Penalized preimage learning in kernel principal component analysis.
Finding the preimage of a feature vector in kernel principal component analysis (KPCA) is of crucial importance when KPCA is applied in some applications such as image preprocessing. Since the exact preimage of a feature vector in the kernel feature space, normally, does not exist in the input data space, an approximate preimage is learned and encouraging results have been reported in the last few years. However, it is still difficult to find a "good" estimation of preimage. As estimation of preimage in kernel methods is ill-posed, how to guide the preimage learning for a better estimation is important and still an open problem. To address this problem, a penalized strategy is developed in this paper, where some penalization terms are used to guide the preimage learning process. To develop an efficient penalized technique, we first propose a two-step general framework, in which a preimage is directly modeled by weighted combination of the observed samples and the weights are learned by some optimization function subject to certain constraints. Compared to existing techniques, this would also give advantages in directly turning preimage learning into the optimization of the combination weights. Under this framework, a penalized methodology is developed by integrating two types of penalizations. First, to ensure learning a well-defined preimage, of which each entry is not out of data range, convexity constraint is imposed for learning the combination weights. More insight effects of the convexity constraint are also explored. Second, a penalized function is integrated as part of the optimization function to guide the preimage learning process. Particularly, the weakly supervised penalty is proposed, discussed, and extensively evaluated along with Laplacian penalty and ridge penalty. It could be further interpreted that the learned preimage can preserve some kind of pointwise conditional mutual information. Finally, KPCA with preimage learning is applied on face image data sets in the aspects of facial expression normalization, face image denoising, recovery of missing parts from occlusion, and illumination normalization. Experimental results show that the proposed preimage learning algorithm obtains lower mean square error (MSE) and better visual quality of reconstructed images.


Yersinia pseudotuberculosis infections in goats and other animals diagnosed at the California Animal Health and Food Safety Laboratory System: 1990-2012.
Yersinia pseudotuberculosis is a recognized zoonotic food-borne pathogen; however, little is known about the ecology and epidemiology of diseases caused by the bacterium in California. The objective of the current study was to contribute to the knowledge of the diseases caused by Y. pseudotuberculosis in goats, the animal species most frequently reported with clinical yersiniosis to the California Animal Health and Food Safety Laboratory System, to better understand the epidemiology of this disease. A 23-year retrospective study was conducted to characterize the syndromes caused by the bacterium in goats and their temporospatial distribution, and to determine the number of cases in other animal species. Yersinia pseudotuberculosis-associated disease was diagnosed in 42 goats from 21 counties, with a strong seasonality in winter and spring. Most cases (88%) were observed within particular years (1999, 2004-2006, 2010-2011). The most frequently diagnosed syndrome was enteritis and/or typhlocolitis (64.3%), followed by abscessation (14.3%), abortion (11.9%), conjunctivitis (4.75%), and hepatitis (4.75%). Among other animal species, 59 cases were diagnosed in non-poultry avian species and 33 in mammals other than goats.


Apparent involvement of a multidrug transporter in the fluoroquinolone resistance of Streptococcus pneumoniae.
A Streptococcus pneumoniae strain selected for resistance to ethidium bromide demonstrated enhanced energy-dependent efflux of this toxic dye. Both the ethidium resistance and the ethidium efflux could be inhibited by the plant alkaloid reserpine. The ethidium-selected cells demonstrated cross-resistance to the fluoroquinolones norfloxacin and ciprofloxacin; this resistance could also be completely reversed by reserpine. Furthermore, reserpine potentiated the susceptibility of wild-type S. pneumoniae to fluoroquinolones and ethidium. The most plausible explanation for these results is that S. pneumoniae, like some other gram-positive bacteria, expresses a reserpine-sensitive multidrug transporter, which may play an important role in both intrinsic and acquired resistances of this pathogen to fluoroquinolone therapy.


Monitoring of gas composition in a laboratory biogas plant using cavity enhanced Raman spectroscopy.
Biogas production from organic raw materials is a highly complex biotechnological process. The responsible anaerobic fermentation process is difficult to measure due to its multi-stage nature. Still, optimization of biogas production and the development of robust and efficient process management strategies require continually updated information about the process. Hence, the development of a comprehensive sensor system with high temporal resolution is key to further advancement in biogas technology. Here, we demonstrate a gas sensor based on cavity enhanced Raman spectroscopy for biogas monitoring. Online detection of all gas components of a biogas mixture enables a comprehensive quantification. In addition, robust calibration routines facilitate the adaptation of the sensor for biogas monitoring. A simulated concentration course of a typical fermentation process with defined gas mixtures consisting of CH4, CO2, N2, O2 and H2 showed reliable results for all relevant biogas components for varying concentration ranges from ppm to 100 vol%. The response time of 5 seconds allows online detection and - as a consequence - real time information is obtained about the biogas composition. A laboratory biogas reactor was designed to operate biogas production on a miniaturized scale and analyze it using the Raman gas sensor. The developed sensor enables the observation of methane production throughout the first 24 h of the fermentation process. The obtained results show the suitability of cavity enhanced Raman spectroscopy as a gas sensor to monitor the entire process of biogas production. As this strategy would allow the process to be manipulated and optimized according to the current state, it is of great biotechnological interest.


Acne vulgaris, mental health and omega-3 fatty acids: a report of cases.
Acne vulgaris is a common skin condition, one that is associated with significant psychological disability. The psychological impairments in acne include higher rates of depression, anxiety, anger and suicidal thoughts. Despite a paucity of clinical research, patients with skin conditions and/or mental health disorders are frequent consumers of dietary supplements. An overlap may exist between nutrients that potentially have both anti-acne and mood regulating properties; examples include omega-3 fatty acids from fish oil, chromium, zinc and selenium. Here we report on five cases of acne treated with eicosapentaenoic acid and antioxidant nutrients. Self-administration of these nutrients may have improved inflammatory acne lesions and global aspects of well-being; the observations suggest a need for controlled trials.


A Novel Ferrocenyl Naphthoquinone Fused Crown Ether as a Multisensor for Water Determination in Acetonitrile and Selective Cation Binding.
A multisensor which is based on a novel multifunctional triad molecule, ferrocenyl naphthoquinone fused crown ether (Fc-cnq) bearing ferrocene, quinone, and crown ether functional groups together, was synthesized and characterized in this study. Sensing performance of a trace amount of water and the selective cation binding capabilities of this multisensor were carried out by the electrochemical, spectroelectrochemical, and spectrophotometric titration techniques in acetonitrile (CH3CN). It was shown that the potential separation (E((Fc))1/2 - E((2))1/2) between the second reduction of naphthoquinone and the oxidation processes of ferrocene in the triad molecule Fc-cnq was proportional to the amount of water due to the hydrogen-bonding interactions between water and the doubly reduced species (Fc-cnq(2-)). This property enabled Fc-cnq to detect the trace amount of water in CH3CN. The half-wave potential (E((Fc))1/2) of the ferrocene in Fc-cnq was used as an internal reference potential, and it defined the accuracy of the detection. In addition, by using the UV-vis spectrophotometric titration technique in CH3CN, it was also shown that the Fc-cnq multisensor could bind Ba(2+) and Ca(2+) cations selectively. We proposed that the intramolecular charge-transfer (CT) transition which occurred between the donor ferrocene and the acceptor naphthoquinone was the principle mechanism for the selective binding property of this multisensor. Quantum chemical calculations were also performed to investigate optical and electronic properties of the Fc-cnq molecule.


Management of the infant born to a mother infected with human immunodeficiency virus type 1 (HIV-1): current concepts.
Despite the use of highly active antiretroviral therapy (HAART) and the success of protocol PACTG-076 in decreasing perinatal transmission of HIV infection in many industrialized countries, a total of 5,600,000 new cases of HIV infection were diagnosed worldwide in 1999. Of those cases, more than 10% are children under 15 years of age. The vast majority of pediatric HIV infection is due to perinatal transmission. More than 95% of HIV-infected people live in the developing world. Different studies are currently being conducted with modifications of the original PACTG-076, especially shorter courses of zidovudine (ZDV), combinations of antiretrovirals (ZDV and 3TC), or comparison of a modified version of the standard ZDV course vs. a single dose of nevirapine for the mother intrapartum and also for the newborn. The results of these studies may provide more affordable, alternative regimens to prevent maternal-to-child HIV-1 transmission for developing countries than the PACTG-076 protocol. It is very important that physicians and physician extenders (nurse practitioners and physician assistants) caring for infants born to HIV-infected mothers have an understanding of the pathophysiology of vertical HIV-1 infection transmission. They should be familiar with the conditions associated with an increased risk of transmission, interventions available to decrease this risk, current medications, and laboratory resources.


[Reaction kinetics investigation of NVP in HPDLC gratings].
In order to get the HPDLC grating with high diffraction efficiency and perfect surface morphology, NVP was added into the reaction system of fabricating gratings and then the influence of NVP on the reaction kinetics of HPDLC was described. The analysis showed that NVP significantly increased the rate of polymerization in HPDLC photopolymerization, and as the highly cross-linked polymer network forms, the small mono-vinyl NVP appeared to react preferentially with double bonds inthe reaction system, facilitating additional conversion of pendant double bonds otherwise trapped in the polymer network. Furthermore, NVP also enhanced the degree of phase separation and got perfect surface morphology as well as higher refractive index modulation. So, the diffraction efficiency of HPDLC gratings was remarkably improved. However, the surface morphology and diffraction efficiency of HPDLC gratings would be worse when the concentration of NVP was too high. In a word, the addition of NVP could significantly increase the polymerization rate and reaction extent of reaction monomer and ultimately get the HPDLC grating with high diffraction efficiency (96.36%) and perfect surface morphology.


Patient safety, resident education and resident well-being following implementation of the 2003 ACGME duty hour rules.
The ACGME-released revisions to the 2003 duty hour standards. To review the impact of the 2003 duty hour reform as it pertains to resident and patient outcomes. Medline (1989-May 2010), Embase (1989-June 2010), bibliographies, pertinent reviews, and meeting abstracts. We included studies examining the relationship between the pre- and post-2003 time periods and patient outcomes (mortality, complications, errors), resident education (standardized test scores, clinical experience), and well-being (as measured by the Maslach Burnout Inventory). We excluded non-US studies. One rater used structured data collection forms to abstract data on study design, quality, and outcomes. We synthesized the literature qualitatively and included a meta-analysis of patient mortality. Of 5,345 studies identified, 60 met eligibility criteria. Twenty-eight studies included an objective outcome related to patients; 10 assessed standardized resident examination scores; 26 assessed resident operative experience. Eight assessed resident burnout. Meta-analysis of the mortality studies revealed a significant improvement in mortality in the post-2003 time period with a pooled odds ratio (OR) of 0.9 (95% CI: 0.84, 0.95). These results were significant for medical (OR 0.91; 95% CI: 0.85, 0.98) and surgical patients (OR 0.86; 95% CI: 0.75, 0.97). However, significant heterogeneity was present (I(2) 83%). Patient complications were more nuanced. Some increased in frequency; others decreased. Outcomes for resident operative experience and standardized knowledge tests varied substantially across studies. Resident well-being improved in most studies. Most studies were observational. Not all studies of mortality provided enough information to be included in the meta-analysis. We used unadjusted odds ratios in the meta-analysis; statistical heterogeneity was substantial. Publication bias is possible. Since 2003, patient mortality appears to have improved, although this could be due to secular trends. Resident well-being appears improved. Change in resident educational experience is less clear.


Body mass index and its association with socioeconomic and behavioral variables among socioeconomically heterogeneous populations of Andhra Pradesh, India.
The nature and extent of relationship between socioeconomic and behavioral variables and body mass index [BMI = weight (kg)/height (m)2] is studied in a sample of 1119 individuals (456 males and 663 females), aged 18 to 75 years, drawn from socioeconomically diverse populations from southern Andhra Pradesh, India. These populations are categorized into four groups, with graded lifestyles toward urbanization. The BMI of the participants ranged from 12.6 to 35.1 in males and from 12.3 to 34.2 in females. There is an increasing trend in mean BMI until about 50 years, followed by a decline, indicating nonlinear nature of age effects. Mean BMI also increases with better socioeconomic status of the constituent groups and with decreased physical activity level. A trend of a decrease in the proportion of individuals with chronic energy deficiency and an increase in the proportion of obese individuals is also seen from the traditional Yerukala tribe (group 1) to the urbanized group 4, from the lower to the higher income categories, and from heavy to light physical activity types. Smokers show a greater proportion of obese cases compared with nonsmokers. The prevalence of obesity (BMI > or = 25) is 6.6% in males and 10% in females. The results of the analysis of variance suggest that three of the four socioeconomic and behavioral variables (except smoking) show significant effects on age-adjusted BMI, and the R2 suggests that these variables explain 27.4% of variation in males and 17% in females. Although income explains the largest amount of variation (24%) in males, followed by physical activity and group affiliation, in females group affiliation (12.5%), followed closely by income, accounted for most of the variation. Inclusion of age in the model improved explanatory power by 5-7%. The positive association between socioeconomic status and BMI observed in the present study is qualitatively different from the negative association that characterizes contemporary Western populations.


Genetic basis of adult migration timing in anadromous steelhead discovered through multivariate association testing.
Migration traits are presumed to be complex and to involve interaction among multiple genes. We used both univariate analyses and a multivariate random forest (RF) machine learning algorithm to conduct association mapping of 15 239 single nucleotide polymorphisms (SNPs) for adult migration-timing phenotype in steelhead (Oncorhynchus mykiss). Our study focused on a model natural population of steelhead that exhibits two distinct migration-timing life histories with high levels of admixture in nature. Neutral divergence was limited between fish exhibiting summer- and winter-run migration owing to high levels of interbreeding, but a univariate mixed linear model found three SNPs from a major effect gene to be significantly associated with migration timing (p < 0.000005) that explained 46% of trait variation. Alignment to the annotated Salmo salar genome provided evidence that all three SNPs localize within a 46 kb region overlapping GREB1-like (an oestrogen target gene) on chromosome Ssa03. Additionally, multivariate analyses with RF identified that these three SNPs plus 15 additional SNPs explained up to 60% of trait variation. These candidate SNPs may provide the ability to predict adult migration timing of steelhead to facilitate conservation management of this species, and this study demonstrates the benefit of multivariate analyses for association studies.


Adaptive divergence in embryonic thermal plasticity among Atlantic salmon populations.
In the context of global changes, the long-term viability of populations of endangered ectotherms may depend on their adaptive potential and ability to cope with temperature variations. We measured responses of Atlantic salmon embryos from four populations to temperature variations and used a QST -FST approach to study the adaptive divergence among these populations. Embryos were reared under two experimental conditions: a low temperature regime at 4 °C until eyed-stage and 10 °C until the end of embryonic development and a high temperature regime with a constant temperature of 10 °C throughout embryonic development. Significant variations among populations and population × temperature interactions were observed for embryo survival, incubation time and length. QST was higher than FST in all but one comparison suggesting an important effect of divergent selection. QST was also higher under the high-temperature treatment than at low temperature for length and survival due to a higher variance among populations under the stressful warmer treatment. Interestingly, heritability was lower for survival under high temperature in relation to a lower additive genetic variance under that treatment. Overall, these results reveal an adaptive divergence in thermal plasticity in embryonic life stages of Atlantic salmon suggesting that salmon populations may differentially respond to temperature variations induced by climate change. These results also suggest that changes in temperature may alter not only the adaptive potential of natural populations but also the selection regimes among them.


Imagery and interpretations in social phobia: support for the combined cognitive biases hypothesis.
Cognitive-behavioral models of clinical problems typically postulate a role for the combined effects of different cognitive biases in the maintenance of a given disorder. It is striking therefore that research has tended to examine cognitive biases in isolation rather than assessing how they work together to maintain psychological dysfunction. The combined cognitive biases hypothesis presented here suggests that cognitive biases influence each another and can interact to maintain a given disorder. Furthermore, it is proposed that the combined effects of cognitive biases may have a greater impact on sustaining a given disorder than if the biases operated in isolation. The combined cognitive biases hypothesis is examined in relation to imagery and interpretation in social phobia. Individuals with social phobia experience negative images of themselves performing poorly in social situations, and they also interpret external social information in a less positive way than those without social anxiety. Evidence of a reciprocal relationship between imagery and interpretations is presented, and the mechanisms underlying the combined effects are discussed. Clinical implications and the potential utility of examining the combined influence of other cognitive biases are highlighted.


Anaphylaxis in Children: Experience of 485 Episodes in 1,272,482 Patient Attendances at a Tertiary Paediatric Emergency Department from 2007 to 2014.
Introduction: Anaphylaxis is a predominantly childhood disease. Most of the literature on anaphylaxis has emerged from Western countries. This study aimed to describe the incidence, triggers and clinical presentation of anaphylaxis among children in Singapore, look for predictors for anaphylaxis with severe outcomes, and study the incidence of biphasic reactions. Materials and Methods: We retrospectively reviewed records of children presenting with anaphylaxis to our paediatric emergency department from 1 January 2007 to 31 December 2014. Results: We identified 485 cases of anaphylaxis in 445 patients. Cutaneous symptoms (urticarial/angio-oedema) were the most common across all age groups (481 cases, 99%), followed by respiratory (412, 85%), gastrointestinal (118, 24%) and cardiovascular (35, 7.2%) symptoms. Central nervous system symptoms (drowsiness/ irritability) were rare across all age groups (11, 2.2%). Food was identified as the most common trigger across all age groups (45% to 63%). Seafood was the most common food trigger (57, 25%). A total of 420 (86.6%) children were treated with adrenaline, 451 (93%) received steroids and 411 (85%) received antihistamines. Sixty-three (13%) children fulfilled the criteria of severe anaphylaxis. There was no statistically significant association between severe anaphylaxis and the type of trigger (P = 0.851), nor an overall past history of atopy (P = 0.428). The only independent predictor for severe anaphylaxis was a previous drug allergy (P = 0.016). A very low prevalence of biphasic reactions (0.6% of study population) was noted in our study. Conclusion: We described the presentation and management of anaphylaxis in the Singapore population. A history of drug allergy is associated with severe presentation. Biphasic reactions are rare in our population.


Acupuncture and women's health: an overview of the role of acupuncture and its clinical management in women's reproductive health.
Acupuncture and other modalities of Chinese/East Asian medicine have been used to treat women's health for many centuries. Gynecology specialties focus particularly on menstrual and reproductive disorders. Both the adoption of the use of acupuncture outside Asia, and the incorporation of scientific analysis in Asia have challenged biomedical conceptions of what can be achieved with this treatment method. The scale of research activity in relation to acupuncture and women's health has increased over the last 20 years. This review aims to explore the research evidence in relation to acupuncture use for women's reproductive disorders, focusing on both clinical findings and experimental research on acupuncture's mechanisms of action in relation to women's health. A narrative literature search was undertaken using searches of electronic databases and manual searches of journals and textbooks. The search included all literature published prior to June 2013. The literature was assessed as to the nature of the study it was reporting and findings synthesized into a commentary. For acupuncture's mechanism of action the search resulted in 114 relevant documents; in relation to clinical reports on the use of acupuncture for women's health 204 documents were found and assessed. There is preliminary data indicating acupuncture may improve menstrual health and coping for women experiencing delays falling pregnant. There is experimental data showing that acupuncture can influence female reproductive functioning, although the actual mechanisms involved are not yet clarified. Further well-conducted clinical research would benefit our understanding of the usefulness of acupuncture to women's health.


Two novel type 2N von Willebrand disease-causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factor.
Two novel mutations, a T-to-C transition at nucleotide 2612 and a T-to-G transversion at nucleotide 3923 of the von Willebrand factor (vWF) complementary DNA, were detected by analysis of the vWF gene in DNA from members of 2 families with atypical von Willebrand disease. The T2612C transition predicts substitution of cysteine by arginine at amino acid position 788 (C788R), and the T3923G transversion predicts substitution of cysteine by glycine at position 1225 (C1225G) of pre-pro-vWF. The patients homozygous for the C788R and C1225G mutations both had a partial vWF deficiency (0. 18 IU/mL and 0.07 IU/mL vWF antigen, respectively); vWF in plasma from patients homozygous for either the C788R or the C1225G mutation failed to bind factor VIII and lacked high molecular weight multimers. Recombinant (r) vWF molecules having the C788R or C1225G mutation were expressed in COS-7 cells. Both rvWF C788R and rvWF C1225G exhibited significantly impaired secretion and failed to bind factor VIII. Recombinant vWF C788R in COS-7 culture medium showed a severe reduction in high molecular weight multimers, whereas rvWF C1225G showed a very mild reduction in high molecular weight multimers when compared with wild-type rvWF. (Blood. 2000;95:2000-2007)


Interprofessional Education and Practice Guide No. 3: Evaluating interprofessional education.
We have witnessed an ongoing increase in the publication of evaluation work aimed at measuring the processes and outcomes related to a range of interprofessional education (IPE) activities and initiatives. Systematic reviews of IPE have, however, suggested that while the quality of evaluation studies is improving, there continues to be a number of empirical weaknesses with this work. In an effort to enhance the quality of IPE evaluation studies, this guide provides a series of ideas and suggestions about how to undertake a robust evaluation of an IPE event. The guide presents a series of key lessons for colleagues to help them undertake a good quality IPE evaluation, covering a range of methodological, practical and ethical issues. These include: the formation of evaluation questions, use of evaluation models and theoretical perspectives, advice about the selection of qualitative, quantitative and mixed methods evaluation designs, managing evaluation resources, and ideas about disseminating evaluation results to the broader IPE community. It is anticipated that this guide will assist IPE colleagues in undertaking high-quality evaluation in order to provide valuable evidence for different stakeholders, and also help inform the scholarly knowledge for the interprofessional field.


The applications of model-based geostatistics in helminth epidemiology and control.
Funding agencies are dedicating substantial resources to tackle helminth infections. Reliable maps of the distribution of helminth infection can assist these efforts by targeting control resources to areas of greatest need. The ability to define the distribution of infection at regional, national and subnational levels has been enhanced greatly by the increased availability of good quality survey data and the use of model-based geostatistics (MBG), enabling spatial prediction in unsampled locations. A major advantage of MBG risk mapping approaches is that they provide a flexible statistical platform for handling and representing different sources of uncertainty, providing plausible and robust information on the spatial distribution of infections to inform the design and implementation of control programmes. Focussing on schistosomiasis and soil-transmitted helminthiasis, with additional examples for lymphatic filariasis and onchocerciasis, we review the progress made to date with the application of MBG tools in large-scale, real-world control programmes and propose a general framework for their application to inform integrative spatial planning of helminth disease control programmes.


Evaluation of the total number of myenteric neurons in the developing chicken gut using cuprolinic blue histochemical staining and neurofilament immunocytochemistry.
The aim of this study was to find an improved method with which to stain the entire population of myenteric neurons in the different segments of the developing chicken intestine. Histochemical staining with cuprolinic blue (quinolinic phthalocyanine) and immunostaining against neurofilament (NF) were performed on whole mounts prepared from intestinal segments of embryonic (day 19 of incubation) and hatched (1, 2, 4 and 7 days after hatching) chickens. Double labelling was performed to evaluate to what extent the two markers visualise the same nerve cell population. Cuprolinic blue stained neuronal somata highly selectively, whereas processes and glia cells were poorly labelled. The cuprolinic blue-positive neurons were uniform in shape. NF immunostaining revealed a morphologically highly variable neuron population. Double labelling with cuprolinic blue and NF resulted in an intensification of both stainings, allowing an accurate morphological classification of NF-stained myenteric neurons. Data obtained from the counting of cuprolinic blue-positive neurons were subjected to two-way ANOVA and the Tukey probe. The densities of ganglia and neurons were found to decrease, and the mean number of neurons per myenteric ganglion to increase, with different dynamics along the longitudinal axis of the gut during the examined time span. The variances in the number of NF-positive neurons were not homogeneous, and the data were therefore not suitable for ANOVA. Accordingly, only semiquantitative conclusions could be drawn.


Cells involved in the middle ear defense system.
Despite the high incidence and prevalence of otitis media, its pathogenesis is not thoroughly understood. In the last decade, many efforts have been made to provide a better understanding, and abundant information has become available. At the same time the field of immunology has advanced at an extremely rapid pace. We have followed the gradual cellular events in the defense reaction of the middle ear, utilizing eustachian tube obstruction to induce otitis. Seventy-five cats were divided in groups and sacrificed at intervals between one day and six months, and their temporal bones were studied. During an initial phase of inflammation, polymorphonuclears appear at three days in connective tissue; at the same time active fibroblasts synthesize tropocollagen and ground substance while epithelial cells secrete mucus and lysozymes. These cells, together with those involved in the mucociliary transport system and a patent functional eustachian tube, constitute the nonspecific system of defense. The transition cells are the macrophages which appear at one week to interact with T and B cells to produce the specific immune response. Plasma cells appear at two weeks to peak at one month with synthesis of immunoglobulins A, G and M. A secretory immune system is observed. At three and six months, lymphocytes are the predominant cells and occasional accumulations of mononuclears are observed. The reaction involves the entire middle ear, including mucoperiosteum, middle ear muscles and round window membrane. We believe that a better understanding of the middle ear defense system will lead in time to a practical clinical assessment of the immunological status during the evolution of each particular process or disease involving the middle ear, and a more rational approach to the treatment and, hopefully, prevention of chronic ear disease.


What Is the Timing of General Health Adverse Events That Occur After Total Joint Arthroplasty?
Despite extensive research regarding risk factors for adverse events after total joint arthroplasty (TJA), there are few publications describing the timing at which such adverse events occur. (1) On which postoperative day do certain adverse events occur? (2) What adverse events occur earlier after TKA than after THA? (3) For each adverse event, what proportion occurred after hospital discharge? We screened the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) to identify all patients undergoing primary THA and primary TKA between 2005 and 2013, resulting in a study population of 124,657 patients evaluated as part of this retrospective database analysis. For each of eight different adverse events, the median postoperative day of diagnosis, interquartile range for day of diagnosis, and middle 80% for day of diagnosis were determined. Multivariate Cox proportional hazards modeling was used to test whether there is a difference of timing for each adverse event as stratified by TKA or THA. The proportion of adverse events occurring after versus before discharge was also calculated. The median day of diagnosis (and interquartile range; middle 80%) for stroke was 2 (1-10; 1-19), myocardial infarction 3 (2-6; 1-15), pulmonary embolism 3 (2-7; 1-19), pneumonia 4 (2-9; 2-17), deep vein thrombosis 6 (3-14; 2-23), urinary tract infection 8 (3-16; 2-24), sepsis 10 (5-19; 2-24), and surgical site infection 17 (11-23; 6-28). For the later occurring adverse events (surgical site infection, sepsis), the rate of occurrence remained high at the end of the 30-day postoperative period. Timing was earlier in patients undergoing TKA for pulmonary embolism (day 3 [interquartile range 2-6] versus 5 [3-17], p < 0.001) and deep vein thrombosis (day 5 [2-11] versus 13 [6-22], p < 0.001). The proportion of events occurring after discharge for myocardial infarction was 97 of 283 (34%), stroke 42 of 118 (36%), pulmonary embolism 223 of 625 (36%), pneumonia 171 of 426 (40%), deep vein thrombosis 576 of 956 (60%), urinary tract infection 958 of 1406 (68%), sepsis 284 of 416 (68%), and surgical site infection 1147 of 1212 (95%). As lengths of hospital stay after TJA continue to decrease, our findings suggest that caution is in order because several acute and immediately life-threatening findings, including myocardial infarction and pulmonary embolism, might occur after discharge. Furthermore, the timing of surgical site infection and sepsis suggests that even the 30-day followup afforded by the ACS-NSQIP may not be sufficient to study the latest occurring adverse events. Additionally, both pulmonary embolism and deep vein thrombosis tend to occur earlier after TKA than THA, and this should guide clinical surveillance efforts in patients undergoing those procedures. These findings also indicate that inpatient-only databases (such as the Nationwide Inpatient Sample) may fail to capture a very large proportion of postoperative adverse events, weakening the conclusions of many published studies using those databases. Level III, therapeutic study.


The community structure of functional brain networks exhibits scale-specific patterns of inter- and intra-subject variability.
The network organization of the human brain varies across individuals, changes with development and aging, and differs in disease. Discovering the major dimensions along which this variability is displayed remains a central goal of both neuroscience and clinical medicine. Such efforts can be usefully framed within the context of the brain's modular network organization, which can be assessed quantitatively using computational techniques and extended for the purposes of multi-scale analysis, dimensionality reduction, and biomarker generation. Although the concept of modularity and its utility in describing brain network organization is clear, principled methods for comparing multi-scale communities across individuals and time are surprisingly lacking. Here, we present a method that uses multi-layer networks to simultaneously discover the modular structure of many subjects at once. This method builds upon the well-known multi-layer modularity maximization technique, and provides a viable and principled tool for studying differences in network communities across individuals and within individuals across time. We test this method on two datasets and identify consistent patterns of inter-subject community variability, demonstrating that this variability - which would be undetectable using past approaches - is associated with measures of cognitive performance. In general, the multi-layer, multi-subject framework proposed here represents an advance over current approaches by straighforwardly mapping community assignments across subjects and holds promise for future investigations of inter-subject community variation in clinical populations or as a result of task constraints.


Optimal management of pulmonary arterial hypertension: prognostic indicators to determine treatment course.
Pulmonary arterial hypertension (PAH) is a rapidly progressive pulmonary vascular disease with a multifactorial etiopathogenesis that can result in right-sided heart failure and death. A number of studies indicate that an early therapeutic intervention yields better results on disease progression as compared to delayed treatment. In this review, we will analyze treatment strategies that may be used for monitoring disease progression and for guiding treatment decisions. Several factors (ie, symptoms, functional class, exercise capacity as assessed by a walking test and cardiopulmonary stress testing, hemodynamic parameters, cardiac magnetic resonance imaging, and plasma levels of biochemical markers) have been prognostic of survival. These indicators may be used both at the time of diagnosis and during treatment follow-up. No resolutive therapy is currently available for PAH; however, in the last decade, the advent of specific pharmacological treatments has given new hope to patients suffering from this debilitating disease with a poor prognosis. Combination drug therapies offer increased benefits over monotherapy, and current guidelines recommend a sequential "add on" design approach for patients in functional class II-IV. The goal-oriented "treat to target" therapy sets the timing for treatment escalation in case of inadequate response to currently known prognostic indicators. To date, further longitudinal studies should be urgently conducted to identify new goals that may improve therapeutic strategies in order to optimize personalized treatment in PAH patients.


Early group bias in the Faroe Islands: Cultural variation in children's group-based reasoning.
Recent developmental research demonstrates that group bias emerges early in childhood. However, little is known about the extent to which bias in minimal (i.e., arbitrarily assigned) groups varies with children's environment and experience, and whether such bias is universal across cultures. In this study, the development of group bias was investigated using a minimal groups paradigm with 46 four- to six-year-olds from the Faroe Islands. Children observed in-group and out-group members exhibiting varying degrees of prosocial behaviour (egalitarian or stingy sharing). Children did not prefer their in-group in the pretest, but a pro-in-group and anti-out-group sentiment emerged in both conditions in the posttest. Faroese children's response patterns differ from those of American children [Schug, M. G., Shusterman, A., Barth, H., & Patalano, A. L. (2013). Minimal-group membership influences children's responses to novel experience with group members. Developmental Science, 16(1), 47-55], suggesting that intergroup bias shows cultural variation even in a minimal groups context.


Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism.
Oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. We have recently shown that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity. Here we report the influence of transdermal estradiol therapy on the coagulation profile of men with advanced prostate cancer. A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated using transdermal estradiol patches and the coagulation profile was assessed before and during 12 months therapy. Activation of coagulation was assessed by assaying the levels of activated factor VII (VIIa), activated factor XII (XIIa), prothrombin fragments 1 and 2 (F1 + 2), thrombin-antithrombin III (TAT III) complex and fibrinogen. Inhibition of the coagulation cascade was assayed by protein C, protein S and activated protein C resistance (APC-R). Fibrinolytic activity was determined by assaying tissue plasminogen activator (TPA) and plasminogen activation inhibitor type 1 (PAI-1). D-Dimer levels assessed both coagulation and fibrinolytic (thrombophilic) activity. Venous Duplex, color Doppler ultrasound and photoplethysmography were used to assess for thrombosis. Levels of VIIa and XIIa were unaffected by transdermal estradiol therapy. Although levels of TAT III were increased in some patients at 12 months, the increase was markedly less than that observed historically with equivalent doses of oral estrogens. Levels of the inhibitory and fibrinolytic factors including protein C, protein S, APC-R, TPA and PAI-1 remained stable. Reductions in F1+F2, fibrinogen and D-Dimer levels represented a normalization from increased levels to the physiological range. These results suggest that transdermal estradiol reduces thrombophilic activation in men with advanced prostate cancer, and protects against the risk of thrombosis.


Polypyrrole-Mo3S13: An Efficient Sorbent for the Capture of Hg2+ and Highly Selective Extraction of Ag+ over Cu2.
The new material Polypyrrole-Mo3S13 (abbr. Mo3S13-Ppy) is a new material prepared by ion-exchange between Ppy-NO3 and (NH4)2Mo3S13. The Mo3S13-Ppy was designed to exhibit strong selectivity for Ag+ and highly toxic Hg2+ in mixtures with other ions. It displays an apparent selectivity ranking of Hg2+ > Ag+ ≥ Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+. The strong affinity of Mo3S13-Ppy for Ag+ and Hg2+ was confirmed with extremely high distribution coefficients (Kd) (∼107 mL/g) and remarkable removal efficiencies (>99.99%), resulting in <1 ppb concentrations of these ions. Furthermore, Mo3S13-Ppy achieved excellent separation selectivity for Ag+ from Cu2+ (even at a high Cu2+/Ag+ ratio, the molar ratio of 867 and mass ratio of 500) because of the special structure of Mo3S132- and its component Mo4+ and (S2)2-. This is promising for the direct extraction of low-grade silver from copper-rich minerals. The maximum Ag uptake capacity of 408 mg/g is redox-based and surprisingly involves the deposition of large, millimeter sized, metallic silver (Ag0) crystals on the surface of Mo3S13-Ppy.


Does a single dose of intravenous dexamethasone reduce Symptoms in Emergency department patients with low Back pain and RAdiculopathy (SEBRA)? A double-blind randomised controlled trial.
To assess the effect of a single dose of intravenous dexamethasone in addition to routine treatment on visual analogue scale (VAS) pain scores at 24 h in emergency department (ED) patients with low back pain with radiculopathy (LBPR). Double-blind randomised controlled trial of 58 adult ED patients with LBPR, conducted in one tertiary and one urban ED. The intervention was 8 mg of intravenous dexamethasone (or placebo) in addition to current routine care. The primary outcome was the change in VAS pain scores between presentation and 24 h. Secondary outcomes included VAS pain scores at 6 weeks, ED length of stay (EDLOS), straight leg raise (SLR) angles and Oswestry functional scores. Patients treated with dexamethasone had a 1.86 point (95% CI 0.31 to 3.42, p=0.019) greater reduction in VAS pain scores at 24 h than placebo (dexamethasone: -2.63 (95% CI -3.63 to -1.63) versus placebo: -0.77 (95% CI -2.04 to 0.51)). At 6 weeks, both groups had similar significant and sustained decrease in VAS scores compared with baseline. Patients receiving dexamethasone had a significantly shorter EDLOS (median: 3.5 h vs 18.8 h, p=0.049) and improved SLR angle at discharge (14.7°, p=0.040). There was no difference in functional scores. In patients with LBPR, a single dose of intravenous dexamethasone in addition to routine management improved VAS pain scores at 24 h, but this effect was not statistically significant at 6 weeks. Dexamethasone may reduce EDLOS and can be considered as a safe adjunct to standard treatment. ACTRN12611001020976.


Acupuncture in clinical neurology.
A majority of people in the United States use alternative or complementary therapy at some point in their lives, and acupuncture is among the most frequently used modalities. Many United States medical schools offer courses in alternative medicine, and a growing number of insurers offer coverage for alternative therapies. This paper critically reviews our current knowledge about the safety and efficacy of acupuncture for neurologic conditions. Acupuncture is a safe procedure when performed by trained professionals. Complications from acupuncture are rare and mainly related to negligence of sterile technique. Studies of the therapeutic value of acupuncture are fraught with challenging methodologic problems, including the choice of a placebo, a suitable control treatment, and the technique of stimulation applied. Clinical trials of the use of acupuncture for pain syndromes (headache, neck, and back pain), stroke rehabilitation, Parkinson's disease, multiple sclerosis, and substance abuse are reviewed. Based on the current literature, no definitive recommendation can be made regarding the efficacy of acupuncture for common pain syndromes including headache, and neck and back pain. Better quality clinical trials fail to demonstrate efficacy for the use of acupuncture as part of a rehabilitation program following stroke or as a treatment for drug addiction. Acupuncture may have a role in the treatment of sleep disturbance associated with Parkinson's disease but was not efficacious for the primary symptoms of either Parkinson's disease or multiple sclerosis. In light of increasing public interest and use of alternative therapies, this review may be helpful in promoting more discussion between patients and physicians about the use of acupuncture.


Isavuconazole for the treatment of patients with invasive fungal diseases involving the central nervous system.
The incidence of invasive fungal diseases (IFDs) with central nervous system (CNS) involvement is increasing due to the rising numbers of immunocompromised individuals, such as patients receiving chemotherapy, transplantation procedures, or immune-modulating therapies. CNS IFDs cause significant morbidity and mortality, and treatments are complicated by difficulties in identifying fungal pathogens and delivering antifungal agents to the CNS. Isavuconazole is a novel triazole with broad-spectrum activity that has shown good blood-brain barrier penetration in animal models. We present a retrospective analysis of isavuconazole in the treatment of patients with CNS IFDs and who either participated in the phase III VITAL or SECURE clinical trials, or were included in a named-patient program. A total of 36 patients were identified, including 27 patients from the clinical trials. Of these patients, 47.2% had hematologic malignancies, while 13.9% had no identifiable underlying conditions. Mucorales, Aspergillus species, and Cryptococcus species accounted for 30.6%, 22.2%, and 13.9% of infections, respectively. The overall survival rate was 80.6% at day 42 and 69.4% at day 84, and at the end of treatment, a complete or partial clinical response was achieved in 58.3% of patients. Isavuconazole exhibited clinical activity in a variety of CNS IFDs.


Correlations between a dedicated orthopaedic complications grading system and early adverse outcomes in joint arthroplasty.
Reliable classification of postoperative complications is important for quality improvement efforts. In 2014, The Knee Society proposed a grading system for complications after TKA, but to our knowledge, a relationship between complication grades and surgical outcomes has not yet been established. We attempted to determine (1) whether an association exists between complication grade and early adverse outcomes after TKA and THA, and (2) what proportion of the variability in complications could be associated with the classification grade (a metric of potential predictive value of the grading schema). A total of 210 primary THAs and TKAs in 201 patients performed at one center from January 1, 2011 to December 31, 2011 were reviewed; of those, 188 patients (94%; 197 procedures) had complete 90-day postoperative data and were evaluated retrospectively for postoperative complications. We defined and graded complications according to the classification system proposed by Iorio et al. and The Knee Society. Early adverse outcomes assessed included length of hospital stay and unplanned readmissions or reoperations. A total of 254 complications were documented in 135 patients (137 procedures); 53 patients (60 procedures) had no complications. Bivariate analyses were conducted to identify associations between complication grade and early adverse outcomes and patient variables; analyses considered patient variables including age, sex, status as a state prisoner (yes or no), American Society of Anesthesiologists score, BMI, and procedure (TKA or THA). Multiple regression and logistic regression analyses were conducted to determine the association between complication grade and early adverse outcomes (length of stay [LOS] and unplanned readmission or reoperations) adjusted for confounding patient variables. Alpha was set at 0.05 for two-sided tests. Maximum complication grade (range, from 0-4) was associated with a longer LOS (for each point increase of maximum grade, LOS increased 0.105 ± 0.024 days, p < 0.001) and more readmissions or reoperations (odds ratio [OR], 3.79; 95% CI, 1.91-7.54; p < 0.001). Total grade (range, 0-22) also was associated with increased LOS (for each point increase of total grade, LOS increased 0.032 ± 0.006 days, p < 0.001) and increased readmissions or reoperations (OR, 1.34; 95% CI, 1.18-1.53; p < 0.001). Total grade could account for 38% of the variation in LOS and readmissions or reoperations (C-statistic = 0.94; 95% CI, 0.90-0.98); whereas maximum complication grade could account for 35% of the variation in LOS and readmissions or reoperations (C-statistic = 0.35; 95% CI, 0.88-0.96). Thus, we found total grade to be a slightly better predictor of LOS and readmissions or reoperations than maximum grade. We found that the proposed grading system is applicable to TKA and THA in terms of documentation of complication severity and as an indicator of increased LOS and increased unplanned readmissions or reoperation rates. That total complication grade was a better predictor of LOS than maximum grade suggests that multiple complications of a lesser grade can be just as important as a single higher grade complication in terms of effect on outcomes.


Analysis of the Pro- and Anti-Inflammatory Cytokines Secreted by Adult Stem Cells during Differentiation.
Adipose-derived stromal/stem cells (ASCs) are adult stem cells that have the potential to differentiate into mesenchymal lineage cells. The abundance of ASCs in adipose tissue and easy accessibility with relatively little donor site morbidity make them attractive candidate cells for tissue engineering and regenerative medicine. However, the underlying inflammatory process that occurs during ASC differentiation into adipocytes and osteoblast has not been extensively investigated. ASCs cultured in osteogenic and adipogenic differentiation medium were characterized by oil red o staining and alizarin red staining, respectively. ASCs undergoing osteogenic and adipogenic differentiation were isolated on days 7, 14, and 21 and assessed by qRT-PCR for the expression of pro- and anti-inflammatory cytokines. ASCs undergoing osteogenic differentiation expressed a distinct panel of cytokines that differed from the cytokine profile of ASCs undergoing adipogenic differentiation at each of the time points analyzed. Mapping the cytokine expression profile during ASC differentiation will provide insight into the role of inflammation in this process and identify potential targets that may aid in enhancing osteogenic or adipogenic differentiation for the purposes of tissue engineering and regenerative medicine.


Brucella abortus as a potential vaccine candidate: induction of interleukin-12 secretion and enhanced B7.1 and B7.2 and intercellular adhesion molecule 1 surface expression in elutriated human monocytes stimulated by heat-inactivated B. abortus.
Development of a vaccine which is capable of generating a strong cellular immune response associated with gamma interferon (IFN-gamma) production and cytotoxic T-cell development requires that the immunogen be capable of inducing the secretion of interleukin-12 (IL-12), which is a pivotal factor for the differentiation of Th1 or Tc1 cells. We have previously shown that the heat-inactivated gram-negative bacterium Brucella abortus can induce IFN-gamma secretion by T cells. In the present study, we demonstrate that B. abortus and lipopolysaccharide (LPS) from B. abortus can induce IL-12 p40 mRNA expression and protein secretion by human elutriated monocytes (99% pure). p40 mRNA was detected within 4 h, and p40 protein could be measured at 24 h. This induction was abrogated by anti-CD14 monoclonal antibody, suggesting that monocytes recognize B. abortus via their receptor for LPS. The biological activity of IL-12 secreted by B. abortus-stimulated monocytes was demonstrated by its ability to upregulate IFN-gamma mRNA expression in T cells separated from monocytes and B. abortus by a transwell membrane. The B. abortus-induced IL-12 also enhanced NK cytolytic activity against K562 target cells. B. abortus was shown to rapidly increase the expression of the costimulatory molecules B7.1 and B7.2 and intercellular adhesion molecule 1 on human monocytes. Together, these data indicate that B. abortus can directly activate human monocytes and provide the cytokine milieu which would direct the immune response towards Th1-Tc1 differentiation.


Habituation and dishabituation during object play in kennel-housed dogs.
Domestic dogs are reported to show intense but transient neophilia towards novel objects. Here, we examine habituation and dishabituation to manipulable objects by kennel-housed dogs. Labrador retrievers (N = 16) were repeatedly presented with one toy for successive 30-s periods until interaction ceased. At this point (habituation), a different toy was presented that contrasted with the first in both colour and odour (since the dog's saliva would have accumulated on the first), colour alone, or odour alone. No effect of the type of contrast was detected in the number of presentations to habituation, the difference in duration of interaction between the first presentation of the first toy and the presentation of the second toy (recovery), or the duration of interaction with the second toy (dishabituation). Varying the time interval between successive presentations of the first toy up to habituation between 10 s and 10 min had no effect on the number of presentations to habituation, nor did it alter the extent of dishabituation. Varying the delay from habituation to presentation of the second toy, between 10 s and 15 min, affected neither the recovery nor the dishabituation. Overall, the study indicates that loss of interest in the object during object-orientated play in this species is due to habituation to the overall stimulus properties of the toy rather than to any single sensory modality and is also atypical in its insensitivity to the interval between presentations.


Molecular cloning and differential expression of the glucocorticoid receptorgene in the estuarine tapertail anchovy Coilia nasus.
To understand the regulation of the glucocorticoid receptor gene (Gcr) during loading and transport stress in fish, the Gcr gene of Coilia nasus was cloned. Gcr in C. nasus is expressed strongly in the liver and muscle, and less stronglyin the gills, brain, spleen, intestine, trunk kidney, and head kidney. Gcr expression in both the liver and muscle was increased by loading and transport stress. NaCl reduced the death rate caused by loading and transport stress, and the expression of Gcr in liver and muscle differed significantly between the NaCl and non-NaCl groups. To investigate whether the elevated Gcr transcripts were translated into protein, proteins extracted from the liver and muscle were analyzed. In both tissues, C. nasus GCR protein expression patterns paralleled those of Gcr mRNA during stress.


Solubilization and characterization of the pyrilamine-binding protein from cultured smooth muscle cells.
The cultured smooth muscle cell line DDT1MF-2 expresses a large number (9.7 x 10(6) receptors/cell) of functional histamine H1-type receptors [J. Cell. Physiol. 134:367-375 1988]. Two different binding assays, gel filtration and polyethylene glycol precipitation, indicated that the [3H]pyrilamine binding activity was solubilized by 1% digitonin with binding characteristics similar to those of intact cells. The solubilized proteins were then purified by sequential gel filtration, chromatofocusing, and reverse phase high pressure liquid chromatography. The calculated molecular weight of this purified pyrilamine-binding protein was 38-40 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. [3H]Pyrilamine binding to these 38-40-kDa proteins indicated a single class of binding site with a Kd of 288 nM, which is equivalent to that of intact cells and digitonin-solubilized proteins. The computer analysis Scatfit also indicated that one molecule of [3H]pyrilamine bound to one molecule of purified protein. Furthermore, a polyclonal antibody raised against the purified protein recognized the 38-40-kDa band by Western blotting techniques, specifically bound to the cell surface of DDT1MF-2 cells, and inhibited [3H]pyrilamine binding to these cells in a dose-dependent manner. These data strongly suggest that the purified 38-40-kDa protein is part of an antagonist binding domain on the histamine H1 receptor on DDT1MF-2 cells.


A feasibility study of the childhood depression medication algorithm: the Texas Children's Medication Algorithm Project (CMAP).
To evaluate the feasibility and impact on clinical response and function associated with the use of an algorithm-driven disease management program (ALGO) for children and adolescents treated for depression with or without attention-deficit/hyperactivity disorder (ADHD) in community mental health centers. Interventions included (1). medication algorithms, (2). clinical and technical support for the physician, (3). uniform chart documentation of outcomes, and (4). a patient/family psychoeducation program. Children eligible for entry into the study were referred to the child psychiatrist for initiation or change in medicine. Outcomes of treatment with the ALGO for up to 4 months are presented. Measures of change included clinical symptoms, functioning, and global improvement (Clinical Global Impression Scale). A historical chart cohort from the same clinics was used as a quasi-control. Thirty-nine individuals (depression = 24; comorbid depression with ADHD = 15) were enrolled for treatment with ALGO. One hundred fourteen children were in the control cohort (74 depressed, 40 comorbid). For the ALGO groups, Children's Depression Rating Scale-Revised depression severity scores decreased from 48.2 to 32.5 and Child Adolescent Functioning Assessment Scale function scores improved from 70.3 to 40.9 (all p < or =.0005). Clinical Global Impression Scale severity scores decreased from 5.7 to 3.7 in ALGO compared to only 5.8 to 4.8 in the control (p <.003). There was clear improvement in clinical symptoms, functioning, and global response with ALGO treatment. The magnitude of the improvement was greater in children and adolescents treated with the ALGO program compared with a historical cohort. These data support the need for controlled studies in larger populations examining the effects of algorithm-driven disease management programs on the clinical outcomes of children with mental illness.


Usefulness of diurnal trunk shrinkage as a water stress indicator in plum trees.
We compared seasonal changes in maximum diurnal trunk shrinkage (MDS) with seasonal changes in midday stem water potential (Psi(s)) over three years in plum trees grown in differing drip-irrigated regimes. In well-irrigated trees, day-to-day variations in Psi(s) and MDS were related to evaporative demand. Reference equations were obtained to predict MDS and Psi(s) values for well-irrigated trees as functions of environmental conditions. A decrease in plant water status toward the end of the growing season occurred even in the well-irrigated trees, probably reflecting a reduced volume of soil wetted by the drip irrigation system. Thus, for the prediction of Psi(s), different reference equations are required for the fruit-growth and after-harvest phenological periods. A seasonal change in the relationship between MDS and Psi(s) was observed, which compensated for the decrease in plant water status such that well-irrigated trees had similar MDS values during both the fruit-growth and after-harvest periods. The influence of tree size on the relationship between MDS and Psi(s) was also investigated. For tree trunk diameters ranging between 8 and 13 cm, MDS increased 13% for each cm of increase in trunk diameter, as a result of the thicker phloem tissues of the larger trees. This finding may allow extrapolation of Psi(s) predictions based on empirical relationships with MDS to plum trees of different sizes.


Graph-theoretic constraints on vesicle traffic networks.
Eukaryotic cells use small membrane-enclosed vesicles to transport molecular cargo between intracellular compartments. Interactions between molecules on vesicles and compartments determine the source and target compartment of each vesicle type. The set of compartment and vesicle types in a cell define the nodes and edges of a transport graph known as the vesicle traffic network. The transmembrane SNARE proteins that regulate vesicle fusion to target compartments travel in cycles through the transport graph, but the paths they follow must be tightly regulated to avoid aberrant vesicle fusion. Here we use graph-theoretic ideas to understand how such molecular constraints place constraints on the structure of the transport graph. We identify edge connectivity (the minimum number of edges that must be removed to disconnect a graph) as a key determinant that separates allowed and disallowed types of transport graphs. As we increase the flexibility of molecular regulation, the required edge connectivity decreases, so more types of vesicle transport graphs are allowed. These results can be used to aid the discovery of new modes of molecular regulation and new vesicle traffic pathways.


Lowering the transmission and spread of human coronavirus.
The emergence of the severe acute respiratory syndrome coronavirus 2 pandemic has created an unprecedented healthcare, social, and economic disaster. Wearing of masks and social distancing can significantly decrease transmission and spread, however, due to circumstances such as medical or dental intervention and personal choice these practices have not been universally adopted. Additional strategies are required to lessen transmission. Nasal rinses and mouthwashes, which directly impact the major sites of reception and transmission of human coronaviruses (HCoV), may provide an additional level of protection against the virus. Common over-the-counter nasal rinses and mouthwashes/gargles were tested for their ability to inactivate high concentrations of HCoV using contact times of 30 s, 1 min, and 2 min. Reductions in titers were measured by using the tissue culture infectious dose 50 (TCID50 ) assay. A 1% baby shampoo nasal rinse solution inactivated HCoV greater than 99.9% with a 2-min contact time. Several over-the-counter mouthwash/gargle products including Listerine and Listerine-like products were highly effective at inactivating infectious virus with greater than 99.9% even with a 30-s contact time. In the current manuscript we have demonstrated that several commonly available healthcare products have significant virucidal properties with respect to HCoV.


Proactive drugs in DFSA cases: Toxicological findings in an eight-years study.
In case of drug-facilitated sexual assault (DFSA), the evidence is frequently anecdotal, with few investigations based on scientific evidences being carried out and thus most cases are diagnosed as an acute drug or alcohol intoxication. The reason may lay in the lack of specific knowledge by the victim on the possibility to retrospectively study the allegedly events and to the absence of standardized and shared protocols among health, forensic and police subjects. On this basis, in 2015 the Unit of Forensic Toxicology of University of Florence and the Sexual Assaults Centre in Hospital Careggi have fixed a common protocol to be applied in case of DFSA. The purpose of the study was to describe the results of the application of the shared protocol for toxicological findings among women seeking health care after sexual assault, and to assess the relationship with so-called proactive DFSA drugs. We conducted a study on female patients above 18 years of age consulting the Sexual Assault Centre between 2010 and July 2018. Among the 256 patients included, 37.1% was positive at least for a substance. Alcohol was the most detected substance (57 cases), followed by Cannabis (19 cases), cocaine (15 cases) and opiates/methadone (heroine: 5; morphine:1; methadone: 6); benzodiazepines and amphetamine were found in 13 and in 2 cases, respectively. Only case of gamma-hydroxybutyrate (GHB) consumption was observed while new psychoactive substances were not detected. Among the patients suspecting proactive DFSA, sedative drug findings, not explained by voluntary intake, were encountered.


Perfluorocarbon particle size influences magnetic resonance signal and immunological properties of dendritic cells.
The development of cellular tracking by fluorine ((19)F) magnetic resonance imaging (MRI) has introduced a number of advantages for following immune cell therapies in vivo. These include improved signal selectivity and a possibility to correlate cells labeled with fluorine-rich particles with conventional anatomic proton ((1)H) imaging. While the optimization of the cellular labeling method is clearly important, the impact of labeling on cellular dynamics should be kept in mind. We show by (19)F MR spectroscopy (MRS) that the efficiency in labeling cells of the murine immune system (dendritic cells) by perfluoro-15-crown-5-ether (PFCE) particles increases with increasing particle size (560>365>245>130 nm). Dendritic cells (DC) are professional antigen presenting cells and with respect to impact of PFCE particles on DC function, we observed that markers of maturation for these cells (CD80, CD86) were also significantly elevated following labeling with larger PFCE particles (560 nm). When labeled with these larger particles that also gave an optimal signal in MRS, DC presented whole antigen more robustly to CD8+ T cells than control cells. Our data suggest that increasing particle size is one important feature for optimizing cell labeling by PFCE particles, but may also present possible pitfalls such as alteration of the immunological status of these cells. Therefore depending on the clinical scenario in which the (19)F-labeled cellular vaccines will be applied (cancer, autoimmune disease, transplantation), it will be interesting to monitor the fate of these cells in vivo in the relevant preclinical mouse models.


Building better tuberculosis control systems in a post-COVID world: learning from Pakistan during the COVID-19 pandemic.
All countries impacted by COVID-19 have had to change routine health service delivery. Although this has reversed some of the progress made in reducing the global burden of tuberculosis (TB) disease, there is an opportunity to incorporate lessons learned to improve TB programmes going forward. We use Pakistan as a case study to discuss three important adaptations in light of COVID-19: bringing care closer to patients; strengthening primary health care systems; and proactively addressing stigma and fear. COVID-19 control in Pakistan has restricted people's ability to travel and this has forced the TB programme to reduce the need for in-person health facility visits and bring care closer to patients' homes. Strategies that may be useful for providing more convenient care to patients in the future include: : remote treatment support using telemedicine; collaborating with private healthcare providers; and establishing community medicine collection points. As part of the response to COVID-19 in Pakistan, the out-patient departments of major tertiary and secondary care hospitals were closed, and this highlighted the importance of strengthening primary healthcare for both better pandemic and TB control. Finally, stigma associated with COVID-19 and TB can be addressed using trusted community-based health workers, such as Lady Health Workers in Pakistan.


Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents.
Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from nonselective accumulation of the contrast agents in normal tissues. Here, we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions and in many premalignant and malignant tumors. After either i.p. or i.v. injection, these reagents become highly enriched in inflamed or tumor tissue compared with normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2-specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high-affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these fluorocoxibs are ideal candidates for detection of inflammatory lesions or early-stage COX-2-expressing human cancers, such as those in the esophagus, oropharynx, and colon.


Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial.
Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma. We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age ≥18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542). Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (<1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA). The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year. AstraZeneca and Kyowa Hakko Kirin.


The chronic kidney disease model: a general purpose model of disease progression and treatment.
Chronic kidney disease (CKD) is the focus of recent national policy efforts; however, decision makers must account for multiple therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions. Monte Carlo simulation of CKD natural history and treatment. Health states include myocardial infarction, stroke with and without disability, congestive heart failure, CKD stages 1-5, bone disease, dialysis, transplant and death. Each cycle is 1 month. Projections account for race, age, gender, diabetes, proteinuria, hypertension, cardiac disease, and CKD stage. Treatment strategies include hypertension control, diabetes control, use of HMG-CoA reductase inhibitors, use of angiotensin converting enzyme inhibitors, nephrology specialty care, CKD screening, and a combination of these. The model architecture is flexible permitting updates as new data become available. The primary outcome is quality adjusted life years (QALYs). Secondary outcomes include health state events and CKD progression rate. The model was validated for GFR change/year -3.0 ± 1.9 vs. -1.7 ± 3.4 (in the AASK trial), and annual myocardial infarction and mortality rates 3.6 ± 0.9% and 1.6 ± 0.5% vs. 4.4% and 1.6% in the Go study. To illustrate the model's utility we estimated lifetime impact of a hypothetical treatment for primary prevention of vascular disease. As vascular risk declined, QALY improved but risk of dialysis increased. At baseline, 20% and 60% reduction: QALYs = 17.6, 18.2, and 19.0 and dialysis = 7.7%, 8.1%, and 10.4%, respectively. The CKD Model is a valid, general purpose model intended as a resource to inform clinical and policy decisions improving CKD care. Its value as a tool is illustrated in our example which projects a relationship between decreasing cardiac disease and increasing ESRD.


Denudations as paracellular routes for alphafetoprotein and creatinine across the human syncytiotrophoblast.
We tested two hypotheses: 1) that fibrin-containing fibrinoid-filled denudations of the syncytiotrophoblast may provide a route for paracellular diffusion and 2) that placentas from women who had elevated maternal serum alphafetoprotein (MSAFP) in midgestation had raised permeability to AFP and greater denudation than in normal pregnancy. We measured AFP and creatinine clearance across term placental cotyledons from the above groups and used light microscope morphometric analysis to determine the volume density of fibrin-containing fibrinoid deposits. There was no significant difference between the two groups in terms of AFP and creatinine clearance or volume density of fibrin-containing fibrinoid deposits. The combined data showed a significant (P < 0.05) positive correlation between creatinine clearance, but not AFP clearance, and volume density of fibrin-containing fibrinoid. We conclude that syncytiotrophoblast denudations, with associated fibrinoid, do provide a route for diffusion of small hydrophilic solutes, but that other anatomic features of the placenta are rate limiting for transfer of AFP and similarly sized molecules.


Outcomes of patients with healthcare-associated pneumonia: worse disease or sicker patients?
Healthcare-associated pneumonia (HCAP) is an entity distinct from community-acquired pneumonia (CAP). HCAP has a higher case-fatality rate, due either to HCAP organisms or to the health status of HCAP patients. The contribution of HCAP criteria to case-fatality rate is unknown. We conducted a retrospective review of adult patients admitted with a diagnosis of pneumonia from July 2007 through November 2011 to 491 US hospitals. HCAP was defined as having at least 1 of the following: prior hospitalization within 90 days, hemodialysis, admission from a skilled nursing facility, or immune suppression. We compared characteristics of patients with CAP and patients with HCAP and explored the contribution of HCAP criteria to case-fatality rate in a hierarchical generalized linear model. Of 436,483 patients hospitalized with pneumonia, 149,963 (34.4%) had HCAP. Compared to CAP patients, HCAP patients were older, had more comorbidities, and were more likely to require intensive care unit (ICU) care. In-hospital case-fatality rate was higher among patients with HCAP, compared to those with CAP (11.1% vs 5.1%, P < .001). After adjustment for demographics, comorbidities, presence of other infections, early ICU admission, chronic and acute medications, early tests and therapies, and length of stay, HCAP remained associated with increased case-fatality rate (odds ratio [OR], 1.35 [95% confidence interval (CI), 1.32-1.39]); odds of death increased for each additional HCAP criterion (OR [95% CI]: 1 criterion, 1.27 [1.23-1.31], 2 criteria, 1.55 [1.49-1.62], and 3 or more criteria, 1.88 [1.72-2.06]). After adjustment for differences in patient characteristics, HCAP was associated with greater case-fatality rate than CAP. This difference may be due to HCAP organisms or to HCAP criteria themselves.


Aerobic exercise is associated with improved weight loss after laparoscopic adjustable gastric banding.
Laparoscopic adjustable gastric banding (LAGB) is a common surgical treatment for obesity. Evidence for and against the association of aerobic exercise (AE) and weight loss after LAGB exists. We hypothesize that aerobic exercise is associated with improved weight loss and resolution of comorbidities after LAGB. A review of a prospectively collected database identified patients who underwent LAGB over a 3-year period at a single institution. Body mass index (BMI), comorbidities, frequency, and duration of exercise were collected preoperatively and at 6, 12, 24, and 36 months postoperatively. Excess weight loss (EWL) was calculated. Groups were analyzed using Fisher's exact test and ANOVA. Of the 145 LAGB patients, 120 had adequate data for analysis. AE had no association with weight loss at 6 months. At 12, 24, and 36 months following LAGB, patients who reported 150 min or more per week of exercise had an EWL of 35.5, 47.3, and 54.1 %, respectively, while those reporting 0-59 min per week of AE had an EWL of 25.3, 32.1, and 33.0 % (p = 0.03, 0.03, and 0.02, respectively). BMI and age was not statistically different among groups. Diabetes and obstructive sleep apnea were significantly improved in patients exercising at least 60 min per week as compared to those exercising 0-59 min. AE is significantly associated with weight loss and comorbidity resolution after LAGB. We propose that patients who perform more AE will have higher levels of EWL.


Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.
Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0·0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. National Health and Medical Research Council, Australia.


Comparative analysis of short tandem repeats and single nucleotide polymorphisms on the Y-chromosome in Germans, Chinese and Thais.
We have typed genomic DNA samples from 95 individuals from Western Germany, 78 individuals from Bangkok/Thailand and 56 individuals from Chengdu/China for 11 Y-chromosomal diallelic polymorphisms and eight short tandem repeat (STR) systems. For single nucleotide polymorphism (SNP) analysis, a rapid method was applied using the single base extension technology (minisequencing) in combination with capillary electrophoresis. PCR products for SRY-8299, Tat, SRY2627, 92R7, SRY1532, M9, M13, M17/M19 and M20 were pooled and used as templates for the commercially available SNaPshot kit. In addition to these ten SNPs we also tested the Y-chromosomal diallelic Alu repeat insertion DYS287 (YAP) by agarose gel electrophoresis as well as the Y-chromosomal STR systems DYS19, DYS389I+II, DYS390, DYS391, DYS392, DYS393 and DYS385 by fluorescent multiplex fragment analysis. Among the 11 diallelic SNP/Alu systems, only six were found to be polymorphic in the three population samples. From these a total number of seven different haplogroups could be identified in the three populations. Of these, five haplogroups were present in Germans, five in Thais, and only two in Chinese. These haplogroup trees clearly represent population-specific structures. Haplogroup 26 is represented at a high frequency in the Thai and Chinese populations whereas it is absent in Germans. The Y-STR data confirm a haplogroup-specific distribution of Y-STR haplotypes. Only a few cases of identical STR haplotypes in the same SNP haplogroups were detected in each of the three populations studied.


cAMP-dependent kinase does not modulate the Slack sodium-activated potassium channel.
The Slack gene encodes a Na(+)-activated K(+) channel and is expressed in many different types of neurons. Like the prokaryotic Ca(2+)-gated K(+) channel MthK, Slack contains two 'regulator of K(+) conductance' (RCK) domains within its carboxy terminal, domains likely involved in Na(+) binding and channel gating. It also contains multiple consensus protein kinase C (PKC) and protein kinase A (PKA) phosphorylation sites and although regulated by protein kinase C (PKC) phosphorylation, modulation by PKA has not been determined. To test if PKA directly regulates Slack, nystatin-perforated patch whole-cell currents were recorded from a human embryonic kidney (HEK-293) cell line stably expressing Slack. Bath application of forskolin, an adenylate cyclase activator, caused a rapid and complete inhibition of Slack currents however, the inactive homolog of forskolin, 1,9-dideoxyforskolin caused a similar effect. In contrast, bath application of 8-bromo-cAMP did not affect the amplitude nor the activation kinetics of Slack currents. In excised inside-out patch recordings, direct application of the PKA catalytic subunit to patches did not affect the open probability of Slack channels nor was open probability affected by direct application of protein phosphatase 2B. Preincubation of cells with the protein kinase A inhibitor KT5720 also did not change current density. Finally, mutating the consensus phosphorylation site located between RCK domain 1 and domain 2 from serine to glutamate did not affect current activation kinetics. We conclude that unlike PKC, phosphorylation by PKA does not acutely modulate the function and gating activation kinetics of Slack channels.


Implementation of 100% smoke-free law in Uganda: a qualitative study exploring civil society's perspective.
In 2016, Uganda became one of few sub-Saharan African countries to implement comprehensive national smoke-free legislation. Since the World Health Organisation recommends Civil Society Organisation's (CSO) involvement to support compliance with smoke-free laws, we explored CSOs' perceptions of law implementation in Kampala, Uganda, and the challenges and opportunities for achieving compliance. Since hospitality workers tend to have the greatest level of exposure to second-hand smoke, we focussed on implementation in respect to hospitality venues (bars/pubs and restaurants). In August 2016, three months after law implementation, we invited key Kampala-based CSOs to participate in face-to-face semi-structured interviews. Interviews probed participants' perceptions about law implementation, barriers impeding compliance, opportunities to enhance compliance, and the role of CSOs in supporting law implementation. Interviews were recorded and transcribed. Qualitative content analysis was conducted using the interview transcripts. Fourteen individuals, comprising mainly senior managers from CSOs, participated and reported poor compliance with the smoke-free law in hospitality venues. Respondents noted that contributing factors included low awareness of the law amongst the general public and hospitality staff, limited implementation activities due to scarce resources and lack of coordinated enforcement. Opportunities for improving compliance included capacity building for enforcement agency staff, routine monitoring, rigorous enactment of penalties, and education about the smoke-free law aimed at hospitality venue staff and the general public. Allegations of tobacco industry misinformation were said to have undermined compliance. Civil Society Organisations saw their role as supporting law implementation through education, stakeholder engagement, and evidence-based advocacy. This study suggests that the process of smoke-free law implementation in Uganda has not aligned with World Health Organisation (WHO) guidelines for implementing smoke-free laws, and highlights that low-income countries may need additional support to enable them to effectively plan for policy implementation and resist industry interference.


The Hippo pathway integrates PI3K-Akt signals with mechanical and polarity cues to control tissue growth.
The Hippo signalling pathway restricts cell proliferation in animal tissues by inhibiting Yes-associated protein (YAP or YAP1) and Transcriptional Activator with a PDZ domain (TAZ or WW-domain-containing transcriptional activator [WWTR1]), coactivators of the Scalloped (Sd or TEAD) DNA-binding transcription factor. Drosophila has a single YAP/TAZ homolog named Yorkie (Yki) that is regulated by Hippo pathway signalling in response to epithelial polarity and tissue mechanics during development. Here, we show that Yki translocates to the nucleus to drive Sd-mediated cell proliferation in the ovarian follicle cell epithelium in response to mechanical stretching caused by the growth of the germline. Importantly, mechanically induced Yki nuclear localisation also requires nutritionally induced insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) via phosphatidyl inositol-3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1 or PDPK1), and protein kinase B (Akt or PKB) in the follicular epithelium. We find similar results in the developing Drosophila wing, where Yki becomes nuclear in the mechanically stretched cells of the wing pouch during larval feeding, which induces IIS, but translocates to the cytoplasm upon cessation of feeding in the third instar stage. Inactivating Akt prevents nuclear Yki localisation in the wing disc, while ectopic activation of the insulin receptor, PI3K, or Akt/PKB is sufficient to maintain nuclear Yki in mechanically stimulated cells of the wing pouch even after feeding ceases. Finally, IIS also promotes YAP nuclear localisation in response to mechanical cues in mammalian skin epithelia. Thus, the Hippo pathway has a physiological function as an integrator of epithelial cell polarity, tissue mechanics, and nutritional cues to control cell proliferation and tissue growth in both Drosophila and mammals.


An international survey of the use and attitudes regarding alternative medicine by patients with inflammatory bowel disease.
There is a perception of increasing and widespread use of alternative medicine for inflammatory bowel disease (IBD). We assessed the usage of alternative therapies among patients with IBD, whether there were similar or contrasting variables that were predictive of such use, and contrasted the use in four different centers in North America and Europe. Patients in four IBD centers completed a self-administered questionnaire regarding alternative medicine. The centers were in Cork, Los Angeles, Stockholm, and Winnipeg. Patient demographics, the use of 18 types of alternative medicine, and attitudes towards alternative and conventional medicine were compared. A multiple logistic regression analysis was used. Fifty-one percent of 289 patients used some form of alternative medicine. The percentages of use by site were Cork = 31%, Los Angeles = 68%, Stockholm = 32%, and Winnipeg = 57%. The six most commonly used therapies in descending order were: exercise (28%), prayer (18%), counseling (13%), massage (11%), chiropractic (11%), and relaxation (10%). Only 7% used acupuncture or homeopathy and 5% used herbal medicine. The highest odds ratios (confidence intervals [CIs]) for using any form of alternative medicine were associated with: being single 3.1 (1.7-5.7), Los Angeles patient 4.4 (2.3-8.3), Winnipeg patient 2.7 (1.3-5.9), and an increase of alternative medicine use of 2.7% for every M.D. visit (CI, 2-11%/visit). The patient age, gender, disease diagnosis, or duration of disease were not predictive of any type of alternative medicine use. Regarding attitudes, respondents from Cork were most favorable toward alternative medicine use and least favorable toward conventional medicine. Based on attitudes, subjects were more likely to use alternative medicine if they were not satisfied with conventional therapy, viewed hospitals as dangerous places, thought that alternative medicine practitioners should have a role in hospitals, and felt their medical situation was hopeless. Fifty-one percent of respondents used some form of alternative medicine. The use was greater among the North American patients than the European ones. Respondents were more likely to use alternative medicine if they were single, in a higher income bracket, and an urban dweller.


Probiotics Reduce Health Care Cost and Societal Impact of Flu-Like Respiratory Tract Infections in the USA: An Economic Modeling Study.
Acute respiratory tract infections (RTIs) of viral origin place a substantial burden on health care resources and society. Randomized controlled trials have shown positive effects of probiotics on clinical outcomes in these commonly occurring RTIs. Two meta-analyses published by the York Health Economics Consortium (YHEC) and Cochrane reported the efficacy of probiotics in reducing incidence and duration of RTIs, number of antibiotic courses, and days absent from work. The aim of this study was to assess the potential health-economic impact of probiotics on RTI-associated events and expenses in the US primary care setting. A state-transition microsimulation model reproduced a study population representative of the US national demographics for age and gender (1/1,000 sample). RTI incidence was based on the influenza-like illness outpatient consultation rate reported by the Centers for Disease Control and Prevention (CDC) FluView. Data on vaccination, on factors that negatively impact RTI outcomes, on resource utilization, and on productivity loss were obtained from US national databases. Analyses were performed for both meta-analyses independently. Outcomes included cost savings for the health care payer, related to a reduced number of RTI episodes, less outpatient consultations, and decreased medical prescriptions as well as cost savings from a broader societal perspective related to productivity loss. The analysis showed that generalized probiotic intake in the US population for 2017-2018 would have allowed cost savings for the health care payer of 4.6 million USD based on the YHEC scenario and 373 million USD for the Cochrane scenario, by averting 19 million and 54.5 million RTI sick days, respectively, compared to no probiotics. Antibiotic prescriptions decreased with 1.39-2.16 million courses, whereas absence from work decreased by 3.58-4.2 million days when applying the YHEC and Cochrane data, respectively. When productivity loss is included, total savings for society represented 784 million or 1.4 billion USD for the YHEC and Cochrane scenarios, respectively. Subgroup analyses demonstrated an incremental benefit of probiotics in at-risk groups, which might be of relevance for targeted interventions. Sensitivity analyses confirmed the robustness of the model outcomes. Our analysis demonstrated a positive impact of probiotics on the health care and economic burden of flu-like RTIs. Improved disease outcomes translated into considerable cost savings for both the payer and society.


Non-protein nitrogen and true protein in infant formulas.
Protein and nitrogen (N) requirements of infants and the optimum protein level of infant formulas are still under debate. Human milk (HM) N is considered adequate although 25% of the N is provided as non-protein nitrogen (NPN), half in the form of urea. Soluble N, insoluble N, NPN and urea N were determined in HM and cow's milk (CM), 5 CM-based infant formulas, 4 soy protein-based formulas (SF), and manufacturers' skim milk and whey protein sources. Total, peptide and free amino acids were also determined in all samples. Levels of NPN and urea N in formulas were highly dependent on the type of whey used, with ion-exchange whey being highest, followed by electrodialyzed and ultrafiltered whey, respectively. SF contained very little NPN with the exception of Soyalac. Consequently, true protein [(Total N-NPN) x 6.38] was lower than the reported levels in several formulas. Levels of peptide and free amino acids were also affected by the method of whey preparation. While it has been recognized that "casein-predominant" CM formulas will have different effects on metabolic indices than "whey-predominant" formulas, this study demonstrates that there are also pronounced differences among "whey-predominant" formulas.