camera sensors to the near-infrared (NIR) part of the spectrum. Dark objects, which confound many shadow detection algorithms, often have much higher reflectance in the NIR. We can thus build an accurate shadow candidate map based on image pixels that are dark both in the visible and NIR representations. We further refine the shadow map by incorporating ratios of the visible to the NIR image, based on the observation that commonly encountered light sources have very distinct spectra in the NIR band. The results are validated on a new database, which contains visible/NIR images for a large variety of real-world shadow creating illuminant conditions, as well as manually labeled shadow ground truth. Both quantitative and qualitative evaluations show that our method outperforms current state-of-the-art shadow detection algorithms in terms of accuracy and computational efficiency.