A facile method of activating graphitic carbon nitride for enhanced photocatalytic activity.
Activated graphitic carbon nitride (g-C3N4) with enhanced photocatalytic capability under visible light irradiation was fabricated by using a facile chemical activation treatment method. In the chemical activation, a mixed solution of hydrogen peroxide and ammonia was employed. The yield can reach as high as 90% after the activation process. The activation process did not change the crystal structure, functional group, morphology and specific surface area of pristine g-C3N4, but it introduced H and O elements into the CN framework of g-C3N4, resulting in a broader optical absorption range, higher light absorption capability and more efficient separation of photogenerated electrons and holes. The photoactivity was investigated by the degradation of rhodamine B (RhB) under visible light irradiation. As compared to the pristine g-C3N4, the activated g-C3N4 exhibited a distinct and efficient two-step degradation process. It was found that the RhB dye in the activated g-C3N4 was mainly oxidized by the photogenerated holes. It is believed that sufficient holes account for the two-step degradation process because they would significantly improve the efficiency of the N-de-ethylation reaction of RhB.


Validation of a diagnostic approach to exclude recurrent venous thromboembolism.
The diagnosis of recurrent venous thromboembolism (VTE) is a challenge in clinical practice. Our objective was to evaluate the safety of a diagnostic strategy utilizing comparison of diagnostic test results with baseline imaging results to rule out suspected recurrent VTE. The REVERSE study was a prospective cohort study whose primary aim was to develop a clinical prediction rule for recurrent VTE. We included and followed patients who completed 5-7 months of anticoagulant therapy after a first unprovoked VTE. Suspected cases of recurrent VTE were assessed according to standardized diagnostic criteria based on comparison of diagnostic test results with those obtained at the time of anticoagulant treatment withdrawal. Out of the 398 suspected events, a recurrent VTE was diagnosed in 106 cases (26.6%) and excluded in 292 cases. In 76 cases (19%), the diagnosis of recurrent VTE was excluded on the basis of the fact that no significant change on diagnostic imaging was detected when compared to baseline imaging. During the ensuing 3 months, six patients received anticoagulant therapy after recurrent VTE was excluded, and two were lost to follow-up. Eight of 284 remaining patients in whom recurrent VTE had been excluded, who were not treated and who were not lost to follow-up were diagnosed with subsequent VTE (3-month risk, 2.8%; 95% confidence interval, 1.4-5.5%). Six of these eight patients with subsequent recurrent VTE had a known superficial or distal thrombosis at the time of initial suspected recurrent VTE. A diagnostic strategy comparing diagnostic test results obtained at the time of the suspected recurrent event with those obtained at baseline can safely and effectively rule out recurrent VTE in a significant proportion of patients. Registered at http://www.clinicaltrials.gov identifier: NCT00261014.


Evaluation of clinical, laboratory, and therapeutic features of 145 tularemia cases: the role of quinolones in oropharyngeal tularemia.
Tularemia outbreaks have occurred in various regions of Turkey in recent years. In this study, clinical (145 patients) and laboratory (97 patients) features of patients with oropharyngeal tularemia were evaluated during the tularemia outbreak in the district of Gölcük in Kocaeli, Turkey. We analyzed the risk factors for therapeutic failure and prolonged recovery time, and compared the efficacy of three antibiotic groups, namely aminoglycoside, tetracycline and quinolone. The most common physical sign and laboratory findings in patients were lymphadenopathy (LAP) and increased erythrocyte sedimentation rate, respectively. Treatment failure was observed in 55 of the 145 (38%) patients during one-year follow-up and the most successful results were obtained in the quinolone group. It was determined that antimicrobial therapy initiated 14 days after onset of symptoms was a statistically significiant risk factor, reducing the success rate (p=0.0001, OR=13.10, 95% CI=5.69-30.15) and prolonging the recovery period (p=0.001, OR=3.23, 95% CI=1.63-6.40) in oropharyngeal tularemia cases. These results suggest that antimicrobial treatment should be started early, and quinolones such as moxifloxacin and ciprofloxacin seem to be new alternatives in the treatment of oropharyngeal tularemia.


Genomic mapping of social behavior traits in a F2 cross derived from mice selectively bred for high aggression.
Rapid response to selection was previously observed in mice selected for high levels of inter-male aggression based on number of attacks displayed in a novel social interaction test after isolation housing. Attack levels in this high aggression line (NC900) increased significantly within just four generations of selective breeding, suggesting the presence of a locus with large effect. We conducted an experiment using a small (n ≈ 100) F2 cross between the ICR-derived, non-inbred NC900 strain and the low aggression inbred strain C57BL/6J, genotyped for 154 fully informative SNPs, to determine if a locus with large effect controls the high-aggression selection trait. A second goal was to use high density SNP genotyping (n = 549,000) in the parental strains to characterize residual patterns of heterozygosity within NC900, and evaluate regions that are identical by descent (IBD) between NC900 and C57BL/6J, to determine what impacts these may have on accuracy and resolution of quantitative trait locus (QTL) mapping in the F2 cross. No evidence for a locus with major effect on aggressive behavior in mice was identified. However, several QTL with genomewide significance were mapped for aggression on chromosomes 7 and 19 and other social behavior traits on chromosomes 4, 7, 14, and 19. High density genotyping revealed that 28% of the genome is still segregating among the six NC900 females used to originate the F2 cross, and that segregating regions are present on every chromosome but are of widely different sizes. Regions of IBD between NC900 and C57BL/6J are found on every chromosome but are most prominent on chromosomes 10, 16 and X. No significant differences were found for amounts of heterozygosity or prevalence of IBD in QTL regions relative to global analysis. While no major gene was identified to explain the rapid selection response in the NC900 line, transgressive variation (i.e. where the allele from the C57BL/6J increased attack levels) and a significant role for dominant gene action were hallmarks of the genetic architecture for aggressive behavior uncovered in this study. The high levels of heterozygosity and the distribution of minor allele frequency observed in the NC900 population suggest that maintenance of heterozygosity may have been under selection in this line.


First chromosome scale genomes of ithomiine butterflies (Nymphalidae: Ithomiini): Comparative models for mimicry genetic studies.
The ithomiine butterflies (Nymphalidae: Danainae) represent the largest known radiation of Müllerian mimetic butterflies. They dominate by number the mimetic butterfly communities, which include species such as the iconic neotropical Heliconius genus. Recent studies on the ecology and genetics of speciation in Ithomiini have suggested that sexual pheromones, colour pattern and perhaps hostplant could drive reproductive isolation. However, no reference genome was available for Ithomiini, which has hindered further exploration on the genetic architecture of these candidate traits, and more generally on the genomic patterns of divergence. Here, we generated high-quality, chromosome-scale genome assemblies for two Melinaea species, M. marsaeus and M. menophilus, and a draft genome of the species Ithomia salapia. We obtained genomes with a size ranging from 396 to 503 Mb across the three species and scaffold N50 of 40.5 and 23.2 Mb for the two chromosome-scale assemblies. Using collinearity analyses we identified massive rearrangements between the two closely related Melinaea species. An annotation of transposable elements and gene content was performed, as well as a specialist annotation to target chemosensory genes, which is crucial for host plant detection and mate recognition in mimetic species. A comparative genomic approach revealed independent gene expansions in ithomiines and particularly in gustatory receptor genes. These first three genomes of ithomiine mimetic butterflies constitute a valuable addition and a welcome comparison to existing biological models such as Heliconius, and will enable further understanding of the mechanisms of adaptation in butterflies.


MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt⁺ T cells.
Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (T(H)17) cells and regulatory T cells (T(regs)) in the intestine. Here, we report that microbiota-induced T(regs) express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to T(H)17 cells. In the absence of RORγt(+) T(regs), T(H)2-driven defense against helminths is more efficient, whereas T(H)2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of type 3 RORγt(+) T(regs) and T(H)17 cells and acts as a key factor in balancing immune responses at mucosal surfaces.


Upscaling Reverse Electrodialysis.
Salinity gradient energy is a sustainable, renewable, and clean energy source. When waters with different salinities are mixed, the change in Gibbs free energy can be harvested as energy and only brackish water remains. Reverse electrodialysis is one of the technologies that can harvest this sustainable energy source. High power densities have been obtained in small lab scale systems, but translation to large industrial scale stacks is essential for commercialization of the technology. Moreover, power density is an important parameter, and efficiency, i.e., the amount of energy harvested compared to the amount of energy available in the feed waters, is critical for commercial processes. In this work, we systematically investigate the influence of stack size and membrane type on power density, thermodynamic efficiency, and energy efficiency. Results show that the residence time is an excellent parameter for comparing differently sized stacks and translating lab scale experimental results to larger pilot stacks. Also, the influence of undesired water permeability and co-ion diffusion (as reflected in permselectivity) is clearly visible when measuring the thermodynamic efficiency. An averaged thermodynamic efficiency of 44.9% is measured using Fujifilm Type 10 anion exchange and cation exchange membranes that have low water permeability and high permselectivity. This value comes close to the thermodynamic maximum of 50%.


Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1.
The primary macrophage growth factor, colony-stimulating factor 1 (CSF-1), is expressed as a secreted glycoprotein or proteoglycan found in the circulation or as a biologically active cell surface glycoprotein (csCSF-1). To investigate the in vivo roles of csCSF-1, we created mice that exclusively express csCSF-1, in a normal tissue-specific and developmental manner, by transgenic expression of csCSF-1 in the CSF-1-deficient osteopetrotic (Csf1(op)/Csf1(op)) background. The gross defects of Csf1(op)/Csf1(op) mice, including growth retardation, failure of tooth eruption, and abnormal male and female reproductive functions were corrected. Macrophage densities in perinatal liver, bladder, sublinguinal salivary gland, kidney cortex, dermis, and synovial membrane were completely restored, whereas only partial or no restoration was achieved in adult liver, adrenal gland, kidney medulla, spleen, peritoneal cavity, and intestine. Residual osteopetrosis, significantly delayed trabecular bone resorption in the subepiphyseal region of the long bone, and incomplete correction of the hematologic abnormalities in the peripheral blood, bone marrow, and spleens of CSF-1-deficient mice were also found in mice exclusively expressing csCSF-1. These data suggest that although csCSF-1 alone is able to normalize several aspects of development in Csf1(op)/Csf1(op) mice, it cannot fully restore in vivo CSF-1 function, which requires the presence of the secreted glycoprotein and/or proteoglycan forms.


Stem-cell therapy for amyotrophic lateral sclerosis.
With the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), and compelling preclinical data, stem-cell research has highlighted this disease as a candidate for stem-cell treatment. Stem-cell transplantation is an attractive strategy for neurological diseases and early successes in animal models of neurodegnerative disease generated optimism about restoring function or delaying degeneration in human beings. The restricted potential of adult stem cells has been challenged over the past 5 years by reports on their ability to acquire new unexpected fates beyond their embryonic lineage (transdifferentiation). Therefore, autologous or allogeneic stem cells, undifferentiated or transdifferentiated and manipulated epigenetically or genetically, could be a candidate source for local or systemic cell-therapies in ALS. Albert Clement and colleagues (Science 2003; 302: 113-17) showed that in SOD1G93A chimeric mice, motorneuron degeneration requires damage from mutant SOD1 acting in non-neuronal cells. Wild-type non-neuronal (glial) cells could delay degeneration and extend survival of mutant-expressing motorneurons. Letizia Mazzini and colleagues (Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 158-61) injected autologous bone-marrow-derived stem cells into the spinal cord of seven ALS patients. These investigators reported that the procedure had a reasonable margin of clinical safety. WHERE NEXT? The success of cell-replacement therapy in ALS will depend a lot on preclinical evidence, because of the complexity and precision of the pattern of connectivity that needs to be restored in degenerating motoneurons. Stem-cell therapy will need to be used with other drugs or treatments, such as antioxidants and/or infusion of trophic molecules.


Lack of pre-antiretroviral care and competition from traditional healers, crucial risk factors for very late initiation of antiretroviral therapy for HIV--a case-control study from eastern Uganda.
Although WHO recommends starting antiretroviral treatment at a CD4 count of 350 cells/[µ]L, many Ugandan districts still struggle with large proportions of clients initiating ART very late at CD4<50 cells/[µ]L. This study seeks to establish crucial risk factors for very late ART initiation in eastern Uganda. All adult HIV-infected clients on ART in Iganga who enrolled between 2005 and 2009 were eligible for this case-control study. Clients who started ART at CD4 cell count of <50 cells/[µ]L (very late initiators) were classified as cases and 50-200 cells/[µ]L (late initiators) as control subjects. A total of 152 cases and 202 controls were interviewed. Multivariate analyses were performed to calculate adjusted odds ratios and 95% confidence intervals. Reported health system-related factors associated with very late ART initiation were stock-outs of antiretroviral drugs stock-outs (affecting 70% of the cases and none of the controls), competition from traditional/spiritual healers (AOR 7.8, 95 CI% 3.7-16.4), and lack of pre-ARV care (AOR 4.6, 95% CI: 2.3-9.3). Men were 60% more likely and subsistence farmers six times more likely (AOR 6.3, 95% CI: 3.1-13.0) to initiate ART very late. Lack of family support tripled the risk of initiating ART very late (AOR 3.3, 95% CI: 1.6-6.6). Policy makers should prevent ARV stock-outs though effective ARV procurement and supply chain management. New HIV clients should seek pre-ARV care for routine monitoring and determination of ART eligibility. ART services should be more affordable, accessible and user-friendly to make them more attractive than traditional healers.


Point-of-care thrombocyte function testing using multiple-electrode aggregometry in dengue patients: an explorative study.
Dengue virus (DENV) causes the hospitalisation of an estimated 500,000 people every year. Outbreaks can severely stress healthcare systems, especially in rural settings. It is difficult to discriminate patients who need to be hospitalized from those that do not. Earlier work identified thrombocyte count and subsequent function as a promising prognostic marker of DENV severity. Herein, we investigated the potential of quantitative thrombocyte function tests in those admitted in the very early phase of acute DENV infections, using Multiplate™ multiple-electrode aggregometry to explore its potential in triage. In this prospective cohort study all patients aged ≥13 admitted to Universitas Airlangga Hospital in Surabaya, Indonesia with a fever (≥38 °C) between 25 January and 1 August 2018 and with a clinical suspicion of DENV, were eligible for inclusion. Exclusion criteria were a thrombocyte count below 100 × 109/L and the use of any medication with a known anticoagulant effect, nonsteroidal anti-inflammatory drugs and acetyl salicylic acid. Clinical data was collected and blood was taken on admission, day 1 and day 7. Samples were tested for acute DENV, using Panbio NS1 ELISA. Platelet aggregation using ADP-, TRAP- and COL-test were presented as Area Under the aggregation Curve (AUC). Significance was tested between DENV+, probably DENV, fever of another origin, and healthy controls (HC). A total of 59 patients (DENV+ n = 10, DENV probable n = 25, fever other origin n = 24) and 20 HC were included. We found a significantly lower thrombocyte aggregation in the DENV+ group, compared with both HCs and the fever of another origin group (p < .001). Low ADP AUC values on baseline correlated to a longer hospital stay in DENV+ and probable DENV cases. Thrombocyte aggregation induced by Adenosine diphosphate, Collagen and Thrombin receptor activating peptide-6 is impaired in human DENV cases, compared with healthy controls and other causes of fever. This explorative study provides insights to thrombocyte function in DENV patients and could potentially serve as a future marker in DENV disease.


Use of an oligonucleotide probe to detect Vibrio parahaemolyticus in artificially contaminated oysters.
A 26-mer oligonucleotide specific to Vibrio parahaemolyticus was synthesized from a 1,275-bp thermostable direct hemolysin (tdh) gene. This oligonucleotide probe specifically reacted with DNA from 89 of 95 V. parahaemolyticus isolates but not with DNA from other vibrios or other enteric and nonenteric organisms (n = 48). The probe hybridized with Southern blots of 0.5-kb HindIII-restricted chromosomal DNA fragments from all but five V. parahaemolyticus test isolates. The probe could be used to directly identify V. parahaemolyticus in artificially contaminated food without an isolation step.


Turbulent Transitions in Optical Wave Propagation.
We report the direct observation of the onset of turbulence in propagating one-dimensional optical waves. The transition occurs as the disordered hosting material passes from being linear to one with extreme nonlinearity. As the response grows, increased wave interaction causes a modulational unstable quasihomogeneous flow to be superseded by a chaotic and spatially incoherent one. Statistical analysis of high-resolution wave behavior in the turbulent regime unveils the emergence of concomitant rogue waves. The transition, observed in a photorefractive ferroelectric crystal, introduces a new and rich experimental setting for the study of optical wave turbulence and information transport in conditions dominated by large fluctuations and extreme nonlinearity.


Increasing sensitivity of methane emission measurements in rice through deployment of 'closed chambers' at nighttime.
This study comprises field experiments on methane emissions from rice fields conducted with an Eddy-Covariance (EC) system as well as test runs for a modified closed chamber approach based on measurements at nighttime. The EC data set covers 4 cropping seasons with highly resolved emission rates (raw data in 10 Hz frequency have been aggregated to 30-min records). The diel patterns were very pronounced in the two dry seasons with peak emissions at early afternoon and low emissions at nighttime. These diel patterns were observed at all growing stages of the dry seasons. In the two wet seasons, the diel patterns were only visible during the vegetative stages while emission rates during reproductive and ripening stages remained within a fairly steady range and did not show any diel patterns. In totality, however, the data set revealed a very strong linear relationship between nocturnal emissions (12-h periods) and the full 24-h periods resulting in an R2-value of 0.8419 for all data points. In the second experiment, we conducted test runs for chamber measurements at nighttime with much longer deployment times (6 h) as compared to measurements at daylight (typically for 30 min). Conducting chamber measurements at nighttime excluded drastic changes of temperatures and CO2 concentrations. The data also shows that increases in CH4 concentrations remained on linear trajectory over a 6h period at night. While end CH4 concentrations were consistently >3.5 ppm, this long-term enclosure represents a very robust approach to quantify emissions as compared to assessing short-term concentration increases over time near the analytical detection limit. Finally, we have discussed the potential applications of this new approach that would allow emission measurements even when conventional (daytime) measurements will not be suitable. Nighttime chamber measurements offer an alternative to conventional (daytime) measurements if either (i) baseline emissions are at a very low level, (ii) differences of tested crop treatments or varieties are very small or (iii) the objective is to screen a large number of rice varieties for taking advantage of progress in genome sequencing.


Assessment of left-to-right intracardiac shunting by velocity-encoded, phase-difference magnetic resonance imaging. A comparison with oximetric and indicator dilution techniques.
Velocity-encoded, phase-difference magnetic resonance imaging (MRI) has been shown to provide an accurate assessment of shunt magnitude in patients with large atrial septal defects, but its ability to determine shunt magnitude in patients with intracardiac left-to-right shunts of various locations and sizes has not been evaluated in a prospective and blinded manner. The objective of the present study was to determine whether velocity-encoded, phase-difference MRI can assess the magnitude of intracardiac left-to-right shunting in humans. Twenty-one subjects (15 women and 6 men; age range, 15 to 72 years) underwent velocity-encoded, phase-difference MRI measurements of flow in the proximal aorta and pulmonary artery, followed immediately by cardiac catheterization. The presence of left-to-right intracardiac shunting was assessed with hydrogen inhalation, after which shunt magnitude was measured by the oximetric and indocyanine green techniques. Of the 21 patients, 12 had left-to-right intracardiac shunting detected by hydrogen inhalation. There was a good correlation (r = .94) between the invasive and MRI assessments of shunt magnitude. In comparison to oximetry and indocyanine green, MRI correctly identified the 12 patients with a ratio of pulmonary to systemic flow (Qp/Qs) of < 1.5 (9 without intracardiac shunting and 3 with small shunts) and the 9 patients with a Qp/Qs of > or = 1.5 (6 with atrial septal defect, 1 with ventricular septal defect, 1 with patent ductus arteriosus, and 1 with both atrial septal defect and patent ductus arteriosus). Compared with measurements obtained during cardiac catheterization, velocity-encoded, phase-difference MRI measurements of flow in the proximal great vessels can reliably assess the magnitude of intracardiac left-to-right shunting.


Development of the Canadian Syncope Risk Score to predict serious adverse events after emergency department assessment of syncope.
Syncope can be caused by serious conditions not evident during initial evaluation, which can lead to serious adverse events, including death, after disposition from the emergency department. We sought to develop a clinical decision tool to identify adult patients with syncope who are at risk of a serious adverse event within 30 days after disposition from the emergency department. We prospectively enrolled adults (age ≥ 16 yr) with syncope who presented within 24 hours after the event to 1 of 6 large emergency departments from Sept. 29, 2010, to Feb. 27, 2014. We collected standardized variables at index presentation from clinical evaluation and investigations. Adjudicated serious adverse events included death, myocardial infarction, arrhythmia, structural heart disease, pulmonary embolism, serious hemorrhage and procedural interventions within 30 days. We enrolled 4030 patients with syncope; the mean age was 53.6 years, 55.5% were women, and 9.5% were admitted to hospital. Serious adverse events occurred in 147 (3.6%) of the patients within 30 days after disposition from the emergency department. Of 43 candidate predictors examined, we included 9 in the final model: predisposition to vasovagal syncope, heart disease, any systolic pressure reading in the emergency department < 90 or > 180 mm Hg, troponin level above 99th percentile for the normal population, abnormal QRS axis (< -30° or > 100°), QRS duration longer than 130 ms, QTc interval longer than 480 ms, emergency department diagnosis of cardiac syncope and emergency department diagnosis of vasovagal syncope (C statistic 0.88, 95% confidence interval [CI] 0.85-0.90; optimism 0.015; goodness-of-fit p = 0.11). The risk of a serious adverse event within 30 days ranged from 0.4% for a score of -3 to 83.6% for a score of 11. The sensitivity was 99.2% (95% CI 95.9%-100%) for a threshold score of -2 or higher and 97.7% (95% CI 93.5%-99.5%) for a threshold score of -1 or higher. The Canadian Syncope Risk Score showed good discrimination and calibration for 30-day risk of serious adverse events after disposition from the emergency department. Once validated, the tool will be able to accurately stratify the risk of serious adverse events among patients presenting with syncope, including those at low risk who can be discharged home quickly.


The effect of probe choice and solution conditions on the apparent photoreactivity of dissolved organic matter.
Excited triplet states of dissolved organic matter (3DOM) are quantified directly with the species-specific probes trans,trans-hexadienoic acid (HDA) and 2,4,6-trimethylphenol (TMP), and indirectly with the singlet oxygen (1O2) probe furfuryl alcohol (FFA). Although previous work suggests that these probe compounds may be sensitive to solution conditions, including dissolved organic carbon concentration ([DOC]) and pH, and may quantify different 3DOM subpopulations, the probes have not been systematically compared. Therefore, we quantify the apparent photoreactivity of diverse environmental waters using HDA, TMP, and FFA. By conducting experiments under ambient [DOC] and pH, with standardized [DOC] and pH, and with solid phase extraction isolates, we demonstrate that much of the apparent dissimilarity in photochemical measurements is attributable to solution conditions, rather than intrinsic differences in 3DOM production. In general, apparent quantum yields (Φ1O2 ≥ Φ3DOM,TMP ≫ Φ3DOM,HDA) and pseudo-steady state concentrations ([1O2]ss > [3DOM]ss,TMP > [3DOM]ss,HDA) show consistent relationships in all waters under standardized conditions. However, intrinsic differences in 3DOM photoreactivity are apparent between DOM from diverse sources, as seen in the higher Φ1O2 and lower Φ3DOM,TMP of wastewater effluents compared with oligotrophic lakes. Additionally, while conflicting trends in photoreactivity are observed under ambient conditions, all probes observe quantum yields increasing from surface wetlands to terrestrially influenced waters to oligotrophic lakes under standardized conditions. This work elucidates how probe selection and solution conditions influence the apparent photoreactivity of environmental waters and confirms that 3DOM or 1O2 probes cannot be used interchangeably in waters that vary in [DOC], pH, or DOM source.


Still a man's world, but why?
Women are generally under-represented in many academic medical settings. Through a brief commentary on this issue, the present article discusses possible explanations for this under-representation as well as potential solutions. Issues examined include women in leadership positions, attrition out of academic medicine, salary imbalance between men and women, potential bias among both genders, and the need for cultural change. We believe this is an extremely important issue of which we all need to be aware and hope that articles such as this will aid in starting a crucial conversation about gender issues in academic medicine.


Functional interactions of an archaeal sliding clamp with mammalian clamp loader and DNA polymerase delta.
By the total genome sequencing of several archaeal organisms, it has been confirmed that many archaeal proteins related to genetic information systems, including DNA replication, transcription and translation, have similar sequences to those of eukaryotes. In eukaryotic DNA replication, proliferating cell nuclear antigen (PCNA) works in clamping DNA polymerases on the DNA template and accomplishes a processive DNA synthesis. Archaea encode PCNA homologues in their genomes and Pyrococcus furiosus PCNA (PfuPCNA) stimulates the DNA synthesizing activities of the DNA polymerases, Pol I and Pol II, in this organism. We have demonstrated that PfuPCNA interacts functionally with calf thymus DNA polymerase delta (Pol delta) and stimulates its activity. Moreover, human replication factor C (RFC) enhances the PfuPCNA-dependent DNA synthesis activity of Pol delta, indicating that human RFC works as the clamp loader for PfuPCNA. These results showed that the three-dimensional structures of archaral PCNA and RFC are actually similar enough to their eukaryotic counterparts to allow a molecular substitution between the two biological domains, albeit at a lower efficiency. We found that the archaeal molecule interacts functionally with the eukaryotic members in the DNA replication process. This finding supports the idea that studies on the DNA replication mechanism of archaeal organisms will provide many important clues for understanding of the intricate molecular recognition that is inherent to the DNA replication machinery in Eukarya.


Predicting Acute Compartment Syndrome (PACS): The Role of Continuous Monitoring.
The diagnosis of acute compartment syndrome (ACS) is a common clinical challenge among patients who sustain high-energy orthopaedic trauma, largely because no validated criteria exist to reliably define the presence of the condition. In the absence of validated diagnostic standards, concern for the potential clinical and medicolegal impact of a missed compartment syndrome may result in the potential overuse of fasciotomy in "at-risk" patients. The goal of the Predicting Acute Compartment Syndrome Study was to develop a decision rule for predicting the likelihood of ACS that would reduce unnecessary fasciotomies while guarding against potentially missed ACS. Of particular interest was the utility of early and continuous monitoring of intramuscular pressure and muscle oxygenation using near-infrared spectroscopy in the timely diagnosis of ACS. In this observational study, 191 participants aged 18-60 with high-energy tibia fractures were prospectively enrolled and monitored for up to 72 hours after admission, then followed for 6 months. Treating physicians were blinded to continuous pressure and oxygenation data. An expert panel of 9 orthopaedic surgeons retrospectively assessed the likelihood that each patient developed ACS based on data collected on initial presentation, clinical course, and known functional outcome at 6 months. This retrospectively assigned likelihood is modeled as a function of clinical data typically available within 72 hours of admission together with continuous pressure and oxygenation data. This study will improve our understanding of the natural history of compartment syndrome and examine the utility of early and continuous monitoring of the physiologic status of the injured extremity in the timely diagnosis of ACS.


Surgical management of juxtahepatic venous injuries in blunt hepatic trauma.
The purpose of this analysis was to understand better the problems faced in the management of blunt juxtahepatic venous injuries and to try and simplify the controversies regarding the optimal surgical approach to these injuries. Charts of 92 blunt liver trauma patients treated between July 1, 1991 to June 30, 1993 were reviewed. Nineteen patients with blunt juxtahepatic venous injuries were identified. The isolated left hepatic vein injury group (five patients) were all treated using a nonshunting approach with no mortalities. Half of the isolated right hepatic vein injury group (ten patients) received an atriocaval shunt, and the other half did not. These two different approaches each produced one survivor, with a combined mortality rate of 80% (eight of ten patients). One of the combined injuries group (four patients) received a total hepatectomy followed by liver transplantation. Another received a shunt. The other two were treated without shunting, but all of them expired. The overall mortality rate was 63.2% (12 of 19 patients), with nine patients dying intraoperatively or immediately postoperatively from exsanguination. The other three died 10, 25, and 30 days postoperatively because of sepsis. Juxtahepatic venous injury should be suspected after failure of the Pringle maneuver to stop bleeding and the different venous injuries differentiated by palpation of the adjacent hepatic parenchymal injuries. If an isolated left hepatic vein injury is found and the liver parenchymal injury is limited to segments II, III, or IV, then a nonshunting approach will achieve the optimal outcome.


Genes Required for the Anti-fungal Activity of a Bacterial Endophyte Isolated from a Corn Landrace Grown Continuously by Subsistence Farmers Since 1000 BC.
Endophytes are microbes that inhabit internal plant tissues without causing disease. Some endophytes are known to combat pathogens. The corn (maize) landrace Chapalote has been grown continuously by subsistence farmers in the Americas since 1000 BC, without the use of fungicides, and the crop remains highly valued by farmers, in part for its natural tolerance to pests. We hypothesized that the pathogen tolerance of Chapalote may, in part, be due to assistance from its endophytes. We previously identified a bacterial endophyte from Chapalote seeds, Burkholderia gladioli strain 3A12, for its ability to combat a diversity of crop pathogens, including Sclerotinia homoeocarpa, the most important fungal disease of creeping bentgrass, a relative of maize used here as a model system. Strain 3A12 represents a unique opportunity to understand the anti-fungal activities of an endophyte associated with a crop variety grown by subsistence farmers since ancient times. Here, microscopy combined with Tn5-mutagenesis demonstrates that the anti-fungal mode of action of 3A12 involves flagella-dependent swarming toward its pathogen target, attachment and biofilm-mediated microcolony formation. The mutant screen revealed that YajQ, a receptor for the secondary messenger c-di-GMP, is a critical signaling system that mediates this endophytic mobility-based defense for its host. Microbes from the traditional seeds of farmers may represent a new frontier in elucidating host-microbe mutualistic interactions.


Rational design, synthesis, purification, and activation of metal-organic framework materials.
The emergence of metal-organic frameworks (MOFs) as functional ultrahigh surface area materials is one of the most exciting recent developments in solid-state chemistry. Now constituting thousands of distinct examples, MOFs are an intriguing class of hybrid materials that exist as infinite crystalline lattices with inorganic vertices and molecular-scale organic connectors. Useful properties such as large internal surface areas, ultralow densities, and the availability of uniformly structured cavities and portals of molecular dimensions characterize functional MOFs. Researchers have effectively exploited these unusual properties in applications such as hydrogen and methane storage, chemical separations, and selective chemical catalysis. In principle, one of the most attractive features of MOFs is the simplicity of their synthesis. Typically they are obtained via one-pot solvothermal preparations. However, with the simplicity come challenges. In particular, MOF materials, especially more complex ones, can be difficult to obtain in pure form and with the optimal degree of catenation, the interpenetration or interweaving of identical independent networks. Once these two issues are satisfied, the removal of the guest molecules (solvent from synthesis) without damaging the structural integrity of the material is often an additional challenge. In this Account, we review recent advances in the synthetic design, purification, and activation of metal-organic framework materials. We describe the rational design of a series of organic struts to limit framework catenation and thereby produce large pores. In addition, we demonstrate the rapid separation of desired MOFs from crystalline and amorphous contaminants cogenerated during synthesis based on their different densities. Finally, we discuss the mild and efficient activation of initially solvent-filled pores with supercritical carbon dioxide, yielding usable channels and high internal surface areas. We expect that the advances in the synthesis, separation, and activation of metal-organic frameworks could lead to MOFs with new structures and functions, better and faster separation and purification of these materials, and processing methods that avoid pore blockage and pore collapse.


Go home, gay boy! Or, why do Singaporean gay men prefer to "go home" and not "come out"?
Anglo-American ontologies posit that gay men should come out to match their outer selves with their inner ones. In Confucianized Singapore, however, gay men refrain from coming out to their parents to avoid shaming their families. Instead, they couch their homosexuality in kinship terms and "go home" with their boyfriends (Chou, 2000). "Going home" gains familial acceptance, but it does not challenge mainstream discourses of homosexuality. By examining how Singaporean gay men negotiate their sexuality with their families, I question the validity of coming out and going home as both ontological discourses and strategies.


Development of a 2-h suicide prevention program for medical staff including nurses and medical residents: A two-center pilot trial.
Suicide is a crucial global health concern and effective suicide prevention has long been warranted. Mental illness, especially depression is the highest risk factor of suicide. Suicidal risk is increased in people not only with mental illness but also with physical illnesses, thus medical staff caring for physically-ill patients are also required to manage people with suicidal risk. In the present study, we evaluated our newly developed suicide intervention program among medical staff. We developed a 2-h suicide intervention program for medical staff, based on the Mental Health First Aid (MHFA), which had originally been developed for the general population. We conducted this program for 74 medical staff members from 2 hospitals. Changes in knowledge, perceived skills, and confidence in early intervention of depression and suicide-prevention were evaluated using self-reported questionnaires at 3 points; pre-program, immediately after the program, and 1 month after program. This suicide prevention program had significant effects on improving perceived skills and confidence especially among nurses and medical residents. These significant effects lasted even 1 month after the program. Design was a single-arm study with relatively small sample size and short-term follow up. The present study suggests that the major target of this effective program is nurses and medical residents. Future research is required to validate the effects of the program with control groups, and also to assess long-term effectiveness and actual reduction in suicide rates.


Bovine lactoferrin: benefits and mechanism of action against infections.
Ingestion of bovine lactoferrin (bLF) has been reported to show anti-infective, anti-cancer, and anti-inflammatory effects. In particular, it has become evident that oral bLF had a beneficial effect on infections of both digestive and nondigestive tract tissue in various animal models. Furthermore, the effects of bLF have been indicated in clinical studies on patients with Helicobacter pylori infection, chronic hepatitis C, tinea pedis, and other diseases. Immunomodulation in the intestine and systemic sites has been suggested to mediate the protective effects of oral bLF against infection. Recently, we demonstrated the beneficial effects of oral bLF in influenza virus infected mice. BLF administration reduced the lung consolidation score and the number of infiltrating leukocytes in bronchoalveolar lavage fluid. We also investigated the effect of oral bLF on the transcription of genes related to immunity in the small intestine of mice using the quantitative RT-PCR method. We found that intake of bLF increased the expression of IL-12p40, IFN-beta, and NOD2. Thus, oral bLF activates the transcription of important immune-related genes in the small intestine, and such transcriptional activation may promote systemic host immunity.


The cost of toxin production in phytoplankton: the case of PST producing dinoflagellates.
Many species of phytoplankton produce toxins that may provide protection from grazing. In that case one would expect toxin production to be costly; else all species would evolve toxicity. However, experiments have consistently failed to show any costs. Here, we show that costs of toxin production are environment dependent but can be high. We develop a fitness optimization model to estimate rate, costs, and benefits of toxin production, using PST (paralytic shellfish toxin) producing dinoflagellates as an example. Costs include energy and material (nitrogen) costs estimated from well-established biochemistry of PSTs, and benefits are estimated from relationship between toxin content and grazing mortality. The model reproduces all known features of PST production: inducibility in the presence of grazer cues, low toxicity of nitrogen-starved cells, but high toxicity of P-limited and light-limited cells. The model predicts negligible reduction in cell division rate in nitrogen replete cells, consistent with observations, but >20% reduction when nitrogen is limiting and abundance of grazers high. Such situation is characteristic of coastal and oceanic waters during summer when blooms of toxic algae typically develop. The investment in defense is warranted, since the net growth rate is always higher in defended than in undefended cells.


Rate of decline of residual renal function is associated with all-cause mortality and technique failure in patients on long-term peritoneal dialysis.
Residual renal function (RRF) at the initiation of peritoneal dialysis (PD) therapy can predict patient outcome. However, RRF declines with time at variable rates in different patients. This study was performed to compare the impact of baseline RRF and the rate of RRF decline on patient survival and on death-censored technique survival after initiation of long-term PD. We enrolled 270 patients with sufficient urine amount (daily urine volume >100 mL) from a medical centre in North Taiwan who began PD between January 1996 and December 2005 and followed them until December 2007. The study population was stratified by the decline rate of RRF into a fast, intermediate and slow decline group. The Kaplan-Meier survival analysis was used to determine patient survival and technique survival. The Cox regression model was used to identify factors associated with patient outcome. The proportional odds polychotomous logistic regression model was used to identify variables associated with rapid decline of RRF. During an average follow-up period of 45 months, 50 (18.5%) deaths, 67 (24.8%) death-censored technique failures (transfer to haemodialysis) and 43 (15.9%) renal transplantations occurred. The median rate of RRF decline was 0.885 mL/min/1.73 m(2) per year. Survival analysis showed that patients with fast RRF decline had worse survival and increased risk of technique failure. The multivariate Cox regression model confirmed that the rate of RRF decline was an independent factor associated with patient and technique survival and was a more powerful prognostic factor than basal RRF. Variables associated with a rapid decline of RRF were larger body mass index, presence of diabetes, prior history of congestive heart failure, use of diuretics, peritonitis episodes and hypotensive events. Our data indicate that the rate of decline of RRF is a more powerful prognostic factor than baseline RRF associated with all-cause mortality and technique failure in patients on long-term PD. To prevent accelerated loss of RRF, it is imperative that every effort be made to avoid overdiuresis, peritonitis and hypotensive episodes, especially in those with diabetes, obesity and congestive heart failure.


Consensus-Building efforts to identify best tools for screening and assessment for supportive services in oncology.
Purpose: To build consensus around an optimal patient-reported outcome measure of cancer symptoms and patient needs to facilitate patient-provider communication and trigger referrals to supportive services.Methods and materials: The Grid-Enabled Measures platform was used to crowdsource and facilitate collaboration to achieve consensus. Respondents were invited to nominate and independently rate the usefulness of measures that: (1) have been actively used at a healthcare institution, (2) have a multiple choice or yes/no type format, (3) are applicable to adults with cancer, (4) are patient-reported, and 5) have psychometric data if possible. Discussion boards within the GEM workspace allowed respondents to identify barriers to implementing patient assessment and referral systems.Results: 166 individuals from various disciplines from 25 organizations participated. Six instruments were nominated, and 553 rating surveys were submitted. The three most highly-rated overall instruments were the Distress Thermometer, the James Supportive Case Screening, and the Functional Assessment of Cancer Therapy-General. Participants noted that wide-scale implementation of this process requires both identifying problems and providing clinicians with algorithms to facilitate appropriate referrals.Conclusions: Consensus reported three most highly-related measures as optimal for comprehensive screening and identification for referral by assessing multiple domains of functioning and quality of life.Implications for RehabilitationGaining consensus on the best patient reported outcome measures is an important step towards improving access to cancer rehabilitation services.A consensus agreed on several measures to use for cancer rehabilitation screening. Functional Assessment of Cancer Therapy-General, National Comprehensive Cancer. Network Distress Thermometer and the James Instrument.The selected measures do not put undue burden on clinicians and patients.


Simultaneous inclusion of sorghum and cottonseed meal or millet in broiler diets: effects on performance and nutrient digestibility.
Two experiments were conducted to investigate the use of sorghum, cottonseed meal and millet in broiler diets and their interaction when they are used simultaneously. In Experiment 1, a corn-soybean meal control diet was compared with eight experimental treatments based on low tannin sorghum (S30, S45 and S60), cottonseed meal (CM15, CM40) or both ingredients included in the same diet (S30/CM40, S45/CM25 and S60CM15). Results showed that BW gain was not affected by the inclusion of sorghum or cottonseed meal. However, feed intake tended to be affected by the cereal type with the highest values with sorghum-based diets. Feed conversion ratio increased (P<0.001) with sorghum-based diets compared with the control diet, whereas a combination of cottonseed meal and sorghum in the same diet did not affect the feed conversion ratio. Significant differences (P<0.001) were observed in apparent ileal digestibility (%) of protein and energy with the cottonseed meal and sorghum/cottonseed meal-based diets having lower protein and energy digestibility compared with corn-based diets. In Experiment 2, a control diet was compared with six diets in which corn was substituted at 60%, 80% or 100% by either sorghum or millet and other three diets with simultaneous inclusion of these two ingredients (S30/M30, S40/M40, S50/M50). Single or combined inclusion of sorghum and millet resulted in similar feed intake and growth performance as the control diet. Apparent ileal digestibility of protein and energy was higher with millet-based diets (P<0.001). Total tract digestibility of protein in sorghum and millet-based diets tended to decrease linearly with the increasing level of substitution. Sorghum-based diets resulted in lower total tract digestibility of fat compared with millet and sorghum/millet-based diets (P<0.001). Higher total tract digestibility of starch were obtained with the control diet and millet-based diets compared with the sorghum-based treatments. Results of the two experiments suggest that broiler growth performance was not affected by the dietary level of sorghum, millet or cottonseed meal. Nutrient digestion can, however, be affected by these feed ingredients.


Pathogenesis of hypertension in the sinoaortic-denervated spontaneously hypertensive rat.
The present study was performed to examine the relation between the gain of the baroreceptor reflex and the pathogenesis of hypertension in the spontaneously hypertensive rat. Spontaneously hypertensive or Wistar-Kyoto rats underwent either sinoaortic baroreceptor denervation or sham denervation at 28-35 days of age. Four months later these rats were chronically instrumented for measurements of arterial pressure and heart rate. Sixty-minute computerized measurements of arterial pressure showed no difference between spontaneously hypertensive sham (163 +/- 5 mm Hg) and spontaneously hypertensive baroreceptor-denervated (166 +/- 5 mm Hg) rats, or Wistar-Kyoto sham (114 +/- 3 mm Hg) and Wistar-Kyoto baroreceptor-denervated (121 +/- 4 mm Hg) rats. The gain of baroreceptor reflex control of heart rate was assessed by measuring maximal heart rate responses to changes in arterial pressure elicited by bolus injection of phenylephrine and nitroprusside (gain = slope of linear regression equation of change in heart rate versus change in arterial pressure). Baroreceptor reflex gain was significantly higher in Wistar-Kyoto sham rats (-2.10 beats/min/mm Hg) than spontaneously hypertensive sham rats (-0.94 beats/min/mm Hg). Baroreceptor denervation significantly decreased baroreceptor reflex gain in both Wistar-Kyoto (-0.26 mm Hg) and spontaneously hypertensive (-0.22 beats/min/mm Hg) groups. Since baroreceptor denervation did not exacerbate the development of hypertension in adult spontaneously hypertensive rats or lead to hypertension in Wistar-Kyoto rats, we conclude that a primary dysfunction in the baroreceptor reflex alone is not responsible for the development of hypertension in this model.


Characteristics and outcomes of gunshot-acquired spinal cord injury in South Africa.
Spinal cord injuries (SCIs) caused by assault present a unique challenge facing the healthcare system, in that very little is known about how these injuries manifest compared with other causes of injury. Understanding the nuances of gunshot SCIs could contribute towards better care provision. To determine the characteristics of gunshot SCI and compare both injury characteristics and outcomes between gunshot SCI and all other traumatic causes taken together. The gunshot SCI sub-cohort was derived from a 1-year prospective, population-based study, including both tertiary-level hospitals providing SCI care in the Cape Metropolitan area of South Africa (SA). All consenting 145 survivors, after a window period of 7 days, were included, and their demographic and injury characteristics were captured according to the International SCI Core Basic Data Set. Further, selected secondary medical complications (outcomes) were prospectively and routinely assessed throughout acute care. Both descriptive and inferential statistics were used to describe and compare characteristics and outcomes, respectively. Of the 145 survivors of traumatic SCIs, 45 (31%) injuries were caused by gunshots. The gunshot SCI group consisted mainly of males (n=43, 96%), and the average age of injury onset was 26 years. Most survivors of the gunshot SCI group were paraplegic (69%), had complete lesions (69%) and vertebral injuries (96%), and presented with significant associated injuries (84%). When comparing gunshot SCI with all other traumatic causes, significant differences were found in relation to demographic and injury characteristics and adverse outcomes, indicating that those survivors with gunshot SCI were typically younger males with complete paraplegia, had more frequent secondary medical complications, and a longer hospital stay. This study contributes to the knowledge base of survivors with gunshot SCIs in a region of SA. Efforts should be made to reduce the occurrence of all gunshot SCIs, since those injuries affect survivors negatively in terms of injury characteristics and adverse outcomes.


Photo-induced copper-catalyzed C-H chalcogenation of azoles at room temperature.
Inexpensive copper catalysts enabled direct C-H chalcogenations at ambient temperature by means of photo-induced catalysis. The expedient copper catalysis set the stage for C-S and C-Se bond formation from readily accessible non-volatile elemental chalcogens. The photo-assisted copper catalysis manifold proved suitable for a wide range of substrates with good functional group tolerance and exhibited high catalytic efficacy even at a reaction temperature of 25 °C.


A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.
The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.


Practice of use of antiemetic in patients for laparoscopic gynaecological surgery and its impact on the early (1st two hrs) postoperative period.
There is no agreed technique for minimizing PONV (Postoperative Nausea and Vomiting) although some techniques are associated with low rate. Best practice involves identifying high risk patients and surgeries and use of prophylactic antiemetic where appropriate. Laparoscopic gynaecological surgery has high incidence of PONV (54-92%). An audit on the practice of antiemetic use in diagnostic laparoscopic gynaecological surgery was done in the department of anaesthesia of Aga Khan University Hospital from 1st January to 30th June 2006. We included all the patients scheduled for this procedure lasting less than 90 minutes. Anaesthetist involved in the audit identified the patient falling into the predetermined risk factors. The following facts about antiemetic were noted; whether the patients received any antiemetics or not, if it was prophylactic or rescue, type, dose route and timing of antiemetic. Patients were rated for any signs of nausea and vomiting (retching) after extubation in the operating room by the anaesthetist and in the recovery room or surgical day care unit (SDC) by the nurse who was briefed about it and was cross checked by the anaesthetist involved in the audit. This was done for two hours postoperatively. Our results showed that only 75% of patients with risk factors received an antiemetic. The most commonly used antiemetic was Metoclopramide. Eight percent of the patients had vomiting and all of them had received a prophylactic antiemetic. They received the same rescue antiemetic. This audit recommended institutional guidelines for the management of PONV. These should be based on evidence obtained from the published peer-reviewed studies. These guidelines could be communicated to health care workers involved in postoperative management of patients to help them achieve an optimal management strategy for this uncomfortable postoperative complication.


Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).
Denisova Cave in southern Siberia uniquely contains evidence of occupation by a recently discovered group of archaic hominins, the Denisovans, starting from the middle of the Middle Pleistocene. Artefacts, ancient DNA and a range of animal and plant remains have been recovered from the sedimentary deposits, along with a few fragmentary fossils of Denisovans, Neanderthals and a first-generation Neanderthal-Denisovan offspring. The deposits also contain microscopic traces of hominin and animal activities that can provide insights into the use of the cave over the last 300,000 years. Here we report the results of a micromorphological study of intact sediment blocks collected from the Pleistocene deposits in the Main and East Chambers of Denisova Cave. The presence of charcoal attests to the use of fire by hominins, but other evidence of their activities preserved in the microstratigraphic record are few. The ubiquitous occurrence of coprolites, which we attribute primarily to hyenas, indicates that the site was visited for much of its depositional history by cave-dwelling carnivores. Microscopic traces of post-depositional diagenesis, bioturbation and incipient cryoturbation are observed in only a few regions of the deposit examined here. Micromorphology can help identify areas of sedimentary deposit that are most conducive to ancient DNA preservation and could be usefully integrated with DNA analyses of sediments at archaeological sites to illuminate features of their human and environmental history that are invisible to the naked eye.


Short-term and longer-term effects of brivaracetam on cognition and behavior in a naturalistic clinical setting-Preliminary data.
To assess short-term and longer-term effects of brivaracetam (BRV) on cognition and behavior in a naturalistic clinical setting. Analyses were based on 43 patients with epilepsy who had undergone a neuropsychological screening before adjunctive treatment with BRV and a follow-up evaluation either after 5 days or 25 weeks. The standard assessment focused on reaction times (Neurocog FX), attention and executive functions (EpiTrack), and verbal memory (short version of the VLMT). Self-perceived cognition and behavior was evaluated by an extended version of the Adverse Events Profile. In addition, health-related quality of life (QOLIE-10) was reassessed at the longer-term interval. Repeated measures analysis of variance revealed a significant improvement under BRV with regard to attention and executive functions (p = .03) without an interaction with the length of the observation interval. A statistical trend in the same direction was also seen for the reaction times (p = .07), but not for the unchanged verbal memory performance. Subjective measures indicated improvements in concentration (p = .02) and especially in comprehension (p < .001), and health-related quality of life (p = .002). Mood and aggression scores were unchanged. At the longer-term follow-up, an at least 50 percent reduction in seizure frequency was observed in 53% of the patients, 21% were seizure free. These preliminary data point to a favorable cognitive profile of BRV similar to its precursor levetiracetam. Objective gains in attention and executive functions were accompanied by self-reported improvements in concentration and comprehension. Future studies with larger sample sizes and better control conditions are needed to confirm these findings.


Magnetophoretic immunoassay of allergen-specific IgE in an enhanced magnetic field gradient.
We demonstrate a novel magnetophoretic immunoassay of allergen-specific immunoglobulin E (IgE) based on the magnetophoretic deflection velocity of a microbead that is proportional to the associated magnetic nanoparticles under enhanced magnetic field gradient in a microchannel. In this detection scheme, two types of house dust mites, Dermatophagoides farinae (D. farinae) and Dermatophagoides pteronyssinus (D. pteronyssinus), were used as the model allergens. Polystyrene microbeads were conjugated with each of the mite extracts followed by incubation with serum samples. The resulting mixture was then reacted with magnetic nanoparticle-conjugated anti-human IgE for detection of allergen-specific IgE by using sandwich immuno-reactions. A ferromagnetic microstructure combined with a permanent magnet was employed to increase the magnetic field gradient ( approximately 10(4) T/m) in a microfluidic device. The magnetophoretic velocities of microbeads were measured in a microchannel under applied magnetic field, and the averaged velocity was well correlated with the concentration of allergen-specific IgE in serum. From the analysis of pooled sera obtained from 44 patients, the detection limits of the allergen-specific human IgEs for D. farinae and D. pteronyssinus were determined to be 565 (0.045 IU/mL) and 268 fM (0.021 IU/mL), respectively. These values are 1 order of magnitude lower than those by a conventional CAP system. For evaluation of reproducibility and accuracy, unknown sera were subjected to a blind test by using the developed assay system, and they were compared with the CAP system. As a result, coefficient of variance was less than 10%, and the developed method enabled a fast assay with a tiny amount of serum ( approximately 10 microL).


Α-arrestins - new players in Notch and GPCR signaling pathways in mammals.
For many years, β-arrestins have been known to be involved in G-protein-coupled receptor (GPCR) desensitization. However, β-arrestins belong to a family of proteins that act as multifunctional scaffolding proteins, in particular during trafficking of transmembrane receptors. The arrestin family comprises visual arrestins, β-arrestins and α-arrestins. In mammals, the functions of the α-arrestins are beginning to be elucidated, and they are described as versatile adaptors that link GPCRs or the Notch receptor to E3 ubiquitin ligases and endocytic factors. These α-arrestins can act in sequence, complementarily or cooperatively with β-arrestins in trafficking and ubiquitylation events. This Commentary will summarize the recent advances in our understanding of the functions and properties of these α-arrestin proteins in comparison to β-arrestins, and will highlight a new hypothesis linking their functional complementarity to their physical interactions. α- and β-arrestins could form transient and versatile heterodimers that form a bridge between cargo and E3 ubiquitin ligases, thus allowing trafficking to proceed.


Reduction of hospital costs and length of stay by good control of blood glucose levels.
To discuss the available literature regarding the potential benefits of improving blood glucose control in hospitalized patients. Subjects with diabetes constitute an increasing proportion of hospitalized patients. Hospital costs attributable to diabetes are in excess of $40 billion annually in the United States. Numerous reports have confirmed a correlation between blood glucose control at the time of hospitalization and adverse inpatient outcomes for various admission diagnoses, in some cases with or without a previous diagnosis of diabetes. Several studies have specifically found a relationship between improved inpatient control of blood glucose levels and decreased hospital length of stay. Likewise, cost savings have been proposed for intensive inpatient glucose management for a few critical admission diagnoses. Although the apparent economic advantage of aggressive control of blood glucose levels is substantial, cost-effectiveness analyses have been few and limited in scope. Improved blood glucose control in the hospital setting appears to reduce the duration of hospital stay and the hospital costs. Comprehensive analyses of cost-effectiveness through prospective, randomized intervention trials are needed, however, to characterize these benefits more precisely.


The rate of intestinal absorption of natural food folates is not related to the extent of folate conjugation.
Evidence is conflicting as to whether the bioavailability of food folates is influenced by the extent of their conjugation. The objective was to compare the bioavailability of 3 representative food folate sources with various degrees of glutamylation-ie, egg yolk, spinach, and yeast, whose polyglutamyl folate content measured 0%, 50%, and 100%, respectively. In a randomized crossover trial, 13 male subjects, after a prestudy folate saturation procedure, received in random order either placebo or 500 mug total folate, which was provided as concentrated freeze-dried extract removed from the normal food matrix of egg yolk, spinach, or yeast. Blood samples (n = 10) were collected before and up to 10 h after treatments, which were administered at weekly intervals. A significant increase from baseline plasma folate concentrations was observed by 0.5 h after treatment with egg yolk folate or spinach folate and by 1 h after treatment with yeast folate, and the concentrations remained significantly elevated for 3-5 h; no plasma folate response was observed after placebo treatment. The overall responses, calculated as plasma folate area under the curve (AUC) for egg yolk, spinach, and yeast folate, were 122.6 +/- 23.6, 136.2 +/- 21.4, and 102.5 +/- 21.1 nmol . h/L, respectively. No significant differences in AUC were seen between monoglutamyl (egg yolk) folate and either of the polyglutamate-containing folates examined. These results suggest that the ratio of monoglutamate to polyglutamate in natural folates is not a factor that limits the extent of intestinal absorption of food folate.


On Deflationary Accounts of Human Action Understanding.
A common deflationary tendency has emerged recently in both philosophical accounts and comparative animal studies concerned with how subjects understand the actions of others. The suggestion emerging from both arenas is that the default mechanism for understanding action involves only a sensitivity to the observable, behavioural (non-mental) features of a situation. This kind of 'smart behaviour reading' thus suggests that, typically, predicting or explaining the behaviour of conspecifics does not require seeing the other through the lens of mental state attribution. This paper aims to explore and assess this deflationary move. In §1 I clarify what might be involved in a smart behaviour reading account via looking at some concrete examples. Then in §2 I critically assess the deflationary move, arguing that, at least in the human case, it would in fact be a mistake to assume that our default method of action understanding proceeds without appeal to mental state attribution. Finally in §3 I consider briefly how the positive view proposed here relates to discussions about standard two-system models of cognition.


Quasicontinuum Simulation of the Effect of Lotus-Type Nanocavity on the Onset Plasticity of Single Crystal Al during Nanoindentation.
Stress concentration around nanosized defects such as cavities always leads to plastic deformation and failure of solids. We investigate the effects of depth, size, and shape of a lotus-type nanocavity on onset plasticity of single crystal Al during nanoindentation on a (001) surface using a quasicontinuum method. The results show that the presence of a nanocavity can greatly affect the contact stiffness (Sc) and yield stress (σy) of the matrix during nanoindentation. For a circular cavity, the Sc and σy gradually increase with the cavity depth. A critical depth can be identified, over which the Sc and σy are insensitive to the cavity depth and it is firstly observed that the nucleated dislocations extend into the matrix and form a y-shaped structure. Moreover, the critical depth varies approximately linearly with the indenter size, regarding the same cavity. The Sc almost linearly decreases with the cavity diameter, while the σy is slightly affected. For an ellipsoidal cavity, the Sc and σy increase with the aspect ratio (AR), while they are less affected when the AR is over 1. Our results shed light in the mechanical behavior of metals with cavities and could also be helpful in designing porous materials and structures.


Residual lumbar curvature that developed during adolescence accelerates intervertebral disc degeneration in adulthood.
To elucidate the influence of spinal deformity in adolescent idiopathic scoliosis (AIS) on lumbar intervertebral disc (IVD) degeneration in adulthood using magnetic resonance imaging (MRI). A total of 102 patients (8 men, 94 women; mean age, 31.4 years) who had developed idiopathic scoliosis at the age of 10-18 years and underwent preoperative lumbar spine MRI at the age of ≥ 20 were included in the study. Twenty volunteers (3 men, 17 women; mean age, 33.6 years) without scoliosis were assessed as controls. We divided the adult scoliosis patients into two groups: Group A consisted of patients with lumbar modifier A, and Group BC consisted of those with modifiers B and C. IVD degeneration from L1/2 to L5/S1 was assessed by MRI. The Scoliosis Research Society-22 (SRS-22) patient questionnaire was used in the patients' clinical assessment. There were 40 patients in the Group A and 62 in the Group BC. Compared to the control groups, significant IVD degeneration was observed at L2/3 and L3/4 in Group A, and at all levels except for L5/S1 in Group BC. The proportion of degenerated IVDs patients (Grades 1c and 2) was significantly higher in Group BC than those in Group A at L3/L4 and L4/L5. Furthermore, the severity of IVD degeneration was significantly greater in the group BC than in the group A at all levels, except for L5/S1, especially in patients aged > 30 years. The mean scores of all subdomains in the SRS-22 questionnaire were comparable between the two groups. Our study showed that the residual lumbar curvature from AIS may have accelerated IVD degeneration in adulthood, especially in patients aged > 30 years. III.


Decisional capacity to consent to research among patients with bipolar disorder: comparison with schizophrenia patients and healthy subjects.
Although clinical trials are needed to advance treatments for bipolar disorder, there has been little empirical research on the capacity of bipolar patients to consent to research. The aim of the present study was to evaluate levels of decisional capacity of bipolar patients compared with those of schizophrenia patients and healthy comparison subjects, as well as to examine whether symptom and neurocognitive deficits correlate with patients' decisional abilities. Participants were 31 outpatients with bipolar disorder, 31 outpatients with schizophrenia, and 28 healthy comparison subjects; each participant's decisional capacity was evaluated with the MacArthur Competence Assessment Tool for Clinical Research. Patient participants were also evaluated with standardized clinical rating scales and neurocognitive tests. Data were collected from April 2002 through November 2005. Bipolar patients had worse understanding than healthy comparison subjects, and their level of decisional capacity did not differ from that of schizophrenia patients. Within the combined patient sample, neurocognitive deficits and negative symptoms were significantly correlated (p < .05) with the level of decisional capacity (particularly, understanding of disclosed information). Repeating the missed information improved the level of understanding in all groups. The presence of bipolar disorder appears to be a risk factor for impaired understanding of information disclosed under standard consent procedures but should not be equated with a lack of competence to consent. The observed improvement in understanding with redisclosure of information suggests that enhanced consent procedures may be useful during enrollment of bipolar patients in research.


Community behavior and spatial regulation within a bacterial microcolony in deep tissue sites serves to protect against host attack.
Bacterial pathogens express virulence-specific transcriptional programs that allow tissue colonization. Although phenotypic variation has been noted in the context of antibiotic exposure, no direct evidence exists for heterogeneity in virulence-specific transcriptional programs within tissues. In a mouse model of Yersinia pseudotuberculosis infection, we show that at least three subpopulations of bacteria develop within a single tissue site in response to distinct host signals. Bacteria growing on the exterior of spleen microcolonies responded to soluble signals and induced the nitric oxide (NO)-detoxifying gene, hmp. Hmp effectively eliminated NO diffusion and protected the interior bacterial population from exposure to NO-derived inducing signals. A third subpopulation, constituting the most peripherally localized bacteria, directly contacted neutrophils and transcriptionally upregulated a virulence factor. These studies demonstrate that growth within tissues results in transcriptional specialization within a single focus of microbial replication, facilitating directed pathogen counterattack against the host response.


Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells.
Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms. TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ. Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells. Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.


Evaluating the test re-test reliability and inter-subject variability of Health Care Provider manual fluid resuscitation performance.
Health Care Providers (HCPs) report that manual techniques of intravascular fluid resuscitation are commonly used during pediatric shock management. The optimal pediatric fluid resuscitation technique is currently unknown. We sought to determine HCP test-retest reliability (repeatability) and inter-subject variability of fluid resuscitation performance outcomes to inform the design of future studies. Fifteen consenting HCPs from McMaster Children's Hospital, in Hamilton, Canada participated in this single-arm interventional trial. Participants were oriented to a non-clinical model representing a 15 kg toddler, which incorporated a 22-gauge IV catheter. Following a standardization procedure, participants administered 600 mL (40 mL/kg) of saline to the simulated child under emergency conditions using prefilled 60-mL syringes. Each participant completed 5 testing trials. All testing was video recorded, with fluid administration time outcome data (in seconds) extracted from trial videos by two blinded outcome assessors. Data describing catheter dislodgement events, volume of saline effectively delivered, and participant demographics were also collected. The primary outcome of fluid administration time test-retest reliability was analyzed by one-way analysis of variance (ANOVA) and intra-class correlation (ICC), with good reliability defined as ICC > 0.70. Differences in HCP fluid administration times are attributable to inter-subject variability rather than intra-subject variability based on one-way ANOVA analysis, F (14,60) = 43.125; p < 0.001. Test-retest reliability of subjects was excellent with ICC = 0.97 (95% CI: 0.95-0.99); p < 0.001. Findings demonstrate excellent test-retest reliability of HCP fluid resuscitation performance in a setting involving a non-clinical model. Investigators can justify a single evaluation of HCP performance in future studies.


Inclusion of coexisting morbidity in a TBSA% and age based model for the prediction of mortality after burns does not increase its predictive power.
Several models for predicting mortality have been developed for patients with burns, and the most commonly used are based on age and total body surface area (TBSA%). They often show good predictive precision as depicted by high values for area under the receiver operating characteristic curves (AUC). However the effect of coexisting morbidity on such prediction models has not to our knowledge been thoroughly examined. We hypothesised that adding it to a previously published model (based on age, TBSA%, full thickness burns, gender, and need for mechanical ventilation) would further improve its predictive power. We studied 772 patients admitted during the period 1997-2008 to the Linköping University Hospital, National Burn Centre with any type of burns. We defined coexisting morbidity as any of the medical conditions listed in the Charlson list, as well as psychiatric disorders or drug or alcohol misuse. We added coexisting medical conditions to the model for predicting mortality (age, TBSA%, and need for mechanical ventilation) to determine whether it improved the model as assessed by changes in deviances between the models. Mean (SD) age and TBSA% was 35 (26) years and 13 (17) %, respectively. Among 725 patients who survived, 105 (14%) had one or more coexisting condition, compared with 28 (60%) among those 47 who died. The presence of coexisting conditions increased with age (p<0.001) among patients with burns. The AUC of the mortality prediction model in this study, based on the variables age, TBSA%, and need for mechanical ventilation was 0.980 (n=772); after inclusion of coexisting morbidity in the model, the AUC improved only marginally, to 0.986. The model was not significantly better either. Adding coexisting morbidity to a model for prediction of mortality after a burn based on age, TBSA%, and the need for mechanical ventilation did not significantly improve its predictive value. This is probably because coexisting morbidity is automatically adjusted for by age in the original model.


IL-9 protects against bleomycin-induced lung injury: involvement of prostaglandins.
IL-9 is a Th2 cytokine that exerts pleiotropic activities, and might be involved in the regulation of lung inflammatory processes. To characterize the activity of IL-9 on lung injury, we compared the pulmonary responses to bleomycin (blm) in IL-9 transgenic (Tg5) and wild-type (FVB) mice. Following intratracheal instillation of lethal doses of blm, the mortality rate was markedly reduced in Tg5 mice compared to their wild-type counterparts (ie, 25% mortality for Tg5 versus 85% for FVB mice, 21 days after instillation of 0.05U blm/mouse). Histological and biochemical analyses showed that blm induced less lung injury and less epithelial damage in Tg5 as compared to FVB animals. This protection of Tg5 mice was accompanied by an expansion of eosinophils and B cells in the lungs. In addition, TGF-beta and prostaglandin-E2 (PGE2) levels in broncho-alveolar lavage fluid were also increased in transgenic mice. The contribution of B cells and eosinophils to the protective mechanism did not appear essential since eosinophil-deficient (IL-5 KO) and B-deficient (muMT) mice overexpressing IL-9 were also resistant to high doses of blm. We could rule out that TGF-beta was a key factor in the protective effect of IL-9 by blocking this mediator with neutralizing antibodies. Indomethacin treatment, which inhibited PGE2 production in both strains, suppressed the protection in Tg5 mice, supporting the idea that IL-9 controls blm-induced lung injury through a prostaglandin-dependent mechanism.


An efficient and inexpensive water-oxidizing manganese-based oxide electrode.
Using inexpensive and environmentally friendly Mn oxide, a very simple method to synthesize an efficient and stable water-oxidizing electrode on the surface of a fluorine doped tin oxide electrode was reported. The electrode at pH = 13 yields a current density of 1 mA cm-2 at an overpotential of 450 mV, which is promising to be used as an anode in water-splitting systems. In higher overpotential (800 mV), a current density of 7 mA cm-2 was observed. Proposed different states of the growth of layered Mn oxide on the surface of FTO based on SEM images were also discussed.


Enhanced lipid peroxidation and platelet activation in the early phase of type 1 diabetes mellitus: role of interleukin-6 and disease duration.
To investigate early events possibly related to the development of diabetic angiopathy, we examined whether 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) formation, a marker of in vivo oxidant stress, is altered in different stages of type 1 diabetes (T1DM) and whether it correlates with the rate of thromboxane (TX) A2 biosynthesis, a marker of in vivo platelet activation. We also investigated the relationship between inflammatory markers and F2-isoprostane formation in this setting. A cross-sectional study was performed in 23 insulin-treated patients aged <18 years with new-onset T1DM (<or=6 weeks, group A), matched for age and gender with 23 patients with stable disease (>1 year, group B). Urinary 8-iso-PGF2alpha and 11-dehydro-TXB2 were measured in all patients and in age- and gender-matched controls. Circulating interleukin-6 (IL-6), tumor necrosis factor-alpha, and C-reactive protein were also determined as markers of the inflammatory response. Fifteen of the 23 children in group A were reexamined after 12 months. Compared with either controls or group B, diabetic children in group A showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, IL-6, tumor necrosis factor-alpha, and C-reactive protein. Statistically significant correlations between IL-6 and both 8-iso-PGF2alpha (r=0.63, P<0.001) and 11-dehydro-TXB2 (r=0.51, P<0.01) were observed. The 15 patients reexamined after 1 year showed a significant reduction in lipid peroxidation and platelet activation (P<0.02 and P<0.001, respectively), consistent with reduced levels of IL-6 and tumor necrosis factor-alpha. These results demonstrate that enhanced lipid peroxidation and platelet activation represent early events in T1DM that are possibly related to an acute inflammatory response. These noninvasive indexes may help in further examining T1DM pathophysiology and monitoring pharmacological interventions to interfere with disease development and progression.


Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.
Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life.


Mice drinking goji berry juice (Lycium barbarum) are protected from UV radiation-induced skin damage via antioxidant pathways.
The goji berry, Lycium barbarum, has long been recognised in traditional Chinese medicine for various therapeutic properties based on its antioxidant and immune-modulating effects. This study describes the potential for orally consumed goji berry juice to alter the photodamage induced in the skin of mice by acute solar simulated UV (SSUV) irradiation. In Skh:hr-1 hairless mice, 5% goji berry juice significantly reduced the inflammatory oedema of the sunburn reaction. Dilutions of goji berry juice between 1% and 10% dose-dependently protected against SSUV-induced immunosuppression, and against suppression induced by the mediator, cis-urocanic acid, measured by the contact hypersensitivity reaction. The immune protection could not be ascribed to either the minor excipients in the goji juice, pear and apple juice, nor the vitamin C content, nor the preservative, and appeared to be a property of the goji berry itself. Antioxidant activity in the skin was demonstrated by the significant protection by 5% goji juice against lipid peroxidation induced by UVA radiation. Furthermore, two known inducible endogenous skin antioxidants, haem oxygenase-1 and metallothionein, were found to be involved in the photoimmune protection. The results suggest that consumption of this juice could provide additional photoprotection for susceptible humans.


Towards an immunodiagnostic test for leprosy.
In addition to multidrug therapy, elimination of leprosy requires improved diagnostic methods. Using a comparative genomics approach, 17 potential protein antigens (MLP) that are restricted to Mycobacterium leprae, or of limited distribution, were produced and tested for antigen-specific immune responses on leprosy patients, healthy contacts of leprosy patients, and tuberculosis patients in Mali and Bangladesh, as well as on non-endemic controls. T-cell antigenicity of MLP was confirmed by IFN-gamma production in whole-blood assays with the highest responses observed in paucibacillary leprosy patients and healthy contacts. Four MLP behaved well in both countries and induced significantly different responses between the study groups. Peptides carrying T cell epitopes from one of the antigens gave promising results in restimulation assays in mice and immune responses were not influenced by prior exposure to BCG or environmental mycobacteria. This study provides the immunological framework for the development of a specific, peptide-based immunodiagnostic test for leprosy.


Find and treat or find and lose? Tuberculosis treatment outcomes among screened newly arrived asylum seekers in Germany 2002 to 2014.
BackgroundGermany has a low tuberculosis (TB) incidence. A relevant and increasing proportion of TB cases is diagnosed among asylum seekers upon screening. Aim: We aimed to assess whether cases identified by screening asylum seekers had equally successful and completely reported treatment outcomes as cases diagnosed by passive case finding and contact tracing in the general population. Methods: We analysed characteristics and treatment outcomes of pulmonary TB cases notified in Germany between 2002 and 2014, stratified by mode of case finding. We performed three multivariable analyses with different dependent variables: Model A: successful vs all other outcomes, Model B: successful vs documented non-successful clinical outcome and Model C: known outcome vs lost to follow-up. Results: TB treatment success was highest among cases identified by contact tracing (87%; 3,139/3,591), followed by passive case finding (74%; 28,804/39,019) and by screening asylum seekers (60%; 884/1,474). Cases identified by screening asylum seekers had 2.4 times higher odds of not having a successful treatment outcome as opposed to all other outcomes (A), 1.4 times higher odds of not having a successful treatment outcome as opposed to known non-successful outcomes (B) and 2.3 times higher odds of loss to follow-up (C) than cases identified by passive case finding. Conclusion: Screened asylum seekers had poorer treatment outcomes and were more often lost to follow-up. Linking patients to treatment facilities and investigating potential barriers to treatment completion are needed to secure screening benefits for asylum seekers and communities.


Development of the malaria parasite in the skin of the mammalian host.
The first step of Plasmodium development in vertebrates is the transformation of the sporozoite, the parasite stage injected by the mosquito in the skin, into merozoites, the stage that invades erythrocytes and initiates the disease. The current view is that, in mammals, this stage conversion occurs only inside hepatocytes. Here, we document the transformation of sporozoites of rodent-infecting Plasmodium into merozoites in the skin of mice. After mosquito bite, ∼50% of the parasites remain in the skin, and at 24 h ∼10% are developing in the epidermis and the dermis, as well as in the immunoprivileged hair follicles where they can survive for weeks. The parasite developmental pathway in skin cells, although frequently abortive, leads to the generation of merozoites that are infective to erythrocytes and are released via merosomes, as typically observed in the liver. Therefore, during malaria in rodents, the skin is not just the route to the liver but is also the final destination for many inoculated parasites, where they can differentiate into merozoites and possibly persist.


Predictors of early death in female patients with breast cancer in the UK: a cohort study.
Objective To identify factors predicting early death in women with breast cancer. Design Cohort study. Setting 29 trusts across seven cancer networks in the North Thames area. Participants 15 037 women with primary breast cancer diagnosed between January 1996 and December 2005. Methods Logistic regression analyses to determine predictors of early death and factors associated with lack of surgical treatment. Main exposures Age at diagnosis, mode of presentation, ethnicity, disease severity, comorbidities, treatment and period of diagnosis in relation to the Cancer Plan (the NHS's strategy in 2000 for investment in and reform of cancer services). Main outcome measures Death from any cause within 1 year of diagnosis, and receipt of surgical treatment. Results By 31 December 2006, 4765 women had died, 980 in the year after diagnosis. Older age and disease severity independently predicted early death. Women over 80 were more likely to die early than women under 50 (OR 8.05, 95% CI 5.96 to 10.88). Presence of distant metastases on diagnosis increased the odds of early death more than eightfold (OR 8.41, 95% CI 6.49 to 10.89). Two or more recorded comorbidities were associated with a nearly fourfold increase. There was a significant decrease in odds associated with surgery (OR 0.29, 95% CI 0.24 to 0.35). Independently of disease severity and comorbidities, women over 70 were less likely than those under 50 to be treated surgically and this was even more pronounced in those aged over 80 (OR 0.09, 95% CI 0.07 to 0.10). Other factors independently associated with a reduced likelihood of surgery included a non-screening presentation, non-white ethnicity and additional comorbidities. Conclusions These findings may partially explain the survival discrepancies between the UK and other European countries in female patients with breast cancer. The study identifies a group of women with a particularly poor prognosis for whom interventions aiming at early detection may be targeted.


Predicting long-term type 2 diabetes with support vector machine using oral glucose tolerance test.
Diabetes is a large healthcare burden worldwide. There is substantial evidence that lifestyle modifications and drug intervention can prevent diabetes, therefore, an early identification of high risk individuals is important to design targeted prevention strategies. In this paper, we present an automatic tool that uses machine learning techniques to predict the development of type 2 diabetes mellitus (T2DM). Data generated from an oral glucose tolerance test (OGTT) was used to develop a predictive model based on the support vector machine (SVM). We trained and validated the models using the OGTT and demographic data of 1,492 healthy individuals collected during the San Antonio Heart Study. This study collected plasma glucose and insulin concentrations before glucose intake and at three time-points thereafter (30, 60 and 120 min). Furthermore, personal information such as age, ethnicity and body-mass index was also a part of the data-set. Using 11 OGTT measurements, we have deduced 61 features, which are then assigned a rank and the top ten features are shortlisted using minimum redundancy maximum relevance feature selection algorithm. All possible combinations of the 10 best ranked features were used to generate SVM based prediction models. This research shows that an individual's plasma glucose levels, and the information derived therefrom have the strongest predictive performance for the future development of T2DM. Significantly, insulin and demographic features do not provide additional performance improvement for diabetes prediction. The results of this work identify the parsimonious clinical data needed to be collected for an efficient prediction of T2DM. Our approach shows an average accuracy of 96.80% and a sensitivity of 80.09% obtained on a holdout set.