Genetic variability of the stable fly assessed on a global scale using amplified fragment length polymorphism.
The stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), is a blood-feeding, economically important pest of animals and humans worldwide. Improved management strategies are essential and their development would benefit from studies on genetic diversity of stable flies. Especially if done on a global scale, such research could generate information necessary for the development and application of more efficient control methods. Herein we report on a genetic study of stable flies using amplified fragment length polymorphism, with samples of 10-40 individuals acquired from a total of 25 locations in the Nearctic, Neotropic, Palearctic, Afrotropic and Australasian biogeographical regions. We hypothesized that genetic differentiation would exist across geographical barriers. Although FST (0.33) was moderately high, the GST (0.05; representing genetic diversity between individuals) was very low; Nm values (representing gene flow) were high (9.36). The mismatch distribution and tests of neutrality suggested population expansion, with no genetic differentiation between locations. The analysis of molecular variance (AMOVA) results showed the majority of genetic diversity was within groups. The mantel test showed no correlation between geographic and genetic distance; this strongly supports the AMOVA results. These results suggest that stable flies did not show genetic differentiation but are panmictic, with no evidence of isolation by distance or across geographical barriers.


[War trauma and PTSD among German war survivors. A comparison of former soldiers and women of World War II].
Stressful war experiences can cause posttraumatic stress disorder (PTSD) in survivors. To what extent were the soldiers and young women of World War II affected by PTSD symptoms over the course of their lives? Do these men and women differ in the traumatic experiences and PTSD symptom severity? To investigate these questions 52 male and 20 female Germans aged 81-95 years were recruited through newspaper advertisements and notices and interviewed regarding war experiences and PTSD symptoms. Of the men 2% and 7% met the criteria for current and lifetime PTSD diagnoses, respectively, as compared to 10% and 30% of the women, respectively. Using multiple linear regression a dose-response relationship between the number of trauma types experienced and PTSD symptom severity could be demonstrated. The slope of the regression curve was steeper for women than for men. When controlling for the number of different traumatic experiences women reported a significantly higher severity of PTSD symptoms than men. It is presumed that this difference in severity of symptoms can be attributed to qualitative differences in the type of traumatic stress factors during the war. The present study provides evidence that even today people continue to be affected by PTSD symptoms due to events which occurred during World War II; therefore, during patient contact with this age group the war experiences specific to each individual need to be considered as potential moderators of symptoms.


Evolutionary and Topological Properties of Genes and Community Structures in Human Gene Regulatory Networks.
The diverse, specialized genes present in today's lifeforms evolved from a common core of ancient, elementary genes. However, these genes did not evolve individually: gene expression is controlled by a complex network of interactions, and alterations in one gene may drive reciprocal changes in its proteins' binding partners. Like many complex networks, these gene regulatory networks (GRNs) are composed of communities, or clusters of genes with relatively high connectivity. A deep understanding of the relationship between the evolutionary history of single genes and the topological properties of the underlying GRN is integral to evolutionary genetics. Here, we show that the topological properties of an acute myeloid leukemia GRN and a general human GRN are strongly coupled with its genes' evolutionary properties. Slowly evolving ("cold"), old genes tend to interact with each other, as do rapidly evolving ("hot"), young genes. This naturally causes genes to segregate into community structures with relatively homogeneous evolutionary histories. We argue that gene duplication placed old, cold genes and communities at the center of the networks, and young, hot genes and communities at the periphery. We demonstrate this with single-node centrality measures and two new measures of efficiency, the set efficiency and the interset efficiency. We conclude that these methods for studying the relationships between a GRN's community structures and its genes' evolutionary properties provide new perspectives for understanding evolutionary genetics.


Colloidal synthesis of urchin-like Fe doped NiSe2 for efficient oxygen evolution.
The search for highly efficient non-precious metal electrocatalysts toward the oxygen evolution reaction (OER) is extremely essential for renewable energy systems. Here, we report the colloidal synthesis of Fe doped NiSe2, which functions as a high-performance electrocatalyst for the OER in alkaline solution. The NiFeSe catalysts are composed of urchin-like dendrites with a high number of active sites, which could provide fast transportation of electrons and electrolytes, and facile release of the evolved O2 bubbles during the OER catalysis. Benefitting from this unique urchin-like structure and strong electron interaction between Fe, Ni, and Se, the Ni1.12Fe0.49Se2 catalyst exhibits excellent electrocatalytic activity and high durability toward the OER in alkaline solution, with an overpotential of 227 mV at a current density of 10 mA cm-2, which is, to the best of our knowledge, higher than most of the reported selenide-based electrocatalysts.


Extended total sacrectomy and reconstruction for sacral tumor.
This case report includes the results of long-term follow-up after extended total sacrectomy in a 13-year-old boy with a sarcoma originating in the sacrum with an extraskeletal extension and infiltration into the left ilium. To report and discuss a case of sacral tumor treated by extended sacrectomy. Sacral tumors are often at an advanced stage with a large volume at diagnosis. Although total or extended sacrectomy is the only radical means to treat the massive sacral tumor, unavoidable complications in total sacrectomy are serious in the treatment selection. Initial histologic findings indicated a synovial sarcoma. Additional genetic analysis redesignated the tumor as an unclassified sarcoma. Preoperative neoadjuvant chemotherapy and radiotherapy were completed. The response to the preoperative treatment appeared as a reduction in tumor size (approximately 50%) on radiographs. After extended sacrectomy, the L5 vertebral body was fixed between the ilia, and the pelvic ring was compressed by the Zielke system. The ISOLA instrumentation system connected the lumbar spine and both ilia. All sacral nerve roots and the L5 root on the left side were cut. At the 5-year follow-up examination, the patient was disease-free, could walk with crutches, and could climb stairs using the handrail and one crutch. The patient's excellent response to preoperative antitumor treatment was considered crucial to the long-term outcome. But the decision between a radical resection with reconstruction and a less extensive procedure with combined therapy remains controversial.


Immunoassay for Detection of Infliximab in Whole Blood Using a Fiber-Optic Surface Plasmon Resonance Biosensor.
Monitoring the concentration of a therapeutic drug antibody, infliximab (IFX), is recommended for enhancing its efficacy in patients with inflammatory bowel disease (IBD). However, IFX concentrations are currently determined in patients' serum/plasma, which requires sample preparation from blood, hence hampering the turnaround time. In this paper, we present a short immunoassay (10 min) using a fiber-optic surface plasmon resonance (FO-SPR) biosensor for detection of IFX spiked in 100-fold diluted serum, plasma, and whole blood. The calculated limits of detection (LOD) based on calibration curves were 1.42, 1.00, and 1.34 ng/mL, respectively, which coincides with expected IFX concentrations in diluted samples from IBD patients. A linear correlation was established among different matrixes, indicating that the matrix effect was insignificant. The established point-of-care (POC) FO-SPR bioassay was also used to measure IFX in 100-fold diluted extracts of dried blood spots (DBS), and LOD achieved was below 2 ng/mL. Although DBS might be ideal for POC, this is the first report of using an SPR biosensor for measuring DBS samples. Finally, the POC FO-SPR immunoassay was validated by using matching serum and plasma samples from five IBD patients. A Pearson correlation of 0.968 was obtained between serum and plasma samples. IFX concentrations determined with FO-SPR were compared to a clinically validated enzyme-linked immunosorbent assay (ELISA), resulting in excellent Pearson correlation and intraclass correlation coefficient, both being 0.99 for serum and plasma samples. In conclusion, this paper demonstrates that our FO-SPR biosensor can be used as a true POC diagnostic tool for determining IFX concentrations in a variety of matrixes.


Public health ethics and a status for pets as person-things : revisiting the place of animals in urbanized societies.
Within the field of medical ethics, discussions related to public health have mainly concentrated on issues that are closely tied to research and practice involving technologies and professional services, including vaccination, screening, and insurance coverage. Broader determinants of population health have received less attention, although this situation is rapidly changing. Against this backdrop, our specific contribution to the literature on ethics and law vis-à-vis promoting population health is to open up the ubiquitous presence of pets within cities and towns for further discussion. An expanding body of research suggests that pet animals are deeply relevant to people's health (negatively and positively). Pet bylaws adopted by town and city councils have largely escaped notice, yet they are meaningful to consider in relation to everyday practices, social norms, and cultural values, and thus in relation to population health. Nevertheless, not least because they pivot on defining pets as private property belonging to individual people, pet bylaws raise emotionally charged ethical issues that have yet to be tackled in any of the health research on pet ownership. The literature in moral philosophy on animals is vast, and we do not claim to advance this field here. Rather, we pragmatically seek to reconcile philosophical objections to pet ownership with both animal welfare and public health. In doing so, we foreground theorizations of personhood and property from sociocultural anthropology.


Serine-401 as a batrachotoxin- and local anesthetic-sensing residue in the human cardiac Na+ channel.
Sequence alignment of four S6 segments in the human cardiac Na+ channel suggests that serine-401 (hNav1.5-S401) at D1S6 along with asparagine-927 (N927) at D2S6, serine-1458 (S1458) at D3S6, and phenylalanine-1760 (F1760) at D4S6 may jointly form a pore-facing S(401)N(927)S(1458)F(1760) ring. Importantly, this pore-facing structure is adjacent to the putative gating-hinge (G(400)G(926)G(1457)S(1759)) and close to the selectivity filter. Within this SNSF ring, only S401 has not yet been identified as a batrachotoxin (BTX) sensing residue. We therefore created S401 mutants with 12 substitutions (S401C,W,P,A,K,F,R,E,L,N,D,G) and assayed their BTX sensitivity. All S401 mutants expressed Na+ currents but often with altered gating characteristics. Ten mutants were found sensitive to 5 muM BTX, which eliminated Na+ channel fast inactivation after repetitive pulses. However, S401K and S401R became BTX resistant. In addition, the block of open and inactivated hNav1.5-S401K Na+ channels by local anesthetic bupivacaine was reduced by approximately 8-10-fold, but not the block of resting Na+ channels. Qualitatively, these ligand-sensing phenotypes of hNav1.5-S401K channels resemble those of S1458K and F1760K channels reported earlier. Together, our results support that residue hNav1.5-S401 at D1S6 is facing the inner cavity and is in close proximity to the receptor sites for BTX and for local anesthetics.


Estimation of biological chromophores using diffuse optical spectroscopy: benefit of extending the UV-VIS wavelength range to include 1000 to 1600 nm.
With an optical fiber probe, we acquired spectra from swine tissue between 500 and 1600 nm by combining a silicon and an InGaAs spectrometer. The concentrations of the biological chromophores were estimated by fitting a mathematical model derived from diffusion theory. The advantage of our technique relative to those presented in previous studies is that we extended the commonly-used wavelength ranges of 500 and 1000 nm to include the range of 1000 to 1600 nm, where additional water and lipid absorption features exist. Hence, a more accurate estimation of these two chromophores is expected when spectra are fitted between 500 and 1600 nm than between 500 and 1000 nm. When extending the UV-VIS wavelength range, the estimated total amount of chromophores approached 100% of the total as present in the probed volume. The confidence levels of the water and lipid related parameters increases by a factor of four.


The epidemiology of chronic pain in a Swedish rural area.
In order to establish basic epidemiological data on chronic pain (duration > 3 months) in a rural population, a survey of pain symptoms was conducted by means of a postal questionnaire. The questionnaire was sent to a random sample (from the population register) of 15% of the population aged 25-74 (n = 1806) in two Swedish primary health care districts. The response rate was 90%. In a follow-up study individuals selected among the responders (neck-shoulder pain, widespread pain and controls without pain; n = 213) were examined and interviewed. They were requestioned about pain symptoms 24 months after the initial survey. Without sex differences 55% of the population had perceived persistent pain for 3 months and 49% for 6 months. Women experienced more multiple localizations of pain and had pain in neck, shoulder, arm and thigh to a greater extent than men. Prevalence of pain increased by age up to 50-59 years for both genders and then slowly decreased. The neck-shoulder area was the most common site of pain (women 32.9%, men 27.5%). Blue-collar workers and employers (including farmers) reported chronic pain to a greater extent than other groups. In 13% of the population, manifest pain problems were associated with reduced functional capacity. Examination of selected pain groups indicated a high proportion of unspecific musculoskeletal symptoms. Diagnosis with definite definitions, explaining the pains, were found in 40% of the individuals. Individuals with widespread pain had a higher pain intensity, more somatic symptoms, were more depressive and had the lowest scores for quality of life.(ABSTRACT TRUNCATED AT 250 WORDS)


Multi-stage open peer review: scientific evaluation integrating the strengths of traditional peer review with the virtues of transparency and self-regulation.
The traditional forms of scientific publishing and peer review do not live up to all demands of efficient communication and quality assurance in today's highly diverse and rapidly evolving world of science. They need to be advanced and complemented by interactive and transparent forms of review, publication, and discussion that are open to the scientific community and to the public. The advantages of open access, public peer review, and interactive discussion can be efficiently and flexibly combined with the strengths of traditional scientific peer review. Since 2001 the benefits and viability of this approach are clearly demonstrated by the highly successful interactive open access journal Atmospheric Chemistry and Physics (ACP, www.atmos-chem-phys.net) and a growing number of sister journals launched and operated by the European Geosciences Union (EGU, www.egu.eu) and the open access publisher Copernicus (www.copernicus.org). The interactive open access journals are practicing an integrative multi-stage process of publication and peer review combined with interactive public discussion, which effectively resolves the dilemma between rapid scientific exchange and thorough quality assurance. Key features and achievements of this approach are: top quality and impact, efficient self-regulation and low rejection rates, high attractivity and rapid growth, low costs, and financial sustainability. In fact, ACP and the EGU interactive open access sister journals are by most if not all standards more successful than comparable scientific journals with traditional or alternative forms of peer review (editorial statistics, publication statistics, citation statistics, economic costs, and sustainability). The high efficiency and predictive validity of multi-stage open peer review have been confirmed in a series of dedicated studies by evaluation experts from the social sciences, and the same or similar concepts have recently also been adopted in other disciplines, including the life sciences and economics. Multi-stage open peer review can be flexibly adjusted to the needs and peculiarities of different scientific communities. Due to the flexibility and compatibility with traditional structures of scientific publishing and peer review, the multi-stage open peer review concept enables efficient evolution in scientific communication and quality assurance. It has the potential for swift replacement of hidden peer review as the standard of scientific quality assurance, and it provides a basis for open evaluation in science.


Cone-beam reconstruction using the backprojection of locally filtered projections.
This paper describes a flexible new methodology for accurate cone beam reconstruction with source positions on a curve (or set of curves). The inversion formulas employed by this methodology are based on first backprojecting a simple derivative in the projection space and then applying a Hilbert transform inversion in the image space. The local nature of the projection space filtering distinguishes this approach from conventional filtered-backprojection methods. This characteristic together with a degree of flexibility in choosing the direction of the Hilbert transform used for inversion offers two important features for the design of data acquisition geometries and reconstruction algorithms. First, the size of the detector necessary to acquire sufficient data for accurate reconstruction of a given region is often smaller than that required by previously documented approaches. In other words, more data truncation is allowed. Second, redundant data can be incorporated for the purpose of noise reduction. The validity of the inversion formulas along with the application of these two properties are illustrated with reconstructions from computer simulated data. In particular, in the helical cone beam geometry, it is shown that 1) intermittent transaxial truncation has no effect on the reconstruction in a central region which means that wider patients can be accommodated on existing scanners, and more importantly that radiation exposure can be reduced for region of interest imaging and 2) at maximum pitch the data outside the Tam-Danielsson window can be used to reduce image noise and thereby improve dose utilization. Furthermore, the degree of axial truncation tolerated by our approach for saddle trajectories is shown to be larger than that of previous methods.


Quantitative differences in developmental profiles of spontaneous activity in cortical and hippocampal cultures.
Neural circuits can spontaneously generate complex spatiotemporal firing patterns during development. This spontaneous activity is thought to help guide development of the nervous system. In this study, we had two aims. First, to characterise the changes in spontaneous activity in cultures of developing networks of either hippocampal or cortical neurons dissociated from mouse. Second, to assess whether there are any functional differences in the patterns of activity in hippocampal and cortical networks. We used multielectrode arrays to record the development of spontaneous activity in cultured networks of either hippocampal or cortical neurons every 2 or 3 days for the first month after plating. Within a few days of culturing, networks exhibited spontaneous activity. This activity strengthened and then stabilised typically around 21 days in vitro. We quantified the activity patterns in hippocampal and cortical networks using 11 features. Three out of 11 features showed striking differences in activity between hippocampal and cortical networks: (1) interburst intervals are less variable in spike trains from hippocampal cultures; (2) hippocampal networks have higher correlations and (3) hippocampal networks generate more robust theta-bursting patterns. Machine-learning techniques confirmed that these differences in patterning are sufficient to classify recordings reliably at any given age as either hippocampal or cortical networks. Although cultured networks of hippocampal and cortical networks both generate spontaneous activity that changes over time, at any given time we can reliably detect differences in the activity patterns. We anticipate that this quantitative framework could have applications in many areas, including neurotoxicity testing and for characterising the phenotype of different mutant mice. All code and data relating to this report are freely available for others to use.


Effects of respiratory-muscle exercise on spinal curvature.
Randomized controlled study. Laboratory. 26 healthy swimmers randomly assigned to an exercise (n = 13; Ex) or control group (n = 13; Cont). The Ex group performed respiratory-muscle exercises for 10 min thrice a week for 4 wk. Respiratory-muscle exercises are used not only in the rehabilitation of patients with respiratory disease but also in endurance training for athletes. Respiration involves the back and abdominal muscles. These muscles are 1 of the elements responsible for posture control, which is integral to injury prevention and physical performance. However, the effects of respiratory-muscle exercise on posture remain unclear. To examine the potential of respiratory-muscle exercise for improving posture. Spinal curvature, pulmonary function, and trunk-muscle strength were measured for both the groups at baseline and after 4 wk. The data were compared between the Ex and Cont groups with Mann-Whitney U test and preintervention and postintervention within groups with a Wilcoxon signed rank-sum test. The spinal curvature was significantly different in the Ex group, indicating a decrease in the thoracic (-13.1%, P < .01) and lumbar (-17.7%, P < .05) angles. The Ex group presented with lower thoracic (-8.6%) and lumbar (-20.9%) angles at postexercise than the Cont group (P < .05). With respect to trunk-muscle strength, only trunk-flexion strength significantly increased from pretest to posttest in the Ex group (P < .05). For pulmonary function, forced vital capacity and forced expiratory volume in 1.0 s were significantly increased after 4 wk in the Ex group (P < .05). The results suggest that respiratory-muscle exercise straightened the spine, leading to good posture control, possibly because of contraction of abdominal muscles.


Primate endocrine function after pancreatico-duodenal-splenic allotransplantation.
In this study the endocrine function following intraperitoneal hetero- and orthotopic pancreatico-duodenal-splenic allotransplantation (PDS) in hemipancreatectomized, non-immune-suppressed chacma baboons was assessed. Significantly reduced K-values and insulin release together with glucose intolerance during IVGTT were observed in hemipancreatectomized recipients (HPS) without grafts. Orthotopic and heterotopic PDS transplantation improved the glucose intolerance of HPS recipients; orthotopically sited grafts rendering the best curves. Normal glucose tolerance was not achieved. Both orthotopic and heterotopic PDS transplantation rendered suboptimal insulin release during IVGTT; heterotopically draining grafts released significantly more insulin than orthotopic grafts. Hyperglucagonaemia during IVGTT was a constant feature in both groups, heterotopic grafts releasing the most glucagon during stimulation. C-peptide release was significantly lower in orthotopic grafts compared to normal animals or heterotopically drained insulin. It is concluded that glucose tolerance was not directly related to insulin or glucagon release in this study as orthotopic grafts rendered near-normal IVGTT curves in the presence of hypoinsulinaemia, hyperglucagonaemia, and reduced C-peptide values. The hormonal response after PDS transplantation was variable and the advantages of portal vs systemic insulin drainage remain to be defined.


Hemostatic properties and the role of cell receptor recognition in human hair keratin protein hydrogels.
Driven by new discoveries in stem-cell biology and regenerative medicine, there is broad interest in biomaterials that go beyond basic interactions with cells and tissues to actively direct and sustain cellular behavior. Keratin biomaterials have the potential to achieve these goals but have been inadequately described in terms of composition, structure, and cell-instructive characteristics. In this manuscript we describe and characterize a keratin-based biomaterial, demonstrate self-assembly of cross-linked hydrogels, investigate a cell-specific interaction that is dependent on the hydrogel structure and mediated by specific biomaterial-receptor interactions, and show one potential medical application that relies on receptor binding - the ability to achieve hemostasis in a lethal liver injury model. Keratin biomaterials represent a significant advance in biotechnology as they combine the compatibility of natural materials with the chemical flexibility of synthetic materials. These characteristics allow for a system that can be formulated into several varieties of cell-instructive biomaterials with potential uses in tissue engineering, regenerative medicine, drug and cell delivery, and trauma.


Gender, body mass index, and PPARγ polymorphism are good indicators in hyperuricemia prediction for Han Chinese.
Hyperuricemia is closely associated with obesity and metabolic abnormalities, which is also an independent risk factor for cardiovascular diseases. The PPARγ gene, which is linked to obesity and metabolic abnormalities in Han Chinese, might be considered a top candidate gene that is involved in hyperuricemia. This study recruited 457 participants, aged 20-40 years old, to investigate the associations of the PPARγ gene and metabolic parameters with hyperuricemia. Three tag-single nucleotide polymorphisms, rs2292101, rs4684846, and rs1822825, of the PPARγ gene were selected to explore their association with hyperuricemia. Risk genotypes on rs1822825 of the PPARγ gene exhibited statistical significance with hyperuricemia (odds ratio: 1.9; 95% confidence interval: 1.05-3.57). Although gender, body mass index (BMI), serum total cholesterol concentration, or protein intake per day were statistically associated with hyperuricemia, the combination of BMI, gender, and rs1822825, rather than that of age, serum lipid profile, blood pressure, and protein intake per day, satisfied the predictability for hyperuricemia (sensitivity: 69.3%; specificity: 83.7%) in Taiwan-born obese Han Chinese. BMI, gender, and the rs1822825 polymorphism in the PPARγ gene appeared good biomarkers in hyperuricemia; therefore, these powerful indicators may be included in the prediction of hyperuricemia to increase the accuracy of the analysis.


Racial and ethnic differences in diabetes mellitus among people with and without psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions.
This study examined racial/ethnic differences in the prevalence of diabetes mellitus in a nationally representative sample of adults with and without common psychiatric disorders. Data were drawn from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (N=34,653). Logistic regression models adjusting for sociodemographic variables and diabetes risk factors were used to examine racial/ethnic differences in 12-month prevalence rates of diabetes by psychiatric status. Among people without psychiatric disorders, African Americans, Hispanics and American Indians/Alaska Natives, but not Asians/Pacific Islanders, had significantly higher rates of diabetes than non-Hispanic whites even after adjusting for sociodemographic variables and diabetes risk factors. In the presence of psychiatric disorders, these health disparities persisted for African Americans and Hispanics, but not for American Indians/Alaska Natives. No significant interactions between race/ethnicity and psychiatric disorders in the odds of diabetes were found across any group. Policies and services that support culturally appropriate prevention and treatment strategies are needed to reduce racial/ethnic disparities in diabetes among people with and without psychiatric disabilities.


eNOS genotype modifies the effect of leisure-time physical activity on serum triglyceride levels in a Japanese population.
Nitric oxide is a key molecule not only in the cardiovascular system, but also in the metabolic-endocrine system. The purpose of this study was to examine possible associations of the NOS3 T-786C polymorphism (rs2070744) with serum lipid levels on the basis of lifestyle factors for tailoring prevention of dyslipidemia. For this cross-sectional study, a total of 2226 subjects aged 35 to 69 years (1084 men and 1142 women) were selected from Japanese participants in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. They were recruited in eight areas throughout Japan between February 2004 and November 2008. In a stratified analysis by leisure-time physical activity, the likelihood of hypertriglyceridemia (serum triglyceride levels ≥ 150 mg/dL) among subjects with the C allele was significantly lower than those without it in the active group (OR = 0.43, 95% CI = 0.22-0.84 in the fasting group), but not in the sedentary group. A gene-environment interaction between the T-786C polymorphism and leisure-time physical activity for hypertriglyceridemia was significant (P = 0.007 in the fasting group). Additionally, serum triglyceride levels (mean ± SD) across leisure-time physical activity classes decreased significantly only in the TC + CC genotype group (111 ± 60 mg/dL for sedentary, 95 ± 48 mg/dL for moderately active, 88 ± 44 mg/dL for very active, P for trend = 0.008 in the fasting group), but not in the TT genotype group. Total cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol levels had no significant association with the polymorphism. This study suggests that the NOS3 T-786C polymorphism modifies the effect of leisure-time physical activity on serum triglyceride levels.


Bite force measurements with hard and soft bite surfaces.
Bite force has been measured by different methods and over a wide variety of designs. In several instruments, the fact that bite surface has been manufactured with stiff materials might interfere in obtaining reliable data, by a more prompt activation of inhibitory reflex mechanisms. The purpose of this study was to compare the maximum voluntary bite force measured by a digital occlusal force gauge (GM10 Nagano Keiki, Japan) between different opponent teeth, employing semi-hard or soft bite surfaces. A sample of 34 young adults with complete natural dentition was studied. The original semi-hard bite surface was exchanged by a soft one, made of leather and rubber. Maximum voluntary bite force recordings were made for each tooth group and for both bite surfaces. Statistical analyses (Student's t-test) revealed significant differences, with higher scores while using the soft surface across sexes and tooth groups (P < 0·05). Differential activation of periodontal mechanoreceptors of a specific tooth group is mainly conditioned by the hardness of the bite surface; a soft surface induces greater activation of elevator musculature, while a hard one induces inhibition more promptly. Thus, soft bite surfaces are recommended for higher reliability in maximum voluntary bite force recordings.


A statistical analysis of the reliability and classification error in application of the mutagen sensitivity assay.
In vitro mutagen hypersensitivity, determined with the bleomycin assay, has been found to be an independent risk factor for developing primary upper aerodigestive tract cancers, lung cancers, and second malignant tumors. The average number of chromatid breaks per cell (b/c) is derived from evaluating an arbitrarily set number of metaphases (usually 50) in each sample. The reliability of such an approach is of key importance in large-scale epidemiological studies. Because evaluating metaphases is a time-consuming task, it is desirable to know the minimum number of readings needed to reach an acceptable reliability. Statistical analyses were performed in 160 observations for which b/c values were determined by the same observer scoring 100 consecutive metaphases per sample. The b/c values were between 0.14 and 1.30 (mean, 0.61). The b/c values were separately calculated for the first and second sets of 50 metaphases. There was essentially no difference in the mean b/c values between the first and second 50 readings (difference, -0.002). The correlation between the two sets of readings was 0.72. The SE of the b/c values, based on scoring 50 metaphases, was 0.15. When scoring 100 metaphases, the SE decreased to 0.11. After evaluating the first 50 metaphases, the theoretical gain in reducing the SE was <1% with each additional reading. When 0.8 was used to dichotomize the mean b/c value into bleomycin-resistant or bleomycin-hypersensitive groups, sensitivity and specificity of reading 50 metaphases were above 75% and 95% when compared to 100 readings. A simulated case control study showed that there is a 15% attenuation in estimating the odds ratio with 50 readings. The findings suggest that the conventional method of reading 50 metaphases can yield an acceptable reliability in our setting and may be applied to other cancer epidemiology studies.


Relation between antithrombin III and clinical and serological parameters in systemic lupus erythematosus.
The increased frequency of thromboembolic events in patients with systemic lupus erythematosus (SLE) has been attributed to reduced or dysfunctional antithrombin III (At-III). We analysed At-III values, measured by three different assay techniques, in SLE patients, patients with rheumatoid arthritis, and normal and hospitalised controls. In addition, attempts were made to correlate At-III activities of SLE patients with specific clinical and serological parameters such as disease activity, renal involvement, previous thrombosis, degree of proteinuria, and serum complement concentrations. Our results failed to show a significantly reduced At-III in SLE with any method. At-III titres did not correlate with disease activity, concentrations of serum complement or albumin (both only minimally reduced in most patients), or a previous history of thrombosis. At-III deficiency does not appear to be an inherent feature of SLE, and reduced activities should only be anticipated when there are specific aetiological factors present, such as massive proteinuria, extensive hepatic disease, or active thrombosis.


Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI.
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase B (ASB), which is involved in degradation of dermatan sulfate and chondroitin 4-sulfate. A MPS VI mouse model was generated by targeted disruption of the ASB gene. Homozygous mutant animals exhibit ASB enzyme deficiency and elevated urinary secretion of dermatan sulfate. They develop progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age facial dysmorphia becomes overt, long bones are shortened, and pelvic and costal abnormalities are observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals are seen. All major parenchymal organs show storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice are fertile and mortality is not elevated up to 15 months of age. This mouse model will be a valuable tool for studying pathogenesis of MPS VI and may help to evaluate therapeutical approaches for lysosomal storage diseases.


Genome expansion and lineage-specific genetic innovations in the forest pathogenic fungi Armillaria.
Armillaria species are both devastating forest pathogens and some of the largest terrestrial organisms on Earth. They forage for hosts and achieve immense colony sizes via rhizomorphs, root-like multicellular structures of clonal dispersal. Here, we sequenced and analysed the genomes of four Armillaria species and performed RNA sequencing and quantitative proteomic analysis on the invasive and reproductive developmental stages of A. ostoyae. Comparison with 22 related fungi revealed a significant genome expansion in Armillaria, affecting several pathogenicity-related genes, lignocellulose-degrading enzymes and lineage-specific genes expressed during rhizomorph development. Rhizomorphs express an evolutionarily young transcriptome that shares features with the transcriptomes of both fruiting bodies and vegetative mycelia. Several genes show concomitant upregulation in rhizomorphs and fruiting bodies and share cis-regulatory signatures in their promoters, providing genetic and regulatory insights into complex multicellularity in fungi. Our results suggest that the evolution of the unique dispersal and pathogenicity mechanisms of Armillaria might have drawn upon ancestral genetic toolkits for wood-decay, morphogenesis and complex multicellularity.


The role of conspiracist ideation and worldviews in predicting rejection of science.
Among American Conservatives, but not Liberals, trust in science has been declining since the 1970's. Climate science has become particularly polarized, with Conservatives being more likely than Liberals to reject the notion that greenhouse gas emissions are warming the globe. Conversely, opposition to genetically-modified (GM) foods and vaccinations is often ascribed to the political Left although reliable data are lacking. There are also growing indications that rejection of science is suffused by conspiracist ideation, that is the general tendency to endorse conspiracy theories including the specific beliefs that inconvenient scientific findings constitute a "hoax." We conducted a propensity weighted internet-panel survey of the U.S. population and show that conservatism and free-market worldview strongly predict rejection of climate science, in contrast to their weaker and opposing effects on acceptance of vaccinations. The two worldview variables do not predict opposition to GM. Conspiracist ideation, by contrast, predicts rejection of all three scientific propositions, albeit to greatly varying extents. Greater endorsement of a diverse set of conspiracy theories predicts opposition to GM foods, vaccinations, and climate science. Free-market worldviews are an important predictor of the rejection of scientific findings that have potential regulatory implications, such as climate science, but not necessarily of other scientific issues. Conspiracist ideation, by contrast, is associated with the rejection of all scientific propositions tested. We highlight the manifold cognitive reasons why conspiracist ideation would stand in opposition to the scientific method. The involvement of conspiracist ideation in the rejection of science has implications for science communicators.


Time Course of Evolution of Disability and Cause-Specific Mortality After Ischemic Stroke: Implications for Trial Design.
Outcome in stroke trials is often based on a 3-month modified Rankin scale (mRS). How 3-month mRS relates to longer-term outcomes will depend on late recovery, delayed stroke-related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3-month mRS and death/disability at 1 and 5 years in a population-based cohort study. In 3-month survivors of ischemic stroke (Oxford Vascular Study; 2002-2014), we related 3-month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index-stroke-related and nonstroke deaths in each poststroke year was categorized according to 3-month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index-stroke-related deaths and 320 other deaths occurred during the subsequent 4866 patient-years of follow-up up to 5 years. Although 69/126 (54.8%) post-3-month index-stroke-related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88-61.09, P<0.0001). Consequently, a 3-month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16-10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38-3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3-month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]). Our results reaffirm use of the 3-month mRS outcome in stroke trials. Although later recovery does occur, extending follow-up to 1 year would capture most long-term stroke-related disability. However, administrative mortality follow-up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long-term mortality without much erosion by non-stroke-related deaths.


Both psychological factors and physical performance are associated with fall-related concerns.
Fall-related concern strongly correlates to activity avoidance in older people. In this complex phenomenon, different terminology and instruments are often used interchangeably. Three main concepts make up fall-related concerns: fear of falling, consequence concern, and falls self-efficacy. It is suggested that fall-related concerns are mediated by psychological and physical factors. Our aims were to describe the prevalence of fall-related concerns and find explanatory factors for its most studied concept-falls self-efficacy-in an older population. We executed a cross-sectional study on a random sample of 153 community-dwelling older people (70 years or older). We used validated and reliable instruments as well as structured interviews to gather data on the three concepts of fall-related concerns and possible mediating factors. We then calculated descriptive statistics on prevalence and regression models for the total group, and men and women, separately. 70% of the total sample (80% of women and 53% of men) reported at least one of the three concepts of fall-related concern. For the total sample, fear of falling, morale, and physical performance were associated factors with falls self-efficacy. For women, the number of prescription medications was added. For men, physical performance and concerns for injury were associated. Fall-related concern is prevalent in large proportions with higher prevalence for women than for men. Important factors are fear of falling, morale, and physical performance. Gender differences in the emergence and variance of fall-related concern and the relation between physical performance and fall-related concern should be targeted in future research endeavors.


For-profit undergraduate medical education: back to the future?
One hundred years ago, Abraham Flexner wrote a report that profoundly influenced U.S. medical education. His conclusion-that medical degree (MD)-granting education programs should occur in not-for-profit universities and include hands-on laboratory and patient care experiences in teaching hospitals and clinics-led to the creation of the current model of U.S. MD education. Although this model has served the United States well, it is lengthy and costly. As the United States struggles to deal with a growing shortage of physicians, other models of medical education, including osteopathic medicine and offshore, MD-granting schools, have increased production of graduates. New private colleges of osteopathic medicine, including one accredited proprietary school, are nimble, cost-effective competitors for MD-granting schools. Do these schools portend the establishment of a U.S. for-profit medical education sector in the same way that proprietary universities have become well established in higher education? How should MD medicine respond? Can and should MD educators shorten the time needed to produce a fully trained MD-holding physician? How can MD educators make the training process shorter and less expensive to respond to the nation's physician shortage while maintaining the appeal of MD careers and without compromising educational quality? Models of shorter, less expensive pathways to earning an MD exist and have proven effective. Now is the time for MD educators to debate whether they should apply these pathways more widely. Six recommendations could help realize the goals of shortening and making less costly the training of MD physicians in the United States.


Fetal ductus arteriosus ligation. Pulmonary vascular smooth muscle biochemical and mechanical changes.
To evaluate the smooth muscle mechanical and biochemical changes associated with persistent pulmonary hypertension syndrome of the newborn, we studied 31 fetal sheep in which the ductus arteriosus was ligated at 125 days of gestation. Sixty-one noninstrumented and six sham-operated fetuses served as controls. All animals were delivered by cesarean section at 137-140 days of gestation, and the experimental group had the ductus arteriosus ligated for 12 +/- 3 days. The ligated group demonstrated a higher mean (+/- SEM) pulmonary artery pressure (72.3 +/- 3.8 versus 54.1 +/- 2 mm Hg, p < 0.01) and right ventricular mean free wall weight (12.5 +/- 0.7 versus 6.8 +/- 0.3 g, p < 0.01) as compared with the sham-operated group. Significant changes in the pulmonary vascular smooth muscle of the ligated group were observed. The myosin content of vessels from the second through fifth generation demonstrated a significant increase in actin and myosin content (p < 0.01), but given their disproportional changes, the noninstrumented group demonstrated a lower actin/myosin ratio than the experimental group (p < 0.01). Changes in the myosin heavy chain isoform stoichiometry, characterized by an increase in both the mean high/low myosin heavy chain isoform ratio (1.8 +/- 0.3 versus 1.0 +/- 0.1, p < 0.05) and the nonmuscle isoform as a percentage of the total myosin heavy chain (12.4 +/- 0.7% versus 2.7 +/- 0.9%, p < 0.01), were also observed in the ligated as compared with the noninstrumented animals. In addition, the muscle Mg-ATPase activity was significantly (p < 0.05) reduced in the experimental group.(ABSTRACT TRUNCATED AT 250 WORDS)


High performance carbon nanotube--polymer nanofiber hybrid fabrics.
Stable nanoscale hybrid fabrics containing both polymer nanofibers and separate and distinct carbon nanotubes (CNTs) are highly desirable but very challenging to produce. Here, we report the first instance of such a hybrid fabric, which can be easily tailored to contain 0-100% millimeter long CNTs. The novel CNT - polymer hybrid nonwoven fabrics were created by simultaneously electrospinning nanofibers onto aligned CNT sheets which were drawn and collected on a grounded, rotating mandrel. Due to the unique properties of the CNTs, the hybrids show very high tensile strength, very small pore size, high specific surface area and electrical conductivity. In order to further examine the hybrid fabric properties, they were consolidated under pressure, and also calendered at 70 °C. After calendering, the fabric's strength increased by an order of magnitude due to increased interactions and intermingling with the CNTs. The hybrids are highly efficient as aerosol filters; consolidated hybrid fabrics with a thickness of 20 microns and areal density of only 8 g m(-2) exhibited ultra low particulate (ULPA) filter performance. The flexibility of this nanofabrication method allows for the use of many different polymer systems which provides the opportunity for engineering a wide range of nanoscale hybrid materials with desired functionalities.


Ligand dependent intra and inter subunit communication in human tryptophanyl tRNA synthetase as deduced from the dynamics of structure networks.
Homodimeric protein tryptophanyl tRNA synthetase (TrpRS) has a Rossmann fold domain and belongs to the 1c subclass of aminoacyl tRNA synthetases. This enzyme performs the function of acylating the cognate tRNA. This process involves a number of molecules (2 protein subunits, 2 tRNAs and 2 activated Trps) and thus it is difficult to follow the complex steps in this process. Structures of human TrpRS complexed with certain ligands are available. Based on structural and biochemical data, mechanism of activation of Trp has been speculated. However, no structure has yet been solved in the presence of both the tRNA(Trp) and the activated Trp (TrpAMP). In this study, we have modeled the structure of human TrpRS bound to the activated ligand and the cognate tRNA. In addition, we have performed molecular dynamics (MD) simulations on these models as well as other complexes to capture the dynamical process of ligand induced conformational changes. We have analyzed both the local and global changes in the protein conformation from the protein structure network (PSN) of MD snapshots, by a method which was recently developed in our laboratory in the context of the functionally monomeric protein, methionyl tRNA synthetase. From these investigations, we obtain important information such as the ligand induced correlation between different residues of this protein, asymmetric binding of the ligands to the two subunits of the protein as seen in the crystal structure analysis, and the path of communication between the anticodon region and the aminoacylation site. Here we are able to elucidate the role of dimer interface at a level of detail, which has not been captured so far.


Maternal employment and the health of low-income young children.
This study examines whether maternal employment affects the health status of low-income, elementary-school-aged children using instrumental variables estimation and experimental data from a welfare-to-work program implemented in the early 1990s. Maternal report of child health status is predicted as a function of exogenous variation in maternal employment associated with random assignment to the experimental group. IV estimates show a modest adverse effect of maternal employment on children's health. Making use of data from another welfare-to-work program we propose that any adverse effect on child health may be tempered by increased family income and access to public health insurance coverage, findings with direct relevance to a number of current policy discussions. In a secondary analysis using fixed effects techniques on longitudinal survey data collected in 1998 and 2001, we find a comparable adverse effect of maternal employment on child health that supports the external validity of our primary result.


Ancestry as a determinant of mean population C-reactive protein values: implications for cardiovascular risk prediction.
Eligibility for rosuvastatin treatment for cardiovascular disease prevention includes a C-reactive protein (CRP) concentration >2 mg/L. Most observational studies of CRP and cardiovascular disease have been in Europeans. We evaluated the influence of ancestry on population CRP concentration to assess the implications for statin targeting in non-Europeans. In a systematic review and meta-analysis among 221 287 people from 89 studies, geometric mean CRP was 2.6 mg/L (95% credible interval, 2.27 to 2.96) in blacks resident in the United States (n=18 585); 2.51 mg/L (95% CI, 1.18 to 2.86) in Hispanics (n=5049); 2.34 mg/L (95% CI, 1.99 to 2.8) in South Asians (n=1053); 2.03 mg/L (95% CI, 1.77 to 2.3) in whites (n=104 949); and 1.01 mg/L (95% CI, 0.88 to 1.18) in East Asians (n=39 521). Differences were not explained by study design or CRP assay and were preserved after adjustment for age and body mass index. At age 60 years, fewer than half of East Asians but more than two thirds of Hispanics were estimated to have CRP values exceeding 2 mg/L. HapMap frequencies of CRP polymorphisms known to associate with CRP concentration but not coronary heart disease events differed by ancestry. In participant data from the Wandsworth Heart and Stroke Study including European, South Asian and African, and Caribbean-descent subjects, body mass index, systolic blood pressure, and smoking contributed to between-group differences in CRP, but the majority of the difference in CRP was unexplained. Differences in CRP concentration in populations of diverse ancestry are sufficiently large to affect statin eligibility, based on a single CRP threshold of 2 mg/L, and only partially influenced by differences in variables related to cardiovascular risk. A single threshold value of CRP for cardiovascular risk prediction could lead to inequalities in statin eligibility that may not accurately reflect underlying levels of cardiovascular risk.


Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha-6 chain as a novel regulator of striatal axonal branching in mice.
Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson's disease motor symptoms are caused by the demise of nigral DA neurons, leading to loss of striatal dopamine (DA). Here, we measured DA concentration in the dorsal striatum of 32 members of Collaborative Cross (CC) family and their eight founder strains. Striatal DA varied greatly in founders, and differences were highly heritable in the inbred CC progeny. We identified a locus, containing 164 genes, linked to DA concentration in the dorsal striatum on chromosome X. We used RNAseq profiling of the ventral midbrain of two founders with substantial difference in striatal DA-C56BL/6 J and A/J-to highlight potential protein-coding candidates modulating this trait. Among the five differentially expressed genes within the locus, we found that the gene coding for the collagen IV alpha 6 chain (Col4a6) was expressed nine times less in A/J than in C57BL/6J. Using single cell RNA-seq data from developing human midbrain, we found that COL4A6 is highly expressed in radial glia-like cells and neuronal progenitors, indicating a role in neuronal development. Collagen IV alpha-6 chain (COL4A6) controls axogenesis in simple model organisms. Consistent with these findings, A/J mice had less striatal axonal branching than C57BL/6J mice. We tentatively conclude that DA concentration and axonal branching in dorsal striatum are modulated by COL4A6, possibly during development. Our study shows that genetic mapping based on an easily measured Central Nervous System (CNS) trait, using the CC population, combined with follow-up observations, can parse heritability of such a trait, and nominate novel functions for commonly expressed proteins.


Dissociable reward and timing signals in human midbrain and ventral striatum.
Reward prediction error (RPE) signals are central to current models of reward-learning. Temporal difference (TD) learning models posit that these signals should be modulated by predictions, not only of magnitude but also timing of reward. Here we show that BOLD activity in the VTA conforms to such TD predictions: responses to unexpected rewards are modulated by a temporal hazard function and activity between a predictive stimulus and reward is depressed in proportion to predicted reward. By contrast, BOLD activity in ventral striatum (VS) does not reflect a TD RPE, but instead encodes a signal on the variable relevant for behavior, here timing but not magnitude of reward. The results have important implications for dopaminergic models of cortico-striatal learning and suggest a modification of the conventional view that VS BOLD necessarily reflects inputs from dopaminergic VTA neurons signaling an RPE.


Spatiotemporal Determinants of Urban Leptospirosis Transmission: Four-Year Prospective Cohort Study of Slum Residents in Brazil.
Rat-borne leptospirosis is an emerging zoonotic disease in urban slum settlements for which there are no adequate control measures. The challenge in elucidating risk factors and informing approaches for prevention is the complex and heterogeneous environment within slums, which vary at fine spatial scales and influence transmission of the bacterial agent. We performed a prospective study of 2,003 slum residents in the city of Salvador, Brazil during a four-year period (2003-2007) and used a spatiotemporal modelling approach to delineate the dynamics of leptospiral transmission. Household interviews and Geographical Information System surveys were performed annually to evaluate risk exposures and environmental transmission sources. We completed annual serosurveys to ascertain leptospiral infection based on serological evidence. Among the 1,730 (86%) individuals who completed at least one year of follow-up, the infection rate was 35.4 (95% CI, 30.7-40.6) per 1,000 annual follow-up events. Male gender, illiteracy, and age were independently associated with infection risk. Environmental risk factors included rat infestation (OR 1.46, 95% CI, 1.00-2.16), contact with mud (OR 1.57, 95% CI 1.17-2.17) and lower household elevation (OR 0.92 per 10m increase in elevation, 95% CI 0.82-1.04). The spatial distribution of infection risk was highly heterogeneous and varied across small scales. Fixed effects in the spatiotemporal model accounted for the majority of the spatial variation in risk, but there was a significant residual component that was best explained by the spatial random effect. Although infection risk varied between years, the spatial distribution of risk associated with fixed and random effects did not vary temporally. Specific "hot-spots" consistently had higher transmission risk during study years. The risk for leptospiral infection in urban slums is determined in large part by structural features, both social and environmental. Our findings indicate that topographic factors such as household elevation and inadequate drainage increase risk by promoting contact with mud and suggest that the soil-water interface serves as the environmental reservoir for spillover transmission. The use of a spatiotemporal approach allowed the identification of geographic outliers with unexplained risk patterns. This approach, in addition to guiding targeted community-based interventions and identifying new hypotheses, may have general applicability towards addressing environmentally-transmitted diseases that have emerged in complex urban slum settings.


Annual and seasonal patterns in etiologies of pediatric community-acquired pneumonia due to respiratory viruses and Mycoplasma pneumoniae requiring hospitalization in South Korea.
Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. The present study provides fundamental data to establish public health policies to decrease the disease burden due to CAP and improve pediatric health.


Factors associated with negative direct sputum examination in Asian and African HIV-infected patients with tuberculosis (ANRS 1260).
To identify factors associated with negative direct sputum examination among African and Cambodian patients co-infected by Mycobacterium tuberculosis and HIV. Prospective multicenter study (ANRS1260) conducted in Cambodia, Senegal and Central African Republic. Univariate and multivariate analyses (logistic regression) were used to identify clinical and radiological features associated with negative direct sputum examination in HIV-infected patients with positive M. tuberculosis culture on Lowenstein-Jensen medium. Between September 2002 and December 2005, 175 co-infected patients were hospitalized with at least one respiratory symptom and pulmonary radiographic anomaly. Acid-fast bacillus (AFB) examination was positive in sputum samples from 110 subjects (63%) and negative in 65 patients (37%). Most patients were at an advanced stage of HIV disease (92% at stage III or IV of the WHO classification) with a median CD4 cell count of 36/mm³. In this context, we found that sputum AFB negativity was more frequent in co-infected subjects with associated respiratory tract infections (OR = 2.8 [95%CI:1.1-7.0]), dyspnea (OR = 2.5 [95%CI:1.1-5.6]), and localized interstitial opacities (OR = 3.1 [95%CI:1.3-7.6]), but was less frequent with CD4 ≤ 50/mm³ (OR = 0.4 [95%CI:0.2-0.90), adenopathies (OR = 0.4 [95%CI:0.2-0.93]) and cavitation (OR = 0.1 [95%CI:0.03-0.6]). One novel finding of this study is the association between concomitant respiratory tract infection and negative sputum AFB, particularly in Cambodia. This finding suggests that repeating AFB testing in AFB-negative patients should be conducted when broad spectrum antibiotic treatment does not lead to complete recovery from respiratory symptoms. In HIV-infected patients with a CD4 cell count below 50/mm3 without an identified cause of pneumonia, systematic AFB direct sputum examination is justified because of atypical clinical features (without cavitation) and high pulmonary mycobacterial burden.


Establishing human leukemia xenograft mouse models by implanting human bone marrow-like scaffold-based niches.
To begin to understand the mechanisms that regulate self-renewal, differentiation, and transformation of human hematopoietic stem cells or to evaluate the efficacy of novel treatment modalities, stem cells need to be studied in their own species-specific microenvironment. By implanting ceramic scaffolds coated with human mesenchymal stromal cells into immune-deficient mice, we were able to mimic the human bone marrow niche. Thus, we have established a human leukemia xenograft mouse model in which a large cohort of patient samples successfully engrafted, which covered all of the important genetic and risk subgroups. We found that by providing a humanized environment, stem cell self-renewal properties were better maintained as determined by serial transplantation assays and genome-wide transcriptome studies, and less clonal drift was observed as determined by exome sequencing. The human leukemia xenograft mouse models that we have established here will serve as an excellent resource for future studies aimed at exploring novel therapeutic approaches.


GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.
We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.


Zebrafish hox genes: genomic organization and modified colinear expression patterns in the trunk.
The Hox genes are implicated in conferring regional identity to the anteroposterior axis of the developing embryo. We have characterized the organization and expression of hox genes in the teleost zebrafish (Danio rerio), and compared our findings with those made for the tetrapod vertebrates. We have isolated 32 zebrafish hox genes, primarily via 3'RACE-PCR, and analyzed their linkage relationships using somatic cell hybrids. We find that in comparison to the tetrapods, zebrafish has several additional hox genes, both within and beyond the expected 4 hox clusters (A-D). For example, we have isolated a member of hox paralogue group 8 lying on the hoxa cluster, and a member of hox paralogue group 10 lying on the b cluster, no equivalent genes have been reported for mouse or human. Beyond the 4 clusters (A-D) we have isolated a further 3 hox genes (the hoxx and y genes), which according to their sequence homologies lie in paralogue groups 4, 6, and 9. The hoxx4 and hoxx9 genes occur on the same set of hybrid chromosomes, hinting at the possibility of an additional hox cluster for the zebrafish. Similar to their tetrapod counterparts, zebrafish hox genes (including those with no direct tetrapod equivalent) demonstrate colinear expression along the anteroposterior (AP) axis of the embryo. However, in comparison to the tetrapods, anterior hox expression limits are compacted over a short AP region; some members of adjacent paralogue groups have equivalent limits. It has been proposed that during vertebrate evolution, the anterior limits of Hox gene expression have become dispersed along the AP axis allowing the genes to take on novel patterning roles and thus leading to increased axial complexity. In the teleost zebrafish, axial organization is relatively simple in comparison to that of the tetrapod vertebrates; this may be reflected by the less dispersed expression domains of the zebrafish hox genes.


Natural products for cancer chemotherapy.
For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti-tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side-effects increase the demand for novel anti-tumour drugs active against untreatable tumours, with fewer side-effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti-tumour compounds of the future.


p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases.
Cdc25A, a phosphatase essential for G1-S transition, associates with, dephosphorylates, and activates the cell cycle kinase cyclin E-cdk2. p21CIP1 and p27 are cyclin-dependent kinase (cdk) inhibitors induced by growth-suppressive signals such as p53 and transforming growth factor beta (TGF-beta). We have identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy (or RR LFG) motif of the p21CIP1 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cyclin E- or cyclin A-cdk2 in vitro and in vivo and selectively interfere with the dephosphorylation of cyclin E-cdk2. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. Cdc25A also protects DNA replication in Xenopus egg extracts from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A-induced oncogenic and p53- or TGF-beta-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.


Human-like rodent amyloid-beta-peptide determines Alzheimer pathology in aged wild-type Octodon degu.
It is generally accepted that human Alzheimer's disease (AD) neuropathology markers are completely absent in rodent brains. We report here that an aged wild-type South American rodent, Octodon degu, expresses neuronal beta-amyloid precursor protein (beta-APP695) displaying both intracellular and extracellular deposits of amyloid-beta-peptide (Abeta), intracellular accumulations of tau-protein and ubiquitin, a strong astrocytic response and acetylcholinesterase (AChE)-rich pyramidal neurons. The high amino acid homology (97.5%) between deguAbeta and humanAbeta sequences is probably a major factor in the appearance of AD markers in this aged rodent. Our results indicate that aged O. degu constitutes the first wild-type rodent model for neurodegenerative processes associated to AD.


Assessment of microRNA expression in mouse epididymal epithelial cells and spermatozoa by next generation sequencing.
The mammalian epididymis is a highly specialized region of the male reproductive tract that is lined with a continuous layer of epithelial cells that display a remarkable level of regionalized secretory and absorptive activity. The luminal environment created by this combined secretory and absorptive activity is directly responsible for promoting the functional maturation of spermatozoa and their maintenance in a quiescent and viable state prior to ejaculation. This study was designed to identify the complement of microRNAs (miRNAs) that are expressed within the mouse epididymal epithelial cells and the maturing populations of spermatozoa. Through the use of Next Generation Sequencing technology we have demonstrated that both epididymal epithelial cells and spermatozoa harbour a complex repertoire of miRNAs that have substantially different expression profiles along the length of the tract. These data, deposited in the Gene Expression Omnibus (GEO) with the accession numbers GSE70197 and GSE70198, afford valuable insight into the post-transcriptional control of gene expression within the epididymis and provide the first evidence for the dynamic transformation of the miRNA content of maturing sperm cells. Ultimately such information promises to inform our understanding of the aetiology of male infertility. Herein we provide a detailed description of the methodology used to generate these important data.


Arthroscopic Partial Meniscectomy or Conservative Treatment for Nonobstructive Meniscal Tears: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
To conduct a meta-analysis of randomized controlled trials comparing the outcome of arthroscopic partial meniscectomy (APM) with conservative treatment in adults with nonobstructive meniscal tears and to recommend a treatment of choice. We systematically searched the databases of MEDLINE, Excerpta Medica Database, Cochrane, the National Health Service Centre for Reviews and Dissemination, and Physiotherapy Evidence Database from inception to May 2, 2016. Two authors independently searched the literature and selected eligible studies. The meta-analyses used a random-effects model. The primary outcome was physical function, measured by knee-specific patient-reported outcomes. Secondary outcomes included knee pain, activity level, the progression of osteoarthritis, adverse events, general health, and quality of life. We included 6 randomized controlled trials, with a total of 773 patients, of whom 378 were randomized to APM and 395 were randomized to the control treatment. After pooling the data of 5 studies, we found small significant differences in favor of the APM group for physical function at 2 to 3 months (mean difference [MD] = 3.31; 95% confidence interval [CI] = 0.69-5.93; P = .01; I(2) = 0% [Lysholm knee score]), and at 6 months (MD = 3.56; 95% CI = 0.24-6.88; P = .04; I(2) = 0% (Knee injury and Osteoarthritis Outcome Score [KOOS] and Western Ontario and McMaster Universities Osteoarthritis Index); standardized MD = 0.17; 95% CI = 0.01-0.32; P = .03; I(2) = 0% [Lysholm knee score, KOOS, and Western Ontario and McMaster Universities Osteoarthritis Index]). We also found small significant differences for pain at 6 months (MD = 3.56; 95% CI = 0.18-6.95; P = .04; I(2) = 0% [KOOS] and MD = 0.56; 95% CI = 0.28-0.83; P ≤ .0001; I(2) = 0% [visual analog scale and numeric rating scale]). We found no significant differences after 12 and 24 months. We found small, although statistically significant, favorable results of APM up to 6 months for physical function and pain. However, we found no differences at longer follow-up. Level I, systematic review and meta-analysis of Level I studies.


Age at introduction of solid foods and feeding difficulties in childhood: findings from the Southampton Women's Survey.
This study aimed to determine whether age at introduction of solid foods was associated with feeding difficulties at 3 years of age. The present study was carried out using data from the Southampton Women's Survey (SWS). Women enrolled in the SWS who subsequently became pregnant were followed-up during pregnancy and postpartum, and the offspring have been studied through childhood. Maternal socio-demographic and anthropometric data and child anthropometric and feeding data were collected through interviews and self-administered questionnaires. When the children were 3 years of age, mothers/carers rated six potential child feeding difficulty questions on a four-point Likert scale, including one general question and five specific feeding difficulty questions. Age at introduction of solids as a predictor of feeding difficulties was examined in 2389 mother-child pairs, adjusting for child (age last breast fed, sex, gestation) and maternal characteristics (parity, pre-pregnancy BMI, age, education, employment, parenting difficulties, diet quality). The majority of mothers/carers (61 %) reported some feeding difficulties (general feeding difficulty question) at 3 years of age, specifically with their child eating enough food (61 %), eating the right food (66 %) and being choosy with food (74 %). Children who were introduced to solids ≥6 months had a lower risk of feeding difficulties (RR 0·73; 95 % CI 0·59, 0·91, P=0·004) than children who were introduced to solids between 4 and 6 months. No other significant associations were found. There were few associations between feeding difficulties in relation to age at introduction of solid foods. However, general feeding difficulties were less common among infants introduced to solid foods ≥6 months of age.


Validation of OMERACT preliminary rheumatoid arthritis flare domains in the NOR-DMARD study.
Domains identified as a result of qualitative research and Delphi exercises to assess rheumatoid arthritis (RA) flare include pain, function, swollen and tender joints, patient and physician global, laboratory measures, participation, stiffness, self-management and fatigue. Here we examine aspects of construct and content validity of these domains in a longitudinal observational study. A total of 1195 patients with RA treated with non-biological disease-modifying antirheumatic drugs (DMARDs) or biologics were eligible for the analyses. Working definitions of 'flare' included patient-reported worsening between 3 and 6 months (primary) and treatment change at 6 months (DMARDs and/or systemic corticosteroids) (secondary). Available outcome measures were mapped to the flare domains. Changes between 3 and 6 months were compared between patients with and without 'flare'. Convergent and divergent construct validity and content validity were assessed by correlation analyses and logistic regression analysis, respectively. Applying the flare working definition based on patient-reported worsening, standardised mean differences (SMDs) were >0.5 for the majority of outcomes. The largest SMDs were observed for Pain visual analogue scale (1.30), SF-36 Bodily pain (1.24), Patient global (1.20) and morning stiffness intensity (1.17). The flare working definition based on treatment change yielded lower SMDs (<0.5 for most variables). Consistently stronger intradomain than corresponding interdomain correlations supported convergent and divergent validity of the domains. Probing a flare definition via outcome measures, the identified flare domains discriminated well between patients with and without worsening. Interdomain and intradomain correlation and logistic regression analyses provide further support for construct and content validity of the identified flare domains.


Sequencing Lys-N proteolytic peptides by ESI and MALDI tandem mass spectrometry.
In this study, we explored the MS/MS behavior of various synthetic peptides that possess a lysine residue at the N-terminal position. These peptides were designed to mimic peptides produced upon proteolysis by the Lys-N enzyme, a metalloendopeptidase issued from a Japanese fungus Grifola frondosa that was recently investigated in proteomic studies as an alternative to trypsin digestion, as a specific cleavage at the amide X-Lys chain is obtained that provides N-terminal lysine peptide fragments. In contrast to tryptic peptides exhibiting a lysine or arginine residue solely at the C-terminal position, and are thus devoid of such basic amino acids within the sequence, these Lys-N proteolytic peptides can contain the highly basic arginine residue anywhere within the peptide chain. The fragmentation patterns of such sequences with the ESI-QqTOF and MALDI-TOF/TOF mass spectrometers commonly used in proteomic bottom-up experiments were investigated.


Nanoscale infrared spectroscopy as a non-destructive probe of extraterrestrial samples.
Advances in the spatial resolution of modern analytical techniques have tremendously augmented the scientific insight gained from the analysis of natural samples. Yet, while techniques for the elemental and structural characterization of samples have achieved sub-nanometre spatial resolution, infrared spectral mapping of geochemical samples at vibrational 'fingerprint' wavelengths has remained restricted to spatial scales >10 μm. Nevertheless, infrared spectroscopy remains an invaluable contactless probe of chemical structure, details of which offer clues to the formation history of minerals. Here we report on the successful implementation of infrared near-field imaging, spectroscopy and analysis techniques capable of sub-micron scale mineral identification within natural samples, including a chondrule from the Murchison meteorite and a cometary dust grain (Iris) from NASA's Stardust mission. Complementary to scanning electron microscopy, energy-dispersive X-ray spectroscopy and transmission electron microscopy probes, this work evidences a similarity between chondritic and cometary materials, and inaugurates a new era of infrared nano-spectroscopy applied to small and invaluable extraterrestrial samples.


highly selective amino acid salt solutions as absorption liquid for CO(2) capture in gas-liquid membrane contactors.
The strong anthropogenic increase in the emission of CO(2) and the related environmental impact force the developments towards sustainability and carbon capture and storage (CCS). In the present work, we combine the high product yields and selectivities of CO(2) absorption processes with the advantages of membrane technology in a membrane contactor for the separation of CO(2) from CH(4) using amino acid salt solutions as competitive absorption liquid to alkanol amine solutions. Amino acids, such as sarcosine, have the same functionality as alkanol amines (e.g., monoethanolamine=MEA), but in contrast, they exhibit a better oxidative stability and resistance to degradation. In addition, they can be made nonvolatile by adding a salt functionality, which significantly reduces the liquid loss due to evaporation at elevated temperatures in the desorber. Membrane contactor experiments using CO(2)/CH(4) feed mixtures to evaluate the overall process performance, including a full absorption/desorption cycle show that even without a temperature difference between absorber and desorber, a CO(2)/CH(4) selectivity of over 70 can be easily achieved with the sarcosine salt solution as absorption liquid. This selectivity reaches values of 120 at a temperature difference between absorber and desorber of 35 degrees C, compared to a value of only 60 for MEA under the same conditions. Although CO(2) permeance values are somewhat lower than the values obtained for MEA, the results clearly show the potential of amino acid salt solutions as competitive absorption liquids for the energy efficient removal of CO(2). In addition, due to the low absorption of CH(4) in sarcosine compared to MEA, the loss of CH(4) is reduced and significantly higher CH(4) product yields can be obtained.


Animal bites to the head and neck.
There is controversy regarding the timing of repair and the use of prophylactic antibiotics in patients with animal bites to the head and neck. In this paper we review our experience with such wounds, and address surgical management and the use of prophylactic antibiotic therapy. A retrospective review of the medical records of 29 patients with animal bites to the head and neck was conducted. All patients were seen and treated at a large teaching hospital in Houston, Texas over an 18-month period. Seventy-six percent of our patients were 12 years old or younger. Most came to the emergency room soon after sustaining their injuries, and their wounds were repaired primarily with favorable results. There were no cases of wound infection. Ninety percent were treated with prophylactic antibiotics. The wounds of the 10% of patients who did receive antibiotics were similar to those of the other patients and healed well without infection. Wounds resulting from animal bites to the head and neck can be repaired primarily when treated shortly after injury. Further prospective, randomized studies are recommended to evaluate the effectiveness and necessity of prophylactic antibiotic therapy in this patient population.


The Self-Regulation of Conformity: Mental Contrasting With Implementation Intentions (MCII).
The self-regulation of conformity has received little attention in previous research. This is surprising because group majorities can exert social strong pressure on people, leading them to overlook the pursuit of their own goals. We investigated if self-regulation by mental contrasting with implementation intentions (MCII) can reduce people's tendency to conform and facilitate their own goal-pursuit despite deviant majority influence. In a computer-based logical reasoning task, we exposed participants to a conformity manipulation, where we presented bogus diagrams showing the supposedly correct answers of a majority ingroup. Compared to participants who were not given a self-regulation strategy (Studies 1, 2, and 4) or who were in an active control group (Study 3), MCII helped participants to self-regulate conforming behavior in trying to solve the task and to independently solve the logical reasoning task, as indicated by increases in correct answers in the task. The findings suggest that MCII is an effective strategy to regulate people's tendency to conform and supports them to attain their goal despite deviant majority influence.


Strategies to maximise study retention and limit attrition bias in a prospective cohort study of men reporting a history of injecting drug use released from prison: the prison and transition health study.
There are significant challenges associated with studies of people released from custodial settings, including loss to follow-up in the community. Interpretation of findings with consideration of differences between those followed up and those not followed up is critical in the development of evidence-informed policies and practices. We describe attrition bias in the Prison and Transition Health (PATH) prospective cohort study, and strategies employed to minimise attrition. PATH involves 400 men with a history of injecting drug use recruited from three prisons in Victoria, Australia. Four interviews were conducted: one pre-release ('baseline') and three interviews at approximately 3, 12, and 24 months post-release ('follow-up'). We assessed differences in baseline characteristics between those retained and not retained in the study, reporting mean differences and 95% confidence intervals (95% CIs). RESULTS: Most participants (85%) completed at least one follow-up interview and 162 (42%) completed all three follow-up interviews. Retained participants were younger than those lost to follow-up (mean diff - 3.1 years, 95% CI -5.3, - 0.9). There were no other statistically significant differences observed in baseline characteristics. The high proportion of participants retained in the PATH cohort study via comprehensive follow-up procedures, coupled with extensive record linkage to a range of administrative datasets, is a considerable strength of the study. Our findings highlight how strategic and comprehensive follow-up procedures, frequent contact with participants and secondary contacts, and established working relationships with the relevant government departments can improve study retention and potentially minimise attrition bias.


Full-length mRNA sequencing and gene expression profiling reveal broad involvement of natural antisense transcript gene pairs in pepper development and response to stresses.
Pepper is an important vegetable with great economic value and unique biological features. In the past few years, significant development has been made toward understanding the huge complex pepper genome; however, pepper functional genomics has not been well studied. To better understand the pepper gene structure and pepper gene regulation, we conducted full-length mRNA sequencing by PacBio sequencing and obtained 57 862 high-quality full-length mRNA sequences derived from 18 362 previously annotated and 5769 newly detected genes. New gene models were built that combined the full-length mRNA sequences and corrected approximately 500 fragmented gene models from previous annotations. Based on the full-length mRNA, we identified 4114 and 5880 pepper genes forming natural antisense transcript (NAT) genes in-cis and in-trans, respectively. Most of these genes accumulate small RNAs in their overlapping regions. By analyzing these NAT gene expression patterns in our transcriptome data, we identified many NAT pairs responsive to a variety of biological processes in pepper. Pepper formate dehydrogenase 1 (FDH1), which is required for R-gene-mediated disease resistance, may be regulated by nat-siRNAs and participate in a positive feedback loop in salicylic acid biosynthesis during resistance responses. Several cis-NAT pairs and subgroups of trans-NAT genes were responsive to pepper pericarp and placenta development, which may play roles in capsanthin and capsaicin biosynthesis. Using a comparative genomics approach, the evolutionary mechanisms of cis-NATs were investigated, and we found that an increase in intergenic sequences accounted for the loss of most cis-NATs, while transposon insertion contributed to the formation of most new cis-NATs. OPEN RESEARCH BADGES: This article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at http://bigd.big.ac.cn/gsa Accession number, CRA001412.


Diagnosis and treatment of Plasmodium vivax malaria.
Infection by Plasmodium vivax poses unique challenges for diagnosis and treatment. Relatively low numbers of parasites in peripheral circulation may be difficult to confirm, and patients infected by dormant liver stages cannot be diagnosed before activation and the ensuing relapse. Radical cure thus requires therapy aimed at both the blood stages of the parasite (blood schizontocidal) and prevention of subsequent relapses (hypnozoitocidal). Chloroquine and primaquine have been the companion therapies of choice for the treatment of vivax malaria since the 1950s. Confirmed resistance to chloroquine occurs in much of the vivax endemic world and demands the investigation of alternative blood schizontocidal companions in radical cure. Such a shift in practice necessitates investigation of the safety and efficacy of primaquine when administered with those therapies, and the toxicity profile of such combination treatments, particularly in patients with glucose-6-phosphate dehydrogenase deficiency. These clinical studies are confounded by the frequency and timing of relapse among strains of P. vivax, and potentially by differing susceptibilities to primaquine. The inability to maintain this parasite in continuous in vitro culture greatly hinders new drug discovery. Development of safe and effective chemotherapies for vivax malaria for the coming decades requires overcoming these challenges.


Age-Related Differences in the Noninvasive Evaluation for Possible Coronary Artery Disease: Insights From the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial.
Although cardiovascular (CV) disease represents the leading cause of morbidity and mortality that increases with age, the best noninvasive test to identify older patients at risk for CV events remains unknown. To determine whether the prognostic utility of anatomic vs functional testing varies based on patient age. Prespecified analysis of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) study, which used a pragmatic comparative effectiveness design. Participants were enrolled from 193 sites across North America and comprised outpatients without known coronary artery disease (CAD) but with symptoms suggestive of CAD. Data were analyzed between October 2018 and April 2019. Randomization to noninvasive testing with coronary computed tomographic angiography or functional testing. The composite of CV death/myocardial infarction (MI) over a median follow-up of 25 months. Among 10 003 PROMISE patients, we included the 8966 who received the noninvasive test to which they were randomized and had interpretable results; 6378 (71.1%) were younger than 65 years, 2062 (23.0%) were between ages 65 and 74 years, and 526 (5.9%) were 75 years and older. More than half of participants were women (4720 of 8966 [52.6%]). Only a minority of patients were of nonwhite race/ethnicity, a proportion that was lower among the older age groups (1071 of 6378 [16.8%] for <65 years; 258 of 2062 [12.5%] for age 65-74 years; 41 of 526 [7.8%] for ≥75 years). Compared with patients younger than 65 years, older patients were more likely to have a positive test result (age 65-74 years: odds ratio, 1.65; 95% CI, 1.42-1.91; age ≥75 years: odds ratio, 2.32; 95% CI, 1.83-2.95), regardless of noninvasive test completed. A positive functional test result was not associated with CV death/MI in patients younger than 65 years (hazard ratio [HR], 1.09; 95% CI, 0.43-2.82) but it was among older patients (age 65-74 years: HR, 3.18; 95% CI, 1.44-7.01; age ≥75 years: HR, 6.55; 95% CI, 1.46-29.35). Conversely, a positive anatomic test result was associated with CV death/MI among patients younger than 65 years (HR, 3.04; 95% CI, 1.46-6.34) but not among older patients (age, 65-74 years: HR, 0.67; 95% CI, 0.15-2.94; age ≥75 years: HR, 1.07; 95% CI, 0.22-5.34; P for interaction = .01). An elevated coronary artery calcium score was predictive of events in patients younger than 65 years (HR, 2.73; 95% CI, 1.31-5.69) but not for older patients (age 65-74 years: HR, 0.44; 95% CI, 0.14-1.42; age ≥75 years: HR, 1.31; 95% CI, 0.25-6.88). Older patients with stable symptoms suggestive of CAD are more likely to have a positive noninvasive test result and more coronary artery calcium. However, only a positive functional test result was associated with risk of CV death/MI. Age-specific approaches to noninvasive evaluation of CAD should be further examined. ClinicalTrials.gov identifier: NCT01174550.


Drugs related to motor vehicle crashes in northern European countries: a study of fatally injured drivers.
The aim of this study was to find which drugs and drug combinations were most common in drivers who died, in particular, in single vehicle crashes where the responsibility for the crash would be referred to the driver killed. The study included all available blood samples from drivers, who died within 24h of the accident, in the years 2001 and 2002 in the five Nordic countries (total population about 24 million inhabitants). The samples were analysed for more than 200 different drugs in addition to alcohol, using a similar analytical programme and cut-off limits in all countries. In three countries (Finland, Norway and Sweden) blood samples were available for more than 70% of the drivers, allowing representative prevalence data to be collected. 60% of the drivers in single vehicle crashes had alcohol and/or drug in their blood samples, compared with 30% of drivers killed in collisions with other vehicles. In single vehicle accidents, 66% of the drivers under 30 years of age had alcohol and/or drugs in their blood (alcohol only - 40%; drugs only - 12%; alcohol and drugs - 14%). The drugs found were mostly illicit drugs and psychoactive medicinal drugs with warning labels (in 57% and 58% respectively of the drivers under 30 with drugs present). Similar findings were obtained for drivers 30-49 years of age (63% with alcohol and/or drugs). In drivers aged 50 years and above, killed in single vehicle crashes (48% with alcohol and/or drugs) illicit drugs were found in only one case, and psychoactive medicinal drugs were detected less frequently than in younger age groups. In 75% of single vehicle crashes, the driver was under 50 years. Thus, the majority of accidents where the drivers must be considered responsible, occurred with drivers who had recently used alcohol, or drugs, alone or in combination. The drugs involved were often illicit and/or psychoactive drugs with warning labels. Therefore a large proportion of single vehicle accidents appear to be preventable, if more effective measures against driving after intake of alcohol and drugs can be implemented.


Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef.
Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.