Olive oil consumption and risk of type 2 diabetes in US women.
Olive oil has been shown to improve various cardiometabolic risk factors. However, to our knowledge, the association between olive oil intake and type 2 diabetes (T2D) has never been evaluated in the US population. We aimed to examine the association between olive oil intake and incident T2D. We followed 59,930 women aged 37-65 y from the Nurses' Health Study (NHS) and 85,157 women aged 26-45 y from the NHS II who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by validated food-frequency questionnaires, and data were updated every 4 y. Incident cases of T2D were identified through self-report and confirmed by supplementary questionnaires. After 22 y of follow-up, we documented 5738 and 3914 incident cases of T2D in the NHS and NHS II, respectively. With the use of Cox regression models with repeated measurements of diet and multivariate adjustment for major lifestyle and dietary factors, the pooled HR (95% CI) of T2D in those who consumed >1 tablespoon (>8 g) of total olive oil per day compared with those who never consumed olive oil was 0.90 (0.82, 0.99). The corresponding HRs (95% CIs) were 0.95 (0.87, 1.04) for salad dressing olive oil and 0.85 (0.74, 0.98) for olive oil added to food or bread. We estimated that substituting olive oil (8 g/d) for stick margarine, butter, or mayonnaise was associated with 5%, 8%, and 15% lower risk of T2D, respectively, in the pooled analysis of both cohorts. Our results suggest that higher olive oil intake is associated with modestly lower risk of T2D in women and that hypothetically substituting other types of fats and salad dressings (stick margarine, butter, and mayonnaise) with olive oil is inversely associated with T2D.


An investigation of left/right driving rules on deviations while walking.
When traversing through an aperture, such as a doorway, people characteristically deviate towards the right. This rightward deviation can be explained by a rightward attentional bias which leads to rightward bisections in far space. It is also possible, however, that left or right driving practices affect the deviation. To explore this possibility, Australian (left-side drivers) and Swiss (right-side drivers) participants (n = 36 & 34) walked through the middle of an aperture. To control for the sway of the body, participants started with either their left or right foot. Sway had a significant effect on participants' position in the doorway and the amount of sway was greater for Australians-perhaps due to national differences in gait. There was a significant rightward deviation for the Swiss, but not for the Australians. It is suggested that driving practices have a small additive effect on rightward attentional biases whereby the bias is increased for people who drive on the right and reduced in people who drive on the left.


Brain metastases in malignant pleural mesothelioma.
The brain is a rare site of metastasis in malignant pleural mesothelioma (MPM), and its clinical features and prognosis remain unclear. The aim of this study was to investigate the incidence, prognosis, and risk factors for brain metastases (BM) in MPM patients. Between July 1993 and October 2014, 150 patients with histologically proven MPM were included in this retrospective study. The cumulative incidence of BM was estimated with the Kaplan-Meier method, and differences between groups were analyzed by the log-rank test. Multivariate logistic regression analysis was applied to assess risk factors for BM. The median follow-up time was 11 months (range 0-154.0 months). A total of eight patients (5.3 %) developed BM during the course of their illness. Multivariate analysis identified age <65 years (odds ratio [OR] = 5.83, p = 0.038) and International Mesothelioma Interest Group stage IV (OR = 1.69, p = 0.040) as independent factors related to increased risk of developing BM. The 1-and 2-year cumulative rates of BM were 4.0 % (95 % confidence intervals [CI] 1.4-8.5 %) and 5.3 % (95 % CI 2.3-10.2 %), respectively. Our study showed that the overall survival (OS) of patients with BM was worse than that of patients without BM (median OS 6.5 vs. 11.0 months, p = 0.037). The prognosis for BM in MPM patients is poor. Clinicians should perform careful screening for BM, especially in patients with risk factors.


The effect of electroacupuncture on pain behaviors and noxious stimulus-evoked Fos expression in a rat model of neuropathic pain.
Chronic-constriction injury (CCI) of the sciatic nerve causes mechanical and heat hyperalgesia and mechanical allodynia in the plantar surface of the hindpaw. The underlying mechanism thought to account for these phenomena include central sensitization induced by peripheral nerve injury, ie, the increase in neuronal activity of spinal dorsal horn neurons. As a marker of neuronal activation of the central nervous system, Fos expression has been used widely to monitor the change in neuronal activity evoked by peripheral input. In this study, we examined the antinociceptive effect of electroacupuncture (EA) on pain behavior and noxious stimulus-evoked Fos expression in dorsal horn neurons of the spinal cord in CCI rats 14 days after injury. Male Sprague-Dawley rats (180 to 200 g) received loose ligation of the left sciatic nerve. Heat and mechanical hyperalgesia and mechanical allodynia were examined by the plantar foot test, the pin-prick test, and the von Frey test before and after the EA treatment (100 Hz, 0.3 millisecond, 3 or 1 mA, 20 minutes) into the Zusanli point (S36). When EA stimulation to the Zusanli point was applied, the mechanical and heat hyperalgesia were significantly suppressed; however, mechanical allodynia was not affected. The EA stimulation to nonacupuncture point did not show any significant effect. Next, pinch stimulation was applied to the plantar surface of the operated hindpaw of the CCI rats for 10 minutes, and the stimulus-evoked Fos expression in dorsal horn neurons in L4-L6 spinal cord levels was then examined by using immunohistochemistry. The number of noxious stimulus-evoked Fos-labeled neurons in both the superficial and deep laminae of the dorsal horn in the CCI rats was increased significantly compared with those in sham-operated rats, suggesting an increased excitability of dorsal horn neurons to noxious stimuli. Concurrent EA treatment to the Zusanli point with the pinch stimulus suppressed the increase in the number of Fos-labeled cells in the spinal dorsal horn in the CCI rats. The present results show that EA treatment has antinociceptive effects on both pain behavior and neuronal activation of the spinal dorsal horn neurons in CCI rats.


Quantification of Plasmodium ex vivo drug susceptibility by flow cytometry.
The emergence and spread of multidrug-resistant Plasmodium falciparum and Plasmodium vivax highlights the need for objective measures of ex vivo drug susceptibility. Flow cytometry (FC) has potential to provide a robust and rapid quantification of ex vivo parasite growth. Field isolates from Papua, Indonesia, underwent ex vivo drug susceptibility testing against chloroquine, amodiaquine, piperaquine, mefloquine, and artesunate. A single nucleic acid stain (i.e., hydroethidine (HE) for P. falciparum and SYBR Green I (SG) for P. vivax) was used to quantify infected red blood cells by FC-based signal detection. Data derived by FC were compared to standard quantification by light microscopy (LM). A subset of isolates was used to compare single and double staining techniques. In total, 57 P. falciparum and 23 P. vivax field isolates were collected for ex vivo drug susceptibility testing. Reliable paired data between LM and FC was obtained for 88 % (295/334) of these assays. The median difference of derived IC50 values varied from -5.4 to 6.1 nM, associated with 0.83-1.23 fold change in IC50 values between LM and FC. In 15 assays (5.1 %), the derived difference of IC50 estimates was beyond the 95 % limits of agreement; in eleven assays (3.7 %), this was attributable to low parasite growth (final schizont count < 40 %), and in four assays (1.4 %) due to low initial parasitaemia at the start of assay (<2000 µl(-1)). In a subset of seven samples, LM, single and double staining FC techniques generated similar IC50 values. A single staining FC-based assay using a portable cytometer provides a simple, fast and versatile platform for field surveillance of ex vivo drug susceptibility in clinical P. falciparum and P. vivax isolates.


Synthetic principles directing charge transport in low-band-gap dithienosilole-benzothiadiazole copolymers.
Given the fundamental differences in carrier generation and device operation in organic thin-film transistors (OTFTs) and organic photovoltaic (OPV) devices, the material design principles to apply may be expected to differ. In this respect, designing organic semiconductors that perform effectively in multiple device configurations remains a challenge. Following "donor-acceptor" principles, we designed and synthesized an analogous series of solution-processable π-conjugated polymers that combine the electron-rich dithienosilole (DTS) moiety, unsubstituted thiophene spacers, and the electron-deficient core 2,1,3-benzothiadiazole (BTD). Insights into backbone geometry and wave function delocalization as a function of molecular structure are provided by density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level. Using a combination of X-ray techniques (2D-WAXS and XRD) supported by solid-state NMR (SS-NMR) and atomic force microscopy (AFM), we demonstrate fundamental correlations between the polymer repeat-unit structure, molecular weight distribution, nature of the solubilizing side-chains appended to the backbones, and extent of structural order attainable in p-channel OTFTs. In particular, it is shown that the degree of microstructural order achievable in the self-assembled organic semiconductors increases largely with (i) increasing molecular weight and (ii) appropriate solubilizing-group substitution. The corresponding field-effect hole mobilities are enhanced by several orders of magnitude, reaching up to 0.1 cm(2) V(-1) s(-1) with the highest molecular weight fraction of the branched alkyl-substituted polymer derivative in this series. This trend is reflected in conventional bulk-heterojunction OPV devices using PC(71)BM, whereby the active layers exhibit space-charge-limited (SCL) hole mobilities approaching 10(-3) cm(2) V(-1) s(-1), and yield improved power conversion efficiencies on the order of 4.6% under AM1.5G solar illumination. Beyond structure-performance correlations, we observe a large dependence of the ionization potentials of the polymers estimated by electrochemical methods on polymer packing, and expect that these empirical results may have important consequences on future material study and device applications.


Correlation between host specificity and genetic diversity for the muscle-dwelling fish parasite Myxobolus pseudodispar: examples of myxozoan host-shift?
Myxobolus pseudodispar Gorbunova, 1936 (Myxozoa) is capable of infecting and developing mature myxospores in several cyprinid species. However, M. pseudodispar isolates from different fish show up to 5% differences in the SSU rDNA sequences. This is an unusually large intraspecific difference for myxozoans and only some of the muscle-dwelling myxozoan species possess such a high genetic variability. We intended to study the correlation between the host specificity and the phylogenetic relationship of the parasite isolates, and to find experimental proof for the putatively wide host range of M. pseudodispar with cross-infection experiments and phylogenetic analyses based on SSU rDNA. The experimental findings distinguished 'primary' and less-susceptible 'secondary' hosts. With some exceptions, M. pseudodispar isolates showed a tendency to cluster according to the fish host on the phylogenetic tree. Experimental and phylogenetic findings suggest the cryptic nature of the species. It is likely that host-shift occurred for M. pseudodispar and the parasite speciation in progress might explain the high genetic diversity among isolates which are morphologically indistinguishable.


[»Shermer's neck« is a rare injury in long-distance cycle races. Association with diplopia described for the first time].
Shermer's neck was first described in 1983 in an ultra-distance cyclist and it is often associated with neck pain (in our patient diplopia as first symptom) and exhaustion and impaired neck motor function with inability to extend the neck against gravity. The diplopia, for the first time described in connection with Shermer's neck, was accentuated when elevating the eyes and looking at distance, most likely reflecting exhaustion in the elevator muscles of the eye. Shermer's neck usually appears after 800 km of non-stop bike racing. Risk factors include former neck injuries, staying low in aerobars for a long time, and wearing helmet light/cameras. Prevention includes neck strength training, muscle stretching, raising of handle bars and different kinds of chin support. The most important treatment is rest and not riding a bike. In our patient the diplopia was normalized after 4 hours of sleep. It can take 2-14 days to regain full neck motor function. The possibility of developing Shermer's neck and diplopia (»Berglund's diplopia«) must be taken into account when many untrained individuals participate in popular shorter races over about 300 km.


Ultrafast fabrication of highly active BiVO4 photoanodes by hybrid microwave annealing for unbiased solar water splitting.
Hybrid microwave annealing (HMA) with a silicon susceptor in a household microwave oven produces BiVO4-based photoanodes of much improved performance in photoelectrochemical water oxidation in only 6 min relative to conventional thermal annealing in a traditional muffle furnace (FA) that needs a much longer time, 300 min. This technique can apply equally effectively to bare as well as modified BiVO4 by Mo-doping, heterojunction formation with WO3, and an oxygen evolution co-catalyst. Relative to FA, HMA forms BiVO4 films of smaller feature sizes, higher porosity, and increased three dimensional roughness, which decrease the diffusion distance of holes to the surface and thereby increase mainly the bulk charge separation efficiency (ηbulk) of the photoanodes. Thus, the HMA-treated BiVO4/WO3 film achieves the state-of-the art ηbulk of ∼90% for water oxidation. Combination of a photoanode of NiOOH/FeOOH/BiVO4/WO3 (HMA, 6 min) with a 2p c-Si solar cell allows a solar to hydrogen conversion efficiency of ∼5.0% in unbiased overall water splitting, which is also comparable to the state-of-the-art for a similar material combination.


Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19.
Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.


DNA copy number variations characterize benign and malignant thyroid tumors.
Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management. Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification. Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology. Tissue and FNA samples were obtained at an academic tertiary referral center. Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue. Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays. Statistically significant differences in CNV patterns between tumor subtypes were identified. Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. We identified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature. Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.


Cation effects on swelling of kappa-carrageenan: a photon transmission study.
Swelling behavior of kappa-carrageenan gels in water and KCl solutions was investigated by photon transmission experiments following the preparation of gels in the presence and absence of externally added K+ ion as a gel promoting agent. Transmitted photon intensity, Itr, increased continuously during swelling depending on the carrageenan and ion content in the gel. This increase in Itr was modeled using the Li-Tanaka equation. Both the experimental work and the model showed that the swelling of low carrageenan and ion content gels took less time than that of high ion content gels. It is confirmed that double helices in a swollen gel move much faster in pure water than in KCl solution during swelling processes. Swelling time constants, tau1, and collective diffusion coefficients, Do, were measured for the gels swollen in water and KCl solutions.


[Burden of major cancers on years of life lost with premature death in crocidolite-contaminated area in Dayao].
To evaluate the effects of environmental low-dose exposure to crocidolite on people's health and the society. METHODS The mortality data of cancer between 1994 and 2003 in an environmental crocidolite-contaminated area was obtained from hospital medical records of Dayao Center for Disease Prevention and Control, and Dayao Public Health Bureau. The years of life lost with premature death (YLLs), was used to measure and assess the death, health losses and social burden of cancer in this area. In the environmental crocidolite-contaminated area, lung cancer was the prime cause of death in all kinds of cancers between 1994 and 2003, followed by liver cancer, mesothelioma stomach cancer and colorectal cancer, with mortality 10.15/10(5), 9.04/10(5), 8.48/10(5), 3.96/10(5) and 3.55/10(5) respectively. The mortality of main cancer in male and female increased with age growing except that of breast cancer in female. Results showed that the types of leading cancers of YLLs were liver cancer, lung cancer, mesothelioma, leukemia and stomach cancer with YLLs 1981.39 person-year, 1886.63 person-year, 1799.23 person-year, 948.01 person-year and 754.18 person-year respectively. The distribution of YLLs was similar in both sexes, higher in the middle age group (aged from 15 to 44 years and 45 to 59 years) and lower in other age groups. The indirect economic loss resulting from lung cancer (15.02% of the total loss), liver cancer (13.98% of the total loss) and mesothelioma (13.01% of the total loss) was relatively great. The YLLs and the indirect economic loss attributable to environmental low-dose exposure to crocidolite were 3092.23 person-year and 5,175,800 Yuan respectively. Lung cancer, liver cancer, mesothelioma, leukemia and breast cancer are the major cancers with an important impact on people's health and premature mortality in the environmental crocidolite-contaminated area. The impact of cancer mortality is more severer in those aged over 45 years. Social burden of cancer is the greatest in persons aged from 15 to 59 years. Policies and plans should be worked out for the protection of environment and the prevention of cancer.


Priorities for research in emergency medical services for children: results of a consensus conference.
To arrive at a consensus on the priorities for future research in emergency medical services for children. A consensus group was convened using the Rand-UCLA Consensus Process. The group took part in a 3-phase process. Round I involved reviewing a compendium of relevant research articles and answering a mailed questionnaire. Panel members were asked to prioritize topics on the basis of the 1993 Institute of Medicine Report on Emergency Medical Services for Children. Participants were asked to rate each topic based on the significance of the research, and whether the topic would (1) improve general knowledge (2), change behavior (3), improve health (4), decrease the cost of care, or (5) change public policy. A 4-point Likert scale was used. Participants were also asked if the research would require a multicenter study and if the research were feasible. Round II of the study involved a meeting of the panel, where the results of Round I were discussed and the topics were reprioritized. The topics were given a rank order and a final ranking was done in Round III. The panel considered a list of 32 topics; these were combined and reworded to give them more precise meaning. Several new topics were also added. Fifteen topics were given a rank order and placed within the 7 broad categories of the Institute of Medicine report. Clinical aspects of emergency care, systems organization, configuration, and operation and injury prevention were given high priority rankings. The first 5 topics were very close in point-rank order. The panel was able to develop a list of important topics for future research in emergency medical services for children that can be used by foundations, governmental agencies, and others in setting research agenda for such services.


Panobinostat sensitizes KRAS-mutant non-small-cell lung cancer to gefitinib by targeting TAZ.
Mutation of KRAS in non-small-cell lung cancer (NSCLC) shows a poor response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy. Currently, there are no direct anti-KRAS therapies available. Thus, new strategies have emerged for targeting KRAS downstream signaling. Panobinostat is a clinically available histone deacetylase inhibitor for treating myelomas and also shows potentiality in NSCLC. However, the therapeutic efficacy of panobinostat against gefitinib-resistant NSCLC is unclear. In this study, we demonstrated that panobinostat overcame resistance to gefitinib in KRAS-mutant/EGFR-wild-type NSCLC. Combined panobinostat and gefitinib synergistically reduced tumor growth in vitro and in vivo. Mechanistically, we identified that panobinostat-but not gefitinib-inhibited TAZ transcription, and the combination of panobinostat and gefitinib synergistically downregulated TAZ and TAZ downstream targets, including EGFR and EGFR ligand. Inhibition of TAZ by panobinostat or short hairpin RNA sensitized KRAS-mutant/EGFR-wild-type NSCLC to gefitinib through abrogating AKT/mammalian target of rapamycin (mTOR) signaling. Clinically, TAZ was positively correlated with EGFR signaling, and coexpression of TAZ/EGFR conferred a poorer prognosis in lung cancer patients. Our findings identify that targeting TAZ-mediated compensatory mechanism is a novel therapeutic approach to overcome gefitinib resistance in KRAS-mutant/EGFR-wild-type NSCLC.


The influence of soil pH on the diversity, abundance and transcriptional activity of ammonia oxidizing archaea and bacteria.
Autotrophic ammonia oxidation occurs in acid soils, even though laboratory cultures of isolated ammonia oxidizing bacteria fail to grow below neutral pH. To investigate whether archaea possessing ammonia monooxygenase genes were responsible for autotrophic nitrification in acid soils, the community structure and phylogeny of ammonia oxidizing bacteria and archaea were determined across a soil pH gradient (4.9-7.5) by amplifying 16S rRNA and amoA genes followed by denaturing gradient gel electrophoresis (DGGE) and sequence analysis. The structure of both communities changed with soil pH, with distinct populations in acid and neutral soils. Phylogenetic reconstructions of crenarchaeal 16S rRNA and amoA genes confirmed selection of distinct lineages within the pH gradient and high similarity in phylogenies indicated a high level of congruence between 16S rRNA and amoA genes. The abundance of archaeal and bacterial amoA gene copies and mRNA transcripts contrasted across the pH gradient. Archaeal amoA gene and transcript abundance decreased with increasing soil pH, while bacterial amoA gene abundance was generally lower and transcripts increased with increasing pH. Short-term activity was investigated by DGGE analysis of gene transcripts in microcosms containing acidic or neutral soil or mixed soil with pH readjusted to that of native soils. Although mixed soil microcosms contained identical archaeal ammonia oxidizer communities, those adapted to acidic or neutral pH ranges showed greater relative activity at their native soil pH. Findings indicate that different bacterial and archaeal ammonia oxidizer phylotypes are selected in soils of different pH and that these differences in community structure and abundances are reflected in different contributions to ammonia oxidizer activity. They also suggest that both groups of ammonia oxidizers have distinct physiological characteristics and ecological niches, with consequences for nitrification in acid soils.


How Much of Me Do I See in Other Minds? Modulating Egocentricity in Emotion Judgments by tDCS.
When inferring the mental states of others, individuals' judgments are influenced by their own state of mind, an effect often referred to as egocentricity. Self-other differentiation is key for an accurate interpretation of other's mental states, especially when these differ from one's own states. It has been suggested that the right supramarginal gyrus (rSMG) is causally involved in overcoming egocentricity in the affective domain. In a double-blind randomized study, 47 healthy adults received anodal (1 mA, 20 min) or sham transcranial direct current stimulation (tDCS) to the rSMG prior to performing a newly developed paradigm, the self-other facial emotion judgment (SOFE) task. In this task, participants made judgments of facial emotional expressions while having been previously confronted with congruent or incongruent emotion-inducing situations. To differentiate between emotional and cognitive egocentricity, participants additionally completed an established visual perspective-taking task. Our results confirmed the occurrence of emotional egocentric biases during the SOFE task. No conclusive evidence of a general role of the rSMG in emotional egocentricity was found. However, active as compared to sham tDCS induced descriptively lower egocentric biases when judging incongruent fearful faces, and stronger biases when judging incongruent happy faces, suggesting emotion-specific tDCS effects on egocentric biases. Further, we found significant tDCS effects on cognitive egocentricity. Results of the present study expanded our understanding of emotional egocentricity and point towards emotion-specific patterns of the underlying functionality.


Time-wise change in neck pain in response to rehabilitation with specific resistance training: implications for exercise prescription.
To determine the time-wise effect of specific resistance training on neck pain among industrial technicians with frequent neck pain symptoms. Secondary analysis of a parallel-group cluster randomized controlled trial of 20 weeks performed at two large industrial production units in Copenhagen, Denmark. Women with neck pain >30 mm VAS (N = 131) were included in the present analysis. The training group (N = 77) performed specific resistance training for the neck/shoulder muscles three times a week, and the control group (N = 54) received advice to stay active. Participants of both groups registered neck pain intensity (0-100 mm VAS) once a week. Neck pain intensity was 55 mm (SD 23) at baseline. There was a significant group by time interaction for neck pain (F-value 2.61, P<0.001, DF = 19). Between-group differences in neck pain reached significance after 4 weeks (11 mm, 95% CI 2 to 20). The time-wise change in pain showed three phases; a rapid decrease in the training group compared with the control group during the initial 7 weeks, a slower decrease in pain during the following weeks (week 8-15), and a plateau during the last weeks (week 16-20). Adherence to training followed a two-phase pattern, i.e. weekly participation rate was between 70-86% during the initial 7 weeks, dropping towards 55-63% during the latter half of the training period. Four weeks of specific resistance training reduced neck pain significantly, but 15 weeks is required to achieve maximal pain reduction. The time-wise change in pain followed a three-phase pattern with a rapid effect during the initial 7 weeks followed by a slower but still positive effect, and finally a plateau from week 15 and onwards. Decreased participation rate may explain the decreased efficacy during the latter phase of the intervention.


Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model.
Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). Where and how oligodendrocyte damage is initiated in MS is not completely understood. Here, we use a combination of light and electron microscopy techniques to provide a dynamic and highly resolved view of oligodendrocyte damage in neuroinflammatory lesions. We show that both in MS and in its animal model structural damage is initiated at the myelin sheaths and only later spreads to the oligodendrocyte cell body. Early myelin damage itself is characterized by the formation of local myelin out-foldings-'myelinosomes'-, which are surrounded by phagocyte processes and promoted in their formation by anti-myelin antibodies and complement. The presence of myelinosomes in actively demyelinating MS lesions suggests that oligodendrocyte damage follows a similar pattern in the human disease, where targeting demyelination by therapeutic interventions remains a major open challenge.


Developments in component-based normalization for 3D PET.
Normalization in positron emission tomography (PET) is the process of ensuring that all lines of response joining detectors in coincidence have the same effective sensitivity. In three-dimensional (3D) PET, normalization is complicated by the presence of a large proportion of scattered coincidences, and by the fact that cameras operating in 3D mode encounter a very wide range of count-rates. In this work a component-based normalization model is presented which separates the normalization of true and scattered coincidences and accounts for variations in normalization effects with count-rate. The effects of the individual components in the model on reconstructed images are investigated, and it is shown that only a subset of these components has a significant effect on reconstructed image quality.


Methods for Assessing Improvement in Specificity when a Biomarker is Combined with a Standard Screening Test.
Biomarkers that can be used in combination with established screening tests to reduce false positive rates are in considerable demand. In this article, we present methods for evaluating the diagnostic performance of combination tests that require positivity on a biomarker test in addition to a standard screening test. These methods rely on relative true and false positive rates to measure the loss in sensitivity and gain in specificity associated with the combination relative to the standard test. Inference about the relative rates follows from noting their interpretation as conditional probabilities. These methods are extended to evaluate combinations with continuous biomarker tests by introducing a new statistical entity, the relative receiver operating characteristic (rROC) curve. The rROC curve plots the relative true positive rate versus the relative false positive rate as the biomarker threshold for positivity varies. Inference can be made by applying existing ROC methodology. We illustrate the methods with two examples: a breast cancer biomarker study proposed by the Early Detection Research Network (EDRN) and a prostate cancer case-control study examining the ability of free prostate-specific antigen (PSA) to improve the specificity of the standard PSA test.


Synapse formation and clustering of neuroligin-2 in the absence of GABAA receptors.
GABAergic synapses are crucial for brain function, but the mechanisms underlying inhibitory synaptogenesis are unclear. Here, we show that postnatal Purkinje cells (PCs) of GABA(A)alpha1 knockout (KO) mice express transiently the alpha3 subunit, leading to the assembly of functional GABA(A) receptors and initial normal formation of inhibitory synapses, that are retained until adulthood. Subsequently, down-regulation of the alpha3 subunit causes a complete loss of GABAergic postsynaptic currents, resulting in a decreased rate of inhibitory synaptogenesis and formation of mismatched synapses between GABAergic axons and PC spines. Notably, the postsynaptic adhesion molecule neuroligin-2 (NL2) is correctly targeted to inhibitory synapses lacking GABA(A) receptors and the scaffold molecule gephyrin, but is absent from mismatched synapses, despite innervation by GABAergic axons. Our data indicate that GABA(A) receptors are dispensable for synapse formation and maintenance and for targeting NL2 to inhibitory synapses. However, GABAergic signaling appears to be crucial for activity-dependent regulation of synapse density during neuronal maturation.


Generation and evaluation of artificial mental health records for Natural Language Processing.
A serious obstacle to the development of Natural Language Processing (NLP) methods in the clinical domain is the accessibility of textual data. The mental health domain is particularly challenging, partly because clinical documentation relies heavily on free text that is difficult to de-identify completely. This problem could be tackled by using artificial medical data. In this work, we present an approach to generate artificial clinical documents. We apply this approach to discharge summaries from a large mental healthcare provider and discharge summaries from an intensive care unit. We perform an extensive intrinsic evaluation where we (1) apply several measures of text preservation; (2) measure how much the model memorises training data; and (3) estimate clinical validity of the generated text based on a human evaluation task. Furthermore, we perform an extrinsic evaluation by studying the impact of using artificial text in a downstream NLP text classification task. We found that using this artificial data as training data can lead to classification results that are comparable to the original results. Additionally, using only a small amount of information from the original data to condition the generation of the artificial data is successful, which holds promise for reducing the risk of these artificial data retaining rare information from the original data. This is an important finding for our long-term goal of being able to generate artificial clinical data that can be released to the wider research community and accelerate advances in developing computational methods that use healthcare data.


An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens.
Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems. One of the most studied neurotransmitters related to pain disorders is serotonin. Estrogen can modify serotonin synthesis and metabolism, promoting a general increase in its tonic effects. Studies evaluating the relationship between serotonin and disorders such as irritable bowel syndrome, fibromyalgia, migraine, and other types of headache suggest a clear impact of this neurotransmitter, thereby increasing the interest in serotonin as a possible future therapeutic target. This literature review describes the importance of substances such as serotonin and ovarian hormones in pain perception and illustrates the relationship between those two, and their direct influence on the presentation of the aforementioned pain-related conditions. Additionally, we review the pathways and receptors implicated in each disorder. Finally, the objective was to stimulate future pharmacological research to experimentally evaluate the potential of serotonin modulators and ovarian hormones as therapeutic agents to regulate pain in specific subpopulations.


Bacterascites: A study of clinical features, microbiological findings, and clinical significance.
Knowledge about bacterascites is limited and management guidelines are based on small patient series. The purpose of this study was to add further insight into the clinical characteristics, microbiological findings, and prognosis of patients diagnosed with bacterascites. Retrospective analysis of patients with advanced chronic liver disease diagnosed with bacterascites and SBP between January 2003 and August 2016. In this study, 123 patients were included with 142 episodes of bacterascites. The median MELD score was 20 and clinical symptoms of infection were present in 78%. Empiric antibiotic treatment was initiated in 68%. In 26 untreated patients undergoing repeated paracentesis, 42% were diagnosed with either ongoing bacterascites or SBP. The presence of signs or symptoms of infection was not an independent predictor for mortality or spontaneous resolution of infection. The 1-month and 1-year mortality rates of the 123 patients studied, were 32% and 60%, respectively; these results were in line with data pertaining to the prognosis of SBP. Patients with bacterascites and SBP are highly comparable with respect to severity of liver disease and overall prognosis. If left untreated, bacterascites is likely to persist or to evolve to SBP in a significant proportion of patients. The results of this study support current guidelines regarding the treatment of ascitic fluid infection, but could not confirm the prognostic relevance of symptomatic disease at the time of diagnosis. We suggest that the threshold to initiate antibiotic treatment, in particular in cases with severely advanced liver disease, should be low.


Cluster of Leptospirosis Acquired Through River Surfing in Switzerland.
Background. In Switzerland, leptospirosis is still considered as a travel-associated disease. After the surprising diagnosis of leptospirosis in a patient who was initially suspected as having primary human immunodeficiency virus infection, we recognized that acquisition of leptospirosis occurred through recreational activities and we identified additional affected individuals. Methods. Detailed anamnesis, excluding occupational exposure, acquisition abroad, and pet contacts, enabled us to detect the source of infection and identify a cluster of leptospirosis. Convalescent sera testing was performed to confirm Leptospira infection. Microscopic agglutination tests were used to determine the infecting serovar. Results. We identified a cluster of leptospirosis in young, previously healthy persons. Acquisition of leptospirosis was traced back to a surfing spot on a river in Switzerland (Reuss, Aargau). Clinical presentation was indistinct. Two of the 3 reported cases required hospitalization, and 1 case even suffered from meningitis. Serologic tests indicated infection with the serovar Grippotyphosa in all cases. With the exception of the case with meningitis, no antibiotics were administered, because leptospirosis was diagnosed after spontaneous resolution of most symptoms. Despite a prolonged period of convalescence in 2 cases, full recovery was achieved. Recent reports on beavers suffering from leptospirosis in this region underline the possible water-borne infection of the 3 cases and raise the question of potential wildlife reservoirs. Conclusions. Insufficient awareness of caregivers, which may be promoted by the missing obligation to report human leptospirosis, combined with the multifaceted presentation of the disease result in significant underdiagnosis. More frequent consideration of leptospirosis as differential diagnosis is inevitable, particularly as veterinary data suggest re-emergence of the disease.


Contrast enhancement of stimulus intermittency in a primary olfactory network and its behavioral significance.
An animal navigating to an unseen odor source must accurately resolve the spatiotemporal distribution of that stimulus in order to express appropriate upwind flight behavior. Intermittency of natural odor plumes, caused by air turbulence, is critically important for many insects, including the hawkmoth, Manduca sexta, for odor-modulated search behavior to an odor source. When a moth's antennae receive intermittent odor stimulation, the projection neurons (PNs) in the primary olfactory centers (the antennal lobes), which are analogous to the olfactory bulbs of vertebrates, generate discrete bursts of action potentials separated by periods of inhibition, suggesting that the PNs may use the binary burst/non-burst neural patterns to resolve and enhance the intermittency of the stimulus encountered in the odor plume. We tested this hypothesis first by establishing that bicuculline methiodide reliably and reversibly disrupted the ability of PNs to produce bursting response patterns. Behavioral studies, in turn, demonstrated that after injecting this drug into the antennal lobe at the effective concentration used in the physiological experiments animals could no longer efficiently locate the odor source, even though they had detected the odor signal. Our results establish a direct link between the bursting response pattern of PNs and the odor-tracking behavior of the moth, demonstrating the behavioral significance of resolving the dynamics of a natural odor stimulus in antennal lobe circuits.


High-power and high-efficiency diode-pumped Nd:LuYAG mixed crystal lasers operating at 939 and 946 nm.
We report on high-performance infrared lasers at 0.94 μm based on quasi-three-level transition of F3/24→I9/24 in Nd:LuYAG mixed crystal, for the first time to our knowledge. The maximum output power was achieved to 5.64 W with slope efficiency of approximately 52.5% at 946 nm. The simultaneous dual-wavelength laser at 939 and 946 nm is also obtained with maximum output power of 3.61 W and slope efficiency of 34.8% by introducing a glass etalon into the cavity. Moreover, a 2.0-W single-wavelength laser at 939 nm can be further attained by suitably tilting the etalon. Using a Cr:YAG saturable absorber, Q-switched laser operation is realized with maximum average output power of 0.68 W and the narrowest pulse width of 8.4 ns, which results in the maximum single pulse energy of approximately 55.3 μJ and the maximum pulse peak power of approximately 6.15 kW. Finally, thermal focal length of the laser crystal is estimated by using a flat-flat laser cavity.


Increased levels of a unique post-translationally modified betaIVb-tubulin isotype in liver cancer.
Identifying changes at the molecular level during the development of hepatocellular carcinoma is important for the detection and treatment of the disease. The characteristic structural reorganization of preneoplastic cells may involve changes in the microtubule cytoskeleton. Microtubules are dynamic protein polymers that play an essential role in cell division, maintenance of cell shape, vesicle transport, and motility. They are comprised of multiple isotypes of alpha- and beta-tubulin. Changes in the levels of these isotypes may affect not only microtubule stability and sensitivity to drugs but also interactions with endogenous proteins. We employed a rat liver cancer model that progresses through stages similar to those of human liver cancer, including metastasis to the lung, to identify changes in the tubulin cytoskeleton during carcinogenesis. Tubulin isotypes in both liver and lung tissue were purified and subsequently separated by isoelectric focusing electrophoresis. The C-terminal isotype-defining region from each tubulin was obtained by cyanogen bromide cleavage and identified by mass spectrometry. A novel post-translational modification of betaIVb-tubulin in which two hydrophobic residues are proteolyzed from the C-terminus, thus exposing a charged glutamic acid residue, was identified. The unique form of betaIVb-tubulin was quantified in the liver tissue of all carcinoma stages and found to be approximately 3-fold more abundant in nodular and tumor tissue than in control tissue. The level of this form was also found to be increased in lung tissue with liver metastasis. This modification alters the C-terminal domain of one of the most abundant beta-tubulin isotypes in the liver and therefore may affect the interactions of microtubules with endogenous proteins.


Phosphorylcholine-carbohydrate-protein conjugates efficiently induce hapten-specific antibodies which recognize both Streptococcus pneumoniae and Neisseria meningitidis: a potential multitarget vaccine against respiratory infections.
Phosphorylcholine (ChoP) is commonly expressed at the surface of pathogens of the respiratory tract, including Streptococcus pneumoniae and Neisseria meningitidis. We designed a synthetic hapten comprising ChoP and part of its native carrier structure in S. pneumoniae, i.e. N-acetyl-D-galactosamine (GalNAc). Protein conjugates of this hapten induced GalNAc-ChoP-specific antibodies which recognized ChoP on both S. pneumoniae and N. meningitidis. GalNAc-ChoP could therefore lead to the rational design of a novel multipurpose vaccine against respiratory infections.


Quality of Life Trajectories Among Stroke Survivors and the Related Changes in Caregiver Outcomes: A Growth Mixture Study.
To identify the distinct quality of life (QOL) trajectories among stroke survivors, and to evaluate the associations with their caregivers' burden, anxiety, and depression. This was a longitudinal dyadic study. Stroke survivors and their informal caregivers were enrolled upon discharge from several rehabilitation hospitals, and they were followed during this multisite longitudinal study. The stroke survivors (N=405, mean age=70.7y) included older adult men (52.0%), most of whom (80.9%) had had ischemic strokes. The caregivers (n=244, mean age=52.7y) included mostly women (65.2%), most of whom were the survivors' children (50.0%) or spouses (36.1%). Not applicable. Latent growth mixture modeling was used to identify the distinct QOL trajectories among the stroke survivors over the course of 12 months of recovery. The longitudinal associations between the stroke survivor QOL trajectories and the caregivers' burden, anxiety, and depression were evaluated. A multinomial regression was then used to identify the predictors of the various survivor QOL trajectories. Three distinct survivor QOL trajectories were identified: high and slightly improving QOL, moderate and slightly worsening QOL, and markedly improving QOL. The caregivers' burden, anxiety, and depression mirrored the survivors' QOL trajectories. In the multinomial models, an older survivor age, hemorrhagic stroke, lower education, and coexisting chronic obstructive pulmonary disease or thyroid disease were significantly associated with a moderate and slightly worsening QOL trajectory. Women and blindness were associated with a markedly improving QOL survivor trajectory. A survivor's QOL trajectory after a stroke was associated with their caregiver's burden, anxiety, and depression. Those survivors belonging to the moderate and slightly worsening QOL trajectory and their caregivers, in particular, need special care, because they are at risk for the worst outcomes.


Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice.
The National Research Council (NRC) Expert Panel Report on Prevention and Treatment of Missing Data in Clinical Trials highlighted the need for clearly defining objectives and estimands. That report sparked considerable discussion and literature on estimands and how to choose them. Importantly, consideration moved beyond missing data to include all postrandomization events that have implications for estimating quantities of interest (intercurrent events, aka ICEs). The ICH E9(R1) draft addendum builds on that research to outline key principles in choosing estimands for clinical trials, primarily with focus on confirmatory trials. This paper provides additional insights, perspectives, details, and examples to help put ICH E9(R1) into practice. Specific areas of focus include how the perspectives of different stakeholders influence the choice of estimands; the role of randomization and the intention-to-treat principle; defining the causal effects of a clearly defined treatment regimen, along with the implications this has for trial design and the generalizability of conclusions; detailed discussion of strategies for handling ICEs along with their implications and assumptions; estimands for safety objectives, time-to-event endpoints, early-phase and one-arm trials, and quality of life endpoints; and realistic examples of the thought process involved in defining estimands in specific clinical contexts.


Assessment of Head Shape by Craniofacial Teams: Structuring Practice Parameters to Optimize Efficiency.
Since the initiation of the "Back to Sleep Campaign" by the American Academy of Pediatrics in 1992, the incidence of referrals for positional plagiocephaly has increased by 600%. Although patients with positional plagiocephaly rarely require operative intervention, they often do require treatment with cranial molding helmets or positioning changes. The increased volume of patients makes the task of separating cases of craniosynostosis from positional head shape problems more difficult. The authors sought to determine how providers are handling this increased workload of head shape abnormality patients, especially with respect to the largest practices. An electronic survey was created and distributed to members of the American Society of Maxillofacial Surgeons and the American Cleft Palate Association (ACPA). Practices were categorized by head shape patient volume as low (<4 new patients/month), medium (5-20 new patients/month), and high (>21 new patients/month). A Pearson's χ test was used to determine characteristics that differed significantly with practice volume. Response rate was 6.6%, with 88 responses. Regarding head shape evaluation, 17.6% of practices used a laser scanner (portable or stationary), 35.3% used caliper anthropometric measurements, 28.5% used two-dimensional digital photography, and 9.4% used three-dimensional digital photography. In high-volume centers, 80% had a dedicated head shape clinic (P < 0.0005), 33.3% used a stationary laser scanner (P = 0.023), and 53.3% used a licensed independent provider (LIP) such as a nurse practitioner or physician assistant in the initial evaluation of head shape abnormalities (P = 0.032). Although using a multidisciplinary clinic was not a significant difference amongst groups, the most common additional provider in multidisciplinary clinic was orthotics (68%). High-volume practices are significantly more likely to use LIPs, stationary laser scanners, and plain films, as well as organizing head shape abnormality patients into a dedicated clinic.


Robotic distal pancreatectomy: cost effective?
Minimally invasive techniques and even robotics in pancreaticobiliary surgery are being used increasingly. Cost-effectiveness is a practical burden associated with the introduction of surgical innovation. This study compares the costs and the outcomes of open, laparoscopic, and robotic distal pancreatectomies. We hypothesized that robotic distal pancreatectomy is cost-effective. Between August 2008 and August 2009, 77 distal pancreatectomies were performed at a single academic medical center. A retrospective analysis of prospectively collected data on demographics, short-term outcomes, and direct cost was performed. Thirty-two open distal pancreatectomies, 28 laparoscopic distal pancreatectomies, and 17 robotic distal pancreatectomies were performed. Age, American Society of Anesthesia preoperative risk score, and specimen length were similar. Indications for laparoscopic distal pancreatectomies and robotic distal pancreatectomies included more cystic neoplasms (49%) and fewer malignancies (29%) versus open distal pancreatectomies (16% and 47%). Spleen preservation occurred in 65% robotic distal pancreatectomies versus 12% and 29% in open distal pancreatectomies and laparoscopic distal pancreatectomies (P < .05). The operative time averaged 298 minutes in robotic distal pancreatectomies versus 245 and 222 minutes in open distal pancreatectomies and laparoscopic distal pancreatectomies (P < .05). Blood loss and morbidity were similar with no mortality. The length of stay was 4 days in robotic distal pancreatectomies versus 8 and 6 in open distal pancreatectomies and laparoscopic distal pancreatectomies (P < .05). The total cost was $10,588 in robotic distal pancreatectomies versus $16,059 and $12,986 in open distal pancreatectomies and laparoscopic distal pancreatectomies. These data suggest direct hospital costs are comparable among all groups. They suggest a shorter length of stay in robotic versus laparoscopic or open approaches. Finally, spleen and vessel preservation rates may improve with a robotic approach at the expense of increased operative time. In summary, robotic distal pancreatectomy is safe and cost effective in selected cases.


Type M Resistance to Macrolides Is Due to a Two-Gene Efflux Transport System of the ATP-Binding Cassette (ABC) Superfamily.
The mef(A) gene was originally identified as the resistance determinant responsible for type M resistance to macrolides, a phenotype frequently found in clinical isolates of Streptococcus pneumoniae and Streptococcus pyogenes. MefA was defined as a secondary transporter of the major facilitator superfamily driven by proton-motive force. However, when characterizing the mef(A)-carrying elements Tn1207.1 and Φ1207.3, another macrolide resistance gene, msr(D), was found adjacent to mef(A). To define the respective contribution of mef(A) and msr(D) to macrolide resistance, three isogenic deletion mutants were constructed by transformation of a S. pneumoniae strain carrying Φ1207.3: (i) Δmef(A)-Δmsr(D); (ii) Δmef(A)-msr(D); and (iii) mef(A)-Δmsr(D). Susceptibility testing of mutants clearly showed that msr(D) is required for macrolide resistance, while deletion of mef(A) produced only a twofold reduction in the minimal inhibitory concentration (MIC) for erythromycin. The contribution of msr(D) to macrolide resistance was also studied in S. pyogenes, which is the original host of Φ1207.3. Two isogenic strains of S. pyogenes were constructed: (i) FR156, carrying Φ1207.3, and (ii) FR155, carrying Φ1207.3/Δmsr(D). FR155 was susceptible to erythromycin, whereas FR156 was resistant, with an MIC value of 8 μg/ml. Complementation experiments showed that reintroduction of the msr(D) gene could restore macrolide resistance in Δmsr(D) mutants. Radiolabeled erythromycin was retained by strains lacking msr(D), while msr(D)-carrying strains showed erythromycin efflux. Deletion of mef(A) did not affect erythromycin efflux. This data suggest that type M resistance to macrolides in streptococci is due to an efflux transport system of the ATP-binding cassette (ABC) superfamily, in which mef(A) encodes the transmembrane channel, and msr(D) the two ATP-binding domains.


At the heart of the budding yeast cell cycle.
It might now seem obvious that the mechanisms regulating cell division would be found to be a highly conserved feature of eukaryotic cells. This was less clear 20 years ago when the pioneering genetic studies of the cell cycle were initiated. This article presents one view as to what lies at the heart of the budding yeast cell cycle. It is written on the premise that most of the key players, such as cyclin-dependent kinases, the anaphase-promoting complex, the origin recognition complex, Cdc6p and Mcm proteins, were performing similar functions in the common ancestor of yeast and man. Ideas about the budding yeast cell cycle might, therefore, have universal significance for other eukaryotic cells.


Preferential HER-2/neu overexpression and/or amplification in aggressive histological subtypes of invasive breast cancer.
To investigate whether alterations of the HER2 gene occur more frequently in histologically unfavourable subtypes of invasive breast cancer. The study was composed of nine invasive apocrine, six lipid-rich, 12 glycogen-rich, 11 micropapillary and 33 pleomorphic lobular breast carcinomas. Lymph node involvement was represented in all subgroups. HER2 status was confirmed in all cases by using immunohistochemistry (CB11, Herceptest) and fluorescent in-situ hybridization (FISH) analysis (Vysis). Micropapillary and apocrine carcinomas showed the highest rate of protein overexpression (72% and 66%) and gene amplification (45% and 44%). Protein overexpression was common in poorly differentiated pleomorphic lobular carcinomas (56%); however, this subgroup failed to show an increased number of gene copies by FISH (31%). The incidence of HER2 overexpression (33% and 50%, respectively) and gene amplification (25% and 33%, respectively) among glycogen-rich and lipid-rich carcinomas was not higher than that observed in breast cancer generally. Our data suggest that preferential involvement of the HER2 gene in micropapillary and apocrine breast carcinomas may contribute to their aggressive behaviour.


The Swedish version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).
We report herein the results of the cross-cultural adaptation and validation into the Swedish language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Swedish CHAQ CHQ were already published and therefore were revalidated in this study. A total of 129 subjects were enrolled: 69 patients with JIA (13% systemic onset, 39% polyarticular onset, 25% extended oligoarticular subtype, and 23% persistent oligoarticular subtype) and 60 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Swedish version of the CHAQ-CHQ are reliable, and valid tools for the functional, physical and psychosocial assessment of children with JIA.


An asymmetric underlying rule in the assignment of codons: possible clue to a quick early evolution of the genetic code via successive binary choices.
Aminoacyl-tRNA synthetases (aaRSs) are responsible for creating the pool of correctly charged aminoacyl-tRNAs that are necessary for the translation of genetic information (mRNA) by the ribosome. Each aaRS belongs to either one of only two classes with two different mechanisms of aminoacylation, making use of either the 2'OH (Class I) or the 3'OH (Class II) of the terminal A76 of the tRNA and approaching the tRNA either from the minor groove (2'OH) or the major groove (3'OH). Here, an asymmetric pattern typical of differentiation is uncovered in the partition of the codon repertoire, as defined by the mechanism of aminoacylation of each corresponding tRNA. This pattern can be reproduced in a unique cascade of successive binary decisions that progressively reduces codon ambiguity. The deduced order of differentiation is manifestly driven by the reduction of translation errors. A simple rule can be defined, decoding each codon sequence in its binary class, thereby providing both the code and the key to decode it. Assuming that the partition into two mechanisms of tRNA aminoacylation is a relic that dates back to the invention of the genetic code in the RNA World, a model for the assignment of amino acids in the codon table can be derived. The model implies that the stop codon was always there, as the codon whose tRNA cannot be charged with any amino acid, and makes the prediction of an ultimate differentiation step, which is found to correspond to the codon assignment of the 22nd amino acid pyrrolysine in archaebacteria.


Exhaled nitric oxide and carbon monoxide in respiratory diseases.
Breath tests have gained increasing interest in recent years mainly driven by the unmet clinical need to monitor airway diseases and to obtain information on unravelled aspects of respiratory disorders. A prototype of such measurement reaching clinical significance besides its use as a research tool is the measurement of exhaled nitric oxide (NO). It took hardly more than a decade after the discovery that exhaled breath contains NO for this measurement to be approved for clinical practice to monitor anti-inflammatory treatment in asthma. Recent studies demonstrate that using exhaled NO measurement to guide anti-inflammatory treatment in asthma may help clinical decision making. A similarly small molecule present in exhaled breath is carbon monoxide, which is not only a biomarker of cigarette smoking but has also been suggested to reflect ongoing oxidative stress/antioxidant defense. The scope of this review is the exciting field of exhaled monoxides. Since several other biomarkers have also been studied in the exhaled breath this review will provide a brief introduction to them.


Does a short breastfeeding period protect from FTO-induced adiposity in children?
A number of studies have reported replicable associations between common genetic loci and obesity indices. One of these loci is the fat mass and obesity associated locus (FTO). We aimed to assess whether breastfeeding mediated the known association between FTO and indices of body fatness. This study includes three independent pediatric cohorts, two of Greek origin (the Gene-Diet Attica Investigation: GENDAI, n=1 138 and the "Growth, Exercise and Nutrition Epidemiological Study In preschoolers": the GENESIS study, n=2 374) and one British (the Avon Longitudinal Study of Parents and Children:ALSPAC, n=4 325). Among other information, breastfeeding history was recorded. A DNA sample was ascertained by either blood or saliva. Genotyping for FTO variants was performed in GENDAI and ALSPAC for the rs9939609, while in GENESIS, for the rs17817449 variant. In all cohorts, multivariate analysis showed that the association between FTO:rs9939609 and measures of obesity was consistent across newly presented cohorts (GENDAI: Body mass index [BMI], β=0.43, p=0.009; Waist Circumference, β=1.067, p=0.019; triceps skinfold, β=0.972, p=0.003; subscapular skinfold, β=0.593, p=0.023; GENESIS: Waist Circumference, β=0.473, p=0.008 and subscapular skinfold, β=0.227, p=0.014). Inclusion of one month of breastfeeding as an interaction term effectively removed these associations with indices of obesity (BMI, Waist-Hip-Ratio and subscapular skinfold). No evidence of such interaction was observed for the independent cohort of British children. Our findings indicate that in two moderately sized Greek samples, breastfeeding may exert a modifying effect on the relationship between variants at the FTO locus and indices of adiposity. These findings were not replicated in a larger British collection.


Reversible physical crosslinking strategy with optimal temperature for 3D bioprinting of human chondrocyte-laden gelatin methacryloyl bioink.
Gelatin methacryloyl is a promising material in tissue engineering and has been widely studied in three-dimensional bioprinting. Although gelatin methacryloyl possesses excellent biocompatibility and tunable mechanical properties, its poor printability/processability has hindered its further applications. In this study, we report a reversible physical crosslinking strategy for precise deposition of human chondrocyte-laden gelatin methacryloyl bioink at low concentration without any sacrificial material by using extrusive three-dimensional bioprinting. The precise printing temperature was determined by the rheological properties of gelatin methacryloyl with temperature. Ten percent (w/v) gelatin methacryloyl was chosen as the printing formula due to highest biocompatibility in three-dimensional cell cultures in gelatin methacryloyl hydrogel disks. Primary human chondrocyte-laden 10% (w/v) gelatin methacryloyl was successfully printed without any construct deformation or collapse and was permanently crosslinked by ultraviolet light. The printed gelatin methacryloyl hydrogel constructs remained stable in long-term culture. Chondrocyte viability and proliferation that were printed under this optimal temperature were better than that of chondrocytes printed under lower temperatures and were similar to that of chondrocytes in the non-printed gelatin methacryloyl hydrogels. The results indicate that with this strategy, 10% (w/v) gelatin methacryloyl bioink presented excellent printability and printing resolution with high cell viability, which appears to be suitable for printing primary human chondrocytes in cartilage biofabrication and can be extensively applied in tissue engineering of other organs or in other biomedical fields.


Starting to smoke: a qualitative study of the experiences of Australian indigenous youth.
Adult smoking has its roots in adolescence. If individuals do not initiate smoking during this period it is unlikely they ever will. In high income countries, smoking rates among Indigenous youth are disproportionately high. However, despite a wealth of literature in other populations, there is less evidence on the determinants of smoking initiation among Indigenous youth. The aim of this study was to explore the determinants of smoking among Australian Indigenous young people with a particular emphasis on the social and cultural processes that underlie tobacco use patterns among this group. This project was undertaken in northern Australia. We undertook group interviews with 65 participants and individual in-depth interviews with 11 youth aged 13-20 years led by trained youth 'peer researchers.' We also used visual methods (photo-elicitation) with individual interviewees to investigate the social context in which young people do or do not smoke. Included in the sample were a smaller number of non-Indigenous youth to explore any significant differences between ethnic groups in determinants of early smoking experiences. The theory of triadic influence, an ecological model of health behaviour, was used as an organising theory for analysis. Family and peer influences play a central role in smoking uptake among Indigenous youth. Social influences to smoke are similar between Indigenous and non-Indigenous youth but are more pervasive (especially in the family domain) among Indigenous youth. While Indigenous youth report high levels of exposure to smoking role models and smoking socialisation practices among their family and social networks, this study provides some indication of a progressive denormalisation of smoking among some Indigenous youth. Future initiatives aimed at preventing smoking uptake in this population need to focus on changing social normative beliefs around smoking, both at a population level and within young peoples' immediate social environment. Such interventions could be effectively delivered in both the school and family environments. Specifically, health practitioners in contact with Indigenous families should be promoting smoke free homes and other anti-smoking socialisation behaviours.


Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90.
A series of macrolactam analogues of the naturally occurring resorcylic acid lactone radicicol have been synthesised from methyl orsellinate in 7 steps, involving chlorination, protection of the two phenolic groups, and hydrolysis to the benzoic acid. Formation of the dianion and quenching with a Weinreb amide results in acylation of the toluene methyl group that is followed by amide formation and ring closing metathesis to form the macrocyclic lactam. Final deprotection of the phenolic groups gives the desired macrolactams whose binding to the N-terminal domain of yeast Hsp90 was studied by isothermal titration calorimetry and protein X-ray crystallography.


Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory.
How the cerebellum is involved in the practice and proficiency of non-motor functions is still unclear. We tested whether transcranial direct current stimulation (tDCS) over the cerebellum (cerebellar tDCS) induces after-effects on the practice-dependent increase in the proficiency of a working memory (WM) task (Sternberg test) in 13 healthy subjects. We also assessed the effects of cerebellar tDCS on visual evoked potentials (VEPs) in four subjects and compared the effects of cerebellar tDCS on the Sternberg test with those elicited by tDCS delivered over the prefrontal cortex in five subjects. Our experiments showed that anodal or cathodal tDCS over the cerebellum impaired the practice-dependent improvement in the reaction times in a WM task. Because tDCS delivered over the prefrontal cortex induced an immediate change in the WM task but left the practice-dependent proficiency unchanged, the effects of cerebellar tDCS are structure-specific. Cerebellar tDCS left VEPs unaffected, its effect on the Sternberg task therefore seems unlikely to arise from visual system involvement. In conclusion, tDCS over the cerebellum specifically impairs the practice-dependent proficiency increase in verbal WM.


Pt nanoparticles residing in the pores of porous LaNiO₃ nanocubes as high-efficiency electrocatalyst for direct methanol fuel cells.
Pt-filled porous LaNiO₃ cubes are prepared through a facile route. The characterizations reveal that large numbers of pores (9-10 nm) are distributed homogeneously in porous LaNiO₃ cubes. The Pt nanoparticles residing in the pores of porous LaNiO₃ cubes are about 5 nm in size. The investigation on the electrocatalytic activity reveals that electrocatalytic activity of the obtained Pt loaded porous LaNiO₃ nanocubes exhibit a significantly improved electrochemical active surface area (EASA) and a remarkably enhanced electrocatalytic performance toward methanol oxidation. The results are significant for improving the efficiency of Pt-based catalysts for DMFCs as well as the applications of perovskite compounds.


Molecular epidemiology of HIV-1 infection among men who have sex with men in Taiwan from 2013 to 2015.
Men who have sex with men (MSM) is the major risk population of HIV-1 infection in Taiwan, and its surveillance has become critical in HIV-1 prevention. We recruited MSM subjects from 17 high-risk venues and 4 community centers in northern and southern Taiwan for anonymous HIV-1 screening during 2013-2015. Blood samples were obtained for genotyping and phylogenetic analysis, and a questionnaire survey covering demographic variables and social behavior was conducted. In total, 4,675 subjects were enrolled, yielding a HIV-1 prevalence rate of 4.3% (201/4675). Eight risk factors including subjects who did not always use condoms (OR = 1.509, p = 0.0123), those who used oil-based lubricants (OR = 1.413, p = 0.0409), and those who used recreational drugs (OR = 2.182, p = < .0001) had a higher risk of HIV-1 infection. The annual prevalence and incidence of HIV-1 showed a downward trend from 2013 to 2015 (6.56%, 5.97 per 100 person-years in 2013; 4.53%, 3.97 per 100 person-years in 2014; 1.84%, 2.08 per 100 person-years in 2015). Factors such as always using condoms, water-based lubricant use, correct knowledge of lubricating substitutes, and recreational drug use were significantly associated with the trend of incidence. Phylogenetic tree analysis showed that the cross-regional and international interaction of the local MSM population may have facilitated transmission of HIV. This survey of high-risk venues showed decreased prevalence and incidence of HIV-1 infection in Taiwan from 2013 to 2015, and this may be related to changes in behavioral patterns. Moreover, cross-regional interaction and recreational drug use need to be considered in future surveillance.


Efficacy of Permethrin Treated Bed Nets Against Leishmania major Infected Sand Flies.
Insecticide treated nets (ITNs) are a potential tool to help control sand flies and prevent Leishmaniasis. However, little is currently known about the response of Leishmania infected sand flies to ITNs. In this study, Phlebotomus duboscqi sand flies were infected with the parasite Leishmania major. Infected and noninfected sand flies were then evaluated against permethrin treated and untreated bed nets in a laboratory assay that required sand flies to pass through suspended netting material to feed on a mouse serving as an attractive host. The number of sand flies passing through the nets and blood feeding was recorded. There was not a significant difference in the ability of infected or noninfected sand flies to move through treated or untreated nets. Fewer sand flies entered the permethrin treated nets compared to the untreated nets, indicating that permethrin creates an effective barrier. The results show that in addition to reducing the nuisance bites of noninfected sand flies, ITNs also protect against Leishmania infected sand flies and therefore can play in key role in reducing the rates of Leishmaniasis. This study is important to the Department of Defense as it continues to develop and field new bed nets to protect service members.


Expansion of a chromosomal repeat in Escherichia coli: roles of replication, repair, and recombination functions.
Previous studies of gene amplification in Escherichia coli have suggested that it occurs in two steps: duplication and expansion. Expansion is thought to result from homologous recombination between the repeated segments created by duplication. To explore the mechanism of expansion, a 7 kbp duplication in the chromosome containing a leaky mutant version of the lac operon was constructed, and its expansion into an amplified array was studied. Under selection for lac function, colonies bearing multiple copies of the mutant lac operon appeared at a constant rate of approximately 4 to 5 per million cells plated per day, on days two through seven after plating. Expansion was not seen in a recA strain; null mutations in recBCD and ruvC reduced the rate 100- and 10-fold, respectively; a ruvC recG double mutant reduced the rate 1000-fold. Expansion occurred at an increased rate in cells lacking dam, polA, rnhA, or uvrD functions. Null mutations of various other cellular recombination, repair, and stress response genes had little effect upon expansion. The red recombination genes of phage lambda could substitute for recBCD in mediating expansion. In the red-substituted cells, expansion was only partially dependent upon recA function. These observations are consistent with the idea that the expansion step of gene amplification is closely related, mechanistically, to interchromosomal homologous recombination events. They additionally provide support for recently described models of RecA-independent Red-mediated recombination at replication forks.


Effect of partial recording protocols on estimates of prevalence of periodontal disease.
The aim of this study was to assess the degree of underreporting in the estimates of prevalence of periodontal attachment loss due to different partial recording protocols (PRP) in epidemiological studies, and to derive a correction factor to adjust for this bias. The study sample included 1,460 dentate persons 14 to 103 years old who were examined clinically to assess the clinical attachment loss at six sites per tooth. Seven PRP based on full-mouth or half-mouth designs were assessed, and the bias and sensitivity in the assessment of attachment loss prevalence for these protocols were assessed. All partial protocols underestimated the prevalence of attachment loss. Bias estimates for any full-mouth PRP were smaller than those for the corresponding site-combination PRP for the half-mouth design. The PRP using the mesio-buccal (MB), mid-buccal (B), and disto-lingual (DL) sites of teeth in all four quadrants showed the smallest bias and highest sensitivity of prevalence estimates among the seven PRP evaluated, uniformly across the range of attachment loss severity level. The three site PRP incorporating the DL site produced less bias than the three site PRP including the disto-buccal (DB) site. There was a 3% to 12% gain in sensitivity for 2 to 5 mm attachment loss thresholds for the three site half-mouth PRP compared with the two site MB, B half-mouth PRP. The bias in the assessment of attachment loss is influenced by the partial recording design and the type and number of sites assessed, and is also influenced by the severity of attachment loss in the study population. These factors should be considered when selecting a partial recording method in large surveys. Furthermore, inflation factors designed to adjust for the bias due to the use of partial systems should be calculated and reported so that comparisons of results with other surveys are more meaningful.


The many projected futures of dengue.
Dengue is a vector-borne disease that causes a substantial public health burden within its expanding range. Several modelling studies have attempted to predict the future global distribution of dengue. However, the resulting projections are difficult to compare and are sometimes contradictory because the models differ in their approach, in the quality of the disease data that they use and in the choice of variables that drive disease distribution. In this Review, we compare the main approaches that have been used to model the future global distribution of dengue and propose a set of minimum criteria for future projections that, by analogy, are applicable to other vector-borne diseases.


CBD: A New Hope?
The nonpsychoactive phytocannabinoid, CBD, was recently approved by the Food and Drug Administration for the treatment of children with drug-resistant epilepsy. This milestone opens new avenues for cannabinoid research. In this Viewpoint, we provide an overview of recent progress in the field highlighting molecular insights into CBD's mechanism of action, as well as its therapeutic potential.


Short-term outcomes after esophagectomy at 164 American College of Surgeons National Surgical Quality Improvement Program hospitals: effect of operative approach and hospital-level variation.
When assessing the effect of operative approach on outcomes, it may be less relevant whether a transhiatal or an Ivor Lewis esophagectomy was performed and may be more important to focus on patient selection and the quality of the hospital performing the operation. Observational study. Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. Individuals undergoing esophagectomy were identified from January 1, 2005, to December 31, 2010. The following 4 groups were created based on operative approach: transhiatal, Ivor Lewis, 3-field, and any approach with an intestinal conduit. Risk-adjusted 30-day outcomes and hospital-level variation in performance. At 164 hospitals, 1738 patients underwent an esophageal resection: 710 (40.9%) were transhiatal, 497 (28.6%) were Ivor Lewis, 361 (20.8%) were 3-field, and 170 (9.8%) were intestinal conduits. Compared with the transhiatal approach, Ivor Lewis esophagectomy was not associated with increased risk for postoperative complications; however, 3-field esophagectomy was associated with increased likelihood of postoperative pneumonia (odds ratio [OR], 1.88; 95% CI, 1.28-2.77) and prolonged ventilation exceeding 48 hours (OR, 1.68; 95% CI, 1.16-2.42). Intestinal conduit use was associated with increased 30-day mortality (OR, 2.65; 95% CI, 1.08-6.47), prolonged ventilation exceeding 48 hours (OR, 1.61; 95% CI, 1.01-2.54), and return to the operating room for any indication (OR, 1.85; 95% CI, 1.16-2.96). Patient characteristics were the strongest predictive factors for 30-day mortality and serious morbidity. After case-mix adjustment, hospital performance varied by 161% for 30-day mortality and by 84% for serious morbidity. Compared with transhiatal dissection, Ivor Lewis esophagectomy did not result in worse postoperative complications. After controlling for case-mix, hospital performance varied widely for all outcomes assessed, indicating that reductions in short-term outcomes will likely result from expanding other aspects of hospital quality beyond a focus on specific technical maneuvers.


Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase.
Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms. Deficiencies in PCC activity in humans are linked to the disease propionic acidaemia, an autosomal recessive disorder that can be fatal in infants. The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa. The alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the beta-subunit supplies the carboxyltransferase (CT) activity. Here we report the crystal structure at 3.2-A resolution of a bacterial PCC alpha(6)beta(6) holoenzyme as well as cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution demonstrating a similar structure for human PCC. The structure defines the overall architecture of PCC and reveals unexpectedly that the alpha-subunits are arranged as monomers in the holoenzyme, decorating a central beta(6) hexamer. A hitherto unrecognized domain in the alpha-subunit, formed by residues between the BC and BCCP domains, is crucial for interactions with the beta-subunit. We have named it the BT domain. The structure reveals for the first time the relative positions of the BC and CT active sites in the holoenzyme. They are separated by approximately 55 A, indicating that the entire BCCP domain must translocate during catalysis. The BCCP domain is located in the active site of the beta-subunit in the current structure, providing insight for its involvement in the CT reaction. The structural information establishes a molecular basis for understanding the large collection of disease-causing mutations in PCC and is relevant for the holoenzymes of other biotin-dependent carboxylases, including 3-methylcrotonyl-CoA carboxylase (MCC) and eukaryotic acetyl-CoA carboxylase (ACC).


Venus southern hemisphere: geologic character and age of terrains in the themis-alpha-lada region.
Arecibo high-resolution radar images of the southern hemisphere of Venus extending to 78 degrees S show that the surface of the Themis-Alpha-Lada region is characterized by linear deformation zones with volcanoes and corona-like features and by regional volcanic deposits (primarily plains, small shields, and large edifices). Large-scale areal deformation is limited to the tessera of Alpha Regio. Lada Terra, in the southern high latitudes, contains several large coronae, in contrast to Ishtar Terra in the northern high latitudes. The density of craters of possible impact origin is somewhat lower than that observed in the Venera 15 and 16 coverage; these data extend to 43 percent of the areas of the surface of Venus with ages of less than about 1 billion years.


Triclosan-coated sutures and sternal wound infections: a prospective randomized clinical trial.
Surgical site infection is a common complication following cardiac surgery. Triclosan-coated sutures have been shown to reduce the rate of infections in various surgical wounds, including wounds after vein harvesting in coronary artery bypass grafting patients. Our purpose was to compare the rate of infections in sternotomy wounds closed with triclosan-coated or conventional sutures. A total of 357 patients that underwent coronary artery bypass grafting were included in a prospective randomized double-blind single-center study. The patients were randomized to closure of the sternal wound with either triclosan-coated sutures (Vicryl Plus and Monocryl Plus, Ethicon, Inc., Somerville, NJ, USA) (n = 179) or identical sutures without triclosan (n = 178). Patients were followed up after 30 days (clinical visit) and 60 days (telephone interview). The primary endpoint was the prevalence of sternal wound infection according to the Centers for Disease Control and Prevention (CDC) criteria. The demographics in both groups were comparable, including age, gender, body mass index, and rate of diabetes and smoking. Sternal wound infection was diagnosed in 43 patients; 23 (12.8%) sutured with triclosan-coated sutures compared to 20 (11.2%) sutured without triclosan (p = 0.640). Most infections were superficial (n = 36, 10.1%), while 7 (2.0%) were deep sternal wound infections. There were 16 positive cultures in the triclosan group and 17 in the non-coated suture group (p = 0.842). The most commonly identified main pathogens were Staphylococcus aureus (45.4%) and coagulase-negative staphylococci (36.4%). Skin closure with triclosan-coated sutures did not reduce the rate of sternal wound infection after coronary artery bypass grafting. (clinicaltrials.gov: NCT01212315).


Hyperandrogenism and Metabolic Syndrome Are Associated With Changes in Serum-Derived microRNAs in Women With Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) remains one of the most common endocrine disorder in premenopausal women with an unfavorable metabolic risk profile. Here, we investigate whether biochemical hyperandrogenism, represented by elevated serum free testosterone, resulted in an aberrant circulating microRNA (miRNAs) expression profile and whether miRNAs can identify those PCOS women with metabolic syndrome (MetS). Accordingly, we measured serum levels of miRNAs as well as biochemical markers related to MetS in a case-control study of 42 PCOS patients and 20 Controls. Patients were diagnosed based on the Rotterdam consensus criteria and stratified based on serum free testosterone levels (≥0.034 nmol/l) into either a normoandrogenic (n = 23) or hyperandrogenic (n = 19) PCOS group. Overall, hyperandrogenic PCOS women were more insulin resistant compared to normoandrogenic PCOS women and had a higher prevalence of MetS. A total of 750 different miRNAs were analyzed using TaqMan Low-Density Arrays. Altered levels of seven miRNAs (miR-485-3p, -1290, -21-3p, -139-3p, -361-5p, -572, and -143-3p) were observed in PCOS patients when compared with healthy Controls. Stratification of PCOS women revealed that 20 miRNAs were differentially expressed between the three groups. Elevated serum free testosterone levels, adjusted for age and BMI, were significantly associated with five miRNAs (miR-1290, -20a-5p, -139-3p, -433-3p, and -361-5p). Using binary logistic regression and receiver operating characteristic curves (ROC), a combination panel of three miRNAs (miR-361-5p, -1225-3p, and -34-3p) could correctly identify all of the MetS cases within the PCOS group. This study is the first to report comprehensive miRNA profiling in different subgroups of PCOS women with respect to MetS and suggests that circulating miRNAs might be useful as diagnostic biomarkers of MetS for a different subset of PCOS.


The impact of urbanization and population density on childhood Plasmodium falciparum parasite prevalence rates in Africa.
Although malaria has been traditionally regarded as less of a problem in urban areas compared to neighbouring rural areas, the risk of malaria infection continues to exist in densely populated, urban areas of Africa. Despite the recognition that urbanization influences the epidemiology of malaria, there is little consensus on urbanization relevant for malaria parasite mapping. Previous studies examining the relationship between urbanization and malaria transmission have used products defining urbanization at global/continental scales developed in the early 2000s, that overestimate actual urban extents while the population estimates are over 15 years old and estimated at administrative unit level. This study sought to discriminate an urbanization definition that is most relevant for malaria parasite mapping using individual level malaria infection data obtained from nationally representative household-based surveys. Boosted regression tree (BRT) modelling was used to determine the effect of urbanization on malaria transmission and if this effect varied with urbanization definition. In addition, the most recent high resolution population distribution data was used to determine whether population density had significant effect on malaria parasite prevalence and if so, could population density replace urban classifications in modelling malaria transmission patterns. The risk of malaria infection was shown to decline from rural areas through peri-urban settlements to urban central areas. Population density was found to be an important predictor of malaria risk. The final boosted regression trees (BRT) model with urbanization and population density gave the best model fit (Tukey test p value <0.05) compared to the models with urbanization only. Given the challenges in uniformly classifying urban areas across different countries, population density provides a reliable metric to adjust for the patterns of malaria risk in densely populated urban areas. Future malaria risk models can, therefore, be improved by including both population density and urbanization which have both been shown to have significant impact on malaria risk in this study.


The benthic sea-silk-thread displacement of a sessile bivalve, Pinctada imbricata radiata (Leach, 1819) in the Arabian-Persian Gulf.
A number of molluscs within the Class Bivalvia are defined by their ability to secrete fine silk like threads known as byssus which are used to anchor themselves to solid substrates. With relatively few exceptions the majority of these species remain in a sedentary state throughout their life attached via their byssal threads. However, observations of adult Pinctada imbricata radiata pearl oysters made during this study revealed this species' ability to implement active movement. Byssal threads were secreted in a sequence of attachment and detachment phases, which resulted in the active displacement of the oyster. The oyster was observed, in the laboratory over a 9 day period, travelling a distance of 28cm in a horizontal path. After horizontal displacement, a vertical climbing phase was observed until the oyster reached the water surface at which point the byssus was discarded and the animal dropped, drifting in accordance with water current intensity. It is possible that these adaptations of byssal use are a result of environmentally induced evolutionary change within P. i. radiata.


Key role in ecosystem functioning of scavengers reliant on a single common species.
The importance of species richness in maintaining ecosystem function in the field remains unclear. Recent studies however have suggested that in some systems functionality is maintained by a few abundant species. Here we determine this relationship by quantifying the species responsible for a key ecosystem role, carcass removal by scavengers. We find that, unlike those within largely unaltered environments, the scavenger community within our highly altered system is dominated by a single species, the Carrion crow, despite the presence of a number of other scavenging species. Furthermore, we find no relationship between abundance of crows and carcass removal. However, the overall activity of crows predicts carcass biomass removal rate in an asymptotic manner, suggesting that a relatively low level of abundance and scavenging activity is required to maintain this component of ecosystem function.


The arginine decarboxylase pathways of host and pathogen interact to impact inflammatory pathways in the lung.
The arginine decarboxylase pathway, which converts arginine to agmatine, is present in both humans and most bacterial pathogens. In humans agmatine is a neurotransmitter with affinities towards α2-adrenoreceptors, serotonin receptors, and may inhibit nitric oxide synthase. In bacteria agmatine serves as a precursor to polyamine synthesis and was recently shown to enhance biofilm development in some strains of the respiratory pathogen Pseudomonas aeruginosa. We determined agmatine is at the center of a competing metabolism in the human lung during airways infections and is influenced by the metabolic phenotypes of the infecting pathogens. Ultra performance liquid chromatography with mass spectrometry detection was used to measure agmatine in human sputum samples from patients with cystic fibrosis, spent supernatant from clinical sputum isolates, and from bronchoalvelolar lavage fluid from mice infected with P. aeruginosa agmatine mutants. Agmatine in human sputum peaks during illness, decreased with treatment and is positively correlated with inflammatory cytokines. Analysis of the agmatine metabolic phenotype in clinical sputum isolates revealed most deplete agmatine when grown in its presence; however a minority appeared to generate large amounts of agmatine presumably driving sputum agmatine to high levels. Agmatine exposure to inflammatory cells and in mice demonstrated its role as a direct immune activator with effects on TNF-α production, likely through NF-κB activation. P. aeruginosa mutants for agmatine detection and metabolism were constructed and show the real-time evolution of host-derived agmatine in the airways during acute lung infection. These experiments also demonstrated pathogen agmatine production can upregulate the inflammatory response. As some clinical isolates have adapted to hypersecrete agmatine, these combined data would suggest agmatine is a novel target for immune modulation in the host-pathogen dynamic.


Effect of APOE ε4 allele on survival and fertility in an adverse environment.
The apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer's disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility. This rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018). Contrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.