Mutations conferring aminoglycoside and spectinomycin resistance in Borrelia burgdorferi.
We have isolated and characterized in vitro mutants of the Lyme disease agent Borrelia burgdorferi that are resistant to spectinomycin, kanamycin, gentamicin, or streptomycin, antibiotics that target the small subunit of the ribosome. 16S rRNA mutations A1185G and C1186U, homologous to Escherichia coli nucleotides A1191 and C1192, conferred >2,200-fold and 1,300-fold resistance to spectinomycin, respectively. A 16S rRNA A1402G mutation, homologous to E. coli A1408, conferred >90-fold resistance to kanamycin and >240-fold resistance to gentamicin. Two mutations were identified in the gene for ribosomal protein S12, at a site homologous to E. coli residue Lys-87, in mutants selected in streptomycin. Substitutions at codon 88, K88R and K88E, conferred 7-fold resistance and 10-fold resistance, respectively, to streptomycin on B. burgdorferi. The 16S rRNA A1185G and C1186U mutations, associated with spectinomycin resistance, appeared in a population of B. burgdorferi parental strain B31 at a high frequency of 6 x 10(-6). These spectinomycin-resistant mutants successfully competed with the wild-type strain during 100 generations of coculture in vitro. The aminoglycoside-resistant mutants appeared at a frequency of 3 x 10(-9) to 1 x10(-7) in a population and were unable to compete with wild-type strain B31 after 100 generations. This is the first description of mutations in the B. burgdorferi ribosome that confer resistance to antibiotics. These results have implications for the evolution of antibiotic resistance, because the 16S rRNA mutations conferring spectinomycin resistance have no significant fitness cost in vitro, and for the development of new selectable markers.


Impacts of poor food availability on positive density dependence in a highly colonial seabird.
For species with positive density dependence, costs and benefits of increasing density may depend on environmental conditions, but this has seldom been tested. By examining a colonial seabird (common guillemot) over a period of unprecedented poor food availability, we test two contrasting hypotheses suggesting that birds breeding at high density have: (i) greater leeway to increase foraging effort owing to more effective defence of unattended chicks against predators; and (ii) less leeway, owing to more attacks on unattended chicks by neighbouring adults. Supporting hypothesis 1, birds at high density increased provisioning rates and hence survival of chicks by foraging simultaneously with their partners, whereas at low density, unattended chicks were liable to be killed by predatory gulls and, unexpectedly, razorbills. Simultaneously, supporting hypothesis 2, heightened aggression towards unattended chicks at high density frequently resulted in infanticide, undermining benefits from collective defence against predators. Consequently, over 25 years, the magnitude of positive density dependence was independent of mean breeding success. These data indicate previously unsuspected trade-offs between costs and benefits of increasing density under changing environments. Previous generalizations about the importance of high density for reproductive success have so far remained robust, but such trade-offs could have unpredictable consequences for future population dynamics.


Long-term oral exposure to bisphenol A induces glucose intolerance and insulin resistance.
Bisphenol A (BPA) is a widely used endocrine disruptor. Recent epidemiologic results have suggested an association between exposure to BPA and cardiovascular disease, type 2 diabetes, and obesity. We investigated the in vivo effects of long-term oral exposure to BPA on insulin resistance and glucose intolerance. In the present study, 4- to 6-week-old male mice on a high-fat diet (HFD) were treated with 50 μg/kg body weight per day of BPA orally for 12 weeks. Long-term oral exposure to BPA along with an HFD for 12 weeks induced glucose intolerance in growing male mice. Intraperitoneal glucose tolerance tests showed that the mice that received an HFD and BPA exhibited a significantly larger area under the curve than did those that received an HFD only (119.9±16.8 vs. 97.9±18.2 mM/min, P=0.027). Body weight, percentage of white adipose tissue, and percentage of body fat did not differ between the two groups of mice. However, treatment with BPA reduced Akt phosphorylation at position Thr308 and GSK3β phosphorylation at position Ser9 in skeletal muscle. BPA tended to decrease serum adiponectin levels and to increase serum interleukin 6 and tumor necrosis factor α, although these findings were not statistically significant. Treatment with BPA did not induce any detrimental changes in the islet area or morphology or the insulin content of β cells. In conclusion, long-term oral exposure to BPA induced glucose intolerance and insulin resistance in growing mice. Decreased Akt phosphorylation in skeletal muscle by way of altered serum adipocytokine levels might be one mechanism by which BPA induces glucose intolerance.


Therapy and prognostic features of primary clear cell carcinoma of the liver.
To clarify the therapeutic strategies and prognosis factors of primary clear cell carcinoma of the liver (PCCCL). The clinical pathological data of 64 patients with PCCCL treated with hepatectomy in our hospital from January 2000 to January 2006 were analyzed retrospectively. The patients were divided into two groups to make treatment analysis: curative resection only (n = 40); and curative resection and postoperative chemotherapy with calcium folinate and tegafur (n = 24). Meanwhile, the PCCCL patients were subdivided into two subgroups on the basis of the proportion of clear cells in the tumor for pathological analysis. There were 36 cases in subgroup A for which the proportion of clear cells was more than 70%, and 28 cases in subgroup B for which the proportion was less or equal to 70%, comparing analysis of median survival time of the counterpart groups. Univariate and multivariate analyses were performed to examine factors that affected clinical prognosis, recurrence and metastasis. Median survival period of the curative surgery group was 38 mo, while the counterpart was 41 mo. Median survival period for group A was 41 mo, while group B was 19 mo. The Kaplan-Meier method showed that capsule formation, preoperative liver function, hepatitis C virus infection, large vascular invasion and multiple tumor occurrences were related to disease-free survival. Cox regression analysis showed that the clear cell ratio, capsule formation, preoperative liver function and large vascular invasion were independent risk factors for overall survival. Postoperative chemotherapy has no obvious effect on survival of patients with PCCCL. Clear cell ratio, capsule formation, preoperative liver function, and vascular invasion were independent risk factors for prognosis.


Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a condition in which continuous bronchodilation may have clinical advantages. This study evaluated salmeterol, a beta-agonist bronchodilator with a duration of action substantially longer than that of short-acting beta-agonists, compared with ipratropium, an anticholinergic bronchodilator, and placebo in patients with COPD. Four hundred and five patients with COPD received either salmeterol 42 microg twice daily, ipratropium bromide 36 microg four times daily, or placebo for 12 wk in this randomized, double-blind, parallel-group study. Patients were stratified on the basis of bronchodilator response to albuterol (> 12% and > 200-ml improvement) and were randomized within each stratum. Bronchodilator response was measured over 12 h four times during the treatment period. Salmeterol provided similar maximal bronchodilatation to ipratropium but had a longer duration of action and a more constant bronchodilatory effect with no evidence of bronchodilator tolerance. Both active treatments were well tolerated. Salmeterol was an effective bronchodilator with a consistent effect over this 12-wk study in patients with COPD, including those "unresponsive" to albuterol. The long duration of action of salmeterol offers the advantage of twice daily dosing compared with the required four times a day dosing with ipratropium.


Safety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder: findings from the Systematic Treatment Enhancement Program for Bipolar Disorder.
Practitioners often combine 2 or more second-generation antipsychotics (SGAs) in patients with bipolar disorder, despite an absence of data to support their safety, tolerability, or efficacy. This study sought to evaluate the safety and tolerability of SGA polytherapy compared to SGA monotherapy in bipolar disorder patients receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A longitudinal cohort of 1,958 patients who were prescribed at least 1 SGA was drawn from 4,035 bipolar patients in STEP-BD recruited between November 1999 and July 2005 and assessed at least quarterly for a mean duration of 21 months. Main outcome measures were the mean quarterly prevalence of adverse events, medical and psychiatric service usage, Global Assessment of Functioning ratings, and percentage of days spent well. Almost 10% of patients taking SGAs were prescribed SGA polytherapy. After controlling for illness onset, age, baseline illness severity, and medication load, patients prescribed SGA polytherapy, compared to monotherapy, exhibited more dry mouth (number needed to harm [NNH] = 4), tremor (NNH = 6), sedation (NNH = 8), sexual dysfunction (NNH = 8), and constipation (NNH = 11) and were almost 3 times as likely to incur more psychiatric and medical care; there was no association with greater global functioning scores or percentage of days spent well. Although SGA polytherapy was fairly common in bipolar disorder, it was associated with increased side effects and health service use but not with improved clinical status or function. Thus, SGA polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.


Timing of human insulin-like growth factor-1 gene transfer in reinnervating laryngeal muscle.
The authors have designed a rat laryngeal paralysis model to study gene transfer strategies using a muscle-specific expression system to enhance local delivery of human insulin-like growth factor-1 (hIGF-1). In preliminary studies, a nonviral vector containing the alpha-actin promoter and human hIGF-1 sequence produced both neurotrophic and myotrophic effects 1 month after single injection of plasmid formulation into paralyzed rat thyroarytenoid muscle in vivo. Based on these findings, it is hypothesized that the effects of hIGF-1 will enhance the results of laryngeal muscle innervation procedures. The timing of gene delivery relative to nerve repair is likely to be important, to optimize the results. Prospective analysis. The effects of nonviral gene transfer for the delivery of hIGF-1 were evaluated in rats treated immediately following recurrent laryngeal nerve transection and repair and in rats receiving a delayed treatment schedule, 30 days after nerve transection and repair. Gene transfer efficiency was determined using polymerase chain reaction and reverse transcriptase-polymerase chain reaction techniques. Muscle fiber diameter, motor endplate length, and percentage of motor endplates with nerve contact were examined to assess hIGF-1 trophic effects. Compared with reinnervated untreated control samples, both early and delayed hIGF-1 transfer resulted in significant increase in muscle fiber diameter. Motor endplate length was significantly decreased and nerve/motor endplate contact was significantly increased following delayed gene transfer, but not after early treatment. We infer from results of the study that delayed hIGF-1 gene transfer delivered by a single intramuscular injection will enhance the process of muscle reinnervation. The clinical relevance of these findings supports the future application of gene therapy using nonviral vectors for management of laryngeal paralysis and other peripheral nerve injuries.


A cluster-randomized trial determining the efficacy of caterpillar cereal as a locally available and sustainable complementary food to prevent stunting and anaemia.
We conducted a cluster-randomized controlled trial to assess the efficacy of a cereal made from caterpillars, a micronutrient-rich, locally available alternative animal-source food, on reducing stunting and anaemia in infants in the Democratic Republic of Congo. Six-month-old infants were cluster randomized to receive either caterpillar cereal daily until 18 months of age or the usual diet. At 18 months of age, anthropometric measurements and biological samples were collected. The rural Equateur Province in the Democratic Republic of Congo. One hundred and seventy-five infants followed from 6 to 18 months of age. Stunting was common at 6 months (35%) and the prevalence increased until 18 months (69%). There was no difference in stunting prevalence at 18 months between the intervention and control groups (67% v. 71%, P = 0.69). Infants in the cereal group had higher Hb concentration than infants in the control group (10.7 v. 10.1 g/dl, P = 0.03) and fewer were anaemic (26 v. 50%, P = 0.006), although there was no difference in estimates of body Fe stores (6.7 v. 7.2 mg/kg body weight, P = 0.44). Supplementation of complementary foods with caterpillar cereal did not reduce the prevalence of stunting at 18 months of age. However, infants who consumed caterpillar cereal had higher Hb concentration and fewer were anaemic, suggesting that caterpillar cereal might have some beneficial effect. The high prevalence of stunting at 6 months and the lack of response to this micronutrient-rich supplement suggest that factors other than dietary deficiencies also contribute to stunting.


Knowledge-based iterative model reconstruction: Comparative image quality with low tube voltage cerebral CT angiography.
The aim of this study was to compare image quality of low tube voltage cerebral computed tomography angiography (CTA) reconstructed with knowledge-based iterative model reconstruction (IMR), filtered back projection (FBP), and hybrid iterative reconstruction (HIR).A total of 101 patients with suspected cerebrovascular diseases were enrolled and randomized into 2 groups, 100 kVp tube voltage (n = 53) and reduced tube voltage (80 kVp) (n = 48). Computed tomography data were reconstructed with IMR, FBP, and HIR algorithms. The image noise, vascular attenuation, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured and calculated. Two blinded radiologists independently evaluated image quality based on diagnostic confidence on a 3-point scale. Quantitative and qualitative assessments were compared between different groups and reconstruction subgroups.Vascular attenuation was higher in the reduced tube voltage group than in 100-kVp tube voltage group, but showed no significant difference within each group. In both groups, the image noise, vascular SNR, and CNR were significantly improved by IMR as compared with FBP and HIR. Inter-group comparison indicated that IMR with reduced tube voltage showed better image quality with lower image noise and higher vascular SNR and CNR than FBP and HIR at 100 kVp, but slightly inferior to IMR at 100 kVp. IMR also yields the best qualitative image quality, and improves the diagnostic confidence of atherosclerosis and aneurysm. Compared with the standard 120-kVp protocol (1.86mSv), the radiation doses of 100 kVp (1.13mSv) and 80 kVp (0.56mSv) were 39% and 70% less, respectively.The quantitative and qualitative image quality obtained by IMR was superior to that obtained by FBP and HIR for low tube voltage cerebral CTA.


Emergence of Developmental Delay in Infants and Toddlers With an FMR1 Mutation.
Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options. Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age. Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected. Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness.


Persistent dose-dependent changes in brain structure in young adults with low-to-moderate alcohol exposure in utero.
Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown. Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed (n = 11, age 19.5 ± 0.3 years) and control (n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range. There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses. These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood.


A role for all-trans-retinoic acid in the early steps of lymphatic vasculature development.
The molecular mechanisms that regulate the earliest steps of lymphatic vascular system development are unknown. To identify regulators of lymphatic competence and commitment, we used an in vitro vascular assay with mouse embryonic stem cell-derived embryoid bodies (EBs). We found that incubation with retinoic acid (RA) and, more potently, with RA in combination with cAMP, induced the expression of the lymphatic competence marker LYVE-1 in the vascular structures of the EBs. This effect was dependent on RA receptor (RAR)-α and protein kinase A signaling. RA-cAMP incubation also promoted the development of CD31+/LYVE-1+/Prox1+ cell clusters. In situ studies revealed that RAR-α is expressed by endothelial cells of the cardinal vein in ED 9.5-11.5 mouse embryos. Timed exposure of mouse and Xenopus embryos to excess of RA upregulated LYVE-1 and VEGFR-3 on embryonic veins and increased formation of Prox1-positive lymphatic progenitors. These findings indicate that RA signaling mediates the earliest steps of lymphatic vasculature development.


CORRELATION OF CLINICAL AND STRUCTURAL PROGRESSION WITH VISUAL ACUITY LOSS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 6-The MacTel Research Group.
To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity. An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization. One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (-1.40 ± 0.14 letters, P < 0.001). Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.


Adrenal venous sampling for catecholamines: a normal value study.
Pheochromocytomas are rare, but potentially fatal, neoplasms. The diagnosis and localization of pheochromocytoma can be challenging, and recently there has been some debate regarding the role for adrenal venous sampling (AVS). The utility of AVS in this setting is hampered by a lack of normative value data for adrenal vein catecholamine concentrations and the reliability of lateralization ratios. We sought to address these concerns by analyzing AVS catecholamine concentrations from patients who did not have pheochromocytoma. Eighteen patients underwent successful AVS for evaluation of cortisol-producing adrenal masses. All had normal 24-h urinary excretion of fractionated catecholamines and metanephrines. There was a wide range of catecholamine concentrations in both the right (epinephrine 389-118326 pg/ml; norepinephrine 156-11193 pg/ml) and left (epinephrine 113-9327 pg/ml; norepinephrine 229-2216 pg/ml) adrenal veins. The right adrenal vein-to-left adrenal vein epinephrine gradient was as high as 83:1 (median 2.1:1; P < 0.02). Although less striking, similar findings were also seen for norepinephrine. This report provides a reference range for adrenal vein catecholamine concentrations in nonpheochromocytoma patients and illustrates the wide variation in epinephrine and norepinephrine concentrations. Epinephrine and norepinephrine concentrations are statistically significantly higher in the right vs. the left adrenal vein; in the case of epinephrine, up to an 83-fold difference was found between the right and left adrenal veins. These data highlight why AVS should not be used in the investigation of adrenal pheochromocytoma.


Nuclear markers of Danube Sturgeons hybridization.
Acipenseriformes are composed of 25 sturgeon species and two paddlefish species distributed exclusively in the northern hemisphere. The Danube River and the Black Sea were originally inhabited by six sturgeon species but two are extinct and only four are still reproducing currently in the Lower Danube: Huso huso, Acipenser stellatus, A. gueldenstaedtii and A. ruthenus. Sturgeon species hybridize more easily than other fish and the determination of pure species or hybrid status is important for conservation and for breeding in fish farms. This survey demonstrated that morphological determination of this status is not reliable and a molecular tool, based on eight microsatellites genotypes is proposed. This method, based on three successive statistical analyses including Factorial Correspondence Analysis (FCA), Structure assignation and NewHybrids status determination, showed a high efficiency in discriminating pure species specimens from F1, F2 and two kinds of backcross individuals involving three of the four reproducing Lower Danube sturgeon species.


Weight maintenance over 12 months after weight loss resulting from participation in a 12-week randomised controlled trial comparing all meal provision to self-directed diet in overweight adults.
The results of weight maintenance after initial weight loss are reported infrequently, although, when they have been reported, the outcomes are generally poor and weight regain is common. After an initial 12-week randomised intervention comparing all meal provision against a self-directed energy restriction, participants re-consented to participate in a follow-on study. Participants were given the option to choose to continue with the same dietary intervention (either all meal provision (provided free of charge) or self-directed diet) or change to the other diet for a further 12 weeks. Participants were followed up at 4-weekly intervals during both intervention periods (a total of 24 weeks), with a final follow up at 12 months. Eighty-five out of 86 individuals who completed the original 12-week randomised phase chose to continue on to the follow-up study. No significant differences in further weight loss between groups (P = 0.138) [mean (SEM): -3.4% (1.1%) for all meal provision only; -3.4% (0.6%) self-directed then all meal provision; -1.1% (1.2%) all meal provision then self-directed] were seen after a further 12 weeks. Meal provision for a total of 24 weeks resulted in 67% of individuals losing at least 10% body weight. The groups switching from self-directed dieting to meal provision (or vice versa) were the only groups to have a lower mean weight at 12 months than at the start of the follow-on study. Structured support for 24 weeks followed by 28 weeks of self-care can result in weight maintenance, with initial weight loss maintained at 12 months from enrolling on a 12-week weight loss intervention, with a 12-week follow-on period.


Life Expectancy in Patients Treated for Osteoporosis: Observational Cohort Study Using National Danish Prescription Data.
Osteoporosis is a chronic disease, carrying an elevated risk of fractures, morbidity, and death. Long-term treatment may be required, but the long-term risks with osteoporosis drugs remain incompletely understood. The competing risk of death may be a barrier to treating the oldest, yet this may not be rational if the risk of death is reduced by treatment. It is difficult to devise goal-directed long-term strategies for managing osteoporosis without firm information about residual life expectancy in treated patients. We conducted an observational study in Danish national registries tracking prescriptions for osteoporosis drugs, comorbid conditions, and deaths. We included 58,637 patients and 225,084 age- and sex-matched control subjects. Information on deaths until the end of 2013 was retrieved, providing a follow-up period of 10 to 17 years. In men younger than 80 years and women younger than 60 years, the relative risk of dying declined from being strongly increased in the first year to a stable but elevated level in subsequent years. In women older than 65 to 70 years, there was only a small elevation in risk in the first year of treatment followed by lower than background population mortality. The residual life expectancy of a 50-year-old man beginning osteoporosis treatment was estimated to be 18.2 years and that of a 75-year-old man was 7.5 years. Estimates in women were 26.4 years and 13.5 years, respectively. This study shows an excess mortality in men and in women younger than 70 years who are treated for osteoporosis compared with the background population. This excess risk is more pronounced in the first few years on treatment. The average life expectancy of osteoporosis patients is in excess of 15 years in women younger than 75 years and in men younger than 60 years, highlighting the importance of developing tools for long-term management.


A new concept for the integration of dynamic occlusion in the digital construction process.
Major advances have been made in dental computer-assisted design and manufacturing (CAD/CAM) technology in recent years. New developments in intraoral optical scanning systems make it possible to rapidly obtain three-dimensional images and measurements of the jaw and entire quadrants, including the prepared teeth, neighboringteeth, and opposing dentition. In addition, the static relationship of the maxillary and mandibular teeth to one another can easily be determined by means of intraoral bite registrations or buccal scans. This information is the starting point for the implementation of digital occlusal surface design and surface reconstruction. Here, too, the knowledge-based concept of biogenerics has crystallized into a new method in which restoration proposals suitable for each individual case are automatically computed by the software. Consequently, the time required to manually edit the digital model has been significantly reduced or completely eliminated. In its current form, the digital workflow still lacks a strategy for integrating the dynamic occlusion into the restoration design with high precision and in atime-saving manner. The preliminary results of new digital concepts and approaches to solving this problem will be presented in this article.


A randomized trial of telemedicine-based collaborative care for depression.
Evidence-based practices designed for large urban clinics are not necessarily portable into smaller isolated clinics. Implementing practice-based collaborative care for depression in smaller primary care clinics presents unique challenges because it is often not feasible to employ on-site psychiatrists. The purpose of the Telemedicine Enhanced Antidepressant Management (TEAM) study was to evaluate a telemedicine-based collaborative care model adapted for small clinics without on-site psychiatrists. Matched sites were randomized to the intervention or usual care. Small VA Community-based outpatient clinics with no on-site psychiatrists, but access to telepsychiatrists. In 2003-2004, 395 primary care patients with PHQ9 depression severity scores > or = 12 were enrolled, and followed for 12 months. Patients with serious mental illness and current substance dependence were excluded. Medication adherence, treatment response, remission, health status, health-related quality of life, and treatment satisfaction. The sample comprised mostly elderly, white, males with substantial physical and behavioral health comorbidity. At baseline, subjects had moderate depression severity (Hopkins Symptom Checklist, SCL-20 = 1.8), 3.7 prior depression episodes, and 67% had received prior depression treatment. Multivariate analyses indicated that intervention patients were more likely to be adherent at both 6 (odds ratio [OR] = 2.1, p = .04) and 12 months (OR = 2.7, p = .01). Intervention patients were more likely to respond by 6 months (OR = 2.0, p = .02), and remit by 12 months (OR = 2.4, p = .02). Intervention patients reported larger gains in mental health status and health-related quality of life, and reported higher satisfaction. Collaborative care can be successfully adapted for primary care clinics without on-site psychiatrists using telemedicine technologies.


Efficient discovery of fluorescent chemosensors based on a biarylpyridine scaffold.
The discovery of several fluorescent chemosensors for Hg(II) and Ag(I) in mixed aqueous solution is reported. The ease with which these fluorionophores were prepared from a common core underscores the utility of conformational restriction as a signaling mechanism. In addition, for the first time, significant changes were observed in biarylpyridine emission wavelength, allowing ratiometric detection of Hg(II) and Ag(I). Finally, on the basis of computational analyses, beneficial structural modifications were predicted for the next generation of chemosensors.


Electrochemical disinfection of dental implants--a proof of concept.
Peri-implantitis has gained significant clinical attention in recent years. This disease is an inflammatory reaction to microorganisms around dental implants. Due to the limited accessibility, non-invasive antimicrobial strategies are of high interest. An unexpected approach to implant disinfection may evolve from electrolysis. Given the electrical conductivity of titanium implants, alkalinity or active oxidants can be generated in body fluids. We investigated the use of dental titanium implants as electrodes for the local generation of disinfectants. Our hypothesis was that electrolysis can reduce viable counts of adhering bacteria, and that this reduction should be greater if active oxidative species are generated. As model systems, dental implants, covered with a mono-species biofilm of Escherichia coli C43, were placed in photographic gelatin prepared with physiological saline. Implants were treated by a continuous current of 0-10 mA for 15 minutes. The reduction of viable counts was investigated on cathodes and anodes. In separate experiments, the local change in pH was visualized using color indicators embedded in the gelatin. Oxidative species were qualitatively detected by potassium iodide-starch paper. The in situ generated alkaline environment around cathodic implants caused a reduction of up to 2 orders of magnitude in viable E. coli counts. On anodic implants, in contrast to cathodic counterparts, oxidative species were detected. Here, a current of merely 7.5 mA caused complete kill of the bacteria. This laboratory study shows that electrochemical treatment may provide access to a new way to decontaminate dental implants in situ.


Global white matter analysis of diffusion tensor images is predictive of injury severity in traumatic brain injury.
Conventional clinical neuroimaging is insensitive to axonal injury in traumatic brain injury (TBI). Immunocytochemical staining reveals changes to axonal morphology within hours, suggesting potential for diffusion-weighted magnetic resonance (MR) in early diagnosis and management of TBI. Diffusion tensor imaging (DTI) characterizes the three-dimensional (3D) distribution of water diffusion, which is highly anisotropic in white matter fibers owing to axonal length. Recently, DTI has been used to investigate traumatic axonal injury (TAI), emphasizing regional analysis in more severe TBI. In the current study, we hypothesized that a global white matter (WM) analysis of DTI data would be sensitive to TAI across a spectrum of TBI severity and injury to scan interval. To investigate this, we compared WM-only histograms of a scalar, fractional anisotropy (FA), between 20 heterogeneous TBI patients recruited from Detroit Medical Center, including six mild TBI (GCS 13-15), and 14 healthy age-matched controls. FA histogram parameters were correlated with admission GCS and posttraumatic amnesia (PTA). In all cases, including mild TBI, patients' FA histograms were globally decreased compared with control histograms. The shape of the TBI histograms also differed from controls, being more peaked and skewed. The mean FA, kurtosis and skewness were highly correlated suggesting a common mechanism. FA histogram properties also correlated with injury severity indexed by GCS and PTA, with mean FA being the best predictor and duration of PTA (r = 0.64) being superior to GCS (r = 0.47). Therefore, in this heterogeneous sample, the FA mean accounted for 40% of the variance in PTA. Increased diffusion in the short axis dimension, likely reflecting dysmyelination and swelling of axons, accounted for most of the FA decrease. FA is globally deceased in WM, including mild TBI, possibly reflecting widespread involvement. FA changes appear to be correlated with injury severity suggesting a role in early diagnosis and prognosis of TBI.


Butrepyrazinone, a new pyrazinone with an unusual methylation pattern from a Ghanaian Verrucosispora sp. K51G.
We report the structural characterization of a new pyrazinone analogue; butrepyrazinone, which was isolated from a new actinomycete strain Verrucosispora sp. K51G recovered from Ghanaian mangrove river sediment. Spectroscopy-guided fractionation led to the isolation of a compound from the fermentation culture and a combination of NMR spectroscopy, high-resolution mass spectrometry and computer-aided calculations revealed that butrepyrazinone (10) possesses an unusual methylation pattern on the pyrazinone ring. Butrepyrazinone (10), however, displayed no antibacterial activity against Gram-positive S. aureus ATCC 25923, the Gram-negative E. coli ATCC 25922 and a panel of clinical isolates of methicillin-resistant S. aureus (MRSA) strains, suggesting that 10 may act as a signal molecule for this strain. Although the same molecule has been synthesized previously, this is the first report to disclose the discovery of butrepyrazinone (10) from nature.


Cholestasis induced by sulphated glycolithocholic acid in the rat: protection by endogenous bile acids.
Sulphated glycolithocholic acid (SGLC) causes cholestasis in experimental animals, despite its sulphated form. In the present study, the cholestatic potency and the pharmacokinetics of SGLC were investigated in rats under two conditions: (a) in the presence of an intact circulating bile acid pool and (b) after exhaustion of the bile acid pool by 24 h of bile diversion. Intravenous administration of SGLC (8 mumol/100 g body weight) to rats with an intact bile acid pool did not cause cholestasis. However, biliary phospholipid and cholesterol concentrations were reduced by 40% and 29% respectively during the first hour after administration. When the same dose of the bile acid was injected in rats with a 24 h biliary drainage, a complete cessation of bile production was observed within 1 h. Twelve hours after the onset of cholestasis, bile production gradually increased again, showed a marked overshoot, and reached control levels after 3 days. In the recovery phase, biliary phospholipid and cholesterol concentrations were greatly reduced. The absence of endogenous bile acids did not change the hepatic clearance rate of a tracer dose of radiolabelled SGLC, but markedly decreased its biliary excretion rate. It was concluded that the hepatotoxic effect of SGLC is much more pronounced in rats with an exhausted bile acid pool, possibly due to a slower biliary excretion of the toxic compound. This phenomenon may have clinical implications for patients with a contracted bile acid pool.


Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines.
The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects.


The impact of capillary dilation on the distribution of red blood cells in artificial networks.
Recent studies suggest that pericytes around capillaries are contractile and able to alter the diameter of capillaries. To investigate the effects of capillary dilation on network dynamics, we performed simulations in artificial capillary networks of different sizes and complexities. The unequal partition of hematocrit at diverging bifurcations was modeled by assuming that each red blood cell (RBC) enters the branch with the faster instantaneous flow. Network simulations with and without RBCs were performed to investigate the effect of local dilations. The results showed that the increase in flow rate due to capillary dilation was less when the effects of RBCs are included. For bifurcations with sufficient RBCs in the parent vessel and nearly equal flows in the branches, the flow rate in the dilated branch did not increase. Instead, a self-regulation of flow was observed due to accumulation of RBCs in the dilated capillary. A parametric study was performed to examine the dependence on initial capillary diameter, dilation factor, and tube hematocrit. Furthermore, the conditions needed for an efficient self-regulation mechanism are discussed. The results support the hypothesis that RBCs play a significant role for the fluid dynamics in capillary networks and that it is crucial to consider the blood flow rate and the distribution of RBCs to understand the supply of oxygen in the vasculature. Furthermore, our results suggest that capillary dilation/constriction offers the potential of being an efficient mechanism to alter the distribution of RBCs locally and hence could be important for the local regulation of oxygen delivery.


Shorter recovery can be achieved from using walking boot after operative treatment of an ankle fracture.
Ankle fractures, even if treated surgically, usually take a long time to heal. For all patients with ankle fracture, immobilisation is a critical part of treatment. Short-leg walking boots (WBs) have been reported to be an effective alternative to plaster casts (PCs) that could shorten this postoperative recuperative period. The aim of this study was to compare the functional recovery of a conventional PC with that of a WB after surgery for ankle fractures. Forty-seven patients (mean age, 53.9 ± 12 years) who had undergone surgical operation for an unstable ankle fracture from January 2008 to October 2014 were reviewed retrospectively. Either a PC or a WB was prescribed postoperatively, with 25 patients and 22 patients, respectively. The time that it took the patient to stand unipedal on the affected side after allowing full-weight bear and to walk without crutches were used for assessment of functional recovery. The prevalence of postoperative loss of reduction and nonunion was also reviewed. Both the time of being able to stand unipedal on the injured side and to walk without crutches were significantly shorter in patients using WBs (WB, 2.6 weeks; PC, 4.5 weeks, p = 0.01; WB, 1.4 weeks; PC, 3.1 weeks, p = 0.03). There were no patients with loss of reduction or nonunion. Patients who used WBs showed a significantly faster recovery. WBs have an adjustable heel lift that allows users to change the ankle position slightly plantarflexed that helps walking in a postoperative swollen ankle. WBs are easy to slip on, and it is easy to adjust the ankle position in conformity with swelling so that the least painful position could be maintained during walking. WBs have good fixity to allow immediate weight-bearing postoperatively, and there were no cases with loss of reduction postoperatively. The Rocker bottom design minimises the sagittal plane motion in the specific joint of the foot, which also facilitates the course of recuperation. An ankle fracture fixed appropriately endures loading when a WB is used. The WB treatment results in faster functional recovery, allowing the patients to return to normal activity at a faster rate.


Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications.
Massive transfusion (MT) protocols have been shown to improve survival in severely injured patients. However, others have noted that these higher fresh frozen plasma (FFP):red blood cell (RBC) ratios are associated with increased risk of organ failure. The purpose of this study was to determine whether MT protocols are associated with increased organ failure and complications. Our institution's exsanguination protocol (TEP) involves the immediate delivery of products in a 3:2 ratio of RBC:FFP and 5:1 for RBC:platelets. All patients receiving TEP between February 2006 and January 2008 were compared with a cohort (pre-TEP) of all patients from February 2004 to January 2006 that (1) went immediately to the operating room and (2) received MT (>or=10 units of RBC in first 24 hours). Two hundred sixty-four patients met inclusion (125 in the TEP group, 141 in the pre-TEP). Demographics and Injury Severity Score were similar. TEP received more intraoperative FFP and platelets but less in first 24 hours (p < 0.01). There was no difference in renal failure or systemic inflammatory response syndrome, but pneumonia, pulmonary failure, open abdomens, and abdominal compartment syndrome were lower in TEP. In addition, severe sepsis or septic shock and multiorgan failure were both lower in the TEP patients (9% vs. 20%, p = 0.011 and 16% vs. 37%, p < 0.001, respectively). Although MT has been associated with higher organ failure and complication rates, this risk appears to be reduced when blood products are delivered early in the resuscitation through a predefined protocol. Our institution's TEP was associated with a reduction in multiorgan failure and infectious complications, as well as an increase in ventilator-free days. In addition, implementation of this protocol was followed by a dramatic reduction in development of abdominal compartment syndrome and the incidence of open abdomens.


New insights into the pathogenesis and nonsurgical management of Graves orbitopathy.
Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patient's quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required. Clinical trials have shown that considerable benefit can be derived from the addition of antiproliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab, which reduces proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. The pathophysiology of Graves orbitopathy has also been revised with identification of new potential therapeutic targets. In this Review we provide an up-to-date overview of the field, outline the optimal management of Graves orbitopathy and summarize the research developments in this area to highlight future research questions and direct future clinical trials.


Actin-based bacterial motility.
Listeria monocytogenes and other bacterial pathogens move in the host cell cytoplasm, propelled by continuous actin assembly at one pole of the bacterium. This actin-based motility requires the presence of the bacterial proteins ActA on L. monocytogenes and IcsA on Shigella flexneri. There have been several major discoveries in the past year: the discovery of the polar distribution of ActA and IcsA on the bacterial surface; the demonstration that bacterial ActA is phosphorylated in infected host cells; the involvement of some host cell proteins, particularly profilin; and the dramatic effect of ActA expression in transfected eukaryotic cells. A cell-free system that reconstitutes faithfully the actin-based motility of L. monocytogenes promises to be instrumental in the further dissection of this fascinating phenomenon.


Pulmonary tumor diagnosed as an undifferentiated sarcoma with epithelioid features: a case report.
Pulmonary sarcomas are uncommon accounting for 0.5 % of all primary lung cancers. Undifferentiated sarcomas account for up to 20 % of soft tissue sarcomas. A lung tumor revealed to be an undifferentiated sarcoma with epithelioid features has never been reported in the literature. A 61-year-old white Moroccan man presented with 2 months' history of hemoptysis and dyspnea. Chest computed tomography showed a cystic mass involving the lower field of his right lung evoking first a hydatid cyst. Abdominal computed tomography revealed bilateral adrenal nodules. Surgical resection of the lung mass was performed. On pathological examination, the tumor was cystic containing necrotic material. A histological diagnosis of undifferentiated sarcoma with epithelioid features was made. A positron emission tomography scan showed involvement of his pleura, left colon, adrenal glands, left thigh muscle, and leptomeninges. Undifferentiated sarcoma with epithelioid features is a rare malignant mesenchymal tumor. Clinical and radiological features are not specific. A differential diagnosis includes sarcomatoid carcinoma, malignant mesothelioma, melanoma, and other epithelioid sarcomas.


Hemisphere-specific episodic memory networks in the human brain: a correlation study between intracarotid amobarbital test and [(18)F]FDG-PET.
The purpose of the present study was to explore the brain regions involved in human episodic memory by correlating unilateral memory performance estimated by the intracarotid amobarbital test (IAT) and interictal cerebral metabolism measured by [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET). Using this method, regional alterations of cerebral metabolism associated with epilepsy pathophysiology are used to predict hemisphere-specific episodic memory function, hence, investigate the differential distribution of memory in each hemisphere. Sixty-two patients with unilateral temporal lobe epilepsy (35 left and 27 right) were studied using [(18)F]FDG-PET with complementary voxel-based statistical parametric mapping (SPM) and region-of-interest (ROI) methods of analysis. Positive regression was analyzed in SPM with a series of different thresholds (p = .001, .01 or .05) with a correction to 100 voxels. IAT memory performance in which left hemisphere was tested by right-sided injection of amobarbital correlated with [(18)F]FDG uptake in left lateral and medial temporal regions, and in the left ventrolateral frontal cortex. Right IAT memory performance correlated with [(18)F]FDG uptake in the right inferior parietal lobule, right dorsolateral frontal cortex, right precentral gyrus, and caudal portion of the right anterior cingulate cortex. ROI analysis corroborated these results. Analyses carried out separately in patients with left (n = 50) and nonleft (n = 12) dominance for language showed that in the nonleft dominant group, right IAT scores correlated with right fronto-temporal regions, whereas left total memory scores correlated with left lateral and medial temporal regions. The findings indicate that (i) episodic memory is subserved by more widespread cortical regions beyond the core mesiotemporal lobe memory structures; (ii) there are different networks functional in the two hemispheres; and (iii) areas involved in memory may be different between patients with left and nonleft dominance for language, particularly in the right hemisphere.


The bioinorganic and medicinal chemistry of carboranes: from new drug discovery to molecular imaging and therapy.
The role of carboranes in medicinal chemistry has diversified in recent years and now extends into areas of drug discovery, molecular imaging, and targeted radionuclide therapy. An introduction to carborane chemistry is provided to familiarize the non-expert with some key properties of these molecules, followed by an overview of current medicinally-orientated research involving carboranes. The broad-ranging nature of this research is illustrated, with emphasis placed on recent highlights and advances in this field.


Barriers to tuberculosis care: a qualitative study among Somali pastoralists in Ethiopia.
At the dawn of the third millennium, while the control of the second biggest infectious killer in the world (tuberculosis [TB]) is an international priority, millions of pastoralist communities in the Horn of Africa are struggling to access TB care. Prompt diagnosis and treatment of pastoralist TB patients remain to be a challenge in TB control programs in many countries in this region, where pastoralism is a common means of livelihood. Better understanding of community perceptions of TB and its management could help identify reasons for the delay in diagnosis of TB among pastoral communities. The aim of this study is to explore barriers delaying diagnosis among pastoralist TB patients in the Somali Regional State (SRS) of Ethiopia. A qualitative study, including 19 respondents was conducted in the SRS of Ethiopia. Participatory Rural Appraisal (PRA) and informal interview techniques were employed to explore pastoralists' migration patterns, their perceptions of TB and their access to TB services. The influence of these factors on the delay of TB patients in receiving biomedical diagnosis was then assessed. We found that lack of access to formal health services as well as traditional beliefs leading to self treatment were barriers to prompt bio-medical diagnosis of TB among pastoralist TB patients in the SRS of Ethiopia. This study highlights that limited access to TB control programs is the most important barrier in early seeking of biomedical diagnosis of TB among pastoral communities with nomadic pastoralist being the most affected. Diagnostic and treatment facilities should be established in strategic villages that pastoralist can reach in both dry and wet seasons. Such facilities may alleviate the observed long distance to health facilities and thus long delay in diagnosis of TB. This strategy should be compounded with a community based TB control approach, whereby basic medical training on TB management such as provision of health education, drug distribution and observations is provided to local traditional healers and religious leaders. This approach may improve pastoralists' perceptions of TB, hence eliminating the observed traditional believes associated with TB in pastoralists' context of the SRS.


Allosensitized helper and cytotoxic T-lymphocyte clones differentially modulate endotoxin-stimulated macrophage function.
Alterations in macrophage function may render the immunocompromised host more susceptible to infectious complications. Although allograft recipients are at increased risk of infection primarily because of pharmacologic immunosuppression, whether the process of allosensitization per se alters this risk is unknown. We therefore studied the effects of cloned allosensitized murine helper or cytotoxic T cells on both interleukin 1 (IL-1) and prostaglandin E2 (PGE2) production by syngeneic resident murine peritoneal macrophages. Endotoxin (lipopolysaccharide [LPS]) stimulated both IL-1 and PGE2 production in macrophages. Cloned T cells alone, with or without LPS pretreatment, produced neither IL-1 nor PGE2. After 48 hours of coculture with LPS-treated macrophages, cloned helper cells augmented IL-1 release by macrophages but inhibited PGE2 production. In contrast, cytotoxic T cells not only reduced IL-1 production by macrophages but also potentiated PGE2 release. These effects were not observed when macrophages were not first exposed to LPS. Thus, endotoxin renders macrophages more susceptible to allosensitized "help" (increases IL-1, decreases PGE2) or "suppression" (decreases IL-1, increases PGE2) by cytotoxic T cells. We hypothesize that, even in the absence of immunosuppression, the process of allosensitization itself may modulate the response to sepsis by altering host macrophage function.


Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.
Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.


Predictive feature remapping before saccadic eye movements.
Saccadic eye movements cause rapid and dramatic displacements of the retinal image of the visual world, yet our conscious perception of the world remains stable and continuous. A popular explanation for this remarkable ability of our visual system to compensate for the displacements is the predictive feature remapping theory. The theory proposes that, before saccades, the representation of a visual stimulus can be predictively transferred from neurons that initially encode the stimulus to neurons whose receptive fields will encompass the stimulus location after the saccade. Visual adaptation aftereffect experiments performed by Melcher (2007) provided psychophysical evidence for this theory. However, it was argued that the visual aftereffects were not measured at the "appropriate" remapped location (Rolfs, Jonikaitis, Deubel, & Cavanagh, 2011). Therefore, whether the remapped representation contains feature information (e.g., orientation, motion direction, or contrast) is still a subject of intense debate. Here, to explore the nature of the predictive transfer during trans-saccadic perception, we measured visual aftereffects (tilt aftereffect, motion aftereffect, and threshold elevation aftereffect) at the appropriate remapped location of adapting stimuli before saccades. We observed a significant tilt aftereffect and motion aftereffect, but little threshold elevation aftereffect. Furthermore, the tilt aftereffect and motion aftereffect exhibited spatial specificity. These findings provide strong evidence for the predictive feature remapping theory and suggest that intermediate visual processing stages (i.e., extrastriate visual cortex) might be critical for feature remapping. Finally, we propose that the feature remapping process might also contribute to the spatiotopic representation of visual features.


Viral shedding in patients infected with pandemic influenza A (H1N1) virus in Kenya, 2009.
Understanding shedding patterns of 2009 pandemic influenza A (H1N1) (pH1N1) can inform recommendations about infection control measures. We evaluated the duration of pH1N1 virus shedding in patients in Nairobi, Kenya. Nasopharyngeal (NP) and oropharyngeal (OP) specimens were collected from consenting laboratory-confirmed pH1N1 cases every 2 days during October 14-November 25, 2009, and tested at the Centers for Diseases Control and Prevention-Kenya by real time reverse transcriptase polymerase chain reaction (rRT-PCR). A subset of rRT-PCR-positive samples was cultured. Of 285 NP/OP specimens from patients with acute respiratory illness, 140 (49%) tested positive for pH1N1 by rRT-PCR; 106 (76%) patients consented and were enrolled. The median age was 6 years (Range: 4 months-41 years); only two patients, both asthmatic, received oseltamivir. The median duration of pH1N1 detection after illness onset was 8 days (95% CI: 7-10 days) for rRT-PCR and 3 days (Range: 0-13 days) for viral isolation. Viable pH1N1 virus was isolated from 132/162 (81%) of rRT-PCR-positive specimens, which included 118/125 (94%) rRT-PCR-positive specimens collected on day 0-7 after symptoms onset. Viral RNA was detectable in 18 (17%) and virus isolated in 7/18 (39%) of specimens collected from patients after all their symptoms had resolved. In this cohort, pH1N1 was detected by rRT-PCR for a median of 8 days. There was a strong correlation between rRT-PCR results and virus isolation in the first week of illness. In some patients, pH1N1 virus was detectable after all their symptoms had resolved.


Airway management at Level 1 trauma center in the era of video laryngoscopy.
Rapid sequence induction and tracheal intubation through direct laryngoscopy (DL) has been the most common approach to secure the airway in trauma patients. The introduction of video laryngoscopy (VL) has changed airway management in many clinical settings. In this retrospective study, we assessed if immediate availability of VL in the trauma suite has changed the approach and outcomes of airway management during acute resuscitation at a dedicated trauma center. We retrospectively collected data from emergency intubation in the 6 resuscitation bays at a high-volume, academic, Level 1 trauma center over a 42-month period following the introduction of immediately available VL in the resuscitation bay. We divided the data into 13-week bins to assess the trend in the use of VL over time. Our measured outcomes were the incidence of failed intubations requiring a surgical airway and the frequency of VL use for airway management. Among 1328 airway management events in the resuscitation bays when intubation was attempted, the failure rate resulting in the placement of a surgical airway was 0.38% (95% confidence interval [CI], 0.12% -0.88%). This was consistent with the surgical airway rate before the introduction of VL into trauma practice (0.3%). VL use (primary or as a rescue technique) throughout the study period was 4.14% (95% CI, 2.76%-5.74%), with no temporal trend. The immediate availability of VL in the resuscitation bay has not changed the prevalence of its use during emergency airway management at our trauma center. DL remains a preferred primary modality for airway management by the trauma anesthesiologists working at this facility, with an acceptably low incidence of both primary failure and the need to establish a surgical airway.


Structure-dependent growth control in nanowire synthesis via on-film formation of nanowires.
On-film formation of nanowires, termed OFF-ON, is a novel synthetic approach that produces high-quality, single-crystalline nanowires of interest. This versatile method utilizes stress-induced atomic mass flow along grain boundaries in the polycrystalline film to form nanowires. Consequently, controlling the magnitude of the stress induced in the films and the microstructure of the films is important in OFF-ON. In this study, we investigated various experimental growth parameters such as deposition rate, deposition area, and substrate structure which modulate the microstructure and the magnitude of stress in the films, and thus significantly affect the nanowire density. We found that Bi nanowire growth is favored in thermodynamically unstable films that facilitate atomic mass flow during annealing. A large film area and a large thermal expansion coefficient mismatch between the film and the substrate were found to be critical for inducing large compressive stress in a film, which promotes Bi nanowire growth. The OFF-ON method can be routinely used to grow nanowires from a variety of materials by tuning the material-dependent growth parameters.


The association between high-sensitivity C-reactive protein and hypertension in women of the CARDIA study.
The aim of this study was to determine the prevalence of hypertension in midlife women, characterize the association between high-sensitivity C-reactive protein (hs-CRP) and hypertension in women, and describe differences in hypertension prevalence by menopausal stage. We included 1,625 women, aged 43 to 55 years, with measurements of hs-CRP and detailed reproductive histories in the Coronary Artery Risk Development in Young Adults study at follow-up year 25. Prevalent hypertension was defined as a systolic blood pressure of 140 mm Hg, or diastolic blood pressure of 90 mm Hg or greater, or use of antihypertensive medications. Logistic regression was used for analysis. The prevalence of hypertension was 25.8%, 37.8%, and 39.0% in premenopausal, perimenopausal, and postmenopausal women, respectively. The median (25th and 75th percentiles) of hs-CRP was 3.08 (1.12, 7.98) μg/mL and 1.18 (0.48, 3.15) μg/mL in women with and without hypertension, respectively. After adjusting for confounders, metabolic factors and body mass index, a doubling (100% increment) in hs-CRP levels was significantly associated with hypertension in premenopausal (1.27 [1.01-1.59]), but not in perimenopausal (1.12 [0.99-1.27]) or postmenopausal (1.09 [0.95-1.26]) women. Hypertension was common in midlife women. The association of hs-CRP and hypertension was consistent across menopausal stages. The association of hs-CRP with hypertension was independent of body mass index in premenopausal but not in perimenopausal or postmenopausal women.


Influence of anteroposterior mandibular positions on facial attractiveness in Japanese adults.
Our aims in this study were to determine the anteroposterior facial relationship that is regarded as most attractive by Japanese laypersons in a questionnaire survey and to evaluate which analysis of the soft-tissue profile is most suitable for Japanese people. We showed 262 Japanese laypersons (121 male, 141 female) 9 morphed profile images with Point B and menton anteriorly or distally moved by software and asked them to number them sequentially according to their attractiveness. To examine which analysis best reflects facial attractiveness as judged by laypersons, we made 5 types of analyses of the facial profile with 11 variables in the 9 images. The normal face was judged favorably; however, an attractive profile might be different for each subject. The 3 highest ranking profiles (normal face and moderate mandibular retrusions) were often favorites, and 2 profiles (severe mandibular protrusions) were liked the least for most subjects. However, the other images showed a wide range of distribution. Mandibular retrusion was generally more favored than mandibular protrusion and bimaxillary protrusion (severe chin retrusion) had a high attractiveness ranking and was well accepted in the Japanese population. To evaluate the profiles of Japanese subjects, it is important to evaluate not only the esthetic line defined by the nose and chin, but also the balance of the upper and lower lips defined by the posterior reference line--ie, Burstone's Sn-Pog' line.


The Isoquinolone Derived Prolyl Hydroxylase Inhibitor ICA Is a Potent Substrate of the Organic Anion Transporters 1 and 3.
Many cellular responses to hypoxia are mediated by the transcription factor complex hypoxia-inducible factor (HIF). HIF stability is governed by a family of dioxygenases called HIF prolyl hydroxylases (PHDs). Isoquinolone-derived PHD inhibitors, like 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), which stabilize the intracellular HIF-α have been suggested as a potentially beneficial therapeutic strategy for the treatment of disorders associated with ischemia. To stabilize HIF-α, ICA has to be taken up into proximal tubule cells (PCTs) across the basolateral membrane by one of the organic anion transporters 1, 2 or 3 (OAT1, OAT2 or OAT3). The release into the urine across the luminal membrane may be mediated by OAT4. To demonstrate interaction of ICA with human OAT1, OAT2, OAT3 and OAT4, ICA was tested on these transporters stably transfected in HEK293 cells by using p-aminohippurate (PAH), cGMP and estrone-3-sulfate (ES) as reference substrates, respectively. Uptakes of PAH and ES in OAT1- and OAT3-transfected HEK293 cells were inhibited by ICA with half-maximal inhibition values of 0.29 ± 0.05 and 2.58 ± 0.16 µM, respectively. OAT2 was less sensitive to ICA. Efflux experiments identified ICA as an OAT1 and OAT3 substrate. Preloading OAT4-transfected HEK293 cells with ICA stimulated ES uptake by 18.3 ± 3.8%. The uptake of ICA across the basolateral membrane of PCTs occurs mainly by OAT1 and the efflux into the tubular lumen by OAT4.


Their pain, our pleasure: stereotype content and schadenfreude.
People often fail to empathize with others, and sometimes even experience schadenfreude-pleasure at others' misfortunes. One potent predictor of schadenfreude is envy, which, according to the stereotype content model, is elicited by high-status, competitive targets. Here we review our recent research program investigating the relationships among stereotypes, envy, schadenfreude, and harm. Experiment 1 demonstrates that stereotypes are sufficient to influence affective responses to targets' misfortunes; participants not only report feeling less negative when misfortunes befall high-status, competitive targets as compared to other targets, they also smile more (assessed with facial EMG). Experiment 2 replicates the self-report findings from Experiment 1 and assesses behavioral tendencies toward envied targets; participants are more willing to endorse harming high-status, competitive targets as compared to other targets. Experiment 3 turns off the schadenfreude response by manipulating status and competition-relevant information regarding envied targets. Finally, Experiment 4 investigates affective and neural markers of intergroup envy and schadenfreude in the context of a long-standing sports rivalry and the extent to which neurophysiological correlates of schadenfreude are related to self-reported likelihood of harming rival team fans. We conclude with implications and future directions.


Thermoelectric Polymers and their Elastic Aerogels.
Electronically conducting polymers constitute an emerging class of materials for novel electronics, such as printed electronics and flexible electronics. Their properties have been further diversified to introduce elasticity, which has opened new possibility for "stretchable" electronics. Recent discoveries demonstrate that conducting polymers have thermoelectric properties with a low thermal conductivity, as well as tunable Seebeck coefficients - which is achieved by modulating their electrical conductivity via simple redox reactions. Using these thermoelectric properties, all-organic flexible thermoelectric devices, such as temperature sensors, heat flux sensors, and thermoelectric generators, are being developed. In this article we discuss the combination of the two emerging fields: stretchable electronics and polymer thermoelectrics. The combination of elastic and thermoelectric properties seems to be unique for conducting polymers, and difficult to achieve with inorganic thermoelectric materials. We introduce the basic concepts, and state of the art knowledge, about the thermoelectric properties of conducting polymers, and illustrate the use of elastic thermoelectric conducting polymer aerogels that could be employed as temperature and pressure sensors in an electronic-skin.


Exploring the concept of interaction computing through the discrete algebraic analysis of the Belousov-Zhabotinsky reaction.
Interaction computing (IC) aims to map the properties of integrable low-dimensional non-linear dynamical systems to the discrete domain of finite-state automata in an attempt to reproduce in software the self-organizing and dynamically stable properties of sub-cellular biochemical systems. As the work reported in this paper is still at the early stages of theory development it focuses on the analysis of a particularly simple chemical oscillator, the Belousov-Zhabotinsky (BZ) reaction. After retracing the rationale for IC developed over the past several years from the physical, biological, mathematical, and computer science points of view, the paper presents an elementary discussion of the Krohn-Rhodes decomposition of finite-state automata, including the holonomy decomposition of a simple automaton, and of its interpretation as an abstract positional number system. The method is then applied to the analysis of the algebraic properties of discrete finite-state automata derived from a simplified Petri net model of the BZ reaction. In the simplest possible and symmetrical case the corresponding automaton is, not surprisingly, found to contain exclusively cyclic groups. In a second, asymmetrical case, the decomposition is much more complex and includes five different simple non-abelian groups whose potential relevance arises from their ability to encode functionally complete algebras. The possible computational relevance of these findings is discussed and possible conclusions are drawn.


Isolation and growth factor inducibility of the Xenopus laevis Lmx1b gene.
This paper reports the cloning of the full length Xenopus laevis Lmx1b gene, Xlmx1b. Xlmx1b is a LIM homeodomain protein with high conservation to homologues identified in human, mouse, hamster and chick. In situ hybridisation and RT-PCR analysis showed that Xlmx1b has a specific temporal expression pattern which can be separated into three main spatial domains. An Xlmx1b probe hybridized to regions of the nervous system from stage 13 onwards; these regions included the placodes and otic vesicles, the eye and specific sets of neurons. Sectioning of in situ hybridised embryos confirmed the location of transcripts as discreet regions of staining in ventrolateral regions of the neural tube. From stage 27, transcripts could be detected in the capsule of pronephric glomus. Finally, transcripts were detected by Northern blot analysis in the developing fore and hind limbs. Xlmx1b transcripts were also detected by Northern blot analysis in eye, brain, muscle and mesonephros tissue in metamorphosing tadpoles. RT-PCR analysis showed that zygotic expression of Xlmx1b is initiated at stage 10.5 and the temporal sequence of Xlmx1b expression is identical in both neural and presumptive pronephros regions. The effects of the growth factors activin A, retinoic acid (RA) and basic fibroblast growth factor (bFGF) on the regulation of Xlmx1b were also studied. Xlmx1b was found to be upregulated by activin A and RA inhibited this upregulation in a concentration dependant manner. In contrast, bFGF had no effect on the regulation of Xlmx1b.


Effects of two cetylpyridinium chloride-containing mouthwashes on bacterial plaque.
The purpose of this single blind clinical study was to determine the effects of two commerical mouthwashes (one containing cetylpyridinium chloride and domiphen bromide and the other containing only cetlypridinium chloride) on existing plaque accumulations. A second purpose was to determine if a residual effect could be shown 2 weeks after cessation of using these mouthwashes. A total of 120 adult subjects, who had been divided into three groups, were initially in the study. For a period of 31 days, the subjects in Group A rinsed with a commercial mouthwash containing cetylpyridinium chloride and domiphen bromide; Group B rinsed with a commercial mouthwash containing only ceytlpyridinium chloride; and Group C served as controls and rinsed with colored flavored water. All subjects continued their normal home oral hygiene practices, except that mothwashes other than as assigned were forbidden. The subjects received three identical examinations to determine their plaque scores. The examinations were conducted the day preceding initiation; the day following cessation; and 15 days after cessation of the rinsing procedures. A total of 105 subjects received the first and second examinations, and 93 subjects received all three examinations. Based upon the data obtained, the daily use of each of the cetylpyridinium chloride mouthwashes tested, appears to be partially effective in reducing existing bacterial plaque accumulations. The cetylpyridinium chloride-domophen bromide product was slightly, but not significantly, more effective than the other commercial mouthwash. Neither commerical product demonstrated a significant residual effect 2 weeks after cessation of use.


Spontaneous Coronary Artery Dissection Treated with Direct Coronary Stenting.
BACKGROUND Spontaneous coronary artery dissection (SCAD) is a rare medical emergency characterized by non-traumatic and non-iatrogenic tearing of the intima of a coronary artery, with an estimated incidence of 1-4%. CASE REPORT A 39-year-old woman with no known cardiac risk factors or recent trauma presented with acute chest pain, electrocardiographic (ECG) changes consistent with ST-elevation acute coronary syndrome, and elevated cardiac enzymes. Coronary angiography revealed near-complete stenosis of the distal left anterior descending (LAD) coronary artery with findings consistent with coronary artery dissection. Due to ongoing chest pain refractory to medical therapy, she underwent successful complex intervention on the distal LAD lesion with a 2.0×30 mm Onyx drug-eluting stent that was post-dilated to high pressure with a 2.5 noncompliant balloon, reducing the 99% stenosis to a 0% residual. She recovered fully and was discharged on aggressive risk factor modification with dual antiplatelet therapy (aspirin and clopidogrel) and high-intensity statin. CONCLUSIONS Spontaneous coronary artery dissection (SCAD) is a rare condition that can present with ECG changes and ischemic symptoms identical to ST-elevation transmural myocardial infarction secondary to plaque rupture. Coronary angiography is required to evaluate patients, and, depending on the catheterization findings, the patient's hemodynamic profile, and severity of ischemic symptoms, complex interventions such as direct coronary stenting can best treat patients such as ours, while medical management might be considered for others.


On the evolution and physiology of cable bacteria.
Cable bacteria of the family Desulfobulbaceae form centimeter-long filaments comprising thousands of cells. They occur worldwide in the surface of aquatic sediments, where they connect sulfide oxidation with oxygen or nitrate reduction via long-distance electron transport. In the absence of pure cultures, we used single-filament genomics and metagenomics to retrieve draft genomes of 3 marine Candidatus Electrothrix and 1 freshwater Ca. Electronema species. These genomes contain >50% unknown genes but still share their core genomic makeup with sulfate-reducing and sulfur-disproportionating Desulfobulbaceae, with few core genes lost and 212 unique genes (from 197 gene families) conserved among cable bacteria. Last common ancestor analysis indicates gene divergence and lateral gene transfer as equally important origins of these unique genes. With support from metaproteomics of a Ca. Electronema enrichment, the genomes suggest that cable bacteria oxidize sulfide by reversing the canonical sulfate reduction pathway and fix CO2 using the Wood-Ljungdahl pathway. Cable bacteria show limited organotrophic potential, may assimilate smaller organic acids and alcohols, fix N2, and synthesize polyphosphates and polyglucose as storage compounds; several of these traits were confirmed by cell-level experimental analyses. We propose a model for electron flow from sulfide to oxygen that involves periplasmic cytochromes, yet-unidentified conductive periplasmic fibers, and periplasmic oxygen reduction. This model proposes that an active cable bacterium gains energy in the anodic, sulfide-oxidizing cells, whereas cells in the oxic zone flare off electrons through intense cathodic oxygen respiration without energy conservation; this peculiar form of multicellularity seems unparalleled in the microbial world.


Segregation distortion in hybrids between the Bogota and USA subspecies of Drosophila pseudoobscura.
We show that, contrary to claims in the literature, "sterile" males resulting from the cross of the Bogota and USA subspecies of Drosophila pseudoobscura are weakly fertile. Surprisingly, these hybrid males produce almost all daughters when crossed to females of any genotype (pure Bogota, pure USA, hybrid F1). Several lines of evidence suggest that this sex ratio distortion is caused by sex chromosome segregation distortion in hybrid males. We genetically analyze this normally cryptic segregation distortion and show that it involves several regions of the Bogota X chromosome that show strong epistatic interactions with each other. We further show that segregation distortion is normally masked within the Bogota subspecies by autosomal suppressors. Our analysis shows that the genetic basis of hybrid segregation distortion is similar to that of hybrid male sterility between the same subspecies. Indeed the severity of segregation distortion is correlated with the severity of sterility among hybrids. We discuss the possibility that hybrid sterility in this paradigmatic case of incipient speciation is caused by segregation distortion.


Approaching clinical proteomics: current state and future fields of application in fluid proteomics.
The field of clinical proteomics offers opportunities to identify new disease biomarkers in body fluids, cells and tissues. These biomarkers can be used in clinical applications for diagnosis, stratification of patients for specific treatment, or therapy monitoring. New protein array formats and improved spectrometry technologies have brought these analyses to a level with potential for use in clinical diagnostics. The nature of the human body fluid proteome with its large dynamic range of protein concentrations presents problems with quantitation. The extreme complexity of the proteome in body fluids presents enormous challenges and requires the establishment of standard operating procedures for handling of specimens, increasing sensitivity for detection and bioinformatical tools for distribution of proteomic data into the public domain. From studies of in vitro diagnostics, especially in clinical chemistry, it is evident that most errors occur in the preanalytical phase and during implementation of the diagnostic strategy. This is also true for clinical proteomics, and especially for fluid proteomics because of the multiple pretreatment processes. These processes include depletion of high-abundance proteins from plasma or enrichment processes for urine where biological variation or differences in proteolytic activities in the sample along with preanalytical variables such as inter- and intra-assay variability will likely influence the results of proteomics studies. However, before proteomic analysis can be introduced at a broader level into the clinical setting, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement and data analysis needs to be improved. In this review, we discuss the recent technological advances and applications that fulfil the criteria for clinical proteomics, with the focus on fluid proteomics. These advances relate to preanalytical factors, analytical standardization and quality-control measures required for effective implementation into routine laboratory testing in order to generate clinically useful information. With new disease biomarker candidates, it will be crucial to design and perform clinical studies that can identify novel diagnostic strategies based on these techniques, and to validate their impact on clinical decision-making.


Multimodal multiplex spectroscopy using photonic crystals.
Spatio-spectral transmission patterns induced on low coherence fields by disordered photonic crystals can be used to construct optical spectrometers. Experimental results suggest that 1-10 nm resolution multimodal spectrometers for diffuse source analysis may be constructed using a photonic crystal mounted on a focal plane array. The relative independence of spatial and spectral modal response in photonic crystals enables high efficiency spectral analysis of diffuse sources..


Predictors of persistent pain after breast cancer surgery: a systematic review and meta-analysis of observational studies.
Persistent pain after breast cancer surgery affects up to 60% of patients. Early identification of those at higher risk could help inform optimal management. We conducted a systematic review and meta-analysis of observational studies to explore factors associated with persistent pain among women who have undergone surgery for breast cancer. We searched the MEDLINE, Embase, CINAHL and PsycINFO databases from inception to Mar. 12, 2015, to identify cohort or case-control studies that explored the association between risk factors and persistent pain (lasting ≥ 2 mo) after breast cancer surgery. We pooled estimates of association using random-effects models, when possible, for all independent variables reported by more than 1 study. We reported relative measures of association as pooled odds ratios (ORs) and absolute measures of association as the absolute risk increase. Thirty studies, involving a total of 19 813 patients, reported the association of 77 independent variables with persistent pain. High-quality evidence showed increased odds of persistent pain with younger age (OR for every 10-yr decrement 1.36, 95% confidence interval [CI] 1.24-1.48), radiotherapy (OR 1.35, 95% CI 1.16-1.57), axillary lymph node dissection (OR 2.41, 95% CI 1.73-3.35) and greater acute postoperative pain (OR for every 1 cm on a 10-cm visual analogue scale 1.16, 95% CI 1.03-1.30). Moderate-quality evidence suggested an association with the presence of preoperative pain (OR 1.29, 95% CI 1.01-1.64). Given the 30% risk of pain in the absence of risk factors, the absolute risk increase corresponding to these ORs ranged from 3% (acute postoperative pain) to 21% (axillary lymph node dissection). High-quality evidence showed no association with body mass index, type of breast surgery, chemotherapy or endocrine therapy. Development of persistent pain after breast cancer surgery was associated with younger age, radiotherapy, axillary lymph node dissection, greater acute postoperative pain and preoperative pain. Axillary lymph node dissection provides the only high-yield target for a modifiable risk factor to prevent the development of persistent pain after breast cancer surgery.


Classical Analog to Entanglement Reversibility.
In this Letter we study the problem of secrecy reversibility. This asks when two honest parties can distill secret bits from some tripartite distribution p(XYZ) and transform secret bits back into p(XYZ) at equal rates using local operation and public communication. This is the classical analog to the well-studied problem of reversibly concentrating and diluting entanglement in a quantum state. We identify the structure of distributions possessing reversible secrecy when one of the honest parties holds a binary distribution, and it is possible that all reversible distributions have this form. These distributions are more general than what is obtained by simply constructing a classical analog to the family of quantum states known to have reversible entanglement. An indispensable tool used in our analysis is a conditional form of the Gács-Körner common information.


Computer-aided heterogeneity analysis in breast MR imaging assessment of ductal carcinoma in situ: Correlating histologic grade and receptor status.
To identify breast MR imaging biomarkers to predict histologic grade and receptor status of ductal carcinoma in situ (DCIS). Informed consent was waived in this Health Insurance Portability and Accountability Act-compliant Institutional Review Board-approved study. Case inclusion was conducted from 7332 consecutive breast MR studies from January 1, 2009, to December 31, 2012. Excluding studies with benign diagnoses, studies without visible abnormal enhancement, and pathology containing invasive disease yielded 55 MR-imaged pathology-proven DCIS seen on 54 studies. Twenty-eight studies (52%) were performed at 1.5 Tesla (T); 26 (48%) at 3T. Regions-of-interest representing DCIS were segmented for precontrast, first and fourth postcontrast, and subtracted first and fourth postcontrast images on the open-source three-dimensional (3D) Slicer software. Fifty-seven metrics of each DCIS were obtained, including distribution statistics, shape, morphology, Renyi dimensions, geometrical measure, and texture, using the 3D Slicer HeterogeneityCAD module. Statistical correlation of heterogeneity metrics with DCIS grade and receptor status was performed using univariate Mann-Whitney test. Twenty-four of the 55 DCIS (44%) were high nuclear grade (HNG); 44 (80%) were estrogen receptor (ER) positive. Human epidermal growth factor receptor-2 (HER2) was amplified in 10/55 (18%), nonamplified in 34/55 (62%), unknown/equivocal in 8/55 (15%). Surface area-to-volume ratio showed significant difference (P < 0.05) between HNG and non-HNG DCIS. No metric differentiated ER status (0.113 < p ≤ 1.000). Seventeen metrics showed significant differences between HER2-positive and HER2-negative DCIS (0.016 < P < 0.050). Quantitative heterogeneity analysis of DCIS suggests the presence of MR imaging biomarkers in classifying DCIS grade and HER2 status. Validation with larger samples and prospective studies is needed to translate these results into clinical applications. 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1748-1759.


Womens' opinions on antenatal care in developing countries: results of a study in Cuba, Thailand, Saudi Arabia and Argentina.
The results of a qualitative study carried out in four developing countries (Cuba, Thailand, Saudi Arabia and Argentina) are presented. The study was conducted in the context of a randomised controlled trial to test the benefits of a new antenatal care protocol that reduced the number of visits to the doctor, rationalised the application of technology, and improved the provision of information to women in relation to the traditional protocol applied in each country. Through focus groups discussions we were able to assess the concepts and expectations underlying women's evaluation of concepts and experiences of the care received in antenatal care clinics. 164 women participated in 24 focus groups discussion in all countries. Three areas are particularly addressed in this paper: a) concepts about pregnancy and health care, b) experience with health services and health providers, and c) opinions about the modified Antenatal Care (ANC) programme. In all three topics similarities were identified as well as particular opinions related to country specific social and cultural values. In general women have a positive view of the new ANC protocol, particularly regarding the information they receive. However, controversial issues emerged such as the reduction in the number of visits, particularly in Cuba where women are used to have 18 ANC visits in one pregnancy period. Recommendations to improve ANC services performance are being proposed. Any country interested in the application of a new ANC protocol should regard the opinion and acceptability of women towards changes.


Energy recovery in high rate algal pond used for domestic wastewater treatment.
High rate algal pond (HRAP) was evaluated according to its energy potential and productivity by two rates, net energy ratio (NER) and specific biomass productivity. All energy inputs were calculated according to one HRAP with pre-ultraviolet disinfection treating anaerobic domestic sewage. The outputs were calculated for two energetic pathways: lipid and biogas production for the raw biomass (RB) and biomass after lipid extraction. The non-polar lipid content in dry biomass was 7.6%, reaching a daily lipid productivity of 0.2 g/m2·day and the biogas production potential was 0.20 m3/kg solids. For the biomass after lipid extraction, the biogas production reached 2.6 m3/kg solids. NER values of 10-3 for the RB were similar for lipids and biogas routes. The specific biomass productivity was 0.7 mg/kJ. For the residual biomass, after lipid extraction, NER value was 10-2 for the integrated route (lipids + biogas) and the specific biomass productivity of the extracted biomass was 0.4 mg/kJ. The best energetic pathway was to integrate both lipids and biogas route.


Scoping future outbreaks: a scoping review on the outbreak prediction of the WHO Blueprint list of priority diseases.
The WHO's Research and Development Blueprint priority list designates emerging diseases with the potential to generate public health emergencies for which insufficient preventive solutions exist. The list aims to reduce the time to the availability of resources that can avert public health crises. The current SARS-CoV-2 pandemic illustrates that an effective method of mitigating such crises is the pre-emptive prediction of outbreaks. This scoping review thus aimed to map and identify the evidence available to predict future outbreaks of the Blueprint diseases. We conducted a scoping review of PubMed, Embase and Web of Science related to the evidence predicting future outbreaks of Ebola and Marburg virus, Zika virus, Lassa fever, Nipah and Henipaviral disease, Rift Valley fever, Crimean-Congo haemorrhagic fever, Severe acute respiratory syndrome, Middle East respiratory syndrome and Disease X. Prediction methods, outbreak features predicted and implementation of predictions were evaluated. We conducted a narrative and quantitative evidence synthesis to highlight prediction methods that could be further investigated for the prevention of Blueprint diseases and COVID-19 outbreaks. Out of 3959 articles identified, we included 58 articles based on inclusion criteria. 5 major prediction methods emerged; the most frequent being spatio-temporal risk maps predicting outbreak risk periods and locations through vector and climate data. Stochastic models were predominant. Rift Valley fever was the most predicted disease. Diseases with complex sociocultural factors such as Ebola were often predicted through multifactorial risk-based estimations. 10% of models were implemented by health authorities. No article predicted Disease X outbreaks. Spatiotemporal models for diseases with strong climatic and vectorial components, as in River Valley fever prediction, may currently best reduce the time to the availability of resources. A wide literature gap exists in the prediction of zoonoses with complex sociocultural and ecological dynamics such as Ebola, COVID-19 and especially Disease X.


Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis.
Active pulmonary tuberculosis is difficult to diagnose and treatment response is difficult to effectively monitor. A WHO consensus statement has called for new non-sputum diagnostics. The aim of this study was to use an integrated multicohort analysis of samples from publically available datasets to derive a diagnostic gene set in the peripheral blood of patients with active tuberculosis. We searched two public gene expression microarray repositories and retained datasets that examined clinical cohorts of active pulmonary tuberculosis infection in whole blood. We compared gene expression in patients with either latent tuberculosis or other diseases versus patients with active tuberculosis using our validated multicohort analysis framework. Three datasets were used as discovery datasets and meta-analytical methods were used to assess gene effects in these cohorts. We then validated the diagnostic capacity of the three gene set in the remaining 11 datasets. A total of 14 datasets containing 2572 samples from 10 countries from both adult and paediatric patients were included in the analysis. Of these, three datasets (N=1023) were used to discover a set of three genes (GBP5, DUSP3, and KLF2) that are highly diagnostic for active tuberculosis. We validated the diagnostic power of the three gene set to separate active tuberculosis from healthy controls (global area under the ROC curve (AUC) 0·90 [95% CI 0·85-0·95]), latent tuberculosis (0·88 [0·84-0·92]), and other diseases (0·84 [0·80-0·95]) in eight independent datasets composed of both children and adults from ten countries. Expression of the three-gene set was not confounded by HIV infection status, bacterial drug resistance, or BCG vaccination. Furthermore, in four additional cohorts, we showed that the tuberculosis score declined during treatment of patients with active tuberculosis. Overall, our integrated multicohort analysis yielded a three-gene set in whole blood that is robustly diagnostic for active tuberculosis, that was validated in multiple independent cohorts, and that has potential clinical application for diagnosis and monitoring treatment response. Prospective laboratory validation will be required before it can be used in a clinical setting. National Institute of Allergy and Infectious Diseases, National Library of Medicine, the Stanford Child Health Research Institute, the Society for University Surgeons, and the Bill and Melinda Gates Foundation.


Changes in occurrence of capsular serotypes of Streptococcus pneumoniae at Boston City Hospital during selected years between 1935 and 1974.
The number of patients with pneumococcal bacteremia, empyema, and meningitis at Boston City Hospital during selected years between 1935 and 1974 is reported. The distribution of specific types in the bacteremic patients during each of the selected years and in the various focal infections in all the years is also detailed. The numbers and rates per 1,000 admissions of bacteremic pneumococcal infections and the numbers of cases of pneumococcal meningitis and empyema varied independently over these years and differed from those previously reported for 1929 to 1936. The types most frequent in pneumococcal bacteremias varied over the years, and the distribution of types among them differed markedly from that among the patients with focal infections. Variations in the distribution of pneumococcal types at different times in the same place, in different places, and in various sites of infection may be important in selecting types to include in pneumococcal vaccines for different populations.