Corrosive extracellular polysaccharides of the rock-inhabiting model fungus Knufia petricola.
Melanised cell walls and extracellular polymeric matrices protect rock-inhabiting microcolonial fungi from hostile environmental conditions. How extracellular polymeric substances (EPS) perform this protective role was investigated by following development of the model microcolonial black fungus Knufia petricola A95 grown as a sub-aerial biofilm. Extracellular substances were extracted with NaOH/formaldehyde and the structures of two excreted polymers studied by methylation as well as NMR analyses. The main polysaccharide (~ 80%) was pullulan, also known as α-1,4-; α-1,6-glucan, with different degrees of polymerisation. Αlpha-(1,4)-linked-Glcp and α-(1,6)-linked-Glcp were present in the molar ratios of 2:1. A branched galactofuromannan with an α-(1,2)-linked Manp main chain and a β-(1,6)-linked Galf side chain formed a minor fraction (~ 20%). To further understand the roles of EPS in the weathering of minerals and rocks, viscosity along with corrosive properties were studied using atomic force microscopy (AFM). The kinetic viscosity of extracellular K. petricola A95 polysaccharides (≈ 0.97 × 10-6 m2 s-1) ranged from the equivalent of 2% (w/v) to 5% glycerine, and could thus profoundly affect diffusion-dominated processes. The corrosive nature of rock-inhabiting fungal EPS was also demonstrated by its effects on the aluminium coating of the AFM cantilever and the silicon layer below.


Lapidus arthrodesis in combination with arthrodesis of the first metatarsophalangeal joint-biomechanical cadaver study comparing two methods of fixation.
To assess the results of a biomechanical test of cadaveric specimens, comparing 2 methods of fixation of modified Lapidus arthrodesis in combination with arthrodesis of the first metatarsophalangeal joint. A total of 12 cadaveric specimens were used in the test. Arthrodesis of the first MTP joint was in all patients fixed with a Variable Angle LCP 1st MTP Fusion Plate 2.4/2.7. Two methods of fixation of the Lapidus arthrodesis were compared, i.e. fixation with two screws in the PS (plate-screw) version versus fixation with X-Locking Plate 2.4/2.7 in the PP (plate-plate) version. Measurements were obtained with the use of a testing machine ZWICK Z 020-TND with an optical device Mercury RT for measuring deformities. Each specimen was subjected to 3 loading options, a. displacement 5 mm, the support is placed under the proximal phalanx, b. displacement 5 mm, the support is placed under the first metatarsal head and c. load to failure, the support is placed under the first metatarsal head. In all specimens the PS construct showed a statistically considerably higher stiffness than the PP construct. In all specimens treated with the PP construct the load to failure was lower than in the PS construct. For loading mode a., at a significance level of 0.05 (P<0.05), the P-value was 0.036, for mode b. the P-value was 0.007 and for loading mode c. the P-value was 0.006. In addition, age-related decrease in stiffness of the specimen was proved at a significance level of 5% (P=0.004). In all the three loading modes, the PS (plate-screw) construct showed a statistically higher stiffness than the PP (plate-plate) construct.


Mitochondrial superoxide dismutase in mature and developing human retinal pigment epithelium.
Human retinal pigment epithelium (RPE) contains two genetically distinct forms of superoxide dismutase (SOD) enzymes that scavenge harmful superoxide anions. Biochemical and immunochemical techniques were used to compare levels of copper-zinc- and manganese-containing forms of SOD (CuZn-SOD and Mn-SOD) in human adult and fetal RPE cells. It was found that Mn-SOD activity was higher in adult than fetal RPE cells, both in vivo and in vitro. Immunolocalization of Mn-SOD in cultured RPE cells showed a greater reactivity in the mitochondria of the adult cells. Primary cultures of adult RPE contained cells with various patterns of mitochondria as shown by immunolabeling for Mn-SOD. Adult RPE cells were more resistant to the effects of a superoxide generator, paraquat, which appeared to disrupt mitochondrial integrity as judged by staining with rhodamine 123. These results suggest that high levels of Mn-SOD protect mitochondria from oxidative damage that probably occurs with aging in the RPE.


Analysis of slow (theta) oscillations as a potential temporal reference frame for information coding in sensory cortices.
While sensory neurons carry behaviorally relevant information in responses that often extend over hundreds of milliseconds, the key units of neural information likely consist of much shorter and temporally precise spike patterns. The mechanisms and temporal reference frames by which sensory networks partition responses into these shorter units of information remain unknown. One hypothesis holds that slow oscillations provide a network-intrinsic reference to temporally partitioned spike trains without exploiting the millisecond-precise alignment of spikes to sensory stimuli. We tested this hypothesis on neural responses recorded in visual and auditory cortices of macaque monkeys in response to natural stimuli. Comparing different schemes for response partitioning revealed that theta band oscillations provide a temporal reference that permits extracting significantly more information than can be obtained from spike counts, and sometimes almost as much information as obtained by partitioning spike trains using precisely stimulus-locked time bins. We further tested the robustness of these partitioning schemes to temporal uncertainty in the decoding process and to noise in the sensory input. This revealed that partitioning using an oscillatory reference provides greater robustness than partitioning using precisely stimulus-locked time bins. Overall, these results provide a computational proof of concept for the hypothesis that slow rhythmic network activity may serve as internal reference frame for information coding in sensory cortices and they foster the notion that slow oscillations serve as key elements for the computations underlying perception.


Psychophysiological determinants of repeated ventilator weaning failure: an explanatory model.
The adverse effects of a failed ventilator weaning trial on the subsequent weaning attempts are not well understood. To examine physiological and psychological factors that may be predictive of risk for repeated weaning failures and prolonged mechanical ventilation. A prospective predictive study of 102 subjects, age 34 to 91 years, whose first ventilator weaning trial was unsuccessful but who were physiologically ready for another weaning attempt. Subjects were recruited from intensive care units and a respiratory care center of a tertiary medical center. Validated self-report scales and a Bicore monitoring system were used to measure ventilator patients' psychophysiological performance during the second weaning trial. Structural equation modeling was used to analyze the data and test the model. Significant causal pathways were found between fear and anxiety (r = 0.77; P < .001), anxiety and respiratory function (r = 0.24; P < .05), and respiratory function and weaning outcomes (r = 0.42; P < .001). The overall model predicted that both physiological and psychological factors were important in determining repeated failure of ventilator weaning, and the data were in support of the model (χ(2) = 29.49, P > .05). Patients whose first ventilator weaning trial is unsuccessful may be markedly fearful. Left unaddressed, these fears cause high anxiety levels that significantly compromise respiratory function and contribute to subsequent weaning failures. Thus begins a vicious cycle of repeated failure of ventilator weaning and prolonged mechanical ventilation.


SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.
Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.


The chemopreventive effect of mifepristone on mammary tumorigenesis is associated with an anti-invasive and anti-inflammatory gene signature.
Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR- and non-PR-mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-α-positive (ER(+)) transgenic mice expressing the dominant-negative Pax8PPARγ (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways.


Fast responsive nonvolatile holographic storage in LiNbO(3) triply doped with Zr, Fe, and Mn.
Iron and manganese doubly doped LiNbO(3) (LN:Fe,Mn) has been suggested for nonvolatile photorefractive recording; however, its response time is still of the order of minutes. Here we present results on LiNbO(3) triply doped with zirconium, iron, and manganese (LN:Zr,Fe,Mn). The codoping with Zr eliminates undesirable intrinsic traps, which strongly enhances the charge transition speed. The response time of LN:Zr,Fe,Mn for nonvolatile holographic storage shortens to only 0.95 s (wavelength of 532 nm and intensity of 400 mW/cm(2)), and the sensitivity reaches 1.31 cm/J. Thus it seems that we have found an excellent recording medium for practical holographic storage devices.


The Surgeon's Role in the Opioid Crisis: A Narrative Review and Call to Action.
Over the past two decades, there has been a sharp rise in the use of prescription opioids. In several countries, most notably the United States, opioid-related harm has been deemed a public health crisis. As surgeons are among the most prolific prescribers of opioids, growing attention is now being paid to the role that opioids play in surgical care. While opioids may sometimes be necessary to provide patients with adequate relief from acute pain after major surgery, the impact of opioids on the quality and safety of surgical care calls for greater scrutiny. This narrative review summarizes the available evidence on rates of persistent postsurgical opioid use and highlights the need to target known risk factors for persistent postoperative use before patients present for surgery. We draw attention to the mounting evidence that preoperative opioid exposure places patients at risk of persistent postoperative use, while also contributing to an increased risk of several other adverse clinical outcomes. By discussing the prevalence of excess opioid prescribing following surgery and highlighting significant variations in prescribing practices between countries, we note that there is a pressing need to optimize postoperative prescribing practices. Guided by the available evidence, we call for specific actions to be taken to address important research gaps and alleviate the harms associated with opioid use among surgical patients.


Polioencephalomalacia associated with closantel overdosage in a goat.
This report describes clinical and pathological findings associated with closantel (a halogenated salicylanilide anthelmintic) overdosage in a 3-year-old goat. The clinical signs included blindness, incoordination, ataxia, depression of the palpebral and pupillary reflexes, and recumbency. No gross lesions were noted in tissue or organs at necropsy, but microscopic lesions were seen in nervous tissue and hepatic cells. Polioencephalomalacia was clearly evident. Bilaterally symmetrical status spongiosus of the white matter of the brain, bilateral laminar necrosis, microcavitations, ischaemic cell change and severe degeneration of the cerebellum were seen in nervous tissue. Fatty change and hydropic degeneration in the liver and hepato-cellular degeneration were observed histologically.


YeastRGB: comparing the abundance and localization of yeast proteins across cells and libraries.
The ability to measure the abundance and visualize the localization of proteins across the yeast proteome has stimulated hypotheses on gene function and fueled discoveries. While the classic C' tagged GFP yeast library has been the only resource for over a decade, the recent development of the SWAT technology has led to the creation of multiple novel yeast libraries where new-generation fluorescent reporters are fused at the N' and C' of open reading frames. Efficient access to these data requires a user interface to visualize and compare protein abundance, localization and co-localization across cells, strains, and libraries. YeastRGB (www.yeastRGB.org) was designed to address such a need, through a user-friendly interface that maximizes informative content. It employs a compact display where cells are cropped and tiled together into a 'cell-grid.' This representation enables viewing dozens of cells for a particular strain within a display unit, and up to 30 display units can be arrayed on a standard high-definition screen. Additionally, the display unit allows users to control zoom-level and overlay of images acquired using different color channels. Thus, YeastRGB makes comparing abundance and localization efficient, across thousands of cells from different strains and libraries.


Catheter-Related Bloodstream Infections in Patients on Emergent Hemodialysis.
This study had 2 objectives: (1) to describe the epidemiology of catheter-related bloodstream infections (CRBSI) in patients with end-stage renal disease (ESRD) who have no access to scheduled dialysis and (2) to evaluate whether a positive culture of the heparin-lock solution is associated with subsequent development of bacteremia. Retrospective observational cohort design for objective 1; and prospective cohort design for objective 2. The study was conducted in a 770-bed public academic tertiary hospital in Dallas, Texas. The participants were patients with ESRD undergoing scheduled or emergent hemodialysis. We reviewed the records of 147 patients who received hemodialysis between January 2011 and May 2011 and evaluated the rate of CRBSI in the previous 5 years. For the prospective study, we cultured the catheter heparin-lock solution in 62 consecutive patients between June 2012 and August 2012 and evaluated the incidence of CRBSI at 6 months. Of the 147 patients on emergent hemodialysis, 125 had a tunneled catheter, with a CRBSI rate of 2.61 per 1,000 catheter days. The predominant organisms were Gram-negative rods (GNR). In the prospective study, we found that the dialysis catheter was colonized more frequently in patients on emergent hemodialysis than in those on scheduled hemodialysis. Colonization with GNR or Staphylococcus aureus was associated with subsequent CRBSI at 6 months follow-up. Patients undergoing emergent hemodialysis via tunneled catheter are predisposed to Gram-negative CRBSI. Culturing the heparin-lock solution may predict subsequent episodes of CRBSI if it shows colonization with GNR or Staphylococcus aureus. Prevention approaches in this population need to be studied further.


Schizophrenia diagnosis using innovative EEG feature-level fusion schemes.
Electroencephalogram (EEG) has become a practical tool for monitoring and diagnosing pathological/psychological brain states. To date, an increasing number of investigations considered differences between brain dynamic of patients with schizophrenia and healthy controls. However, insufficient studies have been performed to provide an intelligent and accurate system that detects the schizophrenia using EEG signals. This paper concerns this issue by providing new feature-level fusion algorithms. Firstly, we analyze EEG dynamics using three well-known nonlinear measures, including complexity (Cx), Higuchi fractal dimension (HFD), and Lyapunov exponents (Lya). Next, we propose some innovative feature-level fusion strategies to combine the information of these indices. We evaluate the effect of the classifier parameter (σ) adjustment and the cross-validation partitioning criteria on classification accuracy. The performance of EEG classification using combined features was compared with the non-combined attributes. Experimental results showed higher classification accuracy when feature-level features were utilized, compared to when each feature was used individually or all fed to the classifier simultaneously. Using the proposed algorithm, the classification accuracy increased up to 100%. These results establish the suggested framework as a superior scheme compared to the state-of-the-art EEG schizophrenia diagnosis tool.


Monkeys spontaneously discriminate their unfamiliar paternal kin under natural conditions using facial cues.
Kin recognition can enhance inclusive fitness via nepotism and optimal outbreeding. Mechanisms allowing recognition of patrilineal relatives are of particular interest in species in which females mate promiscuously, leading to paternity uncertainty. Humans are known to detect facial similarities between kin in the faces of third parties, and there is some evidence for continuity of this ability in nonhuman primates . However, no study has yet shown that this propensity translates into an ability to detect one's own relatives, one of the key prerequisites for gaining fitness benefits. Here we report a field experiment demonstrating that free-ranging rhesus macaques (Macaca mulatta) spontaneously discriminate between facial images of their paternal half-siblings and unrelated individuals, when both animals are unfamiliar to the tested individual. Specifically, subjects systematically biased their inspection time toward nonkin when the animals pictured were of their own sex (potential threats), relative to when they were of the opposite sex (potential mates). Our results provide strong evidence for visual phenotype matching and the first demonstration in any primate that individuals can spontaneously detect their own paternal relatives on the basis of facial cues under natural conditions.


Delivery of epilepsy care to adults with intellectual and developmental disabilities.
Epilepsy is common in people with intellectual and developmental disabilities (IDD). In adulthood, patients with IDD and epilepsy (IDD-E) have neurologic, psychiatric, medical, and social challenges compounded by fragmented and limited care. With increasing neurologic disability, there is a higher frequency of epilepsy, especially symptomatic generalized and treatment-resistant epilepsies. The causes of IDD-E are increasingly recognized to be genetic based on chromosomal microarray analysis to identify copy number variants, gene panels (epilepsy, autism spectrum disorder, intellectual disability), and whole-exome sequencing. A specific genetic diagnosis may guide care by pointing to comorbid disorders and best therapy. Therapy to control seizures should be individualized, with drug selection based on seizure types, epilepsy syndrome, concomitant medications, and comorbid disorders. There are limited comparative antiepileptic drug data in the IDD-E population. Vagus nerve and responsive neural stimulation therapies and resective surgery should be considered. Among the many comorbid disorders that affect patients with IDD-E, psychiatric and sleep disorders are common but often unrecognized and typically not treated. Transition from holistic and coordinated pediatric to adult care is often a vulnerable period. Communication among adult health care providers is complex but essential to ensure best care when these patients are seen in outpatient, emergency room, and inpatient settings. We propose specific recommendations for minimum care standards for people with IDD-E.


Arrested development of gastrointestinal trichostrongylids in goats in Nigeria.
Arrested development of Haemonchus, Cooperia and Trichostrongylus spp. was studied in (1) 14 naturally infected and eight experimentally infected West African Dwarf (WAD) goats reared in the derived savanna zone of eastern Nigeria and (2) 55 naturally infected slaughter goats obtained from the savanna and sahel regions of northern Nigeria. Six of the WAD goats carried natural infections of H. contortus and T. colubriformis and eight other (tracer) goats acquired their infections from a grass paddock artificially contaminated with H. placei, C. pectinata and C. punctata, during May to October. Another three WAD goats were artificially infected with mixed cultures of L3 of the latter three nematodes, while five goats were inoculated with 1500-2000 L3 of H. contortus harvested from cultures incubated at 25-30 degrees C for 8 days either in the dark or under normal laboratory conditions. Approximately 41% (9/22) of the infected WAD goats harboured arrested larvae of Haemonchus and/or Cooperia. No arrested larvae of Trichostrongylus were found in the six animals that were infected with this nematode. The level of inhibition varied from 0.4 to 20% and only three animals showed greater than 10% inhibition. This very low level of inhibition occurred in naturally and experimentally acquired infections, irrespective of the time of year. In the case of Haemonchus, the species and strain of the parasite and infection with L3 cultured in the dark also appeared not to influence the level of inhibition. By contrast, 65.5% (36/55) and 5.5% (3/55) of the northern savanna and sahel goats harboured arrested larvae of H. contortus and T. colubriformis, respectively. The mean percentage inhibition of the former was low (2-25%) during most of the rainy season (June-August) and high (75-90%) during the late rains and the dry season (October-April). The lowest and highest mean percentage inhibitions occurred during July and November, respectively.


Orthotic effect on metatarsophalangeal joint extension. A preliminary study.
The authors evaluated the effect of modified Root orthoses on first metatarsophalangeal joint extension. Motion within the joint was measured dynamically following the insertion of bone markers into the first metatarsal and the hallux. Extension at the joint was greatest when the subjects were barefoot, the mean angle being 62 degrees. Plimsolls restricted extension of the joint to a mean angle of 57 degrees, while orthoses further reduced the angle of metatarsophalangeal joint extension to a mean angle of 55 degrees. The marginal reduction in first metatarsophalangeal joint extension caused by functional orthoses may be of therapeutic value in the early stages of hallux rigidus, when restricting motion at the joint may slow or prevent development of subchondral sclerosis.


JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling.
Leukemia-initiating cells (LICs) are responsible for the initiation, development, and relapse of leukemia. The identification of novel therapeutic LIC targets is critical to curing leukemia. In this report, we reveal that junctional adhesion molecule 3 (JAM3) is highly enriched in both mouse and human LICs. Leukemogenesis is almost completely abrogated upon Jam3 deletion during serial transplantations in an MLL-AF9-induced murine acute myeloid leukemia model. In contrast, Jam3 deletion does not affect the functions of mouse hematopoietic stem cells. Moreover, knockdown of JAM3 leads to a dramatic decrease in the proliferation of both human leukemia cell lines and primary LICs. JAM3 directly associates with LRP5 to activate the downstream PDK1/AKT pathway, followed by the downregulation of GSK3β and activation of β-catenin/CCND1 signaling, to maintain the self-renewal ability and cell cycle entry of LICs. Thus, JAM3 may serve as a functional LIC marker and play an important role in the maintenance of LIC stemness through unexpected LRP5/PDK1/AKT/GSK3β/β-catenin/CCND1 signaling pathways but not via its canonical role in cell junctions and migration. JAM3 may be an ideal therapeutic target for the eradication of LICs without influencing normal hematopoiesis.


Greater Adherence to Secondary Prevention Medications Improves Survival After Stroke or Transient Ischemic Attack: A Linked Registry Study.
Although a target of 80% medication adherence is commonly cited, it is unclear whether greater adherence improves survival after stroke or transient ischemic attack (TIA). We investigated associations between medication adherence during the first year postdischarge, and mortality up to 3 years, to provide evidence-based targets for medication adherence. Retrospective cohort study of 1-year survivors of first-ever stroke or TIA, aged ≥18 years, from the Australian Stroke Clinical Registry (July 2010–June 2014) linked with nationwide prescription refill and mortality data (until August 2017). Adherence to antihypertensive agents, statins, and nonaspirin antithrombotic medications was based on the proportion of days covered from discharge until 1 year. Cox regression with restricted cubic splines was used to investigate nonlinear relationships between medication adherence and all-cause mortality (to 3 years postdischarge). Models were adjusted for age, sex, socioeconomic position, stroke factors, primary care factors, and concomitant medication use. Among 8363 one-year survivors of first-ever stroke or TIA (44% aged ≥75 years, 44% female, 18% TIA), 75% were supplied antihypertensive agents. In patients without intracerebral hemorrhage (N=7446), 84% were supplied statins, and 65% were supplied nonaspirin antithrombotic medications. Median adherence was ≈90% for each medication group. Between 1% and 100% adherence, greater adherence to statins or antihypertensive agents, but not nonaspirin antithrombotic agents, was associated with improved survival. When restricted to linear regions above 60% adherence, each 10% increase in adherence was associated with a reduction in all-cause mortality of 13% for antihypertensive agents (hazard ratio, 0.87 [95% CI, 0.81–0.95]), 13% for statins (hazard ratio, 0.87 [95% CI, 0.80–0.95]), and 15% for nonaspirin antithrombotic agents (hazard ratio, 0.85 [95% CI, 0.79–0.93]). Greater levels of medication adherence after stroke or TIA are associated with improved survival, even among patients with near-perfect adherence. Interventions to improve medication adherence are needed to maximize survival poststroke.


How do different occupational factors influence total, occupational, and leisure-time physical activity?
A better understanding of how occupational indicators influence physical activity levels will aid the design of workplace interventions. Cross-sectional data were collected from 1194 participants through a telephone interview in Queensland, Australia. The IPAQ-long was used to measure physical activity. Multiple logistic regression was applied to examine associations. Of participants, 77.9% were employed full-time, 32.3% had professional jobs, 35.7% were engaged in shift work, 39.5% had physically-demanding jobs, and 66.1% had high physical activity levels. Participants with a physically-demanding job were less likely to have low total (OR = 0.25, 95% CI = 0.17 to 0.38) and occupational (OR = 0.17, 95% CI = 0.12 to 0.25) physical activity. Technical and trade workers were less likely to report low total physical activity (OR = 0.44, 95% CI = 0.20 to 0.97) compared with white-collar workers. Part-time (OR = 1.74, 95% CI = 1.15 to 2.64) and shift workers (OR = 1.86, 95% CI = 1.21 to 2.88) were more likely to report low leisure-time activity. Overall, the impact of different occupational indicators on physical activity was not strong. As expected, the greatest proportion of total physical activity was derived from occupational physical activity. No evidence was found for compensation effects whereby physically-demanding occupations lead to less leisure-time physical activity or vice versa. This study demonstrates that workplaces are important settings to intervene, and that there is scope to increase leisure-time physical activity irrespective of occupational background.


Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.
To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. NCT00104299; post-results.


Multi-model inference of adult and childhood leukaemia excess relative risks based on the Japanese A-bomb survivors mortality data (1950-2000).
Some relatively new issues that augment the usual practice of ignoring model uncertainty, when making inference about parameters of a specific model, are brought to the attention of the radiation protection community here. Nine recently published leukaemia risk models, developed with the Japanese A-bomb epidemiological mortality data, have been included in a model-averaging procedure so that the main conclusions do not depend on just one type of model or statistical test. The models have been centred here at various adult and young ages at exposure, for some short times since exposure, in order to obtain specially computed childhood Excess Relative Risks (ERR) with uncertainties that account for correlations in the fitted parameters associated with the ERR dose-response. The model-averaged ERR at 1 Sv was not found to be statistically significant for attained ages of 7 and 12 years but was statistically significant for attained ages of 17, 22 and 55 years. Consequently, such risks when applied to other situations, such as children in the vicinity of nuclear installations or in estimates of the proportion of childhood leukaemia incidence attributable to background radiation (i.e. low doses for young ages and short times since exposure), are only of very limited value, with uncertainty ranges that include zero risk. For example, assuming a total radiation dose to a 5-year-old child of 10 mSv and applying the model-averaged risk at 10 mSv for a 7-year-old exposed at 2 years of age would result in an ERR=0.33, 95% CI: -0.51 to 1.22. One model (United Nations scientific committee on the effects of atomic radiation report. Volume 1. Annex A: epidemiological studies of radiation and cancer, United Nations, New York, 2006) weighted model-averaged risks of leukaemia most strongly by half of the total unity weighting and is recommended for application in future leukaemia risk assessments that continue to ignore model uncertainty. However, on the basis of the analysis presented here, it is generally recommended to take model uncertainty into account in future risk analyses.


Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs.
To assess the association between exposure to monotherapy with 10 different antiepileptic drugs (AEDs) during the first 2 months of pregnancy and the risk of 23 major congenital malformations (MCMs). This nationwide cohort study, based on the French health care databases, included all pregnancies ≥20 weeks and ending between January 2011 and March 2015. Women were considered to be exposed when an AED had been dispensed between 1 month before and 2 months after the beginning of pregnancy. The reference group included pregnant women with no reimbursement for AEDs. MCMs were detected up to 12 months after birth (24 months for microcephaly, hypospadias, and epispadias). Odds ratios (ORs) were adjusted for potential confounders for MCMs with at least 5 cases. Otherwise, we calculated crude ORs with exact confidence intervals (CIs). The cohort included 1,886,825 pregnancies, 2,997 of which were exposed to lamotrigine, 1,671 to pregabalin, 980 to clonazepam, 913 to valproic acid, 579 to levetiracetam, 517 to topiramate, 512 to carbamazepine, 365 to gabapentin, 139 to oxcarbazepine, and 80 to phenobarbital. Exposure to valproic acid was associated with 8 specific types of MCMs (e.g., spina bifida, OR 19.4, 95% CI 8.6-43.5), and exposure to topiramate was associated with an increased risk of cleft lip (6.8, 95% CI 1.4-20.0). We identified 3 other signals. We found no significant association for lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and gabapentin. These results confirm the teratogenicity of valproic acid and topiramate. Because of the small numbers of cases and possible confounding, the other 3 signals should be interpreted with appropriate caution.


The consequences of childhood overweight and obesity.
Researchers are only gradually becoming aware of the gravity of the risk that overweight and obesity pose for children's health. In this article Stephen Daniels documents the heavy toll that the obesity epidemic is taking on the health of the nation's children. He discusses both the immediate risks associated with childhood obesity and the longer-term risk that obese children and adolescents will become obese adults and suffer other health problems as a result. Daniels notes that many obesity-related health conditions once thought applicable only to adults are now being seen in children and with increasing frequency. Examples include high blood pressure, early symptoms of hardening of the arteries, type 2 diabetes, nonalcoholic fatty liver disease, polycystic ovary disorder, and disordered breathing during sleep. He systematically surveys the body's systems, showing how obesity in adulthood can damage each and how childhood obesity exacerbates the damage. He explains that obesity can harm the cardiovascular system and that being overweight during childhood can accelerate the development of heart disease. The processes that lead to a heart attack or stroke start in childhood and often take decades to progress to the point of overt disease. Obesity in childhood, adolescence, and young adulthood may accelerate these processes. Daniels shows how much the same generalization applies to other obesity-related disorders-metabolic, digestive, respiratory, skeletal, and psychosocial-that are appearing in children either for the first time or with greater severity or prevalence. Daniels notes that the possibility has even been raised that the increasing prevalence and severity of childhood obesity may reverse the modern era's steady increase in life expectancy, with today's youth on average living less healthy and ultimately shorter lives than their parents-the first such reversal in lifespan in modern history. Such a possibility, he concludes, makes obesity in children an issue of utmost public health concern.


Heat transfer between fish and ambient water.
1. The ability of fish gills to transfer heat was measured by applying a heat pulse to blood in the ventral aorta and measuring it before and after passing through the gills of a teleost, Hemitripterus americanus. 2. 80-90% of heat contained in the blood is lost during passage through the gills. 3. The fraction of heat not lost during passage through the gills is due to direct transfer of heat between the afferent and efferent artery within the gill bar. 4. The major fraction of metabolic heat (70 - 90%) is lost through the body wall and fins of the sea raven in sea water at 5 degrees C; the remainder is lost through the gills.


Charge transport properties of open-shell graphene fragments: a computational study of the phenalenyl tilings.
Thinking outside the box of the phenalenyl radical: a systematic structure design strategy, phenalenyl tiling, is found to benefit the electron transport properties of open-shell graphene fragments with one free radical. Compared with the closed-shell species, phenalenyl-based π-radicals exhibit smaller intramolecular reorganization energies and larger intermolecular electronic couplings. However, the on-site Coulomb repulsion can be too strong and impedes the charge transport efficiency of such materials. The repulsion can be weakened in radical species by spin delocalization. In this paper, the extended π-radicals we studied are categorized into three types of open-shell structures: the zigzag, the armchair and the discotic odd alternant hydrocarbons. The latter two belong to phenalenyl tilings. We found that the phenalenyl tilings fully inherit the desirable features of the singly occupied molecular orbital of the phenalenyl radical in a predictable and delocalized fashion, and their on-site Coulomb repulsion is effectively reduced. The zigzag π-radicals are less satisfactory. Therefore, the phenalenyl tilings are favorable candidates for charge transporting materials.


What is the true number needed to screen and treat to save a life with prostate-specific antigen testing?
The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction with prostate-specific antigen (PSA) screening. However, they estimated a number needed to screen (NNS) of 1,410 and a number needed to treat (NNT) of 48 to prevent one prostate cancer death at 9 years. Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, in a survival study setting such as the ERSPC, NNS and NNT are time specific, and reporting values at one time point may lead to misinterpretation of results. Our objective was to re-examine the effect of varying follow-up times on NNS and NNT using data extrapolated from the ERSPC report. On the basis of published ERSPC data, we modeled the cumulative hazard function using a piecewise exponential model, assuming a constant hazard of 0.0002 for the screening and control groups for years 1 to 7 of the trial and different constant rates of 0.00062 and 0.00102 for the screening and control groups, respectively, for years 8 to 12. Annualized cancer detection and drop-out rates were also approximated based on the observed number of individuals at risk in published ERSPC data. According to our model, the NNS and NNT at 9 years were 1,254 and 43, respectively. Subsequently, NNS decreased from 837 at year 10 to 503 at year 12, and NNT decreased from 29 to 18. Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls. With additional follow-up in the ERSPC, if the mortality difference continues to grow, the NNT to save a life with PSA screening will decrease.


Indolocarbazole glycosides in inactive conformations.
Indolocarbazole glycosides related to rebeccamycin represent a promising category of antitumor agents targeting DNA and topoisomerase I. These drugs prefer to adopt a closed conformation with an intramolecular hydrogen bond between the indole NH group and the pyranose oxygen atom. Three pairs of indolocarbazole monoglycosides bearing an NH or an N-methyl indole moiety were synthesized and their biological properties investigated at the molecular and cellular level. Replacing the indole NH proton with a methyl group reduces DNA interaction and abolishes activity against DNA topoisomerase I. Surface plasmon resonance studies performed with a pair of water-soluble indolocarbazole glycosides and two hairpin oligonucleotides containing an [AT]4 or a [CG]4 sequence indicate that both the NH and the N-methyl derivative maintain a relatively high affinity for DNA (Keq = 2 - 6 x 10(5) M(-1)) but the incorporation of the methyl group restricts access to the DNA. The number of ligand binding sites (n) on the oligonucleotides is about twice as high for the NH compound compared to its N-methyl analogue. Modeling and 1H NMR studies demonstrate that addition of the N-methyl group drives a radical change in conformation in which the orientation of the aglycone relative to the beta-glucoside is reversed. The loss of the closed conformation by the N-methyl derivatives perturbs thir ability to access DNA binding sites and prevents the drug from inhibiting topoisomerase I. As a consequence, the NH compounds exhibit potent cytotoxicity against CEM leukemia cells with an IC50 value in the 1 microM range, whereas the N-methyl analogues are 10 to 100 times less cytotoxic. These studies offer circumstantial evidence supporting the importance of the closed conformation in the interaction of indolocarbazole glycosides with their molecular targets, DNA and topoisomerase I.


Behavioral training to improve collision detection.
Young drivers are a high-risk group for vehicle crashes due to inexperience in detecting an impending collision and are one group that may benefit from perceptual learning (PL) training. The present study assessed whether PL could be used to improve performance in collision detection. Ten college-aged subjects participated in the first experiment, which consisted of seven 1-hr sessions conducted on separate days. Thresholds at three observer/object speeds were measured prior to training using a two-alternative forced choice procedure during which they indicated whether an approaching object would result in a collision or noncollision event. Participants were then trained near threshold at one of these speeds for 5 days. After training, participants showed a significant reduction in the time needed to detect a collision at the trained speed. This improvement was also found to transfer to the higher observer speed condition. A second experiment was conducted to determine whether this improvement was due to training near threshold or whether this improvement was merely due to practice with the task. Training with stimuli well above threshold showed no significant improvement in performance, indicating that the improvement seen in the first experiment was not solely due to task practice.


Precise interpolar phasing of abrupt climate change during the last ice age.
The last glacial period exhibited abrupt Dansgaard-Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard-Oeschger cycle and vice versa, suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw. Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision. Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 ± 92 years (2σ) for Dansgaard-Oeschger events, including the Bølling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 ± 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard-Oeschger dynamics.


MO-D-BRB-06: JUNIOR INVESTIGATOR WINNER - Fast and Accurate Patient Specific Collision Detection for Radiation Therapy.
To develop a fast and generalizable method which can identify all possible hardware collisions specific to a given patient setup before treatment planning. An anthropomorphic phantom placed in a typical breast setup using a wingboard was simulated on a CT scanner and the phantom body contour, table, and gantry geometry were made into polygon meshes using 3D modeling software. In the treatment room, a limited physical search of the collision positive zones was performed using the positioned phantom. A software tool that incorporated a generalized hierarchical bounding box (HBB) collision detection algorithm was developed and used to virtually map out the entire collision space by transforming the positions of the polygonal geometry over a given parameter range. The geometry containing 47K polygons was mapped over a space of 6480 states with an average transform/collision check of 5.5ms, for a total time of 35.6s on a 3.14GHz dual core computer with 4GB memory. The computed collision space, using receiver operating curve analysis had an accuracy of 96.35%, and a positive predictive value of 91.2%. This work demonstrates a framework that can provide a fast and accurate map of the collision free space specific to any patient setup. Differences in physical and simulated collision space is attributed to inaccuracies of the geometrical models used. Future work includes improving the efficiency of the algorithm, enhancing the geometrical models and increasing the dimensions of the search.


Canine Tactical Combat Casualty Care (K9TCCC) Guidelines.
First introduced in 1996, Tactical Combat Casualty Care (TCCC) redefined prehospital, point-of-injury (POI), battlefield trauma care for the human combat casualty. Today, many consider TCCC as one of the most influential interventions for reducing combat-related case fatality rates from preventable deaths in human combat casualties. Throughout history, Military Working Dogs (MWDs) have proved and continue to prove themselves as force multipliers in the success of many military operations. Since the start of the Global War on Terror in 2001, these elite canine operators have experienced an upsurge in combat-related deployments, placing them at a higher risk for combat-related injuries. Until recently, consensus- based Canine-TCCC (K9TCCC) guidelines for POI battlefield trauma care did not exist for the MWD, leaving a critical knowledge gap significantly jeopardizing MWD survival. In 2019, the Canine Combat Casualty Care Committee was formed as an affiliate of the Committee on Tactical Combat Casualty Care with the intent of developing evidence- based, best practice K9TCCC guidelines. Modeled after the same principles of the human TCCC, K9TCCC focuses on simple, evidence-based, field-proven medical interventions to eliminate preventable deaths and to improve MWD survival. Customized for the battlefield, K9TCCC uniquely adapts the techniques of TCCC to compensate for canine-specific anatomic and physiological differences.


Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation.
The purpose of this study was to conduct a worldwide survey investigating the methods, efficacy, and safety of catheter ablation (CA) of atrial fibrillation (AF). A detailed questionnaire was sent to 777 centers worldwide. Data relevant to the study purpose were collected from 181 centers, of which 100 had ongoing programs on CA of AF between 1995 and 2002. The number of patients undergoing this procedure increased from 18 in 1995 to 5050 in 2002. The median number of procedures per center was 37.5 (range, 1 to 600). Paroxysmal AF, persistent AF, and permanent AF were the indicated arrhythmias in 100.0%, 53.0%, and 20.0% of responding centers, respectively. The most commonly used techniques were right atrial compartmentalization between 1995 and 1997, ablation of the triggering focus in 1998 and 1999, and electrical disconnection of multiple pulmonary veins between 2000 and 2002. Of 8745 patients completing the CA protocol in 90 centers, of whom 2389 (27.3%) required >1 procedure, 4550 (52.0%; range among centers, 14.5% to 76.5%) became asymptomatic without drugs and another 2094 (23.9%; range among centers, 8.8% to 50.3%) became asymptomatic in the presence of formerly ineffective antiarrhythmic drugs over an 11.6+/-7.7-month follow-up period. At least 1 major complication was reported in 524 patients (6.0%). The findings of this survey provide a picture of the variable and evolving methods, efficacy, and safety of CA for AF as practiced in a large number of centers worldwide and may serve as a guide to clinicians considering therapeutic options in patients suffering from this arrhythmia.


Titin: physiological function and role in cardiomyopathy and failure.
Titin is a giant protein that constitutes the third myofilament of the sarcomere. Single titin molecules anchor in the Z-disk and extend all the way to the M-line region of the sarcomere. Successive titin molecules are arranged head-to-head and tail-to-tail, providing a continuous filament along the full length of the myofibril. The majority of titin's I-band region is extensible and functions as a molecular spring that when extended develops passive force. We will discuss mechanisms for adjusting titin-based force, including alternative splicing and posttranslational modifications. Multiple biological functions can be assigned to different regions of the titin molecule. In addition to titin's role in determining passive muscle stiffness, recent evidence suggests a role in protein metabolism, compartmentalization of metabolic enzymes, binding of chaperones, and positioning of the membrane systems of the T-tubules and sarcoplasmic reticulum. We will also discuss titin-based force adjustments that occur in various muscle diseases and several disease-causing titin mutations that have been discovered. We will focus on the role of titin in heart failure patients that was recently investigated in patients with end-stage heart failure due to non-ischemic dilated cardiomyopathy. In end-stage failing hearts, compliant titin isoforms comprise a greater percentage of titin and changes in titin isoform expression in heart failure patients with DCM significantly impact diastolic filling by lowering myocardial stiffness.


Human isolates of Bartonella tamiae induce pathology in experimentally inoculated immunocompetent mice.
Bartonella tamiae, a newly described bacterial species, was isolated from the blood of three hospitalized patients in Thailand. These patients presented with headache, myalgia, anemia, and mild liver function abnormalities. Since B. tamiae was presumed to be the cause of their illness, these isolates were inoculated into immunocompetent mice to determine their relative pathogenicity in inducing manifestations of disease and pathology similar to that observed in humans. Three groups of four Swiss Webster female mice aged 15-18 months were each inoculated with 10(6-7) colony forming units of one of three B. tamiae isolates [Th239, Th307, and Th339]. A mouse from each experimental group was sampled at 3, 4, 5 and 6 weeks post-inoculation. Two saline inoculated age-matched controls were included in the study. Samples collected at necropsy were evaluated for the presence of B. tamiae DNA, and tissues were formalin-fixed, stained with hematoxylin and eosin, and examined for histopathology. Following inoculation with B. tamiae, mice developed ulcerative skin lesions and subcutaneous masses on the lateral thorax, as well as axillary and inguinal lymphadenopathy. B. tamiae DNA was found in subcutaneous masses, lymph node, and liver of inoculated mice. Histopathological changes were observed in tissues of inoculated mice, and severity of lesions correlated with the isolate inoculated, with the most severe pathology induced by B. tamiae Th239. Mice inoculated with Th239 and Th339 demonstrated myocarditis, lymphadenitis with associated vascular necrosis, and granulomatous hepatitis and nephritis with associated hepatocellular and renal necrosis. Mice inoculated with Th307 developed a deep dermatitis and granulomas within the kidneys. The three isolates of B. tamiae evaluated in this study induce disease in immunocompetent Swiss Webster mice up to 6 weeks after inoculation. The human patients from whom these isolates were obtained had clinical presentations consistent with the multi-organ pathology observed in mice in this study. This mouse model for B. tamiae induced disease not only strengthens the causal link between this pathogen and clinical illness in humans, but provides a model to further study the pathological processes induced by these bacteria.


Replication of genomewide associations with allergic sensitization and allergic rhinitis.
Three genomewide metastudies have recently reported associations with self-reported allergic rhinitis and allergic sensitization. The three studies together identified a set of 37 loci but showed low concordance. This study investigates the reproducibility of the detected single nucleotide polymorphism (SNP) associations in an extensively characterized longitudinal cohort, BAMSE. Phenotypic evaluation of allergic rhinitis (AR) and allergic sensitization was performed on 2153 children from BAMSE at 8 and 16 years of age. Allele frequencies of 39 SNPs were investigated for association with the exact allergic phenotypes of the metastudies. Odds ratios and false discovery rates were calculated, and the impact of asthma was evaluated. The cases were also evaluated for age at onset effects (≤ or >8 years of age). Association tests of the 39 SNPs identified 12 SNPs with P-values < 0.05 and Q-values < 0.10. Two of the four loci (TLR6-TLR1 and HLA-DQA1-HLA-DQB1) identified in all three original studies were also identified in this study. Three SNPs located in the TLR6-TLR1 locus had the lowest P-values and Q-values < 0.1 when using a well-defined AR phenotype. Two loci showed significant age at onset effects, but the effect of asthma on the associations was very limited. The TLR6-TLR1 locus is likely to have a central role in the development of allergic disease. The association between genetic variation in the SSTR1-MIPOL1 and TSLP-SLC25A46 loci and age at onset is the first report of age at onset effects in allergic rhinitis.


Gene Fusion Markup Language: a prototype for exchanging gene fusion data.
An avalanche of next generation sequencing (NGS) studies has generated an unprecedented amount of genomic structural variation data. These studies have also identified many novel gene fusion candidates with more detailed resolution than previously achieved. However, in the excitement and necessity of publishing the observations from this recently developed cutting-edge technology, no community standardization approach has arisen to organize and represent the data with the essential attributes in an interchangeable manner. As transcriptome studies have been widely used for gene fusion discoveries, the current non-standard mode of data representation could potentially impede data accessibility, critical analyses, and further discoveries in the near future. Here we propose a prototype, Gene Fusion Markup Language (GFML) as an initiative to provide a standard format for organizing and representing the significant features of gene fusion data. GFML will offer the advantage of representing the data in a machine-readable format to enable data exchange, automated analysis interpretation, and independent verification. As this database-independent exchange initiative evolves it will further facilitate the formation of related databases, repositories, and analysis tools. The GFML prototype is made available at http://code.google.com/p/gfml-prototype/. The Gene Fusion Markup Language (GFML) presented here could facilitate the development of a standard format for organizing, integrating and representing the significant features of gene fusion data in an inter-operable and query-able fashion that will enable biologically intuitive access to gene fusion findings and expedite functional characterization. A similar model is envisaged for other NGS data analyses.


Olfaction and identification of unrelated individuals: examination of the mysteries of human odor recognition.
Although several studies have examined the effect of human odor on kin recognition and mate choice, few have focused on the impact of familiarity on recognition of nonrelatives by olfactory cues. As part of a program designed to engage students in scientific research, 53 high school students researched, planned, and implemented a project to analyze the effect of odor on human recognition of, and preference for, friends, sex, and self. A total of 37 students, including friends of their choosing, wore T-shirts for three consecutive nights. During that time, subjects were controlled for exposure to extraneous perfumes, household odors, and other humans. The students were then asked to smell a series of five shirts and evaluate them with respect to pleasantness. Students were also asked to identify the shirts belonging to themselves and their friend, and determine the sex of the person who wore each shirt. Although subjects were unable to distinguish sex by olfactory cues alone, a significant percentage of subjects were able to identify their own odor (51.6%), as well as distinguish the odor cue of their friend (38.7%). Additionally, subjects who could not identify their friend's cue were apt to choose the odor of a member of the opposite sex as their friend. This result was not believed to rely on odor preference as neither individual, friend, nor stranger odors were rated significantly different with respect to odor pleasantness. The ability to recognize friends via odor cues lends credence to the hypothesis that association and familiarity are important aspects of conspecific olfactory recognition in humans. Furthermore, this study augments evidence that olfaction may supplement visual and auditory cues used in human conspecific and kin recognition.


Measuring the performance of visual to auditory information conversion.
Visual to auditory conversion systems have been in existence for several decades. Besides being among the front runners in providing visual capabilities to blind users, the auditory cues generated from image sonification systems are still easier to learn and adapt to compared to other similar techniques. Other advantages include low cost, easy customizability, and universality. However, every system developed so far has its own set of strengths and weaknesses. In order to improve these systems further, we propose an automated and quantitative method to measure the performance of such systems. With these quantitative measurements, it is possible to gauge the relative strengths and weaknesses of different systems and rank the systems accordingly. Performance is measured by both the interpretability and also the information preservation of visual to auditory conversions. Interpretability is measured by computing the correlation of inter image distance (IID) and inter sound distance (ISD) whereas the information preservation is computed by applying Information Theory to measure the entropy of both visual and corresponding auditory signals. These measurements provide a basis and some insights on how the systems work. With an automated interpretability measure as a standard, more image sonification systems can be developed, compared, and then improved. Even though the measure does not test systems as thoroughly as carefully designed psychological experiments, a quantitative measurement like the one proposed here can compare systems to a certain degree without incurring much cost. Underlying this research is the hope that a major breakthrough in image sonification systems will allow blind users to cost effectively regain enough visual functions to allow them to lead secure and productive lives.


Impact of calibration fitting models on the clinical value of chromogranin A.
The clinical relevance of chromogranin A (CgA) concentrations depends on the analytical performance of the assay. The goal of the present study was to define the clinical involvements in CgA calibration models by evaluating the confidence intervals (CIs) for values from patients who were undergoing monitoring for disease. Thirty calibration curves for the CgA assay [immunoradiometric assay (IRMA), (CIS-BIO)] were built using linear regression (LR), and four-parameter logistic models were used to estimate CIs for patient concentrations. We reported the inadequacy of the LR curve estimation procedure. We showed: 1) no evidence that the straight calibration line could fit the average responses, 2) non-constant and non-uniform variance of the replicated calibration responses. All tests performed in the analysis of variance and CI calculation for the calibration curve should be invalidated. The four-parameter logistic function yielded results for 16 curves only; this result could be due to the low number and inappropriate concentration of calibrators. This suggests that some aspects of the assay design should be reviewed. However, using the variance function estimated in this model, we could assess the CI for calibration curves and patient samples. We showed that the four-parameter logistic calibration model with estimated variance function should better support clinical interpretation of marker concentration changes in patients serially tested.


Clinicopathologic Significance of Survivin Expression in Relation to CD133 Expression in Surgically Resected Stage II or III Colorectal Cancer.
Cancer stem cells have been investigated as new targets for colorectal cancer (CRC) treatment. We recently reported that CD133+ colon cancer cells showed chemoresistance to 5-fluorouracil through increased survivin expression and proposed the survivin inhibitor YM155 as an effective therapy for colon cancer in an in vitro study. Here, we investigate the relationship between survivin and CD133 expression in surgically resected CRC to identify whether the results obtained in our in vitro study are applicable to clinical samples. We performed immunohistochemical staining for survivin and CD133 in surgically resected tissue from 187 stage II or III CRC patients. We also comparatively analyzed apoptosis according to survivin and CD133 expression using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. The results of the Mantel-Haenszel test established a linear association between nuclear survivin and CD133 expression (p = .018), although neither had prognostic significance, according to immunohistochemical expression level. No correlation was found between survivin expression and the following pathological parameters: invasion depth, lymph node metastasis, or histologic differentiation (p > .05). The mean apoptotic index in survivin+ and CD133+ tumors was higher than that in negative tumors: 5.116 ± 4.894 in survivin+ versus 4.103 ± 3.691 in survivin- (p = .044); 5.165 ± 4.961 in CD133+ versus 4.231 ± 3.812 in CD133- (p = .034). As observed in our in vitro study, survivin expression is significantly related to CD133 expression. Survivin may be considered as a new therapeutic target for chemoresistant CRC.


Extraintestinal Clostridium difficile infections: a single-center experience.
To evaluate the clinical burden of extraintestinal Clostridium difficile infection (CDI) seen at a single institution and to characterize the management and outcomes of these rare infections. A retrospective medical record review was conducted to identify patients with isolation of C difficile from extraintestinal sites from January 1, 2004, through December 31, 2013. Medical records were reviewed and data, including demographic characteristics, microbiology, clinical associations, management, and infection outcomes, were abstracted. Overall, 40 patients with extraintestinal CDI were identified: 25 had abdominopelvic infections, 11 had bloodstream infections, 3 had wound infections, and 1 had pulmonary infection. C difficile was isolated with other organisms in 63% of cases. A total of 85% of infections were nosocomial. Factors associated with extraintestinal CDI included surgical manipulation of the gastrointestinal tract (88%), recent antibiotic exposure (88%), malignant tumors (50%), and proton pump inhibitor use (50%). Diarrhea was present in 18 patients (45%), 12 of whom had C difficile polymerase chain reaction (PCR)-positive stool samples. All isolates tested were susceptible to metronidazole and piperacillin-tazobactam. Management included both antimicrobial therapy and guided drainage or surgical intervention in all but one patient. The infection-associated mortality rate was 25%, with death a median of 16 days (range, 1-61 days) after isolation of C difficile. Extraintestinal CDI is uncommon and often occurs in patients with surgical manipulation of the gastrointestinal tract and well-recognized risk factors for intestinal CDI. Management of extraintestinal CDI includes both antimicrobial and surgical therapies. Extraintestinal CDI is characterized by poor outcome with high mortality.


Hydration status assessment among elite youth amateur boxers.
Weight cutting is a common practice in amateur boxing with the purpose of taking advantage of rivals competing in weight divisions below the athlete's normal weight. Dehydration is a common weight-manipulating technique in boxing, and is known as a serious health-threatening behavior. In this study, we investigated field hydration status differences between the weight class categories in elite junior boxers. The sample of subjects included 21 male junior boxers from Croatia, Germany and Hungary (all national team members). The field assessment was conducted prior to competition. Subjects were divided into three weight class categories: Lightweight (Lw), Middleweight (Mw), and Heavyweight (Hw). The sample variables included urine specific gravity (USG) measured via a refractometer and total body fluid content (BFC) measured via Bioelectric Impedance Analysis (BIA). Data were collected on two occasions, i.e. at national team competitions that took place in preparation for the World Junior Championships. The results showed that there was a statistically significant difference between Lw 1.027±0.004 and Hw 1.019±0.005 (F=8.81, P<0.001) and Mw 1.028±0.003 and Hw (F=7.16, P<0.01) in USG. BIA findings showed conflicting results in relation to the USG findings. The results show a significant difference between Lw 67.84% BFC and Hw 65.14% BFC (P<0.01). These conflicting results, the lack of correlation between the two methods and the discrepancy in the Bland-Altman plot indicate that techniques for non-invasive field assessments of hydration have certain limitations. It seems that refractometry is more sensitive and accurate diagnostic tool to detect body fluid shifts then BIA when applied on athletes involved in chronical weight cycling protocols. Nevertheless, our data suggest that Lw and Mw class athletes seem to be more prone in reaching consequent dehydration state that literature frequently cites as hypohydration.


Development of a valid simulation assessment for a military dismounted assault task.
The Australian Defence Force is currently developing physical standards commensurate with job demands. Vital to this development process has been the accurate profiling of common military tasks. One such task required of all dismounted combat soldiers, an offensive assault on an enemy force, was the subject of in-depth profiling. In addition to overall assault performance, potential differences among patrol roles (scout, gunner, and flank) were investigated. Three different mock assaults of 100 to 150 m were performed by three patrols comprising qualified experienced infantry soldiers. Each soldier was fitted with a heart rate monitor and wore a global positioning device. Average assault duration was 6.5 minutes and required nineteen 7-m bounds performed on a 22-seconds duty cycle at 75% heart rate reserve and a work to rest ratio 1:4. Assaults conducted in more densely vegetated terrain resulted in significantly reduced (p < 0.05) bound distance, bound duration, and movement velocity. Results indicated significant performance differences (p < 0.05) among patrol roles for external load carried, heart rate response, bound duration, and distance covered while movement velocity was not different (p > 0.05). As a result of profiling the assault task, a valid simulation capable of assessing soldiers' physical capacity to perform this task was developed.


The control of experimental Escherichia coli diarrhoea in calves by means of bacteriophages.
Seven phages highly active in vitro and in vivo against one or other of seven bovine enteropathogenic strains of Escherichia coli belonging to six different serotypes were isolated from sewage. Severe experimentally induced E. coli diarrhoea in calves could be cured by a single dose of 10(5) phage organisms. It could be prevented by doses as low as 10(2), by spraying the litter in the calf rooms with aqueous phage suspensions or simply by keeping the calves in uncleaned rooms previously occupied by calves whose E. coli infections had been treated with phage. Microbiological examinations of calves used in these experiments revealed that the phage organisms multiplied rapidly and profusely after gaining entry to the E. coli-infected small intestine, quickly reducing the E. coli to numbers that were virtually harmless. The only phage-resistant E. coli that emerged in the studies on calves infected with one or other of the seven E. coli strains were K-. These organisms were much less virulent than the K+ organisms from which they were derived and did not present a serious problem in calves given adequate amounts of colostrum. Infections produced by oral inoculation of a mixture of six strains of the E. coli could be controlled by administration of a pool of the six phages that were active against them but, in general, the control was less complete than that observed in the single-strain infections. K+ phage-resistant bacteria emerged in some of the calves used in these mixed infections and they were as virulent as their parent organisms; evidence from in vitro studies suggested that they might have arisen by genetic transfer between organisms of the different infecting strains. Infections produced by these K+ mutants and their parents could be controlled by the use of mutant phages derived from phages that were active on their parents. During the experiments with mixed E. coli infection, an extraneous phage active against one of the six E. coli strains suddenly appeared in calves kept in the same rooms. Microbiological examinations revealed that this phage was effectively controlling the multiplication of organisms of that particular strain of E. coli in the small intestines of the calves.


Alternatively expressed genes identified in the CD4+ T cells of allograft rejection mice.
Allograft rejection is a leading cause for the failure of allotransplantation. CD4(+) T cells play critical roles in this process. The identification of genes that alternatively expressed in CD4(+) T cells during allograft rejection will provide critical information for studying the mechanism of allograft rejection, finding specific gene markers for monitoring, predicting allograft rejection, and opening new ways to regulate and prevent allograft rejection. Here, we established allograft and isograft transplantation models by adoptively transferring wild-type BALB/c mouse CD4(+) T cells into severe combined immunodeficient (SCID) mice with a C57BL/6 or BALB/c mouse skin graft. Using the whole transcriptome sequencing-based serial analysis of gene expression (SAGE) technology, we identified 97 increasingly and 88 decreasingly expressed genes that may play important roles in allograft rejection and tolerance. Functional classification of these genes shows that apoptosis, transcription regulation, cell growth and maintenance, and signal transduction are among the frequently changed functional groups. This study provides a genome-wide view for the candidate genes of CD4(+) T cells related to allotransplantation, and this report is a good resource for further microarray studies and for identifying the specific markers that are associated with clinical organ transplantations.


Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias.
We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias. We provide evidence that inhibition of PIM, with the pan-PIM inhibitor SGI-1776, results in suppression of classic PIM effectors and also elements of the mTOR pathway, suggesting interplay between PIM and mTOR signals. Our data demonstrate that PIM inhibition enhances the effects of imatinib mesylate on Ph+ leukemia cells. We also found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate. Importantly, inhibition of PIM results in enhanced suppression of primary leukemic progenitors from patients with CML. Altogether these findings suggest that pharmacological PIM targeting may provide a unique therapeutic approach for the treatment of Ph+ leukemias.


A novel submaximal cycle test to monitor fatigue and predict cycling performance.
The purpose of this study was to determine the reliability and predictive value of performance parameters, measured by a new novel submaximal cycle protocol, on peak power and endurance cycling performance in well-trained cyclists. Seventeen well-trained competitive male road racing cyclists completed four peak power output (PPO) tests and four 40-km time trials (40-km TT). Before each test, all cyclists performed a novel submaximal cycle test (Lamberts and Lambert Submaximal Cycle Test (LSCT)). Parameters associated with performance such as power, speed, cadence and rating of perceived exertion (RPE) were measured during the three stages of the test when cyclists rode at workloads coinciding with fixed predetermined heart rates. Heart rate recovery (HRR) was measured after the last stage of the test. Parameters measured during the second and third stages of the LSCT were highly reliable (intraclass correlation range: R=0.85-1.00) with low typical error of measurements (range: 1.3-4.4%). Good relationships were found between the LSCT and cycling performance measured by the PPO and 40-km TT tests. Mean power had stronger relationships with measures of cycling performance during the second (r=0.80-0.89) and third stages (r=0.91-0.94) of the LSCT than HRR (r=0.55-0.68). The LSCT is a reliable novel test which is able to predict peak and endurance cycling performance from submaximal power, RPE and HRR in well-trained cyclists. As these parameters are able to detect meaningful changes more accurately than VO(2max), the LSCT has the potential to monitor cycling performance with more precision than other current existing submaximal cycle protocols.


The calcified lung nodule: What does it mean?
The aim of this review is to present a pictorial essay emphasizing the various patterns of calcification in pulmonary nodules (PN) to aid diagnosis and to discuss the differential diagnosis and the pathogenesis where it is known. The imaging evaluation of PN is based on clinical history, size, distribution and the gross appearance of the nodule as well as feasibility of obtaining a tissue diagnosis. Imaging is instrumental in the management of PN and one should strive not only to identify small malignant tumors with high survival rates but to spare patients with benign PN from undergoing unnecessary surgery. The review emphasizes how to achieve these goals. One of the most reliable imaging features of a benign lesion is a benign pattern of calcification and periodic follow-up with computed tomography showing no growth for 2 years. Calcification in PN is generally considered as a pointer toward a possible benign disease. However, as we show here, calcification in PN as a criterion to determine benign nature is fallacious and can be misleading. The differential considerations of a calcified lesion include calcified granuloma, hamartoma, carcinoid, osteosarcoma, chondrosarcoma and lung metastases or a primary bronchogenic carcinoma among others. We describe and illustrate different patterns of calcification as seen in PN on imaging.


Comparative analysis of urban atmospheric aerosol by particle-induced X-ray emission (PIXE), proton elastic scattering analysis (PESA), and aerosol mass spectrometry (AMS).
A multifaceted approach to atmospheric aerosol analysis is often desirable in field studies where an understanding of technical comparability among different measurement techniques is essential. Herein, we report quantitative intercomparisons of particle-induced X-ray emission (PIXE) and proton elastic scattering analysis (PESA), performed of fline under a vacuum, with analysis by aerosol mass spectrometry (AMS) carried out in real-time during the MCMA-2003 Field Campaign in the Mexico City Metropolitan Area. Good agreement was observed for mass concentrations of PIXE-measured sulfur (assuming it was dominated by SO4(2-)) and AMS-measured sulfate during most of the campaign. PESA-measured hydrogen mass was separated into sulfate H and organic H mass fractions, assuming the only major contributions were (NH4)2SO4 and organic compounds. Comparison of the organic H mass with AMS organic aerosol measurements indicates that about 75% of the mass of these species evaporated under a vacuum. However approximately 25% of the organics does remain under a vacuum, which is only possible with low-vapor-pressure compounds, and which supports the presence of high-molecular-weight or highly oxidized organics consistent with atmospheric aging. Approximately 10% of the chloride detected by AMS was measured by PIXE, possibly in the form of metal-chloride complexes, while the majority of Cl was likely present as more volatile species including NH4Cl. This is the first comparison of PIXE/PESA and AMS and, to our knowledge, also the first report of PESA hydrogen measurements for urban organic aerosols.


Ambulance Service Associated With Reduced Probabilities Of Neonatal And Infant Mortality In Two Indian States.
India had no large-scale, centralized emergency medical system or ambulance service until 2005. Since then, the GVK Emergency Management and Research Institute (GVK EMRI) has emerged as India's largest ambulance service provider, covering more than 630 million people. This study provides the first quantitative evidence of GVK EMRI's early impact on population-level infant and maternal health outcomes in Andhra Pradesh and Gujarat, two Indian states with a combined population of about 145 million people. We found that GVK EMRI coverage is associated with reductions in the probability of neonatal and infant mortality as well as delivery complications (statewide in Andhra Pradesh and in high-mortality districts in Gujarat). However, we found little change in the probability of institutional delivery or skilled birth attendance. Taken together, our findings suggest that population-level health gains were achieved through improvements in the quality (rather than quantity) of maternal and neonatal health services-an interpretation consistent with qualitative reports. More research on this topic is needed.


Effects of microbiota-directed foods in gnotobiotic animals and undernourished children.
To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM.


Therapeutic potential of icatibant (HOE-140, JE-049).
There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.


Explorations of a crisis intervention service.
Descriptive studies of a crisis intervention service replicated previous findings of relationships between staff members' attitudes towards treatment and their 'personal styles'. The attitudes and personal styles of crisis team members and non-members differed, largely because of differences in the professions making up these groups. While all staff groups shared the same concept of crisis, they differed in their discrimination of crisis cases from 'furores'. Initial crisis intervention interviews exhibited more confrontation and less exploration by therapists than did initial psychiatric out-patient clinic interviews. Patients referred to the crisis team differed from significant other people in their lives, and from control patients referred to the ordinary out-patient clinic, in aspects of their perception of problems.


Nanoscale optical tomography with cathodoluminescence spectroscopy.
Tomography has enabled the characterization of the Earth's interior, visualization of the inner workings of the human brain, and three-dimensional reconstruction of matter at the atomic scale. However, tomographic techniques that rely on optical excitation or detection are generally limited in their resolution by diffraction. Here, we introduce a tomographic technique--cathodoluminescence spectroscopic tomography--to probe optical properties in three dimensions with nanometre-scale spatial and spectral resolution. We first obtain two-dimensional cathodoluminescence maps of a three-dimensional nanostructure at various orientations. We then use the method of filtered back-projection to reconstruct the cathodoluminescence intensity at each wavelength. The resulting tomograms allow us to locate regions of efficient cathodoluminescence in three dimensions across visible and near-infrared wavelengths, with contributions from material luminescence and radiative decay of electromagnetic eigenmodes. The experimental signal can be further correlated with the radiative local density of optical states in particular regions of the reconstruction. We demonstrate how cathodoluminescence tomography can be used to achieve nanoscale three-dimensional visualization of light-matter interactions by reconstructing a three-dimensional metal-dielectric nanoresonator.


Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes.
Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemo-embolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pre-treatment and post-treatment by an interferon-γ enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P=0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC.


Impact of adolescent age on maternal and neonatal outcomes in the Born in Bradford cohort.
Explore associations between maternal and neonatal outcomes and maternal age, with particular reference to adolescent women. Population-based cohort study. Maternity department of a large hospital in Northern England. Primiparous women delivering a singleton at Bradford Royal Infirmary between March 2007 and December 2010 aged ≤19 years (n=640) or 20-34 years (n=3951). Subgroup analysis was performed using women aged ≤16 years (n=68). Women aged 20-34 years were used as the reference group. Maternal and neonatal outcomes. The odds of extremely low birth weight (<1000 g) were significantly higher in the adolescent group (≤19 years) compared with the reference group (adjusted OR (aOR) 4.13, 95% CI 1.41 to 12.11). The odds of very (<32 weeks) and extremely (<28 weeks) preterm delivery were also higher in the adolescent group (aOR 2.12, 95% CI 1.06 to 4.25 and aOR 5.06, 95% CI 1.23 to 20.78, respectively).Women in the adolescent group had lower odds of gestational diabetes (aOR 0.35, 95% CI 0.20 to 0.62), caesarean delivery (aOR 0.53, 95% CI 0.42 to 0.67 and instrumental delivery (aOR 0.53, 95% CI 0.41 to 0.67). This study identifies important differences in maternal and neonatal outcomes between women by age group. These findings could help in identifying at-risk groups for additional support and tailored interventions to minimise the risk of adverse outcomes for these vulnerable groups. Further work is needed to identify the causal mechanisms linking age with outcomes in adolescent women where significant gaps in the literature exist.


Malaria Parasite Liver Infection and Exoerythrocytic Biology.
In their infection cycle, malaria parasites undergo replication and population expansions within the vertebrate host and the mosquito vector. Host infection initiates with sporozoite invasion of hepatocytes, followed by a dramatic parasite amplification event during liver stage parasite growth and replication within hepatocytes. Each liver stage forms up to 90,000 exoerythrocytic merozoites, which are in turn capable of initiating a blood stage infection. Liver stages not only exploit host hepatocyte resources for nutritional needs but also endeavor to prevent hepatocyte cell death and detection by the host's immune system. Research over the past decade has identified numerous parasite factors that play a critical role during liver infection and has started to delineate a complex web of parasite-host interactions that sustain successful parasite colonization of the mammalian host. Targeting the parasites' obligatory infection of the liver as a gateway to the blood, with drugs and vaccines, constitutes the most effective strategy for malaria eradication, as it would prevent clinical disease and onward transmission of the parasite.


The long and the short of it: a global analysis of hawkmoth pollination niches and interaction networks.
1. Proboscis length has been proposed as a key dimension of plant pollination niches, but this niche space has not previously been explored at regional and global scales for any pollination system. Hawkmoths are ideal organisms for exploring pollinator niches as they are important pollinators in most of the biodiverse regions of the earth and vary greatly in proboscis length, with some species having the longest proboscides of all insects. 2. Using datasets for nine biogeographical regions spanning the Old and New World, we ask whether it is possible to identify distinct hawkmoth pollination niches based on the frequency distribution of proboscis length, and whether these niches are reflected in the depths of flowers that are pollinated by hawkmoths. We also investigate the levels of specialization in hawkmoth pollination systems at the regional and community level using data from interaction network studies. 3. We found that most regional hawkmoth assemblages have bimodal or multimodal distributions of proboscis length, and that these are matched by similar distributions of floral tube lengths. Hawkmoths, particularly those with longer proboscides, are polyphagous and at the network level show foraging specialization equivalent to or less than that of bees and hummingbirds. In the case of plants, shorter-tubed flowers are usually visited by numerous hawkmoth species, while those that are longer-tubed tend to exclude shorter-proboscid hawkmoths and thus become ecologically specialized on longer-proboscid hawkmoth species. Longer-tubed flowers tend to have greater nectar rewards and this promotes short-term constancy by long-proboscid hawkmoths. 4. Our results show that pollinator proboscis length is a key niche axis for plants and can account for patterns of evolution in functional traits such as floral tube length and nectar volume. We also highlight a paradoxical trend for nectar resource niche breadth to increase according to proboscis length of pollinators, while pollinator niche breadth decreases according to the tube length of flowers.


Behavioral variables and education are predictors of dietary change in the Women's Health Trial: Feasibility Study in Minority Populations.
Reducing the intakes of fats and increasing consumption of fruits and vegetables are an important goal for improving population health. Analyzing the effects of nutrition education programs on subjects' dietary intakes incorporating factors such as habit persistence in diets, unhealthy eating habits, perceptions of health risks, participation motivation, and expectancies can yield useful insights. A Food Frequency Questionnaire (FFQ) was used to measure intakes at baseline, 6 and 12 months, by 318 and 548 postmenopausal women in, respectively, the Control and Intervention groups of the Women's Health Trial: Feasibility Study in Minority Populations (WHTFSMP). Information on background, behavioral, and anthropometric variables was collected. The Intervention group met in classes led by nutritionists. Dynamic random effects models were estimated for the two groups using the data at baseline, 6 and 12 months on the intakes of carbohydrate, saturated, monounsaturated, and polyunsaturated fats, fiber, beta-carotene, ascorbic acid, and calcium. The nutrition education program lowered the intakes of fats while increasing fiber, beta-carotene, and ascorbic acid intakes especially in subjects scoring high on indices reflecting concerns about health, desirability of change, and participation motivation. In addition, subjects' education was a predictor of dietary intakes in the Intervention group. Nutrition education can be an effective tool for improving diets, but behavioral characteristics deserve greater attention in helping to design the most effective approaches for various target groups.


Robust helical edge transport in gated InAs/GaSb bilayers.
We have engineered electron-hole bilayers of inverted InAs/GaSb quantum wells, using dilute silicon impurity doping to suppress residual bulk conductance. We have observed robust helical edge states with wide conductance plateaus precisely quantized to 2e^{2}/h in mesoscopic Hall samples. On the other hand, in larger samples the edge conductance is found to be inversely proportional to the edge length. These characteristics persist in a wide temperature range and show essentially no temperature dependence. The quantized plateaus persist to a 12 T applied in-plane field; the conductance increases from 2e^{2}/h in strong perpendicular fields manifesting chiral edge transport. Our study presents a compelling case for exotic properties of a one-dimensional helical liquid on the edge of InAs/GaSb bilayers.


Cell-permeant small-molecule modulators of NAADP-mediated Ca2+ release.
Nicotinic acid adenine dinucleotide phosphate (NAADP, 1) is the most potent intracellular Ca2+ mobilizing agent in important mammalian cells and tissues, yet the identity of the NAADP receptor is elusive. Significantly, the coenzyme NADP is completely inactive in this respect. Current studies are restricted by the paucity of any chemical probes beyond NAADP itself, and importantly, none is cell permeant. We report simple nicotinic acid-derived pyridinium analogs as low molecular weight compounds that (1) inhibit Ca2+ release via the NAADP receptor (IC50 approximately 15 microM - 1 mM), (2) compete with NAADP binding, (3) cross the cell membrane of sea urchin eggs to inhibit NAADP-evoked Ca2+ release, and (4) selectively ablate NAADP-dependent Ca2+ oscillations induced by the external gastric peptide hormone agonist cholecystokinin (CCK) in murine pancreatic acinar cells.