Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review.
The aim of this systematic literature review was to summarize the current knowledge regarding the prevalence of, time to recovery from, and influence of glucocorticoid dose and duration on glucocorticoid-induced adrenal insufficiency (AI). Eligible studies were original research articles, which included adult patients with an indication for glucocorticoids and measured adrenal function following exposure to systemic glucocorticoids. Searches were performed in Web of Science and MEDLINE, with further articles identified from reference lists. Screening was performed in duplicate. Data were extracted for each group of glucocorticoid-exposed patients within eligible studies. The reported proportion of patients with AI was summarized as median and inter-quartile range. Results were then stratified by daily dose, cumulative dose, duration of exposure and time since last glucocorticoid use. The risk of bias within and across studies was considered: for randomised controlled trials risk of bias was assessed using the tool developed by the Cochrane Collaboration. Overall, 73 eligible studies were identified out of 673 screened. The percentage of patients with AI ranged from 0% to 100% with a median (IQR) = 37.4% (13-63%). Studies were small-median (IQR) group size 16 (9-38)-and heterogeneous in methodology. AI persisted in 15% of patients retested 3 years after glucocorticoid withdrawal. Results remained widely distributed following stratification. AI was demonstrated at <5mg prednisolone equivalent dose/day, <4 weeks of exposure, cumulative dose <0.5g, and following tapered withdrawal. The heterogeneity of studies and variability in results make it difficult to answer the research questions with confidence based on the current literature. There is evidence of AI following low doses and short durations of glucocorticoids. Hence, clinicians should be vigilant for adrenal insufficiency at all degrees of glucocorticoid exposure.


A screen-printed microband glucose biosensor system for real-time monitoring of toxicity in cell culture.
Microband biosensors, screen-printed from a water-based carbon ink containing cobalt phthalocyanine redox mediator and glucose oxidase (GOD) enzyme, were used to monitor glucose levels continuously in buffer and culture medium. Five biosensors were operated amperometrically (E(app) of +0.4V), in a 12-well tissue culture plate system at 37°C, using a multipotentiostat. After 24 h, a linear calibration plot was obtained from steady-state current responses for glucose concentrations up to 10 mM (dynamic range 30 mM). Within the linear region, a correlation coefficient (R(2)) of 0.981 was obtained between biosensor and spectrophotometric assays. Over 24 h, an estimated 0.15% (89 nmol) of the starting glucose concentration (24 mM) was consumed by the microbiosensor. The sensitivity of the biosensor response in full culture medium was stable between pHs 7.3 and 8.4. Amperometric responses for HepG2 monolayer cultures decreased with time in inverse proportionality to cell number (for 0 to 10(6) cell/ml), as glucose was being metabolised. HepG2 3D cultures (spheroids) were also shown to metabolise glucose, at a rate which was independent of spheroid age (between 6 and 15 days). Spheroids were used to assay the effect of a typical hepatotoxin, paracetamol. At 1 mM paracetamol, glucose uptake was inhibited by 95% after 6 h in culture; at 500 μM, around 15% inhibition was observed after 16 h. This microband biosensor culture system could form the basis for an in vitro toxicity testing system.


A high efficiency architecture for cascaded Raman fiber lasers.
We demonstrate a new high efficiency architecture for cascaded Raman fiber lasers based on a single pass cascaded amplifier configuration. Conversion is seeded at all intermediate Stokes wavelengths using a multi-wavelength seed source. A lower power Raman laser based on the conventional cascaded Raman resonator architecture provides a convenient seed source providing all the necessary wavelengths simultaneously. In this work we demonstrate a 1480nm laser pumped by an 1117nm Yb-doped fiber laser with maximum output power of 204W and conversion efficiency of 65% (quantum-limited efficiency is ~75%). We believe both the output power and conversion efficiency (relative to quantum-limited efficiency) are the highest reported for cascaded Raman fiber lasers.


On-line preconcentration of fluorescent derivatives of catecholamines in cerebrospinal fluid using flow-gated capillary electrophoresis.
Flow-gated capillary electrophoresis (CE) coupled with microdialysis has become an important tool for in vivo bioanalytical measurements because it is capable of performing rapid and efficient separations of complex biological mixtures thus enabling high temporal resolution in chemical monitoring. However, the limit of detection (LOD) is often limited to a micro- or nano-molar range while many important target analytes have picomolar or sub-nanomolar levels in brain and other tissues. To enhance the capability of flow-gated CE for catecholamine detection, a novel and simple on-line sample preconcentration method was developed exclusively for fluorescent derivatives of catecholamines that were fluorogenically derivatized with naphthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide. The effective preconcentration coupled with the sensitive laser-induced fluorescence (LIF) detection lowered the LOD down to 20pM for norepinephrine (NE) and 50pM for dopamine (DA) at 3-fold of S/N ratio, and the signal enhancement was estimated to be over 100-fold relative to normal injection when standard analytes were dissolved in artificial cerebrospinal fluid (aCSF). The basic focusing principle is novel since the sample plug contains borate while the background electrolyte (BGE) is void of borate. This strategy took advantage of the complexation between diols and borate, through which one negative charge was added to the complex entity. The sample derivatization mixture was electrokinetically injected into a capillary via the flow-gated injection, and then NE and DA derivatives were selectively focused to a narrow zone by the reversible complexation. Separation of NE and DA derivatives was executed by incoming surfactants of cholate and deoxycholate mixed in the front BGE plug. This on-line preconcentration method was finally applied to the detection of DA in rat cerebrospinal fluid (CSF) via microdialysis and on-line derivatization. It is anticipated that the method would be valuable for in vivo monitoring of DA and NE in various brain regions of live animals on flow-gated CE or microchip platforms.


[Suicide prevention via the internet and the telephone: 113Online].
113Online is a combination of a website and a telephone help-line for suicidal persons, their relatives and bereaved next of kin. The services it provides include crisis intervention, self-tests and brief psychotherapy. aim: To discover whether 113Online can in fact prevent suicidal behaviour – since it has now been in operation for more than a year. We were able to obtain information about the visitors of the website, check on the usage of services provided by 113Online and study the results of the self-tests. The results for the first year indicated that there was a great need for anonymous online help for persons contemplating suicide. Scores for the self-tests showed that the website was visited by severely suicidal persons. It is surprising that so few of the users thereafter sought assistance from the conventional mental health care services. The 113Online seems to be a promising approach to suicide prevention. The online assistance reaches its target population and seems to fulfil needs that are not being met by the regular health care services.


Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.


Effects of energy drinks on blood pressure, heart rate, and electrocardiographic parameters: An experimental study on healthy young adults.
To evaluate the effects of the consumption of energy drinks on cardiovascular parameters in a group of healthy young individuals. In a quasi-experimental study, 44 healthy adult participants aged between 15 and 30 years were evaluated. The blood pressure (BP) as well as electrocardiographic indices, including heart rate (HR), PR interval, QRS duration, corrected QT (QTc) interval, and ST-T changes were recorded before consumption of a caffeine-containing energy drink and at the specific time points over a 4-h test duration. We found statistically significant HR decline (p=0.004) and more frequent ST-T changes (p=0.004) after the participants consumed the energy drink. However, readings for systolic BP (p=0.44), diastolic BP (p=0.26), PR interval (p=0.449), QRS duration (p=0.235), and QTc interval (p=0.953) showed no significant change post-consumption. In conclusion, we demonstrated that the consumption of energy drinks could contribute to HR decline and ST-T change in healthy young adults.


Relationship of cervical ectopy to chlamydia infection in young women.
Genital Chlamydia trachomatis infection is the most common bacterial sexually transmitted infection (STI) in the UK. Behaviours including multiple sex partners and inconsistent condom use, and biological factors such as cervical ectopy, may increase susceptibility to STIs. Cervical ectopy is thought to increase risk of chlamydia infection by exposing columnar epithelium to a potential infectious inoculum. This study aimed to determine whether chlamydia was more prevalent in young women with cervical ectopy. Clinical notes of women aged 16-24 years attending the Portsmouth Genitourinary Medicine Clinic for an STI screen during the period May-July 2003 were reviewed retrospectively. Information collected included the presence or absence of cervical ectopy, smoking habits, methods of contraception, number of sexual partners in the previous 3 months, and previous STIs. Chlamydia infection was diagnosed by using strand displacement amplification on cervical swabs. A total of 231 women were included in the study. The mean age was 19.8 years. Evidence of cervical ectopy was found in 107 women. Chlamydial infection was detected in 37.4% (40/107) of those women with cervical ectopy and 21.8% (27/124) in those without cervical ectopy. This difference was statistically significant (p = 0.009). The significance remained even when accounting for confounding variables. Cervical ectopy is a common physiological process in young women. Recognition of cervical ectopy should alert the clinician to the possibility of a genital chlamydia infection. Opportunistic screening for chlamydia in young people should be offered to reduce the prevalence of infection and its sequelae.


Eating at restaurants, at work or at home. Is there a difference? A study among adults of 11 European countries in the context of the HECTOR* project.
To compare macronutrient intakes out of home-by location-to those at home and to investigate differences in total daily intakes between individuals consuming more than half of their daily energy out of home and those eating only at home. Data collected through 24-h recalls or diaries among 23 766 European adults. Participants were grouped as 'non-substantial', 'intermediate' and 'very substantial out-of-home' eaters based on energy intake out of home. Mean macronutrient intakes were estimated at home and out of home (overall, at restaurants, at work). Study/cohort-specific mean differences in total intakes between the 'very substantial out-of-home' and the 'at-home' eaters were estimated through linear regression and pooled estimates were derived. At restaurants, men consumed 29% of their energy as fat, 15% as protein, 45% as carbohydrates and 11% as alcohol. Among women, fat contributed 33% of energy intake at restaurants, protein 16%, carbohydrates 45% and alcohol 6%. When eating at work, both sexes reported 30% of energy from fat and 55% from carbohydrates. Intakes at home were higher in fat and lower in carbohydrates and alcohol. Total daily intakes of the 'very substantial out-of-home' eaters were generally similar to those of individuals eating only at home, apart from lower carbohydrate and higher alcohol intakes among individuals eating at restaurants. In a large population of adults from 11 European countries, eating at work was generally similar to eating at home. Alcoholic drinks were the primary contributors of higher daily energy intakes among individuals eating substantially at restaurants.


dj-1β regulates oxidative stress, insulin-like signaling and development in Drosophila melanogaster.
DJ-1 (or PARK-7) is a multifunctional protein implicated in numerous pathologies including cancer, sterility and Parkinson disease (PD). The popular genetic model Drosophila melanogaster has two orthologs, dj-1: α and β. Dysfunction of dj-1β strongly impairs fly mobility in an age-dependent manner. In this study, we analyze in detail the molecular mechanism underlying the dj-1β mutant phenotype. Mitochondrial hydrogen peroxide production, but not superoxide production, was increased in mutant flies. An increase in peroxide leak from mitochondria causes oxidative damage elsewhere and explains the strong reduction in mobility caused by dj-1β mutation. However, at the same time, increased levels of hydrogen peroxide activated a pro-survival program characterized by (1) an alteration in insulin-like signaling, (2) an increase in mitochondrial biogenesis and (3) an increase in the de-acetylase activity of sirtuins. The activation of this pro-survival program was associated with increased longevity under conditions of moderate oxidative stress. Additionally, the dj-1β mutation unexpectedly accelerated development, a phenotype not previously associated with this mutation. Our results reveal an important role of dj-1β in oxidative stress handling, insulin-like signaling and development in Drosophila melanogaster.


The dimeric crystal structure of the human fertility lipocalin glycodelin reveals a protein scaffold for the presentation of complex glycans.
Human glycodelin (Gd) is an abundant glycoprotein from the lipocalin family and is involved in crucial biological processes such as reproduction and immune reaction. In females and males, Gd is found in four distinct glycoforms-A, C, F and S-that arise from different N-linked oligosaccharide side chains at amino acid residues Asn28 and Asn63. We have expressed Gd (carrying two amino acid substitutions to improve solubility) as a non-glycosylated protein in Escherichia coli via periplasmic secretion and determined its X-ray structure at 2.45 Å resolution. Gd reveals a classical lipocalin fold including two disulfide bridges, which is however unusually compact and lacks a pronounced central pocket inside the β-barrel, in line with its low affinity for hydrophobic ligands. Instead, this lipocalin exhibits a unique homodimeric quaternary structure that appears ideally suited as a scaffold for the presentation of specific glycans. In fact, the four oligosaccharides are presented in close proximity on the same side of the dimer surface, which increases avidity for cellular receptors, e.g. during sperm-egg recognition. A bioinformatic analysis indicated that Gd orthologues exclusively occur in certain suborders of primates that have a menstrual cycle, suggesting that this lipocalin with its role in fertility only recently emerged during evolution.


The development of afternoon minisurges of luteinizing hormone secretion in prepubertal female rats is ovary dependent.
We have recently disclosed sustained episodes of LH release (minisurges) during the afternoons of the juvenile-peripubertal transition period in the female rat. To determine if these LH minisurges are gonad independent, i.e. develop in the absence of the ovaries, animals were ovariectomized when neonates, and the mode of LH release was examined using a 5-min blood-sampling regimen at one of three ages corresponding to the juvenile, peripubertal, or adult phase of development. In no instance was a minisurge of LH secretion detected. We were concerned, however, that LH minisurges may have been obscured by the exceedingly high level of LH secretion in these long term ovariectomized rats and, therefore, decided to pursue the study employing a short term (48-h) ovariectomy paradigm. Late juvenile rats which had been ovariectomized for 48 h exhibited conspicuous LH pulses, but, again, LH minisurges were not detected, further suggesting that these sustained secretory episodes do not occur in the absence of the ovaries. Next, plasma estradiol (E2) levels were differentially raised in 48-h ovariectomized juvenile rats via sc implantation of Silastic capsules containing the steroid (dissolved in corn oil at various concentrations), and plasma LH was measured at 1-h intervals. The highest E2 concentration elicited a midafternoon LH increase of preovulatory magnitude in all cases, whereas the lowest E2 concentrations consistently suppressed plasma LH. However, intermediate E2 concentrations (producing plasma E2 levels 20-30% greater than those found in intact controls) elicited, in several instances, an increase in LH release of intermediate magnitude. To clarify the nature of these LH responses, we examined, using a 5-min blood-sampling regimen, the afternoon pulsatile pattern of LH release after treatment with appropriate doses of E2. As expected from the results of the infrequent blood-sampling paradigm, the highest E2 dose induced proestrus-like surges of LH secretion, while the lowest dose suppressed pulsatile LH release. Moreover, an intermediate E2 dose which raised plasma E2 levels just above those of intact animals, was again able to cause suppression of LH pulses, a proestrus-like surges of LH secretion, while the lowest dose suppressed pulsatile LH release. Moreover, an intermediate E2 dose which raised plasma E2 levels just above those of intact animals, was again able to cause suppression of LH pulses, a proestrus-like increase in LH output, or, more importantly, a minisurge of LH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)


Living Legends: students' responses to an intergenerational life review writing program.
The purpose of the study was to examine the effects of participation in the Living Legends program upon health science students' image of older adults and interest in working with older people. A multisite quasi-experimental control group design with a connected qualitative component was used. Program sites included three Naturally Occurring Retirement Communities (NORCs) and one senior center. Health science students (n = 43) from two universities and two community colleges and community-dwelling seniors (n = 39) participated in the program. A baseline questionnaire was used to ascertain demographic characteristics and prior type and amount of contact with older adults. The Image of Aging Scale and Likert-style questions to measure interest in working with older adults were the primary outcome measures. Written responses to program experiences were also collected. Analysis of covariance was used to compare changes in Image of Aging subscale scores from pre- to posttest. Mean change in positive image of older adults subscale scores was 4.6 (SD = 4.4) for the intervention group and -0.6 (SD = 4.8) for the control group. The difference between groups was significant (F = 22.0, P < .001), and the effect size was large (Cohen's d = 1.07). Nine of the 22 students in the intervention group had a greater interest in working with seniors after the program. Qualitative themes that emerged included a positive and beneficial experience, life lessons, seeing the person beyond the visible, power of the written word, and shared lives. Living Legends is an effective program to enhance positive images of older adults in future healthcare professionals and may have a positive impact on some students with regard to interest in working with older adults.


Dynamic analysis of lung metastasis by mouse osteosarcoma LM8: VEGF is a candidate for anti-metastasis therapy.
Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis depends on pulmonary metastases, which arise from multi-step progression of malignant tumors. We herein aimed to clarify the critical step of pulmonary metastasis using the syngeneic mouse spontaneous highly metastatic OS LM8 and parental Dunn cell lines, to identify new candidate molecules to suppress pulmonary metastasis. We first investigated the chronological detection of circulating tumor cells (CTCs) from mice with either cell line. LM8 CTCs appeared faster, at a higher rate and with a greater number compared to Dunn CTCs. Cultured cells from CTCs of LM8 showed higher proliferative ability than cells from the primary site in suspension culture, which mimicked the environment of the bloodstream for CTCs. The proliferative ability of LM8 cells was also higher than that of Dunn cells in 3D collagen culture with low stiffness (-150 Pa; close to conditions in the lung). We next focused on the extravasation step. LM8 showed higher migration ability compared to Dunn with transendothelial migration assay. We also found a disruption in endothelial barrier function throughout co-culture with LM8 using time-lapse imaging. In addition, LM8 secreted high levels of vascular endothelial growth factor (VEGF), while VEGF signal inhibition with a small molecule tyrosine kinase inhibitor (pazopanib) decreased disruption of the vascular barrier and transendothelial migration of LM8. Finally, daily oral administration of pazopanib reduced the rate and size of pulmonary metastasis in vivo. Collectively, these results show anti-VEGF therapy as a candidate for pulmonary metastasis of OS.


Effect of ticlopidine and prostaglandin E on endotoxin-induced pulmonary platelet sequestration in vivo.
Prostaglandin E1 has earlier been shown to decrease pulmonary platelet trapping (PPT) following shock. This experiment was performed to evaluate a new method to study PPT in vivo, and to study the effect of prostaglandin E1 and a new antiplatelet drug (ticlopidine) on PPT in rabbits after i.v. administration of endotoxin. Following platelet labeling with In-111, the rabbits were placed under a scintillation camera for continuous measuring of the activity distribution for 40 minutes. The first five minutes represented reference values, whereafter endotoxin E. coli was injected i.v. The following 2-4 minutes showed a sudden increase of radioactivity over the lungs and a simultaneous decrease over the heart, indicating PPT in the nontreated animals, followed by a slow decrease to almost preshock values during the following 30 minutes. Animals receiving prostaglandin E1 showed a significantly lower activity peak in the lungs after the administration of endotoxin, while the corresponding peak in ticlopidine-treated animals did not differ from that seen in the nontreated animals. In all groups, endotoxin caused a decrease in platelet count, but it was significantly lower in the PGE1-treated animals. The results have shown that this diagnostic model for PPT is reliable and may be used for evaluation of the effect on platelet aggregation in vivo of different drugs.


Determinants of preventable readmissions in the United States: a systematic review.
Hospital readmissions are a leading topic of healthcare policy and practice reform because they are common, costly, and potentially avoidable events. Hospitals face the prospect of reduced or eliminated reimbursement for an increasing number of preventable readmissions under nationwide cost savings and quality improvement efforts. To meet the current changes and future expectations, organizations are looking for potential strategies to reduce readmissions. We undertook a systematic review of the literature to determine what factors are associated with preventable readmissions. We conducted a review of the English language medicine, health, and health services research literature (2000 to 2009) for research studies dealing with unplanned, avoidable, preventable, or early readmissions. Each of these modifying terms was included in keyword searches of readmissions or rehospitalizations in Medline, ISI, CINAHL, The Cochrane Library, ProQuest Health Management, and PAIS International. Results were limited to US adult populations. The review included 37 studies with significant variation in index conditions, readmitting conditions, timeframe, and terminology. Studies of cardiovascular-related readmissions were most common, followed by all cause readmissions, other surgical procedures, and other specific-conditions. Patient-level indicators of general ill health or complexity were the commonly identified risk factors. While more than one study demonstrated preventable readmissions vary by hospital, identification of many specific organizational level characteristics was lacking. The current literature on preventable readmissions in the US contains evidence from a variety of patient populations, geographical locations, healthcare settings, study designs, clinical and theoretical perspectives, and conditions. However, definitional variations, clear gaps, and methodological challenges limit translation of this literature into guidance for the operation and management of healthcare organizations. We recommend that those organizations that propose to reward reductions in preventable readmissions invest in additional research across multiple hospitals in order to fill this serious gap in knowledge of great potential value to payers, providers, and patients.


Isoforms of U1-70k control subunit dynamics in the human spliceosomal U1 snRNP.
Most human protein-encoding genes contain multiple exons that are spliced together, frequently in alternative arrangements, by the spliceosome. It is established that U1 snRNP is an essential component of the spliceosome, in human consisting of RNA and ten proteins, several of which are post-translationally modified and exist as multiple isoforms. Unresolved and challenging to investigate are the effects of these post translational modifications on the dynamics, interactions and stability of the particle. Using mass spectrometry we investigate the composition and dynamics of the native human U1 snRNP and compare native and recombinant complexes to isolate the effects of various subunits and isoforms on the overall stability. Our data reveal differential incorporation of four protein isoforms and dynamic interactions of subunits U1-A, U1-C and Sm-B/B'. Results also show that unstructured post-translationally modified C-terminal tails are responsible for the dynamics of Sm-B/B' and U1-C and that their interactions with the Sm core are controlled by binding to different U1-70k isoforms and their phosphorylation status in vivo. These results therefore provide the important functional link between proteomics and structure as well as insight into the dynamic quaternary structure of the native U1 snRNP important for its function.


Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells.
The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. However, there are only limited reports regarding its expression and biological functions in colon cancer. Here, we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C, and SW620) in the presence or absence of cisplatin that was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was upregulated after cisplatin treatment in a dose-dependent manner. Both immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, cisplatin treatment activated the mammalian target of rapamycin (mTOR) pathway as shown by increased phosphorylation of Akt1, mTOR, S6K, and 4E-BP1, together with the elevated Livin. The PI3K inhibitor LY294002 inhibited both the phosphorylation of mTOR and upregulation of Livin. The stable overexpression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin, while the knockdown of Livin by siRNA rendered colon cancer cells more sensitive to cisplatin. Our study, along with others, highlighted the potential of Livin for cancer therapy in colon cancer.


Roma Never Die Alone.
A common characteristic of Roma as a cultural group is that they do not allow their elderly to die alone. Nevertheless, rooted in a mainstream cultural perspective of health provision services, public institutions usually do not allow Roma people to be with their loved ones in their last moments. Following the communicative methodology, we conducted a communicative case study on the death of the most relevant female Roma leader in Catalonia. She was accompanied by more than two hundred family members and friends in her room and corridor at an important hospital in Barcelona. We performed our research in the 2 years following her death to obtain the reflections of the Roma members involved. These reflections revealed the egalitarian dialogue forged between these Roma members and the hospital personnel, which enabled the former to embrace their culture and support their loved ones before death. Because this dialogue was possible and fruitful, the acknowledgment of cultural diversity and the improvement of the quality of services offered to Roma might also be possible in other health institutions.


Exercise in obesity management.
Obesity is considered a global epidemic by the World Health Organization in both developed and developing countries. It is associated with a higher risk of cardiovascular disease, diabetes mellitus, cancer and other clinical conditions. Visceral fat is the major responsible for metabolic complications, such as insulin-resistance, and it acts as an endocrine organ producing adipokines involved in lipidic and glycaemic metabolism. TNF-α and IL-6, produced by adipose tissue, increase NADPH oxidase activity activating protein kinase C and NFκB leading to an higher oxidative stress. The obesity management includes physical activity: aerobic training improves lipid profile and insulin sensitivity while resistance training increases lean body mass and basal metabolism and has beneficial effects on bone mineral density and glucose tolerance. An exercise program should include 30 to 45 minutes of moderate intensity activity performed 3 to 5 days a week. Weight loss is also associated with lower blood pressure and improved oxidative status, confirmed by reduced oxidative stress markers and increased antioxidant protection. An inverse association between indicators of systemic inflammation and physical activity has been demonstrated, so exercise training may reduce endothelial damage and cardiovascular risk.


A novel dosage approach for evaluation of SMANCS [poly-(styrene-co-maleyl-half-n-butylate) - neocarzinostatin] in the treatment of primary hepatocellular carcinoma.
We report a Phase I/II clinical trial of poly-(styrene-co-maleyl-half-n-butylate)-neocarzinostatin (SMANCS) for intra-arterial treatment of hepatoma. Early patients received 4 or 8 mg SMANCS dissolved in Lipiodol; later patients were treated according to tumour size and degree of filling achieved. SMANCS/Lipiodol drained rapidly from normal liver but was retained within tumour interstitium. Tumour nodules filled with SMANCS/Lipiodol usually stabilised and often regressed. No UICC criteria-defined responses were achieved, partly due to difficulties of filling several lesions simultaneously. Signs of therapeutic activity suggest a more extensive clinical study is warranted.


Defining the characteristics and expectations of fluid bolus therapy: A worldwide perspective.
The purpose of the study is to understand what clinicians believe defines fluid bolus therapy (FBT) and the expected response to such intervention. We asked intensive care specialists in 30 countries to participate in an electronic questionnaire of their practice, definition, and expectations of FBT. We obtained 3138 responses. Despite much variation, more than 80% of respondents felt that more than 250 mL of either colloid or crystalloid fluid given over less than 30 minutes defined FBT, with crystalloids most acceptable. The most acceptable crystalloid and colloid for use as FBT were 0.9% saline and 4% albumin solution, respectively. Most respondents believed that one or more of the following physiological changes indicates a response to FBT: a mean arterial pressure increase greater than 10 mm Hg, a heart rate decrease greater than 10 beats per minute, an increase in urinary output by more than 10 mL/h, an increase in central venous oxygen saturation greater than 4%, or a lactate decrease greater than 1 mmol/L. Despite wide variability between individuals and countries, clear majority views emerged to describe practice, define FBT, and identify a response to it. Further investigation is now required to describe actual FBT practice and to identify the magnitude and duration of the physiological response to FBT and its relationship to patient-centered outcomes.


30 years of contact lens prescribing for keratoconic patients in Turkey.
To assess retrospectively the course, the rate of bilateralness, prognosis, visual acuity with contact lenses, and corneal changes of a cohort with keratoconus. Patients applying to Istanbul Faculty of Medicine, Department of Ophthalmology, Contact Lens Division during the period 1975-2005 with the diagnosis of keratoconus were recruited. The follow-up time ranged from 1.5 years to 25 years. This cohort consisted of 273 male, 245 female patients. The patients' ages ranged from 12 years to 54 years (mean age 34.8+/-10.1 years). 518 cases' 1004 eyes were divided into four groups according to their mean keratometry values. The changes in visual acuity, keratometry values and the measurements of the used contact lenses were compared with each other, and statistical significance was sought. By self-report, the mean starting age of keratoconus was found to be 22.5+/-7.6 years (range 7-35 years). 59 (11.4%) of 518 patients had unilateral keratoconus occurrence. The acute hydrops rate was found to be 0.3% (5 patients). In patients with advanced keratoconus, new contact lenses were applied with steeper radius of curvature. Penetrating keratoplasty was applied to 15 eyes (1.5%). Visual acuity examination on the patients' last visit, when compared to previous examinations, was found to have decreased by 2-3 Snellen lines due to advancing keratoconus. Keratoconus has shown to be a self-limited disease and in our study, with the use of contact lenses, successful outcomes which delayed the need for surgery were achieved in 98.9% of eyes (989/1004 eyes).


A localised soft tissue and bone enlargement in an infant mandible.
A 4-month-old infant was referred by a paediatrician for a rapidly growing swelling on the right side of the mandible of 1.5 months duration. His medical and family history was unremarkable. Palpation divulged a firm and tender enlargement with the overlying soft tissue showing no significant alteration in colour. CT scan revealed cortical irregularity involving the ramus on the right side along with right masseter muscle hypertrophy. Routine haematological investigation yielded values within normal limits except for a raised erythrocyte sedimentation rate. Histopathological examination of the tissue submitted following an open biopsy procedure showed reactive lamellar bone and trabeculae with fibrous marrow exhibiting inflammation. The final diagnosis of infantile cortical hyperostosis was clinched based on the clinicopathological correlation. A rare reactive bone dystrophy which could pose a certain diagnostic dilemma is addressed herewith.


Quasi-phase-matched second-harmonic Talbot self-imaging in a 2D periodically-poled LiTaO3 crystal.
We demonstrate the improved second-harmonic Talbot self-imaging through the quasi-phase-matching technique in a 2D periodically-poled LiTaO(3) crystal. The domain structure not only composes a nonlinear optical grating which is necessary to realize nonlinear Talbot self-imaging, but also provides reciprocal vectors to satisfy the phase-matching condition for second-harmonic generation. Our experimental results show that quasi-phase-matching can improve the intensity of the second-harmonic Talbot self-imaging by a factor of 21.


Management of occupational Hymenoptera allergy.
Certain outdoor activities show a particularly high risk for being stung by Hymenoptera species. Avoidance of such stings is preferable for preventing unwanted local or systemic sting reactions. The purpose of this review is to evaluate the current knowledge on risk factors and management of Hymenoptera venom allergy. We will specifically focus on patients with an intense occupational exposure to Hymenoptera venom. Repeated stings were found to increase the risk for subsequent severe anaphylactic sting reactions. The male preponderance for severe anaphylactic sting reactions probably reflects in part a sex-specific occupational exposure being higher in males. When selecting a specific venom for therapy, current knowledge of cross-reactivity between venoms of various species should be considered. If available, venom immunotherapy should be performed using the venom of the culprit insect. Recently, a pilot study also showed the efficacy of venom immunotherapy when treating large local reactions. If an intensely exposed patient presents with a systemic anaphylactic sting reaction, efficacy of venom immunotherapy should be demonstrated by a tolerated sting challenge before allowing this patient to return to his/her occupation. Patients with bee venom allergy and an intense exposure should be treated with an increased maintenance dose of 200 μg bee venom. Patients with a history of large local reactions should be provided with an emergency kit, which should contain oral antihistamines and corticosteroids. In patients in whom local sting reactions induce symptoms of high clinical significance, an off-label use of venom immunotherapy may be discussed.


[Isolated hypoglossal nerve paralysis: a case report].
Cranial nerve paralysis is an uncommon complication of radiotherapy for head and neck carcinomas because cranial nerves are relatively resistant to radiation. The incidence of this complication has been declared to be 1-5% in different studies. Unlike the other cranial nerves, isolated hypoglossal nerve paralysis in patients who have been treated with radiotherapy for nasopharyngeal carcinomas is a worrisome sign of recurrence. We report a 45-year-old male patient admitted to our clinics with complaints of difficulty in moving his tongue and dysphasia five years after combined radiotherapy and chemotherapy for nasopharyngeal carcinoma. Recurrence of the tumor was thought to be the cause of the isolated hypoglossal nerve paralysis at first, however late toxicity of radiotherapy was found to be the etiological factor after detailed examinations.


A four-month gatifloxacin-containing regimen for treating tuberculosis.
Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).


Fever in the returning traveller.
International travel is increasing and a significant number of travellers will develop a febrile illness during or shortly after their return from the tropics. The differential diagnosis is broad and a systematic approach to the management of these patients is required in order to establish the diagnosis and to initiate prompt and effective treatment. Fever may be due to infectious agents found only in tropical countries, or due to infections unrelated to travel and found worldwide. Important infections that should be considered in all returning travellers include malaria, dengue, enteric fever, rickettsial infections, and HIV seroconversion. Other diagnoses will be considered after a detailed history including countries visited with dates, activities undertaken and symptoms. At a minimum, all travellers from countries where there is malaria transmission should be tested repeatedly for malaria as well as having several sets of blood cultures taken. Many tropical infections are diagnosed serologically at specialist reference laboratories. Specialist advice on the investigation and management of returning travellers should be sought from infectious diseases physicians and microbiologists. Patients with malaria or enteric fever may deteriorate rapidly and travellers should be advised to seek prompt medical attention if they become unwell after travel to the tropics. This review will focus on some of the more important imported infections, diagnostic clues from the history, examination and investigations, and important considerations in their management.


Accurate prediction of personalized olfactory perception from large-scale chemoinformatic features.
The olfactory stimulus-percept problem has been studied for more than a century, yet it is still hard to precisely predict the odor given the large-scale chemoinformatic features of an odorant molecule. A major challenge is that the perceived qualities vary greatly among individuals due to different genetic and cultural backgrounds. Moreover, the combinatorial interactions between multiple odorant receptors and diverse molecules significantly complicate the olfaction prediction. Many attempts have been made to establish structure-odor relationships for intensity and pleasantness, but no models are available to predict the personalized multi-odor attributes of molecules. In this study, we describe our winning algorithm for predicting individual and population perceptual responses to various odorants in the DREAM Olfaction Prediction Challenge. We find that random forest model consisting of multiple decision trees is well suited to this prediction problem, given the large feature spaces and high variability of perceptual ratings among individuals. Integrating both population and individual perceptions into our model effectively reduces the influence of noise and outliers. By analyzing the importance of each chemical feature, we find that a small set of low- and nondegenerative features is sufficient for accurate prediction. Our random forest model successfully predicts personalized odor attributes of structurally diverse molecules. This model together with the top discriminative features has the potential to extend our understanding of olfactory perception mechanisms and provide an alternative for rational odorant design.


Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.
Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade.


(-)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus spontaneous lytic infection involves ERK1/2 and PI3-K/Akt signaling in EBV-positive cells.
Epstein-Barr virus (EBV) reactivation into the lytic cycle plays certain roles in the development of EBV-associated diseases, including nasopharyngeal carcinoma and lymphoma. In this study, we investigated the effects of the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) on EBV spontaneous lytic infection and the mechanism(s) involved in EBV-positive cells. We found that EGCG could effectively inhibit the constitutive lytic infection of EBV at the DNA, gene transcription and protein levels by decreasing the phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. By using cellular signaling pathway-specific inhibitors, we also explored the signaling mechanisms underlying the inhibitory effects of EGCG on EBV spontaneous lytic infection in cell models. Results show that specific inhibitors of Mitogen-Activated Protein Kinase Kinase (MEK) (PD98059) and phosphatidylinositol 3-kinase [PI3-K (LY294002)] markedly downregulated gene transcription and expression of BZLF1 and BMRF1 indicating that the MEK/ERK1/2 and PI3-K/Akt pathways are involved in the EBV spontaneous lytic cycle cascade. Therefore, one of the mechanisms by which EGCG inhibits EBV spontaneous lytic infection appears to involve the suppression of the activation of MEK/ERK1/2 and PI3-K/Akt signaling.


Targeting cancer with kinase inhibitors.
Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology.


Transactional Sex and Preferences for Pre-Exposure Prophylaxis (PrEP) Administration Modalities Among Men Who Have Sex With Men (MSM).
Pre-exposure prophylaxis (PrEP) is an important biomedical human immunodeficiency virus (HIV) prevention tool gaining more popularity among Parisian men who have sex with men (MSM) who engage in transactional sex. This study examines the knowledge of, and willingness to use, different modalities of PrEP among this subgroup. Broadcast advertisements were placed on a geosocial-networking smartphone application with a link to a Web-based survey during three 24-hour periods in October 2016. Modified Poisson regression models were used to assess the association between engagement in transactional sex and preferences for each of these PrEP modalities. A total of 444 respondents were included. About 14% reported engagement in transactional sex. In all, 90% of MSM who engaged in transactional sex were knowledgeable of daily oral PrEP, while 13.3% were knowledgeable about long-acting injectable PrEP or penile or rectal microbicides. They were more likely to be aware of long-acting injectable PrEP (aRR = 2.52, 95% CI = 1.16 to 5.47) and willing to use daily oral PrEP (aRR = 1.48; 95% CI = 1.11 to 1.98) or long-acting injectable PrEP (aRR = 1.40; 95% CI = 1.09 to 1.81) than MSM who had not engaged in transactional sex. Long-acting injectable PrEP may be an important HIV-prevention option for MSM who engage in transactional sex if this modality is proven effective.


The molecular evolution of actin.
We have investigated the molecular evolution of plant and nonplant actin genes comparing nucleotide and amino acid sequences of 20 actin genes. Nucleotide changes resulting in amino acid substitutions (replacement substitutions) ranged from 3-7% for all pairwise comparisons of animal actin genes with the following exceptions. Comparisons between higher animal muscle actin gene sequences and comparisons between higher animal cytoplasmic actin gene sequences indicated less than 3% divergence. Comparisons between plant and nonplant actin genes revealed, with two exceptions, 11-15% replacement substitution. In the analysis of plant actins, replacement substitution between soybean actin genes SAc1, SAc3, SAc4 and maize actin gene MAc1 ranged from 8-10%, whereas these members within the soybean actin gene family ranged from 6-9% replacement substitution. The rate of sequence divergence of plant actin sequences appears to be similar to that observed for animal actins. Furthermore, these and other data suggest that the plant actin gene family is ancient and that the families of soybean and maize actin genes have diverged from a single common ancestral plant actin gene that originated long before the divergence of monocots and dicots. The soybean actin multigene family encodes at least three classes of actin. These classes each contain a pair of actin genes that have been designated kappa (SAc1, SAc6), lambda (SAc2, SAc4) and mu (SAc3, SAc7). The three classes of soybean actin are more divergent in nucleotide sequence from one another than higher animal cytoplasmic actin is divergent from muscle actin. The location and distribution of amino acid changes were compared between actin proteins from all sources. A comparison of the hydropathy of all actin sequences, except from Oxytricha, indicated a strong similarity in hydropathic character between all plant and nonplant actins despite the greater number of replacement substitutions in plant actins. These protein sequence comparisons are discussed with respect to the demonstrated and implicated roles of actin in plants and animals, as well as the tissue-specific expression of actin.


Which social network or support factors are associated with cognitive abilities in old age?
Social networks and support have been proposed as cognitively protective in old age. As studies often consider these social factors in isolation the question of which characteristics of the social environment are beneficial remains. The current study examined associations between measures of social networks (including contact with friends/family, marital status and living arrangement), feelings of loneliness and social support, and a range of cognitive outcomes. Social network, loneliness and support data were available in the Lothian Birth Cohort 1936 (LBC1936, n = 1,091) at age 70. Participants completed a battery of cognitive tests, and factor scores were available for general cognitive ability, and the cognitive domains of processing speed and memory. Childhood cognitive ability data from age 11 were also available. When examined in separate ANCOVAs, lower loneliness and more social support were significantly associated with better cognitive abilities at age 70, though not memory (independently of age, sex, childhood cognitive ability and social class), accounting for about 0.5-1.5% of the variance. When the social factors were considered simultaneously, higher loneliness remained associated with lower general cognitive ability (ηp(2) = 0.005, p = 0.046), and those living alone (ηp(2) = 0.007, p = 0.014) or with less social support (ηp(2) = 0.007, p = 0.016) had slower processing speed. When these final models were repeated including a depression symptoms score as a covariate, the associations between loneliness and general cognitive ability, and social support and processing speed, were no longer significant. However, the association between living alone and processing speed remained (ηp(2) = 0.006, p = 0.031). Of the social factors considered, loneliness, social support and living arrangement were most consistently associated with aspects of cognitive ability in older people, and these associations appeared to be partly, though not wholly, accounted for by symptoms of depression. Although longitudinal follow-up is required to examine the causal direction of the effects more definitively, it may be beneficial to promote the development of interventions to reduce loneliness and social isolation, and to increase social support.


Genomic sequencing is required for identification of tuberculosis transmission in Hawaii.
Tuberculosis (TB) caused an estimated 1.4 million deaths and 10.4 million new cases globally in 2015. TB rates in the United States continue to steadily decline, yet rates in the State of Hawaii are perennially among the highest in the nation due to a continuous influx of immigrants from the Western Pacific and Asia. TB in Hawaii is composed of a unique distribution of genetic lineages, with the Beijing and Manila families of Mycobacterium tuberculosis (Mtb) comprising over two-thirds of TB cases. Standard fingerprinting methods (spoligotyping plus 24-loci Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeats [MIRU-VNTR] fingerprinting) perform poorly when used to identify actual transmission clusters composed of isolates from these two families. Those typing methods typically group isolates from these families into large clusters of non-linked isolates with identical fingerprints. Next-generation whole-genome sequencing (WGS) provides a new tool for molecular epidemiology that can resolve clusters of isolates with identical spoligotyping and MIRU-VNTR fingerprints. We performed WGS and SNP analysis and evaluated epidemiological data to investigate 19 apparent TB transmission clusters in Hawaii from 2003 to 2017 in order to assess WGS' ability to resolve putative Mtb clusters from the Beijing and Manila families. This project additionally investigated MIRU-VNTR allele prevalence to determine why standard Mtb fingerprinting fails to usefully distinguish actual transmission clusters from these two Mtb families. WGS excluded transmission events in seven of these putative clusters, confirmed transmission in eight, and identified both transmission-linked and non-linked isolates in four. For epidemiologically identified clusters, while the sensitivity of MIRU-VNTR fingerprinting for identifying actual transmission clusters was found to be 100%, its specificity was only 28.6% relative to WGS. We identified that the Beijing and Manila families' significantly lower Shannon evenness of MIRU-VNTR allele distributions than lineage 4 was the cause of standard fingerprinting's poor performance when identifying transmission in Beijing and Manila family clusters. This study demonstrated that WGS is necessary for epidemiological investigation of TB in Hawaii and the Pacific.


Bidirectional associations between psychological distress and hearing problems: an 18-year longitudinal analysis of the British Household Panel Survey.
Hearing problems are a significant public health concern. It has been suggested that psychological distress may represent both a cause and a consequence of hearing problems. Prospective data that allow testing such potential bi-directionality have thus far been lacking. The present study aimed to address this knowledge gap. Random (RE) and fixed effects (FE) panel regression models estimated the association of psychological distress (GHQ-12) and participant-reported hearing problems. Data from 18 annual waves of the British Household Panel Survey were used (n = 10,008). Psychological distress was prospectively associated with self-reported hearing problems in women (multivariable odds ratios (ORs) ≥1.44; one-year time lag ≥ 1.16) and men (ORs ≥ 1.15; time lag ≥ 1.17). Conversely, self-reported hearing problems were associated with increases in psychological distress in both sexes (OR ≥ 1.26; time lag ≥ 1.08). These associations were independent of the analytical strategy and of adjustment for sociodemographic variables, lifestyle factors, and measurement period. We present first evidence of a bidirectional association between psychological distress and self-reported hearing problems. These findings suggest that stress management interventions may contribute to the prevention of self-reported hearing problems, and, in turn, alleviating self-reported hearing problems may reduce psychological distress.


Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type-2 mediated autoimmune disease.
We assessed the role of CD40-CD40L, cytotoxic T lymphocyte (CTL)A4/CD28-B7s, and CD2-CD48/CD58 lymphocyte costimulatory pathways in the development of mercury chloride (HgCl2)-induced autoimmune disease in mice, which is believed to be mediated by T helper (Th) subset Th2. Inhibition of CD40-CD40-L and CTLA4/CD28-B7s interactions by anti-CD40-L antibody and soluble CTLA4-immunoglobulin (Ig) fusion protein, respectively, abrogated the autoimmune disease without affecting interleukin 4 (IL-4) production, showing the importance of physical contact between T and B lymphocytes in the Th2-mediated process. In contrast, two anti-CD2 antibodies that have been shown to induce immunosuppression of Th1-mediated events exacerbated the autoantibody response and augmented IgG1, IgE, and IL-4 production, transforming a mild mesangial glomerulopathy into a severe systemic immune complex disease. These observations demonstrate that manipulation of lymphocyte accessory counterreceptor interactions may affect the course of Th2-associated autoimmune disease and suggest that signals resulting from CD2 engagement play an essential role in the regulation of the Th1-Th2 effector equilibrium.


Higher percentage of FISH-determined monosomy 3 and 8q amplification in uveal melanoma cells relate to poor patient prognosis.
To investigate the relation between patient survival and incrementally increasing percentages of fluorescence in situ hybridization-determined complete loss of chromosome 3 (monosomy 3) and gain of chromosome 8q in primary uveal melanoma cells. Clinicopathological factors were related to disease-free survival. Fluorescence in situ hybridization was performed using probes on chromosomes 1, 3, 6, and 8. The percentages of UM cells with monosomy 3 or chromosome 8q gain were classified in groups with incrementally increasing percentages and related to disease-free survival. Correlations between clinical factors and cytogenetic aberrations were also analyzed. Two-hundred twenty choroidal and ciliary body melanomas were analyzed. The following proved to be significant predictors of survival in univariate analysis: older patient age (P = 0.003); large tumor diameter (P < 0.001); mixed cell type (P = 0.001); presence of closed microvascular loops (P < 0.001); loss of chromosome 1p (P = 0.006); monosomy 3 (P < 0.001); gain of 6p (P < 0.001); and gain of chromosome 8q (P < 0.001). Multivariate Cox analysis displayed monosomy 3 (Hazard ratio [HR] 2.83, P = 0.002) and gain of chromosome 8q (HR 3.13, P = 0.002) as the most important independent prognostic factors of poor survival, followed by older patient age (HR 1.02, P = 0.017). Increasing percentages of monosomy 3 and gain of chromosome 8q in tumor cells showed a correlation with worse prognosis (Log-rank test 49.9 and 40.4, both P < 0.001) and increased number of additional copies of 8q correlated with shorter disease-free interval (Log-rank test 45.7, P < 0.001). A high percentage monosomy 3 and chromosome 8q gain in primary UM cells showed a strong relation with poor disease-free survival compared with low percentage aberrations.


Placebo response rate in clinical trials of fistulizing Crohn's disease: systematic review and meta-analysis.
It is important to determine the magnitude and identify modifiers of the rate of response to placebo in clinical trials of fistulizing Crohn's disease (CD), to understand disease progression, and to calculate sample size. We conducted a systematic review and meta-analysis of rates of response to placebo in trials of patients with fistulizing CD. We searched MEDLINE, EMBASE, EMBASE CLASSIC, and the Cochrane central register of controlled trials for randomized controlled trials (RCTs) comparing pharmacologic agents with placebo in adults with fistulizing CD. We identified studies that reported complete fistula closure, partial closure, or response. Data were extracted as intention-to-treat analyses and pooled by using a random-effects model. Proportions of patients who received placebo and had complete or partial fistula(e) closure were calculated, with 95% confidence intervals (CIs). The effects of trial characteristics on the magnitude of response to placebo were examined. Thirteen RCTs were eligible for our analysis; these included 579 patients assigned to placebo groups. The pooled rate of response to placebo, among all RCTs, for complete fistula closure was 15.6% (95% CI, 10.9%-20.9%), with significant heterogeneity (I(2) = 62.5%, P = .001). The pooled rate of response to placebo for partial fistula closure or response in 9 trials, comprising 423 patients, was 18.3% (95% CI, 14.8%-22.1%). Rates of response to placebo were significantly lower in trials with shorter durations of therapy and shorter intervals to assessment of fistula closure. Neither exposure to the pharmacologic agent during the induction phase of the same (or related) RCT nor concomitant medications had any effect. In a meta-analysis of rate of response to placebo in patients with fistulizing CD, we found that fistulae closed in almost 1/6 patients given placebo in RCTs of pharmacologic agents. Future research should identify characteristics of patients that predict response to placebo.


Autocrine fibroblast growth factor 18 mediates dexamethasone-induced osteogenic differentiation of murine mesenchymal stem cells.
The potential of mesenchymal stem cells (MSC) to differentiate into functional bone forming cells provides an important tool for bone regeneration. The identification of factors capable of promoting osteoblast differentiation in MSCs is therefore critical to enhance the osteogenic potential of MSCs. Using microarray analysis combined with biochemical and molecular approach, we found that FGF18, a member of the FGF family, is upregulated during osteoblast differentiation induced by dexamethasone in murine MSCs. We showed that overexpression of FGF18 by lentiviral (LV) infection, or treatment of MSCs with recombinant human (rh)FGF18 increased the expression of the osteoblast specific transcription factor Runx2, and enhanced osteoblast phenotypic marker gene expression and in vitro osteogenesis. Molecular silencing using lentiviral shRNA demonstrated that downregulation of FGFR1 or FGFR2 abrogated osteoblast gene expression induced by either LV-FGF18 or rhFGF18, indicating that FGF18 enhances osteoblast differentiation in MSCs via activation of FGFR1 or FGFR2 signaling. Biochemical and pharmacological analyses showed that the induction of phenotypic osteoblast markers by LV-FGF18 is mediated by activation of ERK1/2-MAPKs and PI3K signaling in MSCs. These results reveal that FGF18 is an essential autocrine positive regulator of the osteogenic differentiation program in murine MSCs and indicate that osteogenic differentiation induced by FGF18 in MSCs is triggered by FGFR1/FGFR2-mediated ERK1/2-MAPKs and PI3K signaling.


A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors.
The transmission of electric fields using insulated electrodes has demonstrated that very low-intensity, properly tuned, intermediate-frequency electric fields, termed tumor-treating fields (TTFields), selectively stunts tumor cell growth and is accompanied by a decrease in tumor angiogenesis. This open, prospective pilot study was designed to evaluate the safety, tolerability, and efficacy profile of TTFields treatment in patients with locally advanced and/or metastatic solid tumors using the NovoTTF100A(TM) device. All 6 patients were heavily pre-treated with several lines of therapy; no additional standard treatment option was available to them. TTFields treatment using continuous NovoTTF-100A lasted a minimum of 14 days and was very well tolerated. No related serious adverse events occurred. Outcomes showed 1 partial response of a treated skin metastasis from a primary breast cancer, 3 cases where tumor growth was arrested during treatment, and 1 case of disease progression. One mesothelioma patient experienced lesion regression near TTFields with simultaneous tumor stability or progression in distal areas. Although the number of patients in this study is small, the lack of therapy toxicity and the efficacy observed in data gathered to date indicate the potential of TTFields as a new treatment modality for solid tumors, definitely warranting further investigation.


Association between socioeconomic and demographic characteristics and utilization of colonoscopy in the EPIC-Heidelberg cohort.
We aimed to describe the utilization of colonoscopy and its association with sociodemographic characteristics within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort study. We included 15 014 study participants (43% men) of the EPIC-Heidelberg cohort recruited between 1994 and 1998. At baseline recruitment, as well as in the 3-yearly follow-up surveys, study participants completed questionnaires on lifestyle, socioeconomic background variables, health status, and use of medications and medical services, including colonoscopy examinations. The present analyses focused on participants who completed the question on colonoscopy examination in all follow-up rounds. Our results show that by the end of the fourth follow-up round, more than half of all participants of the EPIC-Heidelberg cohort had had a colonoscopy. Colonoscopy was associated with some socioeconomic and demographic characteristics: a positive association with vocational training level as well as overall socioeconomic status level [International Standard Classification of Education (ISCED) classification]. A negative association was found for household size and employment status. Colonoscopy usage increased steeply within the subgroup of participants older than 55 years of age and decreased again within the subgroup of participants older than 75 years of age. Organized colorectal cancer screening should include a written invitation system, to overcome the problem of sociodemographic-related differential awareness of and attendance at colonoscopy examinations. Also, the high proportion of prescreened individuals should be taken into account to avoid unnecessary re-examinations.


Estimating relative risk of within-lake aquatic plant invasion using combined measures of recreational boater movement and habitat suitability.
Effective monitoring, prevention and impact mitigation of nonindigenous aquatic species relies upon the ability to predict dispersal pathways and receiving habitats with the greatest risk of establishment. To examine mechanisms affecting species establishment within a large lake, we combined observations of recreational boater movements with empirical measurements of habitat suitability represented by nearshore wave energy to assess the relative risk of Eurasian watermilfoil (Myriophyllum spicatum) establishment. The model was evaluated using information from a 17 year (1995-2012) sequence of M. spicatum presence and absence monitoring. M. spicatum presence was not specifically correlated with recreational boater movements; however its establishment appears to be limited by wave action in Lake Tahoe. Of the sites in the "High" establishment risk category (n = 37), 54% had current or historical infestations, which included 8 of the 10 sites with the highest relative risk. Of the 11 sites in the "Medium" establishment risk category, 5 had current or historical M. spicatum populations. Most (76%) of the sites in the "Low" establishment risk category were observed in locations with higher wave action. Four sites that received zero boater visits from infested locations were occupied by M. spicatum. This suggests that the boater survey either represents incomplete coverage of boater movement, or other processes, such as the movement of propagules by surface currents or introductions from external sources are important to the establishment of this species. This study showed the combination of habitat specific and dispersal data in a relative risk framework can potentially reduce uncertainty in estimates of invasion risk.


A Binaural Neuromorphic Auditory Sensor for FPGA: A Spike Signal Processing Approach.
This paper presents a new architecture, design flow, and field-programmable gate array (FPGA) implementation analysis of a neuromorphic binaural auditory sensor, designed completely in the spike domain. Unlike digital cochleae that decompose audio signals using classical digital signal processing techniques, the model presented in this paper processes information directly encoded as spikes using pulse frequency modulation and provides a set of frequency-decomposed audio information using an address-event representation interface. In this case, a systematic approach to design led to a generic process for building, tuning, and implementing audio frequency decomposers with different features, facilitating synthesis with custom features. This allows researchers to implement their own parameterized neuromorphic auditory systems in a low-cost FPGA in order to study the audio processing and learning activity that takes place in the brain. In this paper, we present a 64-channel binaural neuromorphic auditory system implemented in a Virtex-5 FPGA using a commercial development board. The system was excited with a diverse set of audio signals in order to analyze its response and characterize its features. The neuromorphic auditory system response times and frequencies are reported. The experimental results of the proposed system implementation with 64-channel stereo are: a frequency range between 9.6 Hz and 14.6 kHz (adjustable), a maximum output event rate of 2.19 Mevents/s, a power consumption of 29.7 mW, the slices requirements of 11141, and a system clock frequency of 27 MHz.


Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy.
The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.


The Interactive Origin of Iconicity.
We investigate the emergence of iconicity, specifically a bouba-kiki effect in miniature artificial languages under different functional constraints: when the languages are reproduced and when they are used communicatively. We ran transmission chains of (a) participant dyads who played an interactive communicative game and (b) individual participants who played a matched learning game. An analysis of the languages over six generations in an iterated learning experiment revealed that in the Communication condition, but not in the Reproduction condition, words for spiky shapes tend to be rated by naive judges as more spiky than the words for round shapes. This suggests that iconicity may not only be the outcome of innovations introduced by individuals, but, crucially, the result of interlocutor negotiation of new communicative conventions. We interpret our results as an illustration of cultural evolution by random mutation and selection (as opposed to by guided variation).


A Review of Pathophysiology, Clinical Features, and Management Options of COVID-19 Associated Coagulopathy.
There is increasing evidence that novel coronavirus disease 2019 (COVID-19) leads to a significant coagulopathy, a phenomenon termed "COVID-19 associated coagulopathy." COVID-19 has been associated with increased rates of both venous and arterial thromboembolic events, a source of significant morbidity and mortality in this disease. Further evidence suggests a link between the inflammatory response and coagulopathy associated with COVID-19. This presents a unique set of challenges for diagnosis, prevention, and treatment of thrombotic complications. In this review, we summarize and discuss the current literature on laboratory coagulation disruptions associated with COVID-19 and the clinical effects of thromboembolic events including pulmonary embolism, deep vein thrombosis, peripheral arterial thrombosis, and acute ischemic stroke in COVID-19. Endothelial injury and augmented innate immune response are implicated in the development of diffuse macro- and microvascular thrombosis in COVID-19. The pathophysiology of COVID-19 associated coagulopathy is an important determinant of appropriate treatment and monitoring of these complications. We highlight the importance of diagnosis and management of dysregulated coagulation in COVID-19 to improve outcomes in COVID-19 patients with thromboembolic complications.


A review of methods available to estimate solvent-accessible surface areas of soluble proteins in the folded and unfolded states.
Solvent accessible surface area (SASA) of proteins has always been considered as a decisive factor in protein folding and stability studies. It is defined as the surface characterized around a protein by a hypothetical centre of a solvent sphere with the van der Waals contact surface of the molecule. Based on SASA values, amino acid residues of a protein can be classified as buried or exposed. There are various types of SASAs starting from relative solvent accessibility to absolute surface areas. Direct estimation of accurate SASAs of folded proteins experimentally at the atomic level is not possible. However, the SASA of a native protein can be estimated computationally from the atomic coordinates. Similarly, various simulation methods are available to compute the SASA of a protein in its unfolded state. In efforts to estimate the changes in SASA related to the protein folding, a number of the unfolded state models have been proposed. In this review, we have summarized different algorithms and computational tools for SASA estimations. Furthermore, online resources for SASA calculations and representations have also been discussed in detail. This review will be useful for protein chemists and biologists for the accurate measurements of SASA and its subsequent applications for the calculation of various biophysical and thermodynamic properties of proteins.


3-dimensional imaging of the pelviocaliceal system by computerized tomographic reconstruction.
Safe and efficient performance of percutaneous nephrolithotomy requires 3-dimensional visualization of the pelviocaliceal anatomy. However, currently available modalities offer only 2-dimensional images, from which the operator must mentally reconstruct a 3-dimensional picture of the pelviocaliceal configuration. We evaluated the feasibility of obtaining 3-dimensional images of the pelviocaliceal system with the aid of computerized tomographic reconstruction and present 3 illustrative cases.


Dentinal tubule occlusion and root hypersensitivity.
Previous studies have established that root sensitivity is due in part to open dentinal tubules at the root surface. The purpose of this study was to longitudinally evaluate the occlusion of dentinal tubules by various clinical procedures including scaling and root planing and the application of potassium oxalate. A model was developed to evaluate dentinal surfaces in vivo. Six 2 mm x 3 mm sections were taken from the roots of extracted teeth immediately below the CEJ. One half of the treated dentin samples from each donor was incorporated into the removable denture worn by the donor and the other half served as baseline. The dentin samples were evaluated at 1 week by scanning electron microscopy. At day zero no open tubules were observed in any of the samples due to the presence of a smear layer or oxalate crystals. Evaluation of root planed samples revealed that by 7 days the tubules had re-opened. The samples which had been treated with potassium oxalate showed few oxalate crystals by 7 days revealing open tubules. Control samples were etched with EDTA and evaluated in the same manner. Although the number of tubules did not significantly change in the EDTA etched control samples, the diameter of the tubules dramatically decreased by 4 weeks. It can be concluded that the creation of a smear layer or application of oxalates to occlude dentinal tubules to reduce sensitivity are relatively short-lived. These procedures may provide patient comfort prior to natural occlusion of the tubules.


A vascular endothelial growth factor receptor-2 kinase inhibitor potentiates the activity of the conventional chemotherapeutic agents paclitaxel and doxorubicin in tumor xenograft models.
Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 microM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition, JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs doxorubicin and paclitaxel in xenograft models when administered orally in combination therapy. An orally available angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of cancer and preventing metastasis.


Structural and biochemical characterization of the salicylyl-acyltranferase SsfX3 from a tetracycline biosynthetic pathway.
SsfX3 is a GDSL family acyltransferase that transfers salicylate to the C-4 hydroxyl of a tetracycline intermediate in the penultimate step during biosynthesis of the anticancer natural product SF2575. The C-4 salicylate takes the place of the more common C-4 dimethylamine functionality, making SsfX3 the first acyltransferase identified to act on a tetracycline substrate. The crystal structure of SsfX3 was determined at 2.5 Å, revealing two distinct domains as follows: an N-terminal β-sandwich domain that resembles a carbohydrate-binding module, and a C-terminal catalytic domain that contains the atypical α/β-hydrolase fold found in the GDSL hydrolase family of enzymes. The active site lies at one end of a large open binding pocket, which is spatially defined by structural elements from both the N- and C-terminal domains. Mutational analysis in the putative substrate binding pocket identified residues from both domains that are important for binding the acyl donor and acceptor. Furthermore, removal of the N-terminal carbohydrate-binding module-like domain rendered the stand-alone α/β-hydrolase domain inactive. The additional noncatalytic module is therefore proposed to be required to define the binding pocket and provide sufficient interactions with the spatially extended tetracyclic substrate. SsfX3 was also demonstrated to accept a variety of non-native acyl groups. This relaxed substrate specificity toward the acyl donor allowed the chemoenzymatic biosynthesis of C-4-modified analogs of the immediate precursor to the bioactive SF2575; these were used to assay the structure activity relationships at the C-4 position.


International consensus on a standard set of outcome measures for child and youth anxiety, depression, obsessive-compulsive disorder, and post-traumatic stress disorder.
A major barrier to improving care effectiveness for mental health is a lack of consensus on outcomes measurement. The International Consortium for Health Outcomes Measurement (ICHOM) has already developed a consensus-based standard set of outcomes for anxiety and depression in adults (including the Patient Health Questionnaire-9, the Generalised Anxiety Disorder 7-item Scale, and the WHO Disability Schedule). This Position Paper reports on recommendations specifically for anxiety, depression, obsessive-compulsive disorder, and post-traumatic stress disorder in children and young people aged between 6 and 24 years. An international ICHOM working group of 27 clinical, research, and lived experience experts formed a consensus through teleconferences, an exercise using an adapted Delphi technique (a method for reaching group consensus), and iterative anonymous voting, supported by sequential research inputs. A systematic scoping review identified 70 possible outcomes and 107 relevant measurement instruments. Measures were appraised for their feasibility in routine practice (ie, brevity, free availability, validation in children and young people, and language translation) and psychometric performance (ie, validity, reliability, and sensitivity to change). The final standard set recommends tracking symptoms, suicidal thoughts and behaviour, and functioning as a minimum through seven primarily patient-reported outcome measures: the Revised Children's Anxiety and Depression Scale, the Obsessive Compulsive Inventory for Children, the Children's Revised Impact of Events Scale, the Columbia Suicide Severity Rating Scale, the KIDSCREEN-10, the Children's Global Assessment Scale, and the Child Anxiety Life Interference Scale. The set's recommendations were validated through a feedback survey involving 487 participants across 45 countries. The set should be used alongside the anxiety and depression standard set for adults with clinicians selecting age-appropriate measures.


Rayleigh scattering, absorption, and birefringence of large-size bulk single-crystal sapphire.
While the thermomechanical properties of sapphire make it an excellent candidate of test mass for advanced laser interferometers, its optical quality is not well understood or well controlled. We have studied the results from high-resolution measurements of scattering, absorption, and birefringence in test-mass samples to better understand issues of quality. Samples show large-scale scattering structures clearly linked to the crystal-growth process. Samples characterized by the presence of point defects have significantly lower scattering (except at the point defects). In general on a large scale, high scattering also correlates with higher absorption and higher average birefringence inhomogeneity. However, on a smaller scale there is not a clear point-to-point correlation between scattering and absorption. Often a large-scale scattering structure is spatially displaced by tens of millimeters from a similar absorption structure, indicating that quite separate microscopic mechanisms give rise to scattering and absorption. The spatial displacements indicate that absorption centers and scattering centers are laid down during crystal growth at different distances from the solid-liquid interface. We suggest that absorption may be linked to F centers, while scattering may be linked to impurities such as iron.


Compliance of medical students with voluntary use of personal data assistants for clerkship assessments.
For several years, final-year students at McMaster University have been required to complete 10 mini-CEX type assessments per rotation. A similar system was being introduced at Ottawa. To facilitate data capture, we decided to introduce a personal data assistant (PDA)-based system and evaluate its impact. A randomized trial was designed to compare the acceptability of PDA and printed evaluation forms. The trial failed because of clerks' unwillingness to use PDAs. A focus group was held and user surveys were administered, chiefly by e-mail, to explore students' preference for printed forms. Thirty percent of invited clerks (52/176) agreed to use a PDA; 6% (11; 21% of those agreeing) recorded one or more encounters; 2% (4) recorded at least the minimum number of evaluations required by their program. Most survey respondents expressed concerns related primarily to the relative inconvenience of PDAs compared to paper, a judgment reflecting the time required both to install required software and to become familiar with the software and data entry form, and to record information via the form. A minority were also concerned about assessors' willingness or ability to use PDA forms. Before asking students and clinical supervisors to use a PDA-based encounter-evaluation form in clerkship, planners should conduct a careful assessment of the advantages and disadvantages for students of the system they hope to implement. The prima facie greater convenience and efficiency of the PDA may actually be offset by workplace disincentives and inefficiencies in data recording, relative to the incentives and efficiencies associated with a system based on printed (paper) forms.


Urban ponds as an aquatic biodiversity resource in modified landscapes.
Urbanization is a global process contributing to the loss and fragmentation of natural habitats. Many studies have focused on the biological response of terrestrial taxa and habitats to urbanization. However, little is known regarding the consequences of urbanization on freshwater habitats, especially small lentic systems. In this study, we examined aquatic macro-invertebrate diversity (family and species level) and variation in community composition between 240 urban and 782 nonurban ponds distributed across the United Kingdom. Contrary to predictions, urban ponds supported similar numbers of invertebrate species and families compared to nonurban ponds. Similar gamma diversity was found between the two groups at both family and species taxonomic levels. The biological communities of urban ponds were markedly different to those of nonurban ponds, and the variability in urban pond community composition was greater than that in nonurban ponds, contrary to previous work showing homogenization of communities in urban areas. Positive spatial autocorrelation was recorded for urban and nonurban ponds at 0-50 km (distance between pond study sites) and negative spatial autocorrelation was observed at 100-150 km and was stronger in urban ponds in both cases. Ponds do not follow the same ecological patterns as terrestrial and lotic habitats (reduced taxonomic richness) in urban environments; in contrast, they support high taxonomic richness and contribute significantly to regional faunal diversity. Individual cities are complex structural mosaics which evolve over long periods of time and are managed in diverse ways. This facilitates the development of a wide range of environmental conditions and habitat niches in urban ponds which can promote greater heterogeneity between pond communities at larger scales. Ponds provide an opportunity for managers and environmental regulators to conserve and enhance freshwater biodiversity in urbanized landscapes whilst also facilitating key ecosystem services including storm water storage and water treatment.


Robust two-stage influenza prediction model considering regular and irregular trends.
Influenza causes numerous deaths worldwide every year. Predicting the number of influenza patients is an important task for medical institutions. Two types of data regarding influenza-like illnesses (ILIs) are often used for flu prediction: (1) historical data and (2) user generated content (UGC) data on the web such as search queries and tweets. Historical data have an advantage against the normal state but show disadvantages against irregular phenomena. In contrast, UGC data are advantageous for irregular phenomena. So far, no effective model providing the benefits of both types of data has been devised. This study proposes a novel model, designated the two-stage model, which combines both historical and UGC data. The basic idea is, first, basic regular trends are estimated using the historical data-based model, and then, irregular trends are predicted by the UGC data-based model. Our approach is practically useful because we can train models separately. Thus, if a UGC provider changes the service, our model could produce better performance because the first part of the model is still stable. Experiments on the US and Japan datasets demonstrated the basic feasibility of the proposed approach. In the dropout (pseudo-noise) test that assumes a UGC service would change, the proposed method also showed robustness against outliers. The proposed model is suitable for prediction of seasonal flu.


Stent graft types for endovascular repair of thoracic aortic aneurysms.
The UK prevalence of thoracic aneurysm is estimated at 10.4 per 100,000 person-years. Progressive and unpredictable enlargement can lead to rupture. Endovascular repair of thoracic aortic aneurysms involves a stent graft system being introduced via the femoral artery and manipulated within the aorta under radiological guidance. Following endograft deployment, a seal is formed at the proximal and distal landing zones to exclude the aneurysm sac from the circulation. With the increasing popularity of endovascular repair there has been an increase in the number of commercially available stent graft designs on the market. This review aimed to assess the different stent graft types for endovascular repair of thoracic aortic aneurysms. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched November 2012) and CENTRAL (2012, Issue 11). Trial databases were searched by the TSC for details of ongoing and unpublished studies. All published and unpublished randomised controlled trials (RCTs) of stent graft types in the repair of thoracic aortic aneurysms were sought without language restriction. Data collection and analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. No studies were identified that met the inclusion criteria. Unfortunately, no data exist regarding direct comparisons of the performance of different stent graft types. Therefore, this review cannot recommend guidance to clinicians in their selection of stent graft types. High quality RCTs evaluating stent graft types in thoracic endovascular aneurysm repair are required.


Lycium barbarum L. Polysaccharide (LBP) Reduces Glucose Uptake via Down-Regulation of SGLT-1 in Caco2 Cell.
Lycium barbarum L. polysaccharide (LBP) is prepared from Lycium barbarum L. (L. barbarum), which is a traditional Chinese medicine. LPB has been shown to have hypoglycemic effects. In order to gain some mechanistic insights on the hypoglycemic effects of LBP, we investigated the uptake of LBP and its effect on glucose absorption in the human intestinal epithelial cell line Caco2 cell. The uptake of LBP through Caco2 cell monolayer was time-dependent and was inhibited by phloridzin, a competitive inhibitor of SGLT-1. LPB decreased the absorption of glucose in Caco2 cell, and down-regulated the expression of SGLT-1. These results suggest that LBP might be transported across the human intestinal epithelium through SGLT-1 and it inhibits glucose uptake via down-regulating SGLT-1.