[Is it possible to identify dengue in children on the basis of Ministry of Health criteria for suspected dengue cases?].
To identify clinical characteristics indicative of dengue and to evaluate the applicability to children of the Health Ministry criteria for suspected cases. A cross-sectional study undertaken at the General Pediatrics Center of the Fundação Hospitalar de Minas Gerais. Children were enrolled if presenting acute febrile conditions with no definite etiology, lasting > 24 hours and < or = 7 days and if resident in the Metropolitan Region of Belo Horizonte. Clinical variables were investigated, specific tests were performed and aspartate-aminotransferase assayed, during a period considered both endemic and epidemic for the disease. The subset of children who did have dengue was compared with the subset of nonspecific acute febrile diseases. The Health Ministry criteria for suspected cases was evaluated. Dengue was diagnosed in 50.4% of the 117 children studied. There were no statistically significant associations between the disease and the majority of the symptoms analyzed. Only exanthema was more often associated with dengue (Prevalence Ratio = 1.49; 95% CI: 1.05-2.11). The criteria for suspected cases of dengue had a sensitivity of just 50.8% and a positive predictive value of 62.5%. These values were greater among schoolchildren and during the period of greater disease incidence. Dengue is common among febrile diseases of childhood, with prevalence that varies according to the epidemiological situation. The clinical status of children with dengue was very similar to that of children with other nonspecific diseases. The Health Ministry criteria for suspected cases was shown to be of little use, particularly with smaller children and during periods of reduced incidence.


Leech Infestation in the Vulvar Region: Causes of Vaginal Bleeding in a Six years old Child.
Leeches are hermaphroditic rare blood-sucking human endoparasitesof phylum Annelida and class Hirudinea. Leech infestation is a zoonotic disease acquired by drinking contaminated water, swimming in ponds and streams.1 Epidemiology of leech bites in literature is limited and the majority of existing data are case reports from the tropics or subtropics.2-4 Leech bites can occur on various orifices of the body including internal body cavities and orifices, such as the uterus, rectum, urinary bladder, vulva, nasal cavity, peritoneal cavity, nasopharynx, oropharynx, oesophagus, trachea, bronchi and the vagina.5 Different chemicals for leech removal have been utilized and include anesthetics drugs like lidocaine and topical anesthetic spray. Salt, saline, vinegar, alcohol, and heat are also viable options. Of these, saltwater has been shown to be effective in causing the leech to relax and release. Vaginal bleeding resulting from leech bite is rare, but when it occurs, it may be of severe morbidity.2-4 In the present case report that happened at Kabaya district hospital, a six year old child with vaginal bleeding that turned out to be caused by vaginal leech infestation is presented. Kabaya district hospital is a rural hospital with 144-bed capacity and serves 188,902 inhabitants and is geographically difficult to access due to the lack of reliable roads and bridges, especially in the rainy season.


Prolonged vitamin C supplementation and recovery from demanding exercise.
The aim of the present study was to investigate whether 2 weeks of vitamin C supplementation affects recovery from an unaccustomed bout of exercise. Sixteen male subjects were allocated to either a placebo (P; n = 8) or vitamin C group (VC; n = 8). The VC group consumed 200 mg of ascorbic acid twice a day, whereas the P group consumed identical capsules containing 200 mg of lactose. Subjects performed a prolonged (90-min) intermittent shuttle-running test 14 days after supplementation began. Post-exercise serum creatine kinase activities and myoglobin concentrations were unaffected by supplementation. However, vitamin C supplementation had modest beneficial effects on muscle soreness, muscle function, and plasma concentrations of malondialdehyde. Furthermore, although plasma interleukin-6 increased immediately after exercise in both groups, values in the VC group were lower than in the P group 2 hours after exercise (p < .05). These results suggest that prolonged vitamin C supplementation has some modest beneficial effects on recovery from unaccustomed exercise.


Data-driven prediction of drug effects and interactions.
Adverse drug events remain a leading cause of morbidity and mortality around the world. Many adverse events are not detected during clinical trials before a drug receives approval for use in the clinic. Fortunately, as part of postmarketing surveillance, regulatory agencies and other institutions maintain large collections of adverse event reports, and these databases present an opportunity to study drug effects from patient population data. However, confounding factors such as concomitant medications, patient demographics, patient medical histories, and reasons for prescribing a drug often are uncharacterized in spontaneous reporting systems, and these omissions can limit the use of quantitative signal detection methods used in the analysis of such data. Here, we present an adaptive data-driven approach for correcting these factors in cases for which the covariates are unknown or unmeasured and combine this approach with existing methods to improve analyses of drug effects using three test data sets. We also present a comprehensive database of drug effects (Offsides) and a database of drug-drug interaction side effects (Twosides). To demonstrate the biological use of these new resources, we used them to identify drug targets, predict drug indications, and discover drug class interactions. We then corroborated 47 (P < 0.0001) of the drug class interactions using an independent analysis of electronic medical records. Our analysis suggests that combined treatment with selective serotonin reuptake inhibitors and thiazides is associated with significantly increased incidence of prolonged QT intervals. We conclude that confounding effects from covariates in observational clinical data can be controlled in data analyses and thus improve the detection and prediction of adverse drug effects and interactions.


Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression.
Inflammasomes can prevent systemic dissemination of enteropathogenic bacteria. As adapted pathogens including Salmonella Typhimurium (S. Tm) have evolved evasion strategies, it has remained unclear when and where inflammasomes restrict their dissemination. Bacterial population dynamics establish that the NAIP/NLRC4 inflammasome specifically restricts S. Tm migration from the gut to draining lymph nodes. This is solely attributable to NAIP/NLRC4 within intestinal epithelial cells (IECs), while S. Tm evades restriction by phagocyte NAIP/NLRC4. NLRP3 and Caspase-11 also fail to restrict S. Tm mucosa traversal, migration to lymph nodes, and systemic pathogen growth. The ability of IECs (not phagocytes) to mount a NAIP/NLRC4 defense in vivo is explained by particularly high NAIP/NLRC4 expression in IECs and the necessity for epithelium-invading S. Tm to express the NAIP1-6 ligands-flagella and type-III-secretion-system-1. Imaging reveals both ligands to be promptly downregulated following IEC-traversal. These results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.


Identification of microRNA targets in tomato fruit development using high-throughput sequencing and degradome analysis.
MicroRNAs (miRNAs) play important roles in plant development through regulation of gene expression by mRNA degradation or translational inhibition. Despite the fact that tomato (Solanum lycopersicum) is the model system for studying fleshy fruit development and ripening, only a few experimentally proven miRNA targets are known, and the role of miRNA action in these processes remains largely unknown. Here, by using parallel analysis of RNA ends (PARE) for global identification of miRNA targets and comparing four different stages of tomato fruit development, a total of 119 target genes of miRNAs were identified. Of these, 106 appeared to be new targets. A large part of the identified targets (56) coded for transcription factors. Auxin response factors, as well as two known ripening regulators, colorless non-ripening (CNR) and APETALA2a (SlAP2a), with developmentally regulated degradation patterns were identified. The levels of the intact messenger of both CNR and AP2a are actively modulated during ripening, by miR156/157 and miR172, respectively. Additionally, two TAS3-mRNA loci were identified as targets of miR390. Other targets such as Argonaute 1 (AGO1), shown to be involved in miRNA biogenesis in other plant species, were identified, which suggests a feedback loop regulation of this process. In this study, it is shown that miRNA-guided cleavage of mRNAs is likely to play an important role in tomato fruit development and ripening.


Identification of population substructure among Jews using STR markers and dependence on reference populations included.
Detecting population substructure is a critical issue for association studies of health behaviors and other traits. Whether inherent in the population or an artifact of marker choice, determining aspects of a population's genetic history as potential sources of substructure can aid in design of future genetic studies. Jewish populations, among which association studies are often conducted, have a known history of migrations. As a necessary step in understanding population structure to conduct valid association studies of health behaviors among Israeli Jews, we investigated genetic signatures of this history and quantified substructure to facilitate future investigations of these phenotypes in this population. Using 32 autosomal STR markers and the program STRUCTURE, we differentiated between Ashkenazi (AJ, N = 135) and non-Ashkenazi (NAJ, N = 226) Jewish populations in the form of Northern and Southern geographic genetic components (AJ north 73%, south 23%, NAJ north 33%, south 60%). The ability to detect substructure within these closely related populations using a small STR panel was contingent on including additional samples representing major continental populations in the analyses. Although clustering programs such as STRUCTURE are designed to assign proportions of ancestry to individuals without reference population information, when Jewish samples were analyzed in the absence of proxy parental populations, substructure within Jews was not detected. Generally, for samples with a given grandparental country of birth, STRUCTURE assignment values to Northern, Southern, African and Asian clusters agreed with mitochondrial DNA and Y-chromosomal data from previous studies as well as historical records of migration and intermarriage.


Post hoc analyses: after the facts.
Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.


Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.
This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.


Chromosome-level hybrid de novo genome assemblies as an attainable option for nonmodel insects.
The emergence of third-generation sequencing (3GS; long-reads) is bringing closer the goal of chromosome-size fragments in de novo genome assemblies. This allows the exploration of new and broader questions on genome evolution for a number of nonmodel organisms. However, long-read technologies result in higher sequencing error rates and therefore impose an elevated cost of sufficient coverage to achieve high enough quality. In this context, hybrid assemblies, combining short-reads and long-reads, provide an alternative efficient and cost-effective approach to generate de novo, chromosome-level genome assemblies. The array of available software programs for hybrid genome assembly, sequence correction and manipulation are constantly being expanded and improved. This makes it difficult for nonexperts to find efficient, fast and tractable computational solutions for genome assembly, especially in the case of nonmodel organisms lacking a reference genome or one from a closely related species. In this study, we review and test the most recent pipelines for hybrid assemblies, comparing the model organism Drosophila melanogaster to a nonmodel cactophilic Drosophila, D. mojavensis. We show that it is possible to achieve excellent contiguity on this nonmodel organism using the dbg2olc pipeline.


Effects of an over-the-counter lactic-acid containing intra-vaginal douching product on the vaginal microbiota.
Over-the-counter intra-vaginal lactic-acid containing douches are marketed as vaginal hygiene products that support optimal vaginal pH balance. We report the effect of a commercially available douche (Etos®) on the vaginal microbiota (VM) in a prospective study. Twenty-five healthy women were recruited through advertisements in 2015-2017 (ethical approval: METC-2014_413) and followed over three menstrual cycles. The participants had a median age of 24 years [IQR: 22-29], were mostly Dutch-Caucasian (88%), and 60% used combined oral contraceptives. All participants douched three times a week during the second cycle, starting on the first day of that cycle. Participants completed a questionnaire at baseline, kept a daily diary to report douching, menses, and sexual activity, self-collected vaginal swabs every other day during the first and third cycle and daily during the second cycle, and measured vaginal pH mid-cycle. A median of 44 vaginal swabs [inter-quartile range (IQR): 41-50] were assessed per participant by 16S rRNA gene (V3-V4 region) sequencing and a Candida albicans PCR was done at four time-points. At baseline, 21 participants (84%) had Lactobacillus-dominated VM (Lactobacillus crispatus (n = 14), L. iners (n = 6), or diverse Lactobacillus species (n = 1) and 4 participants (16%) had VM consisting of diverse anaerobes. In multinomial logistic regression models, a trend towards increased odds were observed for having diverse anaerobic VM in the second and third cycle, compared to the first cycle, after adjusting for menses [odds ratio (OR) = 1.4 (95% CI: 0.9-2.1) and OR = 1.7 (95% CI: 0.9-3.1), respectively] (p = 0.376). Douching did not affect vaginal pH. Menses increased the odds for having VM consisting of diverse anaerobes almost two-fold (OR = 1.7; 95% CI: 1.0-2.8), while douching during menses increased the odds 2.6 fold (OR = 2.6; 95% CI: 1.0-6.5), compared to not menstruating (p = 0.099). Participants were more likely to test positive for C. albicans after cycle 2, compared to cycle 1 [OR = 3.0 (95% CI: 1.2-7.2); p = 0.017]. The Etos® douche did not significantly affect the vaginal pH or VM composition, although increased odds for having diverse anaerobic VM was observed, especially when douching during menses. Furthermore, douching may promote C. albicans infections.


Effect of cigarette smoking and coffee drinking on time to conception.
To test the hypothesis that coffee consumption and cigarette smoking are associated with time to conception, we analyzed data collected from 1,341 primigravidas participating in the Child Health and Development Studies in the San Francisco Bay Area between 1959 and 1966. Women were interviewed in person about their reproductive and medical history, habits (smoking, coffee and alcohol consumption), and sociodemographic characteristics. Logistic regression models showed that after adjusting for covariates, women who smoked cigarettes had about one-half the fertility [odds ratio (OR) = 0.5-0.6] of nonsmoker-noncoffee drinkers for times to conception of 6 and 12 months, regardless of whether they drank coffee. On the other hand, coffee consumers who did not smoke did not have decreased fertility compared with nondrinkers who did not smoke (adjusted OR = 1.0-1.2). Coffee drinking did not increase the risk of delayed conception among smokers over the risk posed by the smoking exposure by itself (adjusted OR = 0.6-0.8). We observed an effect of smoking even at low doses (1-9 cigarettes per day). The present study adds to the evidence of an association between cigarette smoking and reduced fertility.


Pulmonary schistosomiasis in a young male: A case report and review of the literature.
Schistosoma is a parasitic infection that affects many people worldwide. However, pulmonary Schistosomiasis is very rare entity which defined as pulmonary involvement develops in persons living or travelling in endemic areas. We report a rare case of 23-year-old Yamani patient admitted as an emergency with a 1-week history of productive cough, hemoptysis, and chest pain. Chest X-ray and computed tomography scan showed right upper lobe peripheral abscess cavity. All routine blood investigations and interventions such as bronchoscopy and bronchoalveolar lavage failed to confirm the diagnosis. However, he underwent right thoracoscopy and excision of this abscess, which unexpectedly showed in the histopathology of the resected specimen Schistosoma parasite infection.


The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue.
Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold-organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified. In this study, we demonstrate that the incorporation of a specific antioxidant phenol fragment can counterbalance the pro-oxidative potential of the Au containing complex molecule. The electrochemical studies of AuPPh3SR (1, R= 3,5-di-tert-butyl-4-hydroxyphenyl) and its precursors AuPPh3Cl (2) and RSH (3) showed that complex 1 and phenol 3 efficiently scavenged the radicals (as detected by cyclic voltammetry) whereas 2 had no effect. Compound 1 inhibited TrxR in vitro with IC50 0.57 ± 0.15 μM, a value one order of magnitude bigger than the potency reported for auranofin. Compound 1 (5 mg kg-1 daily gavage for 14 days) caused a decrease in ex vivo spontaneous and ascorbate-induced lipid peroxidation in the homogenates of rat lung, heart muscle, spleen, liver, kidneys, testicles and brain as assessed by the thiobarbituric acid reactive substances. Importantly, in animals fed with 1, no discernible general toxicity was registered suggesting that this compound is well tolerated. Our results provide evidence for an efficient synthetic route to obtain gold containing anti-inflammatory drug candidates with balanced pro/anti-oxidative properties.


Near-infrared light penetration profile in the rodent brain.
Near-infrared (NIR) lasers find applications in neuro-medicine both for diagnostic and treatment purposes. Penetration depth and profile into neural tissue are critical parameters to be considered in these applications. Published data on the optical properties of rodent neural tissue are rare, despite the frequent use of rats as an animal model. The aim of this study was to measure the light intensity profile inside the rat brain using a direct method, while the medium is being illuminated by an NIR laser beam, and compare the results with in vitro measurements of transmittance in the rat brain slices. The intensity profile along the vertical axis had an exponential decline with multiple regions that could be approximated with different coefficients. The Monte Carlo method that was used to simulate light-tissue interactions and predict the scattering coefficient of brain tissue from the measurements suggested that more scattering occurred in deeper layers of the cortex. A single scattering coefficient of 125 cm-1 was estimated for cortical layers from 300 to 1500 μm and a gradually increasing value from 125 to 370 cm-1 for depths of 1500 to 3000 μm. The deviations of in vivo results from the in vitro transmittance measurements, as well as the postmortem in vivo results from the alive measurements were significant.


Outbreak of Mycobacterium chelonae infection associated with use of jet injectors.
Between January 1 and May 15, 1988, foot infections due to Mycobacterium chelonae subspecies abscessus were diagnosed in eight persons who had undergone invasive procedures at a podiatry office. A cohort study was performed to evaluate risk factors for disease. Persons who underwent procedures before 10:30 AM were more likely to have developed infection than those with procedures after that time (relative risk, 5.6). In addition, procedures involving any of the second through fourth toes were more likely to have resulted in infection than procedures involving only the first and/or fifth toes (relative risk, 4.4). Persons with 0, 1, or 2 risk factors had attack rates of 5%, 14%, and 60%, respectively. Mycobacterium chelonae subspecies abscessus organisms of the same antimicrobial resistance pattern as the patients' strains were cultured from distilled water in a reusable, nonsterilized container. A jet injector used to administer lidocaine was held between procedures in a mixture of the distilled water and a disinfectant as recommended by the manufacturer. Inoculation of patients with mycobacteria by the jet injector may have only occurred early in the day due to slow killing of the bacteria by the disinfectant. The outbreak emphasizes the pathogenicity of this water-associated organism and the need for high-level disinfection of jet injectors.


Correlation between pulmonary functions and respiratory muscle activity in patients with forward head posture.
[Purpose] The purpose of this study is to determine the effect that secondary postural deformities and chronic postural abnormalities have on lung capacity, as well as correlate the activity of the respiratory muscles. The results provide basic objective data about the forward head posture and respiratory muscle activity that can be used in clinical situations. [Subjects and Methods] The subjects used in this study were 24 patients aged 25 to 35 years old who visited a hospital in Jeollanam-do Province, Korea, between September 2015 and January 2016. The patients were diagnosed with forward head posture because the vertical line between the acromion process and the external acoustic meatus was at least 5 cm. We measured the craniovertebral angle, pulmonary functions, and respiratory muscle activity of the subjects for correlation analysis. [Results] A positive correlation was found between the craniovertebral angle and the forced vital capacity (r=0.63), while a negative correlation was found between the craniovertebral angle and the sternocleidomastoid muscle (r=-0.77). The craniovertebral angle and the anterior scalene muscle showed a negative correlation (r=-0.65). There were positive correlations between the forced vital capacity and the sternocleidomastoid muscle (r=0.71), and between the forced vital capacity and the anterior scalene muscle (r=0.59). [Conclusion] Severe forward head posture increased the activities of the sternocleidomastoid muscles and the anterior scalene muscles, and decreased the forced vital capacity. Thus, it is necessary to develop more efficient interventions for managing forward head posture based on pulmonary function and the activity of the respiratory synergist muscles.


Deletions of endocytic components VPS28 and VPS32 affect growth at alkaline pH and virulence through both RIM101-dependent and RIM101-independent pathways in Candida albicans.
Ambient pH signaling involves a cascade of conserved Rim or Pal products in ascomycetous yeasts or filamentous fungi, respectively. Recent evidences in the fungi Aspergillus nidulans, Saccharomyces cerevisiae, Yarrowia lipolytica, and Candida albicans suggested that components of endosomal sorting complexes required for transport (ESCRT) involved in endocytic trafficking were needed for signal transduction along the Rim pathway. In this study, we confirm these findings with C. albicans and show that Vps28p (ESCRT-I) and Vps32p/Snf7p (ESCRT-III) are required for the transcriptional regulation of known targets of the Rim pathway, such as the PHR1 and PHR2 genes encoding cell surface proteins, which are expressed at alkaline and acidic pH, respectively. We additionally show that deletion of these two VPS genes, particularly VPS32, has a more drastic effect than a RIM101 deletion on growth at alkaline pH and that this effect is only partially suppressed by expression of a constitutively active form of Rim101p. Finally, in an in vivo mouse model, both vps null mutants were significantly less virulent than a rim101 mutant, suggesting that VPS28 and VPS32 gene products affect virulence both through Rim-dependent and Rim-independent pathways.


Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities.
Cognitive function was examined in 227 patients three months after admission to hospital for ischaemic stroke, and in 240 stroke-free controls, using 17 scored items that assessed memory, orientation, verbal skills, visuospatial ability, abstract reasoning, and attentional skills. After adjusting for demographic factors with standardised residual scores in all subjects, the fifth percentile was used for controls as the criterion for failure on each item. The mean (SD) number of failed items was 3.4 (3.6) for patients with stroke and 0.8 (1.3) for controls (p < 0.001). Cognitive impairment, defined as failure on any four or more items, occurred in 35.2% of patients with stroke and 3.8% of controls (p < 0.001). Cognitive domains most likely to be defective in stroke compared with control subjects were memory, orientation, language, and attention. Among patients with stroke, cognitive impairment was most frequently associated with major cortical syndromes and with infarctions in the left anterior and posterior cerebral artery territories. Functional impairment was greater with cognitive impairment, and dependent living after discharge either at home or nursing home was more likely (55.0% with, v 32.7% without cognitive impairment, p = 0.001). In a logistic model examining the risks related to dependent living after stroke, cognitive impairment was a significant independent correlate (odds ratio, OR = 2.4), after adjusting for age (OR = 5.2, 80 + v 60-70 years) and physical impairment (OR = 3.7, Barthel index < or = 40 v > 40). It is concluded that cognitive impairment occurs frequently after stroke, commonly involving memory, orientation, language, and attention. The presence of cognitive impairment in patients with strike has important functional consequences, independent of the effects of physical impairment. Studies of stroke outcome and intervention should take into account both cognitive and physical impairments.


Alveolar injury and regeneration following deletion of ABCA3.
Adaptation to air breathing after birth is dependent upon the synthesis and secretion of pulmonary surfactant by alveolar type 2 (AT2) cells. Surfactant, a complex mixture of phospholipids and proteins, is secreted into the alveolus, where it reduces collapsing forces at the air-liquid interface to maintain lung volumes during the ventilatory cycle. ABCA3, an ATP-dependent Walker domain containing transport protein, is required for surfactant synthesis and lung function at birth. Mutations in ABCA3 cause severe surfactant deficiency and respiratory failure in newborn infants. We conditionally deleted the Abca3 gene in AT2 cells in the mature mouse lung. Loss of ABCA3 caused alveolar cell injury and respiratory failure. ABCA3-related lung dysfunction was associated with surfactant deficiency, inflammation, and alveolar-capillary leak. Extensive but incomplete deletion of ABCA3 caused alveolar injury and inflammation, and it initiated proliferation of progenitor cells, restoring ABCA3 expression, lung structure, and function. M2-like macrophages were recruited to sites of AT2 cell proliferation during the regenerative process and were present in lung tissue from patients with severe lung disease caused by mutations in ABCA3. The remarkable and selective regeneration of ABCA3-sufficient AT2 progenitor cells provides plausible approaches for future correction of ABCA3 and other genetic disorders associated with surfactant deficiency and acute interstitial lung disease.


Enhance anchorage independence and tumorigenicity of aneuploid Chinese hamster cells with nearly doubled chromosome complements.
The role of a cell's chromosome complement in its tumorigenic and anchorage-independent growth properties in vitro was investigated by injecting a Chinese hamster cell line and its subclones into immunodeficient nude mice and by plating the cells in a semisolid medium containing methylcellulose. The parental WOR-6 cell clone originally consisted of 89% 1s cells and 11% cells with a nearly double (2s) complement. Tumors that developed from WOR-6 were found to consis entirely or primarily of cells with near 2s chromosome complements. Subclones of WOR-6 that contained only 1s cells rarely produced tumors in nude mice, even at high inoculum doses, whereas clones containing a high fraction of 2s cells were consistently tumorigenition, serial passage of WOR-6 cells in semisolid medium resulted in selective enrichment for near 2s cells and, concomitantly, greatly enhanced tumorigenicity. Analyses of G-banded chromosomes revealed that the 1s cells of the WOR-6 parental clone, which has a modal chromosome number of 21 and a range of 18 to 23, is completely or partially monosomic for some chromosomes and trisomic for others. The 2s cells, selected both in vivo through growth as tumors in nude mice and in vitro in semisolid medium, appeared to have resulted from preferential duplication of certain chromosomes of the 1s cells. Our results therefore suggest that cells which develop multiple copies of selected genes, while remaining functionally hemizygous for other loci, acquire an enhanced anchorage-independent growth potential in vitro and increased tumorigenicity. This conclusion is consistent with the observation that cellular tumorigenicity is correlated with anchorage independence (Rreedman and Shin, 1974) and leads support to OHNO'S (1974) suggesting that aneuploidy is a possible means employed by cells to express recessive phenotypes and increase their tumorigenicity.


Alcohol risk management in college settings: the safer California universities randomized trial.
Potentially effective environmental strategies have been recommended to reduce heavy alcohol use among college students. However, studies to date on environmental prevention strategies are few in number and have been limited by their nonexperimental designs, inadequate sample sizes, and lack of attention to settings where the majority of heavy drinking events occur. To determine whether environmental prevention strategies targeting off-campus settings would reduce the likelihood and incidence of student intoxication at those settings. The Safer California Universities study involved 14 large public universities, half of which were assigned randomly to the Safer intervention condition after baseline data collection in 2003. Environmental interventions took place in 2005 and 2006 after 1 year of planning with seven Safer intervention universities. Random cross-sectional samples of undergraduates completed online surveys in four consecutive fall semesters (2003-2006). Campuses and communities surrounding eight campuses of the University of California and six in the California State University system were utilized. The study used random samples of undergraduates (∼500-1000 per campus per year) attending the 14 public California universities. Safer environmental interventions included nuisance party enforcement operations, minor decoy operations, driving-under-the-influence checkpoints, social host ordinances, and use of campus and local media to increase the visibility of environmental strategies. Proportion of drinking occasions in which students drank to intoxication at six different settings during the fall semester (residence hall party, campus event, fraternity or sorority party, party at off-campus apartment or house, bar/restaurant, outdoor setting), any intoxication at each setting during the semester, and whether students drank to intoxication the last time they went to each setting. Significant reductions in the incidence and likelihood of intoxication at off-campus parties and bars/restaurants were observed for Safer intervention universities compared to controls. A lower likelihood of intoxication was observed also for Safer intervention universities the last time students drank at an off-campus party (OR=0.81, 95% CI=0.68, 0.97); a bar or restaurant (OR=0.76, 95% CI=0.62, 0.94); or any setting (OR=0.80, 95% CI=0.65, 0.97). No increase in intoxication (e.g., displacement) appeared in other settings. Further, stronger intervention effects were achieved at Safer universities with the highest level of implementation. Environmental prevention strategies targeting settings where the majority of heavy drinking events occur appear to be effective in reducing the incidence and likelihood of intoxication among college students.


Distinctly different dynamics and kinetics of two steroid receptors at the same response elements in living cells.
Closely related transcription factors (TFs) can bind to the same response elements (REs) with similar affinities and activate transcription. However, it is unknown whether transcription is similarly orchestrated by different TFs bound at the same RE. Here we have compared the recovery half time (t1/2), binding site occupancy and the resulting temporal changes in transcription upon binding of two closely related steroid receptors, the androgen and glucocorticoid receptors (AR and GR), to their common hormone REs (HREs). We show that there are significant differences at all of these levels between AR and GR at the MMTV HRE when activated by their ligands. These data show that two TFs bound at the same RE can have significantly different modes of action that can affect their responses to environmental cues.


Efficacy and safety of novel oral anticoagulants in patients with cervical artery dissections.
American and European guidelines support antiplatelet agents and anticoagulants as reasonable treatments of cervical artery dissection (CAD), though randomized clinical trials are lacking. The utility of novel oral anticoagulants (NOAC), effective in reducing embolic stroke risk in non-valvular atrial fibrillation (NVAF), has not been reported in patients with CAD. We report on the use, safety, and efficacy of NOACs in the treatment of CAD. We retrospectively identified patients diagnosed with CAD at a single academic center between January 2010 and August 2013. Patients were categorized by their antithrombotic treatment at hospital discharge with a NOAC (dabigatran, rivaroxaban, or apixaban), traditional anticoagulant (AC: warfarin or treatment dose low-molecular weight heparin), or antiplatelet agent (AP: aspirin, clopidogrel, or aspirin/extended-release dypyridamole). Using appropriate tests, we compared the baseline medical history, presenting clinical symptoms and initial radiographic characteristics among patients in the 3 treatment groups. We then evaluated for the following outcomes: recurrent stroke, vessel recanalization, and bleeding complications. p values <0.05 were considered significant. Of the 149 included patients (mean age 43.4 years; 63.1% female; 70.5% vertebral artery CAD), 39 (26.2%), 70 (47.0%), and 40 (26.8%) were treated with a NOAC, AC, and AP, respectively. More patients with severe stenosis or occlusion were treated with NOAC than with AC or AP (61.8 vs. 60.0 vs. 22.5%, p = 0.002). Other baseline clinical and radiographic findings, including the presence of acute infarction and hematoma, did not differ between the 3 treatment groups. One hundred and thirty-five (90.6%) patients had clinical follow-up (median time 7.5 months) and 125 (83.9%) had radiographic follow-up (median time 5 months) information. There were 2 recurrent strokes in the NOAC group and 1 in each of the AC and AP groups (p = 0.822). There were more major hemorrhagic events in the AC group (11.4%) compared to the NOAC (0.0%) and AP (2.5%) groups (p = 0.034). Three patients treated with NOAC and none treated with AC or AP had a worsened degree of stenosis on follow-up imaging (8.6 vs. 0.0 vs. 0.0%, p = 0.019). Compared to traditional anticoagulants for CAD, treatment with NOACs is associated with similar rates of recurrent stroke, fewer hemorrhagic complications, but greater rates of radiographic worsening. These data suggest that NOACs may be a reasonable alternative in the management of CAD. Prospective validation of these findings is needed.


Influence of hypotension and hypotensive technique on the area of profound reduction in cerebral blood flow during focal cerebral ischaemia in the rat.
We have studied the effect of induced hypotension on reduction in regional cerebral blood flow (CBF) during middle cerebral artery occlusion (MCAO). Rats were anaesthetized with 2% isoflurane. MCAO was performed during four conditions: normotension (mean arterial pressure (MAP) 107 (SD 15) mm Hg); hypovolaemic hypotension (blood withdrawn to reduce MAP to 43 (2) mm Hg); nitroprusside (SNP) hypotension (MAP reduced to 45 (3) mm Hg); isoflurane hypotension (MAP reduced to 44 (3) mm Hg with 3.5 (0.48)% isoflurane). Hypotension was established before MCAO and was maintained for 10 min, at which time the dimension of the brain areas with zero CBF was determined autoradiographically. All hypotensive regimens were associated with significantly larger areas of extreme CBF reduction. In a coronal section at the centre of the MCA distribution, the area with zero CBF (expressed as a percentage of the area of the entire coronal section) was: normotension 4.7 (4.5)%; hypovolaemic hypotension 10.1 (2.8)%; nitroprusside hypotension 13.5 (2.0)%; and isoflurane hypotension 11.8 (3.9)%. There were no differences between the three hypotensive regimens. The data indicate that, when focal cerebral ischaemia occurs during hypotension (MAP 45 mm Hg) induced by any of the three regimens evaluated, extreme CBF reduction occurs over larger areas than are observed during normotension. These data confirm the importance of arterial pressure as a determinant of collateral flow during focal cerebral ischaemia.


Pathogenesis of XJ and Romero strains of Junin virus in two strains of guinea pigs.
Argentine hemorrhagic fever (AHF), a systemic infectious disease caused by infection with Junin virus, affects several organs, and patients can show hematologic, cardiovascular, renal, or neurologic symptoms. We compared the virulence of two Junin virus strains in inbred and outbred guinea pigs with the aim of characterizing this animal model better for future vaccine/antiviral efficacy studies. Our data indicate that this passage of the XJ strain is attenuated in guinea pigs. In contrast, the Romero strain is highly virulent in Strain 13 as well as in Hartley guinea pigs, resulting in systemic infection, thrombocytopenia, elevated aspartate aminotransferase levels, and ultimately, uniformly lethal disease. We detected viral antigen in formalin-fixed, paraffin-embedded tissues. Thus, both guinea pig strains are useful animal models for lethal Junin virus (Romero strain) infection and potentially can be used for preclinical trials in vaccine or antiviral drug development.


Colonization potential to reconstitute a microbe community in patients detected early after fecal microbe transplant for recurrent C. difficile.
Fecal microbiota transplants (FMT) are an effective treatment for patients with gut microbe dysbiosis suffering from recurrent C. difficile infections. To further understand how FMT reconstitutes the patient's gut commensal microbiota, we have analyzed the colonization potential of the donor, recipient and recipient post transplant fecal samples using transplantation in gnotobiotic mice. A total of nine samples from three human donors, recipient's pre and post FMT were transplanted into gnotobiotic mice. Microbiome analysis of three donor fecal samples revealed the presence of a high relative abundance of commensal microbes from the family Bacteriodaceae and Lachnospiraceae that were almost absent in the three recipient pre FMT fecal samples (<0.01%). The microbe composition in gnotobiotic mice transplanted with the donor fecal samples was similar to the human samples. The recipient samples contained Enterobacteriaceae, Lactobacillaceae, Enterococcaceae in relative abundance of 43, 11, 8%, respectively. However, gnotobiotic mice transplanted with the recipient fecal samples had an average relative abundance of unclassified Clostridiales of 55%, approximately 7000 times the abundance in the recipient fecal samples prior to transplant. Microbiome analysis of fecal samples from the three patients early (2-4 weeks) after FMT revealed a microbe composition with the relative abundance of both Bacteriodaceae and Lachnospiraceae that was approximately 7% of that of the donor. In contrast, gnotobioitc mice transplanted with the fecal samples obtained from the three at early times post FMT revealed increases in the relative abundance of Bacteriodaceae and Lachnospiraceae microbe compositions to levels similar to the donor fecal samples. Furthermore, the unclassified Clostridiales in the recipient samples post FMT was reduced to an average of 10%. We have used transplantation into gnotobiotic mice to evaluate the colonization potential of microbiota in FMT patients early after transplant. The commensal microbes present at early times post FMT out competed non-commensal microbes (e.g. such as unclassified Clostridiales) for niche space. The selective advantage of these commensal microbes to occupy niches in the gastrointestinal tract helps to explain the success of FMT to reconstitute the gut microbe community of patients with recurrent C. difficile infections.


Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice.
Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice. We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified. Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice (P = .001) and fewer liver metastases (P = .018) with less peritoneal dissemination (P = .018) compared to PSCs not exposed to autophagy inhibitors. Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.


Combined Anti-inflammatory and Neuroprotective Treatments Have the Potential to Impact Disease Phenotypes in Cln3 -/- Mice.
Batten disease, or juvenile NCL, is a fatal neurodegenerative disorder that occurs due to mutations in the CLN3 gene. Because the function of CLN3 remains unclear, experimental therapies for JNCL have largely concentrated upon the targeting of downstream pathomechanisms. Neuron loss is preceded by localized glial activation, and in this proof-of-concept study we have investigated whether targeting this innate immune response with ibuprofen in combination with the neuroprotective agent lamotrigine improves the previously documented beneficial effects of immunosuppressants alone. Drugs were administered daily to symptomatic Cln3 -/- mice over a 3 month period, starting at 6 months of age, and their impact was assessed using both behavioral and neuropathological outcome measures. During the treatment period, the combination of ibuprofen and lamotrigine significantly improved the performance of Cln3 -/- mice on the vertical pole test, slowing the disease-associated decline, but had less of an impact upon their rotarod performance. There were also moderate and regionally dependent effects upon astrocyte activation that were most pronounced for ibuprofen alone, but there was no overt effect upon microglial activation. Administering such treatments for longer periods will enable testing for any impact upon the neuron loss that occurs later in disease progression. Given the partial efficacy of these treatments, it will be important to test further drugs of this type in order to find more effective combinations.


The influence of chromosome flexibility on chromosome transport during anaphase A.
The role of protein flexibility in molecular motor function has previously been studied by considering a Brownian ratchet motor that is connected to its cargo by an elastic spring, with the result that the average velocity of the motor/cargo system is increased by reducing the stiffness of the linkage. Here, we extend this investigation to the case of chromosome transport during anaphase A, in which the relevant flexibility is not primarily in the motor/cargo linkage but rather in the cargo itself, i.e., in the chromosome. We model the motor mechanism as an imperfect Brownian ratchet with a built-in opposing load and the chromosome as a collection of discrete segments linked by an elastic energy function that discretizes the potential energy of an elastic rod. Thermal fluctuations are produced in the model by random forces, as in Brownian dynamics. All of the parameters that characterize the chromosome are known or can be estimated from experimental data, as can all but one of the motor parameters, which is adjusted to give the correct transport velocity of normal-length chromosomes. With the parameters so determined, we then reproduce the experimental finding of Nicklas [Nicklas, R. B. (1965) J. Cell Biol. 25, 119-135] that chromosome speed is essentially independent of chromosome length, even though our model contains no "velocity governor." We find instead that this effect is a consequence of chromosome flexibility, as it disappears when stiffer than normal chromosomes are considered.


Focus plane detection criteria in digital holography microscopy by amplitude analysis.
We propose and test a focus plane determination method that computes the digital refocus distance of an object investigated by digital holographic microscopy working in transmission. For this purpose we analyze the integrated amplitude modulus as a function of the digital holographic reconstruction distance. It is shown that when the focus distance is reached, the integrated amplitude is minimum for pure amplitude object and maximum for pure phase object. After a theoretical analysis, the method is demonstrated on actual digital holograms for the refocusing of pure amplitude and of pure phase microscopic samples.


Desensitization and internalization of metabotropic glutamate receptor 1a following activation of heterologous Gq/11-coupled receptors.
In this study we characterized the heterologous desensitization and internalization of the metabotropic glutamate receptor 1 (mGluR1) splice variants mGluR1a and mGluR1b following activation of endogenous G(q/11)-coupled receptors in HEK293 cells. Agonist activation of M1 muscarinic acetylcholine or P2Y1 purinergic receptors triggered the PKC- and CaMKII-dependent internalization of mGluR1a. In co-immunoprecipitation studies, both glutamate and carbachol increased the association of GRK2 with mGluR1a. Co-addition of the protein kinase C (PKC) inhibitor GF109203X and the Ca(2+) calmodulin-dependent kinase II (CaMKII) inhibitor KN-93 blocked the ability of glutamate and carbachol to increase the association of GRK2 with mGluR1a. Glutamate also increased the association of GRK2 with mGluR1b, whereas carbachol did not. However, unlike mGluR1a, glutamate-stimulated association of GRK2 with mGluR1b was not reduced by PKC/CaMKII inhibition. Pretreatment of cells expressing mGluR1a or mGluR1b with carbachol rapidly desensitized subsequent glutamate-stimulated inositol phosphate accumulation. The carbachol-induced heterologous desensitization and internalization of mGluR1a was blocked by LY367385, an mGluR1a antagonist with inverse agonist activity. Furthermore, LY367385 blocked the ability of carbachol to increase the association of GRK2 with mGluR1a. On the other hand, LY367385 had no effect on the carbachol-induced desensitization and internalization of the nonconstitutively active mGluR1b splice variant. These results demonstrate that the internalization of mGluR1a, triggered homologously by glutamate or heterologously by carbachol, is PKC/CaMKII-, GRK2-, arrestin-, and clathrin-dependent and that PKC/CaMKII activation appears to be necessary for GRK2 to associate with mGluR1a. Furthermore, the heterologous desensitization of mGluR1a is dependent upon the splice variant being in an active conformation.


Late spinal metastases from an isolated pineal region germinoma mimicking a schwannoma.
A 20-year-old male with a prior history of germinoma presented 8 years after the initial diagnosis with progressive lower back pain. The preoperative diagnosis was schwannoma based on the appearances of a tumor in the lumbosacral region on MRI; however, histologically, a germinoma "drop" metastasis was seen. This report emphasizes the need for long-term follow-up in patients with germinoma. In addition, this patient is unusual in that the preoperative assessment favored schwannoma.


Management of Clostridium difficile Infection in Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates Committee of the AGA Institute.
The purpose of this expert review is to synthesize the existing evidence on the management of Clostridium difficile infection in patients with underlying inflammatory bowel disease. The evidence reviewed in this article is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. This review is a summary of expert opinion in the field without a formal systematic review of evidence. Best Practice Advice 1: Clinicians should test patients who present with a flare of underlying inflammatory bowel disease for Clostridium difficile infection. Best Practice Advice 2: Clinicians should screen for recurrent C difficile infection if diarrhea or other symptoms of colitis persist or return after antibiotic treatment for C difficile infection. Best Practice Advice 3: Clinicians should consider treating C difficile infection in inflammatory bowel disease patients with vancomycin instead of metronidazole. Best Practice Advice 4: Clinicians strongly should consider hospitalization for close monitoring and aggressive management for inflammatory bowel disease patients with C difficile infection who have profuse diarrhea, severe abdominal pain, a markedly increased peripheral blood leukocyte count, or other evidence of sepsis. Best Practice Advice 5: Clinicians may postpone escalation of steroids and other immunosuppression agents during acute C difficile infection until therapy for C difficile infection has been initiated. However, the decision to withhold or continue immunosuppression in inflammatory bowel disease patients with C difficile infection should be individualized because there is insufficient existing robust literature on which to develop firm recommendations. Best Practice Advice 6: Clinicians should offer a referral for fecal microbiota transplantation to inflammatory bowel disease patients with recurrent C difficile infection.


Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice.
Both tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) are found in synovial fluid from arthritic joints of humans and of rodents with experimental arthritis. The role of endogenously produced TGF-beta and TNF in the pathogenesis of collagen type II-induced arthritis (CIA) in DBA/1 mice was examined by determining the effect of neutralizing monoclonal antibodies to these factors on the course of the disease. Endogenously produced as well as systemically administered TGF-beta 1 and TNF-alpha had opposite effects, since TGF-beta 1 and anti-TNF protected against CIA, whereas anti-TGF-beta and TNF-alpha increased CIA incidence and/or severity. Intraperitoneally injected TGF-beta 1 at a dose of 2 micrograms per day for 14 days significantly ameliorated arthritis, even when started at the time of arthritis development, although it did not reverse established disease. The resistance to CIA induction caused by a prior intravenous injection of collagen type II was not significantly influenced by the simultaneous injection of TGF-beta 1, TNF-alpha, or interleukin 1 alpha. It is concluded that the endogenous production of TNF and TGF-beta is important in determining the course of CIA.


A dynamic panel model of the associations of sweetened beverage purchases with dietary quality and food-purchasing patterns.
Investigating the association between consumption of sweetened beverages and dietary quality is challenging because issues such as reverse causality and unmeasured confounding might result in biased and inconsistent estimates. Using a dynamic panel model with instrumental variables to address those issues, we examined the independent associations of beverages sweetened with caloric and low-calorie sweeteners with dietary quality and food-purchasing patterns. We analyzed purchase data from the Homescan survey, an ongoing, longitudinal, nationally representative US survey, from 2000 to 2010 (n = 34,294). Our model included lagged measures of dietary quality and beverage purchases (servings/day in the previous year) as exposures to predict the outcomes (macronutrient (kilocalories per capita per day; %), total energy, and food purchases) in the next year after adjustment for other sociodemographic covariates. Despite secular declines in purchases (kilocalories per capita per day) from all sources, each 1-serving/day increase in consumption of either beverage type resulted in higher purchases of total daily kilocalories and kilocalories from food, carbohydrates, total sugar, and total fat. Each 1-serving/day increase in consumption of either beverage was associated with more purchases of caloric-sweetened desserts or sweeteners, which accounted for a substantial proportion of the increase in total kilocalories. We concluded that consumers of both beverages sweetened with low-calorie sweeteners and beverages sweetened with caloric sweeteners had poorer dietary quality, exhibited higher energy from all purchases, sugar, and fat, and purchased more caloric-sweetened desserts/caloric sweeteners compared with nonconsumers.


Altered gut microbiota and activity in a murine model of autism spectrum disorders.
Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.


Polarizable charge equilibration model for predicting accurate electrostatic interactions in molecules and solids.
Electrostatic interactions play a critical role in determining the properties, structures, and dynamics of chemical, biochemical, and material systems. These interactions are described well at the level of quantum mechanics (QM) but not so well for the various models used in force field simulations of these systems. We propose and validate a new general methodology, denoted PQEq, to predict rapidly and dynamically the atomic charges and polarization underlying the electrostatic interactions. Here the polarization is described using an atomic sized Gaussian shaped electron density that can polarize away from the core in response to internal and external electric fields, while at the same time adjusting the charge on each core (described as a Gaussian function) so as to achieve a constant chemical potential across all atoms of the system. The parameters for PQEq are derived from experimental atomic properties of all elements up to Nobelium (atomic no. = 102). We validate PQEq by comparing to QM interaction energy as probe dipoles are brought along various directions up to 30 molecules containing H, C, N, O, F, Si, P, S, and Cl atoms. We find that PQEq predicts interaction energies in excellent agreement with QM, much better than other common charge models such as obtained from QM using Mulliken or ESP charges and those from standard force fields (OPLS and AMBER). Since PQEq increases the accuracy of electrostatic interactions and the response to external electric fields, we expect that PQEq will be useful for a large range of applications including ligand docking to proteins, catalytic reactions, electrocatalysis, ferroelectrics, and growth of ceramics and films, where it could be incorporated into standard force fields as OPLS, AMBER, CHARMM, Dreiding, ReaxFF, and UFF.


Feeding-patch choice by red deer in relation to foraging efficiency : An experiment.
We tested the idea that ruminants allocate their feeding time to habitat patches in relation to foraging efficiency. We used five tame red deer (Cervus elaphus) in an enclosure planted with four treatment of timothy grass (Phleum pratense) differing in their stage of growth. Older swards offered higher biomass but lower nutritional quality than younger swards. We observed time spent feeding in each treatment during each of seven trials. We measured goodness-of-fit between observed times and predictions from two alternative hypotheses differing in optimization strategy (maximizing versus matching), and a third, null hypothesis. We tested the hypotheses using two alternative currecies: digestible protein, and digestible dry matter or energy. Although digestible protein concentration and dry-matter digestibility were highly correlated (r=0.763, P<0.001), the wider range of digestible protein made it the much more sensitive measure of forage quality. Distributions of feeding time closely matched estimated intake rates of digestible protein (R infPredsup2 =0.899) across all animals and trials. The other hypotheses were rejected. The results have important ecological implications in showing the underlying role of food in the selection of habitat by ruminants, and that simple, mechanistic models of forage intake and digestion can be scaled up to the level of animal behavioural choices.


ADMET biosensors: up-to-date issues and strategies.
This insight review introduces the new concepts, theories, technology, instruments, frontier issues, and key strategies of ADMET (absorption, distribution, metabolism, elimination, and toxicity) biosensors, from the fermi to the quantum levels. Information about ADMET, originating from one author's invention, a patented pharmacotherapy for rescuing cardio-cerebral vascular stunning and regulating vascular endothelial growth-factor signaling at the post-genomic level, can be detected by a new generation of ADMET biosensor. This is a single-cell/single-molecule field-effect transistor (FET) hybrid system, where single molecules or single cells are assembled at the FET surface in a high density array manner via complementary metal-oxide-semiconductor (CMOS)-compatible technologies. Within a given nanometer distance, ADMET-mediated oxidation-reduction (redox) potentials, electrochemistry responses, and electron transfer processes can be simultaneously and directly probed by the gates of field-effect transistor arrays. The nanometer details of the functional coupling principles and characterization technologies of DNA single-molecule/single-cell FETs, as well as the design of lab-on-a-chip instruments, are indicated. Four frontier issues and key strategies are elucidated in detail. This can lead to innovative technology for high-throughout screening of labs-on-chips to resolve the pharmaceutical industry's current bottleneck via novel, FET-based drug discovery and single-molecule/single-cell screening methods, which can bring about a pharmaceutical industry revolution in the 21st century.


Surgical Outcome Predictor in Degenerative Lumbar Spinal Disease Based on Health Related Quality of Life Using Euro-Quality 5 Dimensions Analysis.
We aim to introduce the predictive value of a quantitatively described formula model in a multicenter prospective analysis using the EuroQol-5 dimensions (EQ-5D) health scale to anticipate postoperative improvement in patients with degenerative lumbar spine disease (DLSD). Quality of life was evaluated in 376 patients from 17 tertiary hospitals before and after spinal decompression and fusion surgery. The five items of the EQ-5D, mobility (M), self-care (S), usual activities (A), pain/discomfort (P), and anxiety/depression (D), were checked as level 1, 2, or 3, with 3 being the worst. A minimal significant change in the calculated EQ-5D (cEQ-5D) was set as 0.05. Logistic regression analysis was performed to predict the highest successful outcome (cEQ-5D improvement after operation >0.05) with the given sets of 5 items of the EQ-5D. In the cEQ-5D analysis, among patients with a formula score of S+A+2×P+D≤8, 18/68 (27%) showed significant improvement in the cEQ-5D at 1 year postoperatively (p<0.05). However, in patients with a formula score of ≥9, 265/308 (86%) demonstrated significant improvements in the cEQ-5D at 1 year postoperatively (p<0.05). We suggest that S+A+2×P+D≥9 in the EQ-5D can quantitatively describe the better surgical outcome predictors for DLSD. With a definite DLSD lesion confirmed by an imaging study, patients who meet the formula scores of 9 or over and have refractory symptoms to non-operative treatment could be better surgical candidates resulting in satisfactory surgical outcomes of over 86%, than those who scored 8 or lower.


Adsorption of small hydrocarbons on the three-fold PdGa surfaces: the road to selective hydrogenation.
Intermetallic compounds are a promising class of materials as stable and selective heterogeneous catalysts. Here, the (111) and (-1-1-1) single crystal surfaces of the PdGa intermetallic compound were studied as model catalysts with regard to the selective hydrogenation of acetylene (C2H2) to ethylene (C2H4). The distinct atomic surface structures exhibit isolated active centers of single atomic and three atomic Pd ensembles, respectively. For the two prototypal model catalyst surfaces, the adsorption sites and configurations for hydrogen (H2), acetylene, and ethylene were investigated by combining scanning tunneling microscopy, temperature-programmed desorption, and ab initio modeling. The topmost Pd surface atoms provide the preferred adsorption sites for all studied molecules. The structural difference of the Pd ensembles has a significant influence on the adsorption energy and configuration of C2H2, while the influence of the ensemble structure is weak for C2H4 and H2 adsorption. To approach the question of catalytic performance, we simulated the reaction pathways for the heterogeneous catalytic hydrogenation of acetylene on the two surfaces by means of density functional theory. Due to the geometrical separation of the Pd sites on the surfaces, the steric approach of the reactants (H and C2Hx) was found to be of importance to the energetics of the reaction. The presented study gives a direct comparison of binding properties of catalytic Pd on-top sites vs three-fold Pd hollow sites and is therefore of major relevance to the knowledge-based design of highly selective hydrogenation catalysts.


Declining emergency department visits and costs during the severe acute respiratory syndrome (SARS) outbreak.
The immediate and long-term impact of severe acute respiratory syndrome (SARS) outbreak on emergency department (ED) visits and hospital expenditures for these visits has not been thoroughly investigated. The objectives of this retrospective observational study investigated the impact of SARS outbreak on ED visits and the cost of these visits in a designated SARS medical center. Data related to the total number of ED visits and their costs were collected for the SARS epidemic period in 2003 and the same period in the preceding year in 2002. Data collected included total number of ED visits, services provided, triage categories, and total expenditures for all patients. Data for before and during the outbreak were retrieved and compared. At the peak of the SARS epidemic, the reduction in daily ED visits reached 51.6% of pre-epidemic numbers (p < 0.01). In pediatric, trauma and non-trauma patients, the maximum mean decreases in number of visits were 80.0% (p < 0.01), 57.6% (p < 0.01) and 40.8% (p < 0.01), respectively. In triage 1, 2 and 3 patients, the maximum mean decreases were 18.1% (p < 0.01), 55.9% (p < 0.01) and 53.7% (p < 0.01), respectively. The maximum decrease in total costs was 37.7% (p < 0.01). The maximum mean costs per patient increased 35.9% (p < 0.01). The proportions of increases in mean costs for each patient were attributed to laboratory investigations (31.4%), radiography (21.9%) and medications (29.5%). The SARS outbreak resulted in a marked reduction in the number of ED visits which persisted for 3 months after the end of the epidemic. Total cost of treating individual patients showed a simultaneous marked increase, while overall operational costs in the ED showed a marked decrease. The increased total cost for each patient was attributed to the increased number of diagnostic procedures to screen for possible SARS in the ED.


Modeling pattern formation in hydra: a route to understanding essential steps in development.
Modeling of pattern formation in hydra has revealed basic mechanisms that underlie the reproducible generation of complex and self-regulating patterns. Organizing regions can be generated by a local self-enhancing reaction that is coupled with an inhibitory effect of longer range. Such reactions enable pattern formation even in an initially almost homogeneous assembly of cells. A long-ranging feedback of the organizer onto the competence to perform the pattern-forming reaction stabilizes the polar axial pattern during growth and allows for regeneration with preserved polarity. Hypostome formation is assumed to be under the control of two positive feedback loops in which Wnt3 is a common element. In addition to the well-established loop employing beta-catenin, a second cell-local loop is involved, possibly with Brachyury as an additional component. This model accounts for the different expression patterns of beta-catenin and Wnt3. Wnt molecules are proposed to play a dual role, functioning as activators and, after processing, as inhibitors. Since Wnt genes code for complete pattern-forming systems, gene duplication and diversification lead to a family of genes whose expression regions have a precise relation to each other. Tentacle formation is an example of positioning a second pattern-forming system by medium-ranging activation and local exclusion exerted by the primary system. A model for bud formation suggests that a transient pre-bud signal is involved that initiates the formation of the foot of the bud, close to the normal foot, as well as close to the bud tip. Many dynamic regulations, as observed in classical and molecular observations, are reproduced in computer simulations. A case is made that hydra can be regarded as a living fossil, documenting an evolutionary early axis formation before trunk formation and bilaterality were invented. Animated simulations are available in the supplementary information accompanying this paper.


The Swedish version of the Normalization Process Theory Measure S-NoMAD: translation, adaptation, and pilot testing.
The original British instrument the Normalization Process Theory Measure (NoMAD) is based on the four core constructs of the Normalization Process Theory: Coherence, Cognitive Participation, Collective Action, and Reflexive Monitoring. They represent ways of thinking about implementation and are focused on how interventions can become part of everyday practice. To translate and adapt the original NoMAD into the Swedish version S-NoMAD and to evaluate its psychometric properties based on a pilot test in a health care context including in-hospital, primary, and community care contexts. A systematic approach with a four-step process was utilized, including forward and backward translation and expert reviews for the test and improvement of content validity of the S-NoMAD in different stages of development. The final S-NoMAD version was then used for process evaluation in a pilot study aimed at the implementation of a new working method for individualized care planning. The pilot was executed in two hospitals, four health care centres, and two municipalities in a region in northern Sweden. The S-NoMAD pilot results were analysed for validity using confirmatory factor analysis, i.e. a one-factor model fitted for each of the four constructs of the S-NoMAD. Cronbach's alpha was used to ascertain the internal consistency reliability. In the pilot, S-NoMAD data were collected from 144 individuals who were different health care professionals or managers. The initial factor analysis model showed good fit for two of the constructs (Coherence and Cognitive Participation) and unsatisfactory fit for the remaining two (Collective Action and Reflexive Monitoring) based on three items. Deleting those items from the model yielded a good fit and good internal consistency (alphas between 0.78 and 0.83). However, the estimation of correlations between the factors showed that the factor Reflexive Monitoring was highly correlated (around 0.9) with the factors Coherence and Collective Action. The results show initial satisfactory psychometric properties for the translation and first validation of the S-NoMAD. However, development of a highly valid and reliable instrument is an iterative process, requiring more extensive validation in various settings and populations. Thus, in order to establish the validity and reliability of the S-NoMAD, additional psychometric testing is needed.


Comparison of mitral valve geometrical effect of percutaneous edge-to-edge repair between central and eccentric functional mitral regurgitation: clinical implications.
Percutaneous edge-to-edge repair alters mitral valve (MV) geometry in functional mitral regurgitation (FMR). We sought to characterize MV morphology in patients with central and eccentric FMR, compare the geometrical effect of MitraClip therapy, and elucidate different mechanisms of MR improvement according to FMR subtypes. Seventy-six symptomatic patients with Grade 3 to 4+ FMR (central, n = 39; eccentric, n = 37) underwent three-dimensional transoesophageal echocardiography during MitraClip implantation. We defined procedural success as a reduction of MR by ≥1 grade with having a residual mitral regurgitation (MR) of ≤ grade 2+. Procedural success rate was similar between central and eccentric FMR (77% vs. 78%, P = 0.55). After MitraClip, the reduction in anterior-posterior diameter did not differ between FMR subtypes, but patients with eccentric FMR had a greater reduction in the averaged tethering angle difference (P < 0.001) with less reduction in tenting volume and height (both P < 0.001) than did patients with central FMR. On multivariable analysis, in central FMR, MR reduction post-clip was associated with shortening in anterior-posterior diameter [coefficient 0.388, 95% confidence interval (CI) 0.216-0.561; P < 0.001] and an increase in coaptation area (coefficient 0.117, 95% CI 0.039-0.194; P = 0.004), whereas in eccentric FMR MR reduction was mainly associated with a decrease in the averaged tethering angle difference (coefficient 0.050, 95% CI 0.021-0.078; P = 0.001). MV geometrical effect and its association with MR improvement after MitraClip therapy differ according to FMR subtypes. Our results indicate the MR jet direction and the leaflet tethering pattern may be considered in the strategy for percutaneous treatment for FMR.


The role of free radical-mediated processes in oxygen-related damage in cultured murine myocardial cells.
A new approach to quantifying myocyte cell death utilizing fluorescence-activated sorting of antimyosin antibody-labeled cells was used to study the effects of oxygen-generated free radicals on cell survival. Uptake of antimyosin, reflecting sarcolemmal damage, increased under conditions which promoted elevated free radical formation and decreased in the presence of increased levels of free radical-scavenging agents. Superoxide dismutase decreased antimyosin uptake at pH 6.7 and 7.5. Mannitol decreased antimyosin uptake at pH 6.5 and 6.7 but not at pH 7.5, and dimethyl sulfoxide decreased antimyosin uptake at pH 6.4 but not at pH 7.5. These data suggest that a greater portion of hydroxyl radicals are produced at higher concentrations of hydrogen ion. Mannitol, a scavenger of hydroxyl radicals, was effective in reducing antimyosin uptake at pH 7.5 in the presence of ferrous sulfate, but had no effect on antimyosin uptake in the absence of ferrous sulfate, suggesting possible iron-mediated catalysis of hydroxyl radical formation. The data suggest that oxygen-derived free radicals can cause significant loss of membrane integrity in cultured myocytes, that the species of radical formed is dependent both on pH and the concentration of iron salts, and that this injury is, at least in part, preventable by the administration of exogenous radical scavenging agents.


A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.
Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells--a SPTLC1 deficient CHO cell line--could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP.


Temporal trends in the treatment and outcomes of elderly patients with acute coronary syndrome.
To determine whether treatment and outcomes of older acute coronary syndrome (ACS) patients changed over time. We analysed the use of guideline-recommended therapies and in-hospital outcomes of 13 662 ACS patients ≥70 years enrolled in the prospective Acute Myocardial Infarction in Switzerland (AMIS) cohort between 2001 and 2012 according to 4-year periods (2001-2004, 2005-2008, and 2009-2012). Between first and last 4-year period, percutaneous coronary intervention (PCI) use increased from 43.8 to 69.6% of older ACS patients ( ITALIC! P < 0.001). Use of guideline-recommended drugs as well increased. At the same time, in-hospital mortality of the overall population decreased from 11.6% in the first to 10.0% in the last 4-year period ( ITALIC! P = 0.020), and in-hospital major adverse cardiac and cerebrovascular events from 14.4 to 11.3% ( ITALIC! P < 0.001). Percutaneous coronary intervention was used in increasingly older and co-morbid patients over time (mean age of patients treated with PCI 76.2 years in 2001-2004 and 78.1 years in 2009-2012, ITALIC! P < 0.001; Charlson score ≥2 was found for 27.6% of patients treated with PCI in 2001-2004 and for 32.1% in 2009-2012, ITALIC! P = 0.003). Percutaneous coronary intervention use was associated with similar odds ratios (ORs) of in-hospital mortality over time (adjusted OR 0.29, 95% confidence interval, CI, 0.22-0.40, in 2001-2004; and, adjusted OR 0.26, 95% CI 0.20-0.35, in 2009-2012). Use of guideline-recommended therapies for ACS increased and in-hospital outcomes improved over the observed 12-year period. Though PCI was used in increasingly older and co-morbid patients, PCI use was associated with similar ORs of in-hospital mortality over time. This study suggests that increasing use of guideline-recommended therapies was appropriate. ClinicalTrials.gov Identifier: NCT01305785.


Malorientation in half-bivalents at anaphase: analysis of autosomal laggards in untreated, cold-treated, and cold-recovering crane fly spermatocytes.
Exposing crane fly larvae to 6 degrees C or returning them to 22 degrees C after exposure to 6, 2, or 0.2 degrees C can induce any number of autosomes in their primary spermatocytes to lag near the spindle equator at anaphase. Autosomal laggards in cold-recovering cells are contained in bivalents until anaphase (Janicke, M. A., and J. R. LaFountain, 1982, Chromosoma, 85:619-631). We report here documentation that lagging autosomes in cold-treated and cold-recovering cells are maloriented. During meiosis I, half-bivalents usually associate with only one pole via kinetochore fibers, with sister chromatids being oriented to the same pole. In contrast, laggards had kinetochore microtubules (kMTs) extending from them toward both poles: one sister was oriented to one pole and the other had some or all of its kMTs extending toward the opposite pole. Bipolar malorientation of autosomal laggards also was observed in one untreated cell. The number of kMTs per half-bivalent was similar in lagging and non-lagging autosomes, and those kMTs were contained in long birefringent kinetochore fibers. The overall spindle structure in cold-recovering cells was similar to that observed in untreated anaphase cells. Giemsa-stained centromeric dots of sister chromatids were contiguous in non-laggards and separated in laggards at anaphase. We conclude that bipolar malorientations can exist at anaphase in chromosomes that remain paired until anaphase, that cold recovery increases the frequency of that anomaly, and that such malorientations may be one cause of anaphase lag.


Modeling the Morphodynamics of Coastal Responses to Extreme Events: What Shape Are We In?
This review focuses on recent advances in process-based numerical models of the impact of extreme storms on sandy coasts. Driven by larger-scale models of meteorology and hydrodynamics, these models simulate morphodynamics across the Sallenger storm-impact scale, including swash,collision, overwash, and inundation. Models are becoming both wider (as more processes are added) and deeper (as detailed physics replaces earlier parameterizations). Algorithms for wave-induced flows and sediment transport under shoaling waves are among the recent developments. Community and open-source models have become the norm. Observations of initial conditions (topography, land cover, and sediment characteristics) have become more detailed, and improvements in tropical cyclone and wave models provide forcing (winds, waves, surge, and upland flow) that is better resolved and more accurate, yielding commensurate improvements in model skill. We foresee that future storm-impact models will increasingly resolve individual waves, apply data assimilation, and be used in ensemble modeling modes to predict uncertainties.


The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders.
Schizotypy provides a useful construct for understanding the development of schizophrenia spectrum disorders. As research on the epidemiology of psychotic symptoms and clinical risk for psychosis has expanded, conceptual challenges have emerged to comprehend the nature and borders of the space comprised between personality variation and psychosis. Schizotypy is considered in light of these more recent constructs. It is suggested that rather than being superseded by them due to their higher specificity and predictive power for transition to psychosis, schizotypy integrates them as it constitutes a dynamic continuum ranging from personality to psychosis. The advantages of schizotypy for studying schizophrenia etiology are discussed (eg, it facilitates a developmental approach and the identification of causal, resilience, and compensating factors and offers a multidimensional structure that captures etiological heterogeneity). An overview of putative genetic, biological, and psychosocial risk factors is presented, focusing on communalities and differences between schizotypy and schizophrenia spectrum disorders. The found notable overlap supports etiological continuity, and, simultaneously, differential findings appear that are critical to understanding resilience to schizophrenia. For example, discrepant findings in genetic studies might be interpreted as suggestive of sets of independent genetic factors playing a differential role in schizotypy and schizophrenia: some would influence variation specifically on schizotypy dimensions (ie, high vs low schizotypy, thereby increasing proneness to psychosis), some would confer unspecific liability to disease by impacting neural properties and susceptibility to environmental factors (ie, high vs low resilience to disorder) and some might contribute to disease-specific characteristics. Finally, schizotypy's promise for studying gene-environment interactions is considered.


Coronary Artery Anomalies: When You Need to Worry.
There is a broad spectrum of coronary artery anomalies that cardiologists may encounter either incidentally or during evaluation for cardiac symptoms. These anomalies include anomalous coronary arteries arising from the opposite sinus of Valsalva (ACAOS), coronary fistulae, and coronary artery aneurysms. This manuscript outlines the unique features, diagnostic characteristics, and treatment considerations for these lesions. Intravenous ultrasound (IVUS), computed tomographic angiography (CTA), and magnetic resonance imaging (MRI) are becoming more sophisticated and will be increasingly used to facilitate the optimal treatment approach for coronary anomalies. There are a wide variety of coronary artery anomalies and their clinical ramifications range from benign to potentially fatal. Coronary anomalies often have complex anatomy and require advanced imaging modalities for comprehensive characterization. Due to the heterogeneity in lesion characteristics and outcomes, physicians should consider clinical and imaging features to create individualized management plans, along with referral to adult congenital heart disease centers.


A Hybrid Residual Dilated LSTM and Exponential Smoothing Model for Midterm Electric Load Forecasting.
This work presents a hybrid and hierarchical deep learning model for midterm load forecasting. The model combines exponential smoothing (ETS), advanced long short-term memory (LSTM), and ensembling. ETS extracts dynamically the main components of each individual time series and enables the model to learn their representation. Multilayer LSTM is equipped with dilated recurrent skip connections and a spatial shortcut path from lower layers to allow the model to better capture long-term seasonal relationships and ensure more efficient training. A common learning procedure for LSTM and ETS, with a penalized pinball loss, leads to simultaneous optimization of data representation and forecasting performance. In addition, ensembling at three levels ensures a powerful regularization. A simulation study performed on the monthly electricity demand time series for 35 European countries confirmed the high performance of the proposed model and its competitiveness with classical models such as ARIMA and ETS as well as state-of-the-art models based on machine learning.


Early Machine-Human Interface around Sepsis Severity Identification: From Diagnosis to Improved Management?
To investigate the statistical measures of the performance of 2 interventions: a) early sepsis identification by a computerized sepsis "sniffer" algorithm (CSSA) in the emergency department (ED) and b) human decision to activate a multidisciplinary early resuscitation sepsis and shock response team (SSRT). This study used a prospective and historical cohort study design to evaluate the performance of two interventions. A computerized sepsis sniffer algorithm (CSSA) to aid in early diagnosis and a multidisciplinary sepsis and shock response team (SSRT) to improve patient care by increasing compliance with Surviving Sepsis Campaign (SSC) bundles. The CSSA yielded a sensitivity of 100% (95% CI, 99.13-100%) and a specificity of 96.2% (95% CI, 95.55-96.45%) to identifying sepsis in the ED (Table 1). The SSRT resource was activated appropriately in 34.1% (86/252) of patients meeting severe sepsis or septic shock criteria; the SSRT was inappropriately activated only three times in sepsis-only patients. In 53% (134/252) of cases meeting criteria for SSRT activation, the critical care team was consulted as opposed to activating the SSRT resource. Our two-step machine-human interface approach to patients with sepsis utilized an outstandingly sensitive and specific electronic tool followed by more specific human decision-making.


Early childhood aggressive behaviour: Negative interactions with paternal antisocial behaviour and maternal postpartum depressive symptoms across two international cohorts.
Early childhood aggressive behaviour is a predictor of future violence. Therefore, identifying risk factors for children's aggressive behaviour is important in understanding underlying mechanisms. Maternal postpartum depression is a known risk factor. However, little research has focused on the influence of paternal behaviour on early childhood aggression and its interaction with maternal postpartum depression. This study was performed in two cohorts: the Fathers Project, in the United Kingdom (n = 143) and the Generation R Study, in The Netherlands (n = 549). In both cohorts, we related paternal antisocial personality (ASP) traits and maternal postpartum depressive (PPD) symptoms to childhood aggressive behaviour at age two (Fathers Project) and age three (Generation R Study). We additionally tested whether the presence of paternal ASP traits increased the association between maternal PPD-symptoms and early childhood aggression. The association between paternal ASP traits and early childhood aggressive behaviour, corrected for maternal PPD-symptoms, was similar in magnitude between the cohorts (Fathers Project: standardized β = 0.12, p = 0.146; Generation R: β = 0.14, p = 0.001), although the association was not statistically significant in the Fathers Project. Strikingly, and in contrast to our expectations, there was evidence of a negative interaction between paternal ASP traits and maternal PPD-symptoms on childhood aggressive behaviour (Fathers Project: β = -0.20, p = 0.020; Generation R: β = -0.09, p = 0.043) in both studies. This meant that with higher levels of paternal ASP traits the association between maternal PPD-symptoms and childhood aggressive behaviour was less and vice versa. Our findings stress the importance of including both maternal and paternal psychopathology in future studies and interventions focusing on early childhood aggressive behaviour.


Multivoxel patterns in fusiform face area differentiate faces by sex and race.
Although prior research suggests that fusiform gyrus represents the sex and race of faces, it remains unclear whether fusiform face area (FFA)-the portion of fusiform gyrus that is functionally-defined by its preferential response to faces-contains such representations. Here, we used functional magnetic resonance imaging to evaluate whether FFA represents faces by sex and race. Participants were scanned while they categorized the sex and race of unfamiliar Black men, Black women, White men, and White women. Multivariate pattern analysis revealed that multivoxel patterns in FFA-but not other face-selective brain regions, other category-selective brain regions, or early visual cortex-differentiated faces by sex and race. Specifically, patterns of voxel-based responses were more similar between individuals of the same sex than between men and women, and between individuals of the same race than between Black and White individuals. By showing that FFA represents the sex and race of faces, this research contributes to our emerging understanding of how the human brain perceives individuals from two fundamental social categories.


The Unique Lipidomic Signatures of Saccharina latissima Can Be Used to Pinpoint Their Geographic Origin.
The aquaculture of macroalgae for human consumption and other high-end applications is experiencing unprecedented development in European countries, with the brown algae Saccharina latissima being the flag species. However, environmental conditions in open sea culture sites are often unique, which may impact the biochemical composition of cultured macroalgae. The present study compared the elemental compositions (CHNS), fatty acid profiles, and lipidomes of S. latissima originating from three distinct locations (France, Norway, and the United Kingdom). Significant differences were found in the elemental composition, with Norwegian samples displaying twice the lipid content of the others, and significantly less protein (2.6%, while French and UK samples contained 6.3% and 9.1%, respectively). The fatty acid profiles also differed considerably, with UK samples displaying a lower content of n-3 fatty acids (21.6%), resulting in a higher n-6/n-3 ratio. Regarding the lipidomic profile, samples from France were enriched in lyso lipids, while those from Norway displayed a particular signature of phosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine. Samples from the UK featured higher levels of phosphatidylethanolamine and, in general, a lower content of galactolipids. These differences highlight the influence of site-specific environmental conditions in the shaping of macroalgae biochemical phenotypes and nutritional value. It is also important to highlight that differences recorded in the lipidome of S. latissima make it possible to pinpoint specific lipid species that are likely to represent origin biomarkers. This finding is relevant for future applications in the field of geographic origin traceability and food control.