Regenerating matrix-based therapy for chronic wound healing: a prospective within-subject pilot study.
The aim of this study was to determine whether a skin-specific bioengineered regenerating agent (RGTA) heparan sulphate mimetic (CACIPLIQ20) improves chronic wound healing. The design of this article is a prospective within-subject study. The setting was an urban hospital. Patients were 16 African-American individuals (mean age 42 years) with 22 wounds (mean duration 2.5 years) because of either pressure, diabetic, vascular or burn wounds. Two participants each were lost to follow-up or removed because of poor compliance, resulting in 18 wounds analysed. Sterile gauze was soaked with CACIPLIQ20 saline solution, placed on the wound for 5 min, then removed twice weekly for 4 weeks. Wounds were otherwise treated according to the standard of care. Twenty-two percent of wounds fully healed during the treatment period. Wounds showed a 15.2-18.1% decrease in wound size as measured by the vision engineering research group (VERG) digital wound measurement system and total PUSH scores, respectively, at 4 weeks (P = 0.014 and P = 0.003). At 8 weeks there was an 18-26% reduction in wound size (P = 0.04) in the remaining patients. Wound-related pain measured by the visual analogue pain scale and the wound pain scale declined 60% (P = 0.024) and 70% (P = 0.001), respectively. Patient and clinician satisfaction remained positive throughout the treatment period. It is concluded that treatment with CACIPLIQ20 significantly improved wound-related pain and may facilitate wound healing. Patient and clinician satisfaction remained high throughout the trial.


Attention-deficit/hyperactivity disorder as a risk factor for being involved in intimate partner violence and sexual violence: a systematic review and meta-analysis.
Intimate partner violence (IPV) and sexual violence (SV) are significant problems world-wide, and they affect women disproportionally. Whether individuals with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of being involved in these types of violence is unclear. We carried out a systematic review and meta-analysis (PROSPERO registration CRD42022348165) of the associations between ADHD and being the victim or perpetrator of IPV and SV. Ratios of occurrence of violence were pooled in random-effects models and study risk of bias was evaluated using the Newcastle-Ottawa Scale. A search on multiple databases, carried out on 7 October 2022, yielded 14 eligible studies (1 111 557 individuals). Analyses showed a higher risk of ADHD individuals being involved in IPV as perpetrators (six studies, OR 2.5, 95% CI 1.51-4.15) or victims (four studies, OR 1.78, 95% CI 1.06-3.0). Likewise, individuals with ADHD were at increased risk of being perpetrators (three studies, OR 2.73, 95% CI 1.35-5.51) or victims of SV (six studies, OR 1.84, 95% CI 1.51-2.24). Results were overall robust to different analytical choices. Individuals with ADHD are at an increased risk of being involved in cases of violence, namely IPV and SV, either as victims or perpetrators. Although the causal path or mediating variables for these results are still unclear, this increased risk should inform evidence-based psychoeducation with individuals with ADHD, their families, and partners about romantic relationships and sexuality.


Interleukin-6 and interleukin-10 as acute kidney injury biomarkers in pediatric cardiac surgery.
Children undergoing cardiac surgery may exhibit a pronounced inflammatory response to cardiopulmonary bypass (CPB). Inflammation is recognized as an important pathophysiologic process leading to acute kidney injury (AKI). The aim of this study was to evaluate the association of the inflammatory cytokines interleukin (IL)-6 and IL-10 with AKI and other adverse outcomes in children after CPB surgery. This is a sub-study of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) cohort, including 106 children ranging in age from 1 month to 18 years undergoing CPB. Plasma IL-6 and IL-10 concentrations were measured preoperatively and postoperatively [day 1 (within 6 h after surgery) and day 3]. Stage 2/3 AKI, defined by at least a doubling of the baseline serum creatinine concentration or dialysis, was diagnosed in 24 (23%) patients. The preoperative IL-6 concentration was significantly higher in patients with stage 2/3 AKI [median 2.6 pg/mL, interquartile range (IQR) 2.6 0.6-4.9 pg/mL] than in those without stage 2/3 AKI (median 0.6 pg/mL, IQR 0.6-2.2 pg/mL) (p = 0.03). After adjustment for clinical and demographic variables, the highest preoperative IL-6 tertile was associated with a sixfold increased risk for stage 2/3 AKI compared with the lowest tertile (adjusted odds ratio 6.41, 95 % confidence interval 1.16-35.35). IL-6 and IL-10 levels increased significantly after surgery, peaking postoperatively on day 1. First postoperative IL-6 and IL-10 measurements did not significantly differ between patients with stage 2/3 AKI and those without stage 2/3 AKI. The elevated IL-6 level on day 3 was associated with longer hospital stay (p = 0.0001). Preoperative plasma IL-6 concentration is associated with the development of stage 2/3 AKI and may be prognostic of resource utilization.


Interfering ribonucleic acids that suppress expression of multiple unrelated genes.
Short interfering RNAs (siRNAs) have become the research tool of choice for gene suppression, with human clinical trials ongoing. The emphasis so far in siRNA therapeutics has been the design of one siRNA with complete complementarity to the intended target. However, there is a need for multi-targeting interfering RNA in diseases in which multiple gene products are of importance. We have investigated the possibility of using a single short synthetic duplex RNA to suppress the expression of VEGF-A and ICAM-1; genes implicated in the progression of ocular neovascular diseases such as diabetic retinopathy. Duplex RNA were designed to have incomplete complementarity with the 3'UTR sequences of both target genes. One such duplex, CODEMIR-1, was found to suppress VEGF and ICAM-1 by 90 and 60%, respectively in ARPE-19 cells at a transfected concentration of 40 ng/mL. Use of a cyan fusion reporter with target sites constructed in its 3'UTR demonstrated that the repression of VEGF and ICAM-1 by CODEMIR-1 was indeed due to interaction with the target sequence. An exhaustive analysis of sequence variants of CODEMIR-1 demonstrated a clear positive correlation between activity against VEGF (but not ICAM-1) and the length of the contiguous complementary region (from the 5' end of the guide strand). Various strategies, including the use of inosine bases at the sites of divergence of the target sequences were investigated. Our work demonstrates the possibility of designing multitargeting dsRNA to suppress more than one disease-altering gene. This warrants further investigation as a possible therapeutic approach.


Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus on primary anatomic site.
The aetiology of marginal zone lymphoma (MZL) is purported to differ by anatomic site. While this is supported by clinical series of single MZL sites, no population-based study has comprehensively assessed incidence patterns across sites. To gain insight into disease aetiology, we assessed MZL incidence by site using data from 18 U.S. Surveillance, Epidemiology and End Results (SEER) Program population-based registries. We calculated age-adjusted incidence rates (IRs) by sex, race, and calendar year. During 2001-2009, 4,081 (IR = 5·7/1,000,000 person-years) and 8,821 (IR = 12·3) individuals were diagnosed with nodal MZL and extranodal MZL, respectively. The most common extranodal sites were stomach (IR = 3·8), spleen (IR = 1·6), eye/adnexa (IR = 1·4), and lung, skin, and salivary glands (IRs = 0·9-1·0). We observed distinct age-specific patterns by MZL site, with IRs increasing steeply at younger ages and less prominently after mid-life at several sites, except skin. Gender and racial/ethnic disparities were also apparent across sites. Between 2001-2005 and 2006-2009, MZL IRs decreased significantly for gastric (-15%) and soft tissue (-28%) sites, whereas IRs increased significantly for lung (18%), skin (43%), and kidney/renal pelvis (116%). In combination, our findings support the contention that MZL is characterized by aetiological heterogeneity across sites and susceptibility is probably influenced by intrinsic characteristics and environmental exposures.


Cofilin nuclear-cytoplasmic shuttling affects cofilin-actin rod formation during stress.
Cofilin protein is involved in regulating the actin cytoskeleton during typical steady state conditions, as well as during cell stress conditions where cofilin saturates F-actin, forming cofilin-actin rods. Cofilin can enter the nucleus through an active nuclear localization signal (NLS), accumulating in nuclear actin rods during stress. Here, we characterize the active nuclear export of cofilin through a leptomycin-B-sensitive, CRM1-dependent, nuclear export signal (NES). We also redefine the NLS of cofilin as a bipartite NLS, with an additional basic epitope required for nuclear localization. Using fluorescence lifetime imaging microscopy (FLIM) and Förster resonant energy transfer (FRET) between cofilin moieties and actin, as well as automated image analysis in live cells, we have defined subtle mutations in the cofilin NLS that allow cofilin to bind actin in vivo and affect cofilin dynamics during stress. We further define the requirement of cofilin-actin rod formation in a system of cell stress by temporal live-cell imaging. We propose that cofilin nuclear shuttling is critical for the cofilin-actin rod stress response with cofilin dynamically communicating between the nucleus and cytoplasm during cell stress.


Prevalence of Yersinia pestis in rodents and fleas associated with black-tailed prairie dogs (Cynomys ludovicianus) at Thunder Basin National Grassland, Wyoming.
Rodents (and their fleas) that are associated with prairie dogs are considered important for the maintenance and transmission of the bacterium (Yersinia pestis) that causes plague. Our goal was to identify rodent and flea species that were potentially involved in a plague epizootic in black-tailed prairie dogs at Thunder Basin National Grassland. We collected blood samples and ectoparasites from rodents trapped at off- and on-colony grids at Thunder Basin National Grassland between 2002 and 2004. Blood samples were tested for antibodies to Y. pestis F-1 antigen by a passive hemagglutination assay, and fleas were tested by a multiplex polymerase chain reaction, for the presence of the plague bacterium. Only one of 1,421 fleas, an Oropsylla hirsuta collected in 2002 from a deer mouse, Peromyscus maniculatus, tested positive for Y. pestis. Blood samples collected in summer 2004 from two northern grasshopper mice, Onychomys leucogaster, tested positive for Y. pestis antibodies. All three positive samples were collected from on-colony grids shortly after a plague epizootic occurred. This study confirms that plague is difficult to detect in rodents and fleas associated with prairie dog colonies, unless samples are collected immediately after a prairie dog die-off.


Kidneys for sale: who disapproves, and why?
The shortage of transplant kidneys has spurred debate about legalizing monetary payments to donors to increase the number of available kidneys. However, buying and selling organs faces widespread disapproval. We survey a representative sample of Americans to assess disapproval for several forms of kidney market, and to understand why individuals disapprove by identifying factors that predict disapproval, including disapproval of markets for other body parts, dislike of increased scope for markets and distrust of markets generally. Our results suggest that while the public is potentially receptive to compensating kidney donors, among those who oppose it, general disapproval toward certain kinds of transactions is at least as important as concern about specific policy details. Between 51% and 63% of respondents approve of the various potential kidney markets we investigate, and between 42% and 58% want such markets to be legal. A total of 38% of respondents disapprove of at least one market. Respondents who distrust markets generally are not more disapproving of kidney markets; however we find significant correlations between kidney market disapproval and attitudes reflecting disapproval toward certain transactions-including both other body markets and market encroachment into traditionally nonmarket exchanges, such as food preparation.


Applying Novel Methods for Assessing Individual- and Neighborhood-Level Social and Psychosocial Environment Interactions with Genetic Factors in the Prediction of Depressive Symptoms in the Multi-Ethnic Study of Atherosclerosis.
Complex illnesses, like depression, are thought to arise from the interplay between psychosocial stressors and genetic predispositions. Approaches that take into account both personal and neighborhood factors and that consider gene regions as well as individual SNPs may be necessary to capture these interactions across race and ethnic groups. We used novel gene-region based analysis methods [Sequence Kernel Association Test (SKAT) and meta-analysis (MetaSKAT), gene-environment set association test (GESAT)], as well as traditional linear models to identify gene region and SNP × psychosocial factor interactions at the individual- and neighborhood-level, across multiple race/ethnicities. Multiple regions identified in SKAT analyses showed evidence of a significant gene-region association with averaged depressive symptom scores across race/ethnicity (MetaSKAT p values <0.001). One region × neighborhood-environment interaction was significantly associated with averaged depressive symptom score across race/ethnicity after multiple testing correction (chr 18:21454070-21494070, Fisher's combined p value = 0.001). The examination of gene regions jointly with environmental factors measured at multiple levels (individuals and their contexts) may shed light on the etiology of depressive illness across race/ethnicities.


Water distribution system and diarrheal disease transmission: a case study in Uzbekistan.
Deteriorating water treatment facilities and distribution systems pose a significant public health threat, particularly in republics of the former Soviet Union. Interventions to decrease the disease burden associated with these water systems range from upgrading distribution networks to installing reverse osmosis technology. To provide insight into this decision process, we conducted a randomized intervention study to provide epidemiologic data for water policy decisions in Nukus, Uzbekistan, where drinking water quality is suboptimal. We interviewed residents of 240 households, 120 with and 120 without access to municipal piped water. Residents of 62 households without piped water were trained to chlorinate their drinking water at home in a narrow-necked water container with a spout. All study subjects (1583 individuals) were monitored biweekly for self-reported diarrheal illness over a period of 9.5 weeks. The home chlorination intervention group had the lowest diarrheal rate (28.8/1,000 subjects/month) despite lack of access to piped water in their homes. Compared with the two groups that did not receive the intervention this rate was one-sixth that of the group with no piped water (179.2/1,000 subjects/month) and one-third that of the households with piped water (75.5/1,000 subjects/month). More than 30% of the households with piped water lacked detectable levels of chlorine residues in their drinking water, despite two-stage chlorination of the source water, and were at increased risk of diarrhea. Forty-two percent of these municipal users reported that water pressure had been intermittent within the previous two days. The dramatic reduction in diarrheal rates in the home-chlorination intervention group indicates that a large proportion of diarrheal diseases in Nukus are water-borne. The home-chlorination group had less diarrhea than the group with piped water, implicating the distribution system as a source of disease transmission. Taken together, these epidemiologic data would support the hypothesis that diarrhea in the piped water group could be attributed to cross-contamination between the municipal water supply and sewer, due to leaky pipes and lack of water pressure. Relatively inexpensive steps, including chlorination, maintaining water pressure, and properly maintaining the distribution system, rather than reverse osmosis technology, should reduce diarrheal rates.


Dysregulation of Kisspeptin and Leptin, as Anorexigenic Agents, Plays Role in the Development of Obesity in Postmenopausal Women.
During the menopausal period, women have a higher tendency to develop obesity and any other metabolic syndromes. Dysregulation of leptin and kisspeptin signaling as anorexigenic agents is believed to be the connection between metabolic disorders and altered reproductive function. Therefore, this study aimed at investigating the association between leptin, soluble leptin receptor (sOBR), free leptin index, kisspeptin concentrations, and body mass index (BMI) in postmenopausal women. A cross-sectional study was carried out among 171 postmenopausal women aged 40-75 years from 2017 to 2018. Subjects were assigned into 2 groups according to their BMIs: obese group (84 subjects) and nonobese group (87 subjects). In addition to anthropometric measurement, blood sample was collected from each subject for leptin, sOBR, free leptin index (FLI), and kisspeptin evaluation. Bivariate and correlation analysis discovered that leptin and FLI were positively correlated with BMI, while sOBR and kisspeptin were negatively correlated with BMI. Among those variables, multivariate analysis found that leptin, sOBR, and kisspeptin were independently associated with obesity. Therefore, it can be concluded that higher serum leptin concentration and FLI, as well as lower serum sOBR and kisspeptin concentrations, are significantly associated with obesity in postmenopausal women.


Stopping or reducing dietary fiber intake reduces constipation and its associated symptoms.
To investigate the effect of reducing dietary fiber on patients with idiopathic constipation. Sixty-three cases of idiopathic constipation presenting between May 2008 and May 2010 were enrolled into the study after colonoscopy excluded an organic cause of the constipation. Patients with previous colon surgery or a medical cause of their constipation were excluded. All patients were given an explanation on the role of fiber in the gastrointestinal tract. They were then asked to go on a no fiber diet for 2 wk. Thereafter, they were asked to reduce the amount of dietary fiber intake to a level that they found acceptable. Dietary fiber intake, symptoms of constipation, difficulty in evacuation of stools, anal bleeding, abdominal bloating or abdominal pain were recorded at 1 and 6 mo. The median age of the patients (16 male, 47 female) was 47 years (range, 20-80 years). At 6 mo, 41 patients remained on a no fiber diet, 16 on a reduced fiber diet, and 6 resumed their high fiber diet for religious or personal reasons. Patients who stopped or reduced dietary fiber had significant improvement in their symptoms while those who continued on a high fiber diet had no change. Of those who stopped fiber completely, the bowel frequency increased from one motion in 3.75 d (± 1.59 d) to one motion in 1.0 d (± 0.0 d) (P < 0.001); those with reduced fiber intake had increased bowel frequency from a mean of one motion per 4.19 d (± 2.09 d) to one motion per 1.9 d (± 1.21 d) on a reduced fiber diet (P < 0.001); those who remained on a high fiber diet continued to have a mean of one motion per 6.83 d (± 1.03 d) before and after consultation. For no fiber, reduced fiber and high fiber groups, respectively, symptoms of bloating were present in 0%, 31.3% and 100% (P < 0.001) and straining to pass stools occurred in 0%, 43.8% and 100% (P < 0.001). Idiopathic constipation and its associated symptoms can be effectively reduced by stopping or even lowering the intake of dietary fiber.


Evidence from prospective cohort studies did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review.
National dietary guidelines were introduced in 1977 and 1983, by the USA and UK governments to reduce coronary heart disease (CHD) mortality by reducing dietary fat intake. Our 2015 systematic review examined randomised controlled trial (RCT) evidence available to the dietary committees at the time; we found no support for the recommendations to restrict dietary fat. What epidemiological evidence was available to the dietary guideline committees in 1983? A systematic review of prospective cohort studies, published prior to 1983, which examined the relationship between dietary fat, serum cholesterol and the development of CHD. Across 6 studies, involving 31 445 participants, there were 1521 deaths from all-causes and 360 deaths from CHD during the mean follow-up of 7.5±6.2 years. The death rates were 4.8% and 1.1% from all-causes and CHD respectively. One study included men with previous heart disease. The death rate from CHD for those with, and without previous myocardial infarction was 20.9% and 1.0% respectively. None of the six studies found a significant relationship between CHD deaths and total dietary fat intake. One of the six studies found a correlation between CHD deaths and saturated dietary fat intake across countries; none found a relationship between CHD deaths and saturated dietary fat in the same population. 1983 dietary recommendations for 220 million US and 56 million UK citizens lacked supporting evidence from RCT or prospective cohort studies. The extant research had been undertaken exclusively on males, so lacked generalisability for population-wide guidelines.


Facial allergic granulomatous reaction and systemic hypersensitivity associated with microneedle therapy for skin rejuvenation.
Microneedle therapy includes skin puncture with multiple micro-sized needles to promote skin rejuvenation or increase transdermal delivery of topical medications. In cosmetic practices, various cosmeceuticals are applied before microneedling to enhance the therapeutic effects. This results in intradermal tattooing of the topical product. Despite rapid increase in the use of microneedles in dermatology, there are few data about their safety. We describe 3 women, aged 40s to 60s, who developed open [corrected] facial granulomas following microneedle therapy for skin rejuvenation. Two patients had undergone microinjection of the same branded topical moisturizer (Vita C Serum; Sanítas Skincare) during microneedle therapy. Biopsy in all cases showed foreign body-type granulomas. Results of tissue cultures were negative. Chest radiography and serum angiotensin-converting enzyme findings were normal. The first 2 patients had a positive patch test reaction to Vita C Serum. Initial treatment with topical and oral corticosteroids was ineffective. Therapy with doxycycline hydrochloride and minocycline hydrochloride led to partial improvement in one case and resolution in another. Application of topical products prior to microneedling can introduce immunogenic particles into the dermis and potentiate local or systemic hypersensitivity reactions. Because the microneedle therapy system is accessible for home use, health care providers need to be aware of its potential consequences.


Molecular insights into human daily behavior.
Human beings exhibit wide variation in their timing of daily behavior. We and others have suggested previously that such differences might arise because of alterations in the period length of the endogenous human circadian oscillator. Using dermal fibroblast cells from skin biopsies of 28 subjects of early and late chronotype (11 "larks" and 17 "owls"), we have studied the circadian period lengths of these two groups, as well as their ability to phase-shift and entrain to environmental and chemical signals. We find not only period length differences between the two classes, but also significant changes in the amplitude and phase-shifting properties of the circadian oscillator among individuals with identical "normal" period lengths. Mathematical modeling shows that these alterations could also account for the extreme behavioral phenotypes of these subjects. We conclude that human chronotype may be influenced not only by the period length of the circadian oscillator, but also by cellular components that affect its amplitude and phase. In many instances, these changes can be studied at the molecular level in primary dermal cells.


Laboratory features of severe vs. non-severe COVID-19 patients in Asian populations: a systematic review and meta-analysis.
More severe cases of COVID- 19 are more likely to be hospitalized and around one-fifth, needing ICU admission. Understanding the common laboratory features of COVID-19 in more severe cases versus non-severe patients could be quite useful for clinicians and might help to predict the model of disease progression. This systematic review and meta-analysis aimed to compare the laboratory test findings in severe vs. non-severe confirmed infected cases of COVID-19. Electronic databases were systematically searched in PubMed, EMBASE, Scopus, Web of Science, and Google Scholar from the beginning of 2019 to 3rd of March 2020. Heterogeneity across included studies was determined using Cochrane's Q test and the I2 statistic. We used the fixed or random-effect models to pool the weighted mean differences (WMDs) or standardized mean differences and 95% confidence intervals (CIs). Out of a total of 3009 citations, 17 articles (22 studies, 21 from China and one study from Singapore) with 3396 ranging from 12 to1099 patients were included. Our meta-analyses showed a significant decrease in lymphocyte, monocyte, and eosinophil, hemoglobin, platelet, albumin, serum sodium, lymphocyte to C-reactive protein ratio (LCR), leukocyte to C-reactive protein ratio (LeCR), leukocyte to IL-6 ratio (LeIR), and an increase in the neutrophil, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, blood urea nitrogen (BUN), creatinine (Cr), erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), Procalcitonin (PCT), lactate dehydrogenase (LDH), fibrinogen, prothrombin time (PT), D-dimer, glucose level, and neutrophil to lymphocyte ratio (NLR) in the severe group compared with the non-severe group. No significant changes in white blood cells (WBC), Creatine Kinase (CK), troponin I, myoglobin, IL-6 and K between the two groups were observed. This meta-analysis provides evidence for the differentiation of severe cases of COVID-19 based on laboratory test results at the time of ICU admission. Future well-methodologically designed studies from other populations are strongly recommended.


Risk of dementia in first-degree relatives of patients with Alzheimer's disease and related disorders.
First-degree relatives of patients with Alzheimer's disease (AD) are at greater risk for dementia when compared with the relatives of their healthy peers, but not when compared with the relatives of patients with Parkinson's disease. This may indicate that the risk of dementia in these relatives is not specific to AD or that these studies are biased. We obtained a family history and vital status information on each first-degree relative of patients attending a clinic and in a group of recruited healthy elderly subjects. Patients formed two groups: probable AD and other forms of dementia or cognitive disorders without dementia. The odds of dementia in first-degree relatives did not differ between patient groups. The odds of dementia in relatives of patients with probable AD or other forms of dementia was six times that in the relatives of the healthy elderly subjects. The cumulative incidence of dementia increased with age in the first-degree relatives of all subjects. Approximately 50% of the first-degree relatives of patients with AD were demented by age 91 years, but almost the same number of the other patient group's relatives were demented as well. That figure was never reached in the healthy elderly subject's relatives. Because the risk of dementia in first-degree relatives of patients with AD was similar to that for patients with other disorders, we cannot exclude the possibility that this is the result of selection and information biases. Our investigation implies that the increased risk of dementia may not be specific to relatives of patients with AD; the risk may also be increased in first-degree relatives of patients with other neurologic disorders.


Application of a simple, affordable quality metric tool to colorectal, upper gastrointestinal, hernia, and hepatobiliary surgery patients: the HARM score.
Quality is the major driver for both clinical and financial assessment. There remains a need for simple, affordable, quality metric tools to evaluate patient outcomes, which led us to develop the HospitAl length of stay, Readmission and Mortality (HARM) score. We hypothesized that the HARM score would be a reliable tool to assess patient outcomes across various surgical specialties. From 2011 to 2015, we identified colorectal, hepatobiliary, upper gastrointestinal, and hernia surgery admissions using the Vizient Clinical Database. Individual and hospital HARM scores were calculated from length of stay, 30-day readmission, and mortality rates. We evaluated the correlation of HARM scores with complication rates using the Clavien-Dindo classification. We identified 525,083 surgical patients: 206,981 colorectal, 164,691 hepatobiliary, 97,157 hernia, and 56,254 upper gastrointestinal. Overall, 53.8% of patients were admitted electively with a mean HARM score of 2.24; 46.2% were admitted emergently with a mean HARM score of 1.45 (p < 0.0001). All HARM components correlated with patient complications on logistic regression (p < 0.0001). The mean length of stay increased from 3.2 ± 1.8 days for a HARM score < 2 to 15.1 ± 12.2 days for a HARM score > 4 (p < 0.001). In elective admissions, for HARM categories of < 2, 2-< 3, 3-4, and > 4, complication rates were 9.3, 23.2, 38.8, and 71.6%, respectively. There was a similar trend for increasing HARM score in emergent admissions as well. For all surgical procedure categories, increasing HARM score, with and without risk adjustment, correlated with increasing severity of complications by Clavien-Dindo classification. The HARM score is an easy-to-use quality metric that correlates with increasing complication rates and complication severity across multiple surgical disciplines when evaluated on a large administrative database. This inexpensive tool could be adopted across multiple institutions to compare the quality of surgical care.


[Cutis marmorata telangiectatica congenita. Review of 33 cases].
Cutis marmorata telangiectatica congenita (CMTC) is an uncommon congenital vascular malformation characterized by the presence of a localized or generalized pattern, frequently asymmetrical, with reticulated, erythematous or violaceous macules, present at birth or shortly thereafter. Retrospective study of 33 cases of CMTC diagnosed between 1994 and 2007 in our hospital. Clinical and follow-up data were recorded in all cases. In some patients additional tests were performed. Most of the patients (51.5%) were female. In 87.9% of the cases lesions were observed at birth. All the cases were sporadic. CMTC was localized in 72.7% of the patients, being distributed mainly over the lower limbs. Associated anomalies were noted in 60.6%, with predominance of skin alterations (14 cases). Extracutaneous anomalies were present in 11 patients, most commonly atrophy and hypertrophy in the involved limbs. In none of the cases were there ocular or neurological manifestations. The average follow-up time was 14 months. Improvement of the lesions was observed in 45%, and in one case there was complete resolution. CMTC is a malformative disease which is frequently associated with other abnormalities. An appropriate assessment and follow-up of these patients is advisable. Performing a thorough medical history, including full physical examination is necessary. If the head is affected, ocular and neurological examination should be performed. The prognosis is generally good, with a tendency to improvement or disappearance in most cases.


Highly sensitive flexible three-axis tactile sensors based on the interface contact resistance of microstructured graphene.
The lack of high-performance tactile sensors, especially for pressure/force, is a huge obstacle for the widespread application of intelligent robots. Current pressure sensors are often operated in the high range of pressure and normal direction, showing a little ability in the low range of pressure and three-axis direction simultaneously. Herein, a highly sensitive flexible tactile sensor with three-axis force sensing capacity is presented by combining microstructured polydimethylsiloxane (PDMS) arrays and a reduced graphene oxide (rGO) film. The deformation of microstructured rGO/PDMS results in a change in the contact area between the rGO film and electrode, leading to a high sensitivity of -1.71 kPa-1 in the low range pressure of 0-225 Pa with a fast response time of 6 ms at a large feature size of 100 μm. To realize three-axis sensing, a sensing unit was built up, which was composed of the adjacent four parts of patterns and electrodes underneath a bump. A mechanical model of the exerted spatial force was established to calculate each axis force component via the deformation of the rGO/PDMS pattern. The experimental results show that the current difference between the adjacent two parts has a strong relationship with the applied force. As a proof of concept, we have demonstrated a 3 × 3 array sensor for arbitrary force sensing. Our tactile sensor would be used in transmitting information from a gentle spatial force and would exhibit broad applications as e-skin in integrated robots.


Porphyromonas gingivalis and the pathogenesis of rheumatoid arthritis: analysis of various compartments including the synovial tissue.
We evaluated the presence of Porphyromonas gingivalis (Pg) DNA in the synovial tissue through synovial biopsy and in other compartments of rheumatoid arthritis (RA) patients in comparison with patients affected by other arthritides. Possible links with clinical, immunologic and genetic features were assessed. Peripheral blood (PB), sub-gingival dental plaque, synovial fluid (SF) and synovial tissue samples were collected from 69 patients with active knee arthritis (32 with RA and 37 with other arthritides, of which 14 had undifferentiated peripheral inflammatory arthritis - UPIA). Demographic, clinical, laboratory and immunological data were recorded. The presence of Pg DNA was evaluated through PCR. The HLA-DR haplotype was assessed for 45 patients with RA and UPIA. No differences arose in the positivity for Pg DNA in the sub-gingival plaque, PB and SF samples between RA and the cohort of other arthritides. Full PB samples showed a higher positivity for Pg DNA than plasma samples (11.8% vs. 1.5%, P = 0.04). Patients with RA showed a higher positivity for Pg DNA in the synovial tissue compared to controls (33.3% vs. 5.9%, P <0.01). UPIA and RA patients carrying the HLA DRB1*04 allele showed a higher positivity for Pg DNA in the synovial tissue compared to patients negative for the allele (57.1% vs. 16.7%, P = 0.04). RA patients positive for Pg DNA in the sub-gingival plaque had a lower disease duration and a higher peripheral blood leucocyte and neutrophil count. The presence of Pg DNA did not influence disease activity, disease disability or positivity for autoantibodies. The presence of Pg DNA in the synovial tissue of RA patients suggests a pathogenic role of the bacterium. The higher positivity of Pg DNA in full peripheral blood and synovial tissue samples compared to plasma and synovial fluid suggests a possible intracellular localization of Pg, in particular in patients positive for HLA-DR4.


Two design strategies for enhancement of multilayer-DNA-origami folding: underwinding for specific intercalator rescue and staple-break positioning.
Single-layer DNA origami is an efficient method for programmable self-assembly of nanostructures approximating almost any desired two-dimensional shape from ~5 MDa of DNA building material. In this method, a 7 kilobase single "scaffold" strand is assembled with hundreds of oligodeoxyribonucleotide "staple" strands to form a parallel array of double helices. Multiple layers of such DNA sheets also can be designed to assemble into a stack, enabling construction of solid three-dimensional shapes with considerably greater mechanical rigidity than two-dimensional shapes; however, the folding yield often is much lower and the required folding times are much longer. Here we introduce two strategies for designing multi-layer DNA origami that demonstrate potential for boosting assembly yield: (1) individual base pairs can be inserted between crossovers, allowing for greater bowing of helices at positions away from crossovers and therefore reduced electrostatic repulsion. At the same time, this underwinding of double helices increases a destabilizing torsional strain energy but then also increases affinity for intercalators, and binding of such intercalators can relieve this stress. We also have exploited this enhanced affinity for intercalators to PEGylate the surface of the nanostructures in a noncovalent fashion using PEG-tris-acridine. (2) Positioning of staple-strand breaks in the DNA origami such that each staple strand includes a 14 nucleotide (nt) continuous segment that binds to a complementary 14 nt continuous segment of the scaffold can greatly improve folding yields.


Effects of equal-volume resistance training with different training frequencies in muscle size and strength in trained men.
The objective of the present study was to compare the effects of equal-volume resistance training (RT) performed with different training frequencies on muscle size and strength in trained young men. Sixteen men with at least one year of RT experience were divided into two groups, G1 and G2, that trained each muscle group once and twice a week, respectively, for 10 weeks. Elbow flexor muscle thickness (MT) was measured using a B-Mode ultrasound and concentric peak torque of elbow extensors and flexors were assessed by an isokinetic dynamometer. ANOVA did not reveal group by time interactions for any variable, indicating no difference between groups for the changes in MT or PT of elbow flexors and extensors. Notwithstanding, MT of elbow flexors increased significantly (3.1%, P < 0.05) only in G1. PT of elbow flexors and extensors did not increase significantly for any group. The present study suggest that there were no differences in the results promoted by equal-volume resistance training performed once or twice a week on upper body muscle strength in trained men. Only the group performing one session per week significantly increased the MT of their elbow flexors. However, with either once or twice a week training, adaptations appear largely minimal in previously trained males.


Paxel: A Generic Framework to Superimpose High-Frequency Print Patterns using Projected Light.
In this paper, we propose Paxel, a generic framework for modeling the interaction between a projector and a high-frequency pattern surface. Using this framework, we present two different application setups (cf. Fig. 1a): a novel colorchanging effect, created with a single projected image and only when the projection surface is changed from a pattern surface to a uniform white surface. The observed effect relies on the spatially different reflectance properties of these two surfaces. Using this approach, one can alter color proprieties of the projected image such as hue or chroma. Furthermore, for a specific color range, defined by an full color-changing sub-gamut, one can embed two completely different images, within a single static projection, from which either one will be revealed depending on the surface. The second application allows the creation of color images using a single channel projector. For this application, we present a full color projection created using a 365 nm ultraviolet (UV) projector in combination with fluorescent pigments (cf. Fig. 1b), enabling new display possibilities, such as projection through participating media, e.g. fog, while hiding the scattering of the projection light outside of the visible spectrum. Both presented approaches create effects that might be striking to the observer, making this framework useful for art exhibitions, advertisements, entertainment and visual cryptography. Finally, in Sec. VI, we provide an in-depth analysis of the reproducible colors based on input parameters, used in the presented algorithm, such as: pattern layout, dot size of the pattern and the number of the clusters formed by k-means algorithm (IV-B).


Diagnostic exome sequencing in 266 Dutch patients with visual impairment.
Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.


The management of solitary tumours of Hoffa's fat pad.
Hoffa's fat pad (HFP) of the knee is affected by a variety of tumours and tumour-like conditions. HFP can be affected by diffuse or solitary, focal disease. This paper reports a consecutive series of 19 cases of solitary symptomatic HFP tumours. The commonest presenting symptom was anterior knee pain. All patients underwent open excision after diagnostic magnetic resonance imaging (MRI). Histology revealed varied diagnoses with the commonest being pigmented villonodular synovitis (PVNS) and ganglia. American Knee Society scores improved from 76 pre-operatively to 96 post-operatively with an improvement in functional scores from 92 to 100. In conclusion the majority of solitary HFP tumours are benign and may be either cystic or solid. MRI and plain radiographs are the imaging of choice. The definitive treatments of both cystic and solid tumours should be selective arthrotomy and excision biopsy. All patients in this series reported substantial improvement in symptoms following surgery.


How Reliable Are Ligand-Centric Methods for Target Fishing?
Computational methods for Target Fishing (TF), also known as Target Prediction or Polypharmacology Prediction, can be used to discover new targets for small-molecule drugs. This may result in repositioning the drug in a new indication or improving our current understanding of its efficacy and side effects. While there is a substantial body of research on TF methods, there is still a need to improve their validation, which is often limited to a small part of the available targets and not easily interpretable by the user. Here we discuss how target-centric TF methods are inherently limited by the number of targets that can possibly predict (this number is by construction much larger in ligand-centric techniques). We also propose a new benchmark to validate TF methods, which is particularly suited to analyse how predictive performance varies with the query molecule. On average over approved drugs, we estimate that only five predicted targets will have to be tested to find two true targets with submicromolar potency (a strong variability in performance is however observed). In addition, we find that an approved drug has currently an average of eight known targets, which reinforces the notion that polypharmacology is a common and strong event. Furthermore, with the assistance of a control group of randomly-selected molecules, we show that the targets of approved drugs are generally harder to predict. The benchmark and a simple target prediction method to use as a performance baseline are available at http://ballester.marseille.inserm.fr/TF-benchmark.tar.gz.


A global meta-analysis of Tuber ITS rDNA sequences: species diversity, host associations and long-distance dispersal.
Truffles (Tuber) are ectomycorrhizal fungi characterized by hypogeous fruitbodies. Their biodiversity, host associations and geographical distributions are not well documented. ITS rDNA sequences of Tuber are commonly recovered from molecular surveys of fungal communities, but most remain insufficiently identified making it difficult to determine whether these sequences represent conspecific or novel taxa. In this meta-analysis, over 2000 insufficiently identified Tuber sequences from 76 independent studies were analysed within a phylogenetic framework. Species ranges, host associates, geographical distributions and intra- and interspecific ITS variability were assessed. Over 99% of the insufficiently identified Tuber sequences grouped within clades composed of species with little culinary value (Maculatum, Puberulum and Rufum). Sixty-four novel phylotypes were distinguished including 36 known only from ectomycorrhizae or soil. Most species of Tuber showed 1-3% intraspecific ITS variability and >4% interspecific ITS sequence variation. We found 123 distinct phylotypes based on 96% ITS sequence similarity and estimated that Tuber contains a minimum of 180 species. Based on this meta-analysis, species in Excavatum, Maculatum and Rufum clades exhibit preference for angiosperm hosts, whereas those in the Gibbosum clade are preferential towards gymnosperms. Sixteen Tuber species (>13% of the known diversity) have putatively been introduced to continents or islands outside their native range.


Laparoscopic management of duodenal obstruction resulting from superior mesenteric artery syndrome.
Duodenal obstruction by compression from the superior mesenteric artery (SMA) can be managed using minimally invasive techniques initially developed for bariatric patients requiring gastric bypass. This retrospective review evaluates 12 patients with SMA syndrome who were treated with laparoscopic enteric bypass. Technical considerations are presented in detail. The study group comprised 5 men and 7 women, with ages ranging from 21 to 65 years (mean, 36.8 years). Operative times ranged from 53 to 126 minutes (mean, 72.4 minutes). Mean length of hospital stay was 4.2 days (range, 3-7 days). Obstructive symptoms were improved or eliminated in 11 patients (92%). One patient required readmission for inadequate control of generalized abdominal pain. No patients in this series developed postoperative bowel obstruction, wound complications, or anastomotic leaks or died. Laparoscopic duodenojejunostomy is safe and effective and should be considered the optimal treatment for patients presenting with duodenal obstruction from SMA syndrome. Advances in minimally invasive surgery have demonstrated the safety and low morbidity of laparoscopically created enteric anastomoses. The shorter hospital stay, low morbidity, and high success of laparoscopic enteric bypass make this approach favorable to traditional open techniques.


Characterization of near death experiences using text mining analyses: A preliminary study.
The notion that death represents a passing to an afterlife, where we are reunited with loved ones and live eternally in a utopian paradise, is common in the reports of people who have encountered a "Near-Death Experience" (NDE). NDEs are thoroughly portrayed by the media but empirical studies are rather recent. The definition of the phenomenon as well as the identification of NDE experiencers is still a matter of debate. To date, NDEs' identification and description in studies have mostly derived from answered items in questionnaires. However, questionnaires' content could be restricting and subject to personal interpretation. We believe that in addition to their use, user-independent statistical text examination of freely expressed NDEs narratives is of prior importance to help capture the phenomenology of such a subjective and complex phenomenon. Towards that aim, we included 158 participants with a firsthand retrospective narrative of their self-reported NDE that we analyzed using an automated text-mining method. The output revealed the top words expressed by experiencers. In a second step, a hierarchical clustering analysis was conducted to visualize the relationships between these words. It revealed three main clusters of features: visual perceptions, emotions and spatial components. We believe the user-independent and data-driven text mining approach used in this study is promising by contributing to the building a rigorous description and definition of NDEs.


Identification of Genes Involved in Biogenesis of Outer Membrane Vesicles (OMVs) in Salmonella enterica Serovar Typhi.
Outer membrane vesicles (OMVs) are nano-sized proteoliposomes discharged from the cell envelope of Gram-negative bacteria. OMVs normally contain toxins, enzymes and other factors, and are used as vehicles in a process that has been considered a generalized, evolutionarily conserved delivery system among bacteria. Furthermore, OMVs can be used in biotechnological applications that require delivery of biomolecules, such as vaccines, remarking the importance of their study. Although it is known that Salmonella enterica serovar Typhi (S. Typhi), the etiological agent of typhoid fever in humans, delivers toxins (e.g., HlyE) via OMVs, there are no reports identifying genetic determinants of the OMV biogenesis in this serovar. In the present work, and with the aim to identify genes participating in OMV biogenesis in S. Typhi, we screened 15,000 random insertion mutants for increased HlyE secretion. We found 9 S. Typhi genes (generically called zzz genes) determining an increased HlyE secretion that were also involved in OMV biogenesis. The genes corresponded to ompA, nlpI, and tolR (envelope stability), rfaE and waaC (LPS synthesis), yipP (envC), mrcB (synthesis and remodeling of peptidoglycan), degS (stress sensor serine endopeptidase) and hns (global transcriptional regulator). We found that S. Typhi Δzzz mutants were prone to secrete periplasmic, functional proteins with a relatively good envelope integrity. In addition, we showed that zzz genes participate in OMV biogenesis, modulating different properties such as OMV size distribution, OMV yield and OMV protein cargo.


Provision of antiretroviral treatment in conflict settings: the experience of Médecins Sans Frontières.
Many countries ravaged by conflict have substantial morbidity and mortality attributed to HIV/AIDS yet HIV treatment is uncommonly available. Universal access to HIV care cannot be achieved unless the needs of populations in conflict-affected areas are addressed. From 2003 Médecins Sans Frontières introduced HIV care, including antiretroviral therapy, into 24 programmes in conflict or post-conflict settings, mainly in sub-Saharan Africa. HIV care and treatment activities were usually integrated within other medical activities. Project data collected in the Fuchia software system were analysed and outcomes compared with ART-LINC data. Programme reports and other relevant documents and interviews with local and headquarters staff were used to develop lessons learned. In the 22 programmes where ART was initiated, more than 10,500 people were diagnosed with HIV and received medical care, and 4555 commenced antiretroviral therapy, including 348 children. Complete data were available for adults in 20 programmes (n = 4145). At analysis, 2645 (64%) remained on ART, 422 (10%) had died, 466 (11%) lost to follow-up, 417 (10%) transferred to another programme, and 195 (5%) had an unclear outcome. Median 12-month mortality and loss to follow-up were 9% and 11% respectively, and median 6-month CD4 gain was 129 cells/mm 3.Patient outcomes on treatment were comparable to those in stable resource-limited settings, and individuals and communities obtained significant benefits from access to HIV treatment. Programme disruption through instability was uncommon with only one program experiencing interruption to services, and programs were adapted to allow for disruption and population movements. Integration of HIV activities strengthened other health activities contributing to health benefits for all victims of conflict and increasing the potential sustainability for implemented activities. With commitment, simplified treatment and monitoring, and adaptations for potential instability, HIV treatment can be feasibly and effectively provided in conflict or post-conflict settings.


Effects of acupuncture on post-cesarean section pain.
Post-operation pain is a very subjective phenomenon. The aim of this study was to find out the effects of acupuncture or electro-acupuncture on post-cesarean pain. Sixty women, who had had spinal anesthesia during cesarean section at the Department of Obstetrics of China Medical University Hospital, were randomly assigned to the control group, the acupuncture group, and the electro-acupuncture group. After the operation, we applied subjects with acupuncture or electro-acupuncture on the bilateral acupuncture point, San Yin Jiao (Sp6), and the patient controlled analgesia (PCA). The first time of requesting morphine, the frequency of PCA demands in 24 hours, and the doses of PCA used were recorded double blindly. In addition, monitoring the subjects' vital signs, the opioid-related side effects, and the pain scores was done. The results showed that the acupuncture group and the electro-acupuncture group could delay the time of requesting morphine up to 10 - 11 minutes when compared with the control group. The total dose of PCA used within the first 24 hours was 30% - 35% less in the acupuncture group and the electro-acupuncture group when compared with the control group, which was indicated in statistical significance. However, there was no significant difference between the acupuncture group and the electro-acupuncture group. The electro-acupuncture group's and the acupuncture group's pain scores were lower than the control group's within the first 2 hours. Both were statistically significant. However, two hours later, there were no significant differences of the visual analogue scale (VAS) scores between either of the treatment groups and the control group. Finally, the incidence of opioid-related side effects, such as dizziness, was less in the acupuncture group and electro-acupuncture group than in the control group. This study shows that the application of acupuncture and electro-acupuncture could definitely delay the time of requesting pain relief medication after cesarean section and decrease the PCA doses used within the first 24 hours.


A strong constitutive ethylene-response phenotype conferred on Arabidopsis plants containing null mutations in the ethylene receptors ETR1 and ERS1.
The ethylene receptor family of Arabidopsis consists of five members, falling into two subfamilies. Subfamily 1 is composed of ETR1 and ERS1, and subfamily 2 is composed of ETR2, ERS2, and EIN4. Although mutations have been isolated in the genes encoding all five family members, the only previous insertion allele of ERS1 (ers1-2) is a partial loss-of-function mutation based on our analysis. The purpose of this study was to determine the extent of signaling mediated by subfamily-1 ethylene receptors through isolation and characterization of null mutations. We isolated new T-DNA insertion alleles of subfamily 1 members ERS1 and ETR1 (ers1-3 and etr1-9, respectively), both of which are null mutations based on molecular, biochemical, and genetic analyses. Single mutants show an ethylene response similar to wild type, although both mutants are slightly hypersensitive to ethylene. Double mutants of ers1-3 with etr1-9, as well as with the previously isolated etr1-7, display a constitutive ethylene-response phenotype more pronounced than that observed with any previously characterized combination of ethylene receptor mutations. Dark-grown etr1-9;ers1-3 and etr1-7;ers1-3 seedlings display a constitutive triple-response phenotype. Light-grown etr1-9;ers1-3 and etr1-7;ers1-3 plants are dwarfed, largely sterile, exhibit premature leaf senescence, and develop novel filamentous structures at the base of the flower. A reduced level of ethylene response was still uncovered in the double mutants, indicating that subfamily 2 receptors can independently contribute to signaling, with evidence suggesting that this is due to their interaction with the Raf-like kinase CTR1. Our results are consistent with the ethylene receptors acting as redundant negative regulators of ethylene signaling, but with subfamily 1 receptors playing the predominant role. Loss of a single member of subfamily 1 is largely compensated for by the activity of the other member, but loss of both subfamily members results in a strong constitutive ethylene-response phenotype. The role of subfamily 1 members is greater than previously suspected and analysis of the double mutant null for both ETR1 and ERS1 uncovers novel roles for the receptors not previously characterized.


Nutritional errors in the first months of life and their association with asthma and atopy in preschool children.
To evaluate the impact of exclusive breastfeeding and introduction of cow's milk in the first year of life on the diagnosis of asthma, wheezing, and atopy in children aged 3 to 4 years. This is a cohort study nested in a randomized field trial investigating the effectiveness of dietary guidelines during the first year of life of children in the city of São Leopoldo, southern Brazil. Children who had their diet monitored during the first year of life, in a primary study, were revisited three years later, when their parents answered a questionnaire related to respiratory problems, applied during home visits by trained interviewers. Children were also skin-prick tested to assess responses to common environmental allergens. Of the 397 children followed during the first year of life, 354 were reassessed between 3 and 4 years of age. Prevalence of wheezing, evaluated for the 12 months prior to questionnaires, was 21.3%, while prevalence of asthma and atopy was 5.5 and 28.7%, respectively. Children fed cow's milk previous to being four months of life were significantly more likely to have asthma between three and four years of age (OR 3.22; 95%CI 1.05-9.80). In the same line, exclusive breastfeeding for a period shorter than six months was marginally associated with atopy. The early introduction of cow's milk was an important risk factor for triggering asthma/wheeze symptoms at the age of 4 years. Exclusive breastfeeding for longer than six months was also potentially associated with protection against the development of atopy. The results of this study suggest that dietary interventions during the first year of life have the potential to reduce the impact of asthma, and possibly, atopy.


What Constitutes Emergent Quantum Reality? A Complex System Exploration from Entropic Gravity and the Universal Constants.
In this work, it is acknowledged that important attempts to devise an emergent quantum (gravity) theory require space-time to be discretized at the Planck scale. It is therefore conjectured that reality is identical to a sub-quantum dynamics of ontological micro-constituents that are connected by a single interaction law. To arrive at a complex system-based toy-model identification of these micro-constituents, two strategies are combined. First, by seeing gravity as an entropic phenomenon and generalizing the dimensional reduction of the associated holographic principle, the universal constants of free space are related to assumed attributes of the micro-constituents. Second, as the effective field dynamics of the micro-constituents must eventually obey Einstein's field equations, a sub-quantum interaction law is derived from a solution of these equations. A Planck-scale origin for thermodynamic black hole characteristics and novel views on entropic gravity theory result from this approach, which eventually provides a different view on quantum gravity and its unification with the fundamental forces.


Smart information system for gachon university gil hospital.
In this research, the hospital information system of Gachon University Gil hospital is introduced and a future strategy for hospital information systems is proposed. This research introduces the development conditions of hospital information system at Gachon University Gil hospital, information about the development of the enterprise resource planning (ERP), a medical service process improvement system, and the personal health record (PHR) system. The medical service process and work efficiency were improved through the medical service process improvement system, which is the most common hospital information system at Gachon University Gil hospital and which includes an emergency medical service system, an online evaluation system and a round support system. Gachon University Gil hospital developed medical service improvement systems to increase work efficiency of medical team and optimized the systems to prove the availability of high-quality medical services for patients and their families. The PHR-based personalized health care solution is under development and will provide higher quality medical service for more patients in the future.


Safety and efficacy of locoregional therapy for metastatic pancreatic ductal adenocarcinoma to the liver: a single-center experience.
Many patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with liver metastatic disease (mPDAC), and few are surgical candidates. Interventional oncology (IO) locoregional therapies (LRT) have proven beneficial in other primary and metastatic hepatic malignancies. Systemic chemotherapy is the standard of care for patients with mPDAC. This study assessed the safety and efficacy of LRT including thermal ablation, chemoembolization, and radioembolization for mPDAC. A retrospective analysis was performed of 28 patients with mPDAC referred to IR clinic for consideration of LRT from 01/2006 to 08/2017, of whom 20 underwent treatment. Laboratory values were analyzed at 0, 3, and 6 months post-treatment. Imaging response was evaluated at 1, 3, and 6 months post-intervention by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Adverse events (AE) were classified by CTCAE v5.0. Overall survival (OS) from the diagnosis of PDAC, survival from the time of mPDAC diagnosis, and survival from the time of LRT were calculated. Median OS (mOS) was 25 months. Median survival from time of mPDAC diagnosis and post LRT were 16.25 and 9.7 months, respectively. At one month post-intervention, 12 of 17 patients demonstrated disease response (CR or PR per mRECIST). Survival among responders was 9 months vs. 6 months for patients with stable or progressive disease (P=0.08). There were two grade 3 AE which included post-embolization syndrome and transient renal failure. Chemotherapy was briefly delayed in one of these patients, but ultimately resumed. The use of LRT in patients with mPDAC is safe. Additionally, no significant chemotherapy limiting toxicities were observed. Responders to therapy demonstrated a survival benefit trend in this small and heterogeneous cohort. Further investigations with randomized trials are warranted.


Nucleosome-coupled expression differences in closely-related species.
Genome-wide nucleosome occupancy is negatively related to the average level of transcription factor motif binding based on studies in yeast and several other model organisms. The degree to which nucleosome-motif interactions relate to phenotypic changes across species is, however, unknown. We address this challenge by generating nucleosome positioning and cell cycle expression data for Saccharomyces bayanus and show that differences in nucleosome occupancy reflect cell cycle expression divergence between two yeast species, S. bayanus and S. cerevisiae. Specifically, genes with nucleosome-depleted MBP1 motifs upstream of their coding sequence show periodic expression during the cell cycle, whereas genes with nucleosome-shielded motifs do not. In addition, conserved cell cycle regulatory motifs across these two species are more nucleosome-depleted compared to those that are not conserved, suggesting that the degree of conservation of regulatory sites varies, and is reflected by nucleosome occupancy patterns. Finally, many changes in cell cycle gene expression patterns across species can be correlated to changes in nucleosome occupancy on motifs (rather than to the presence or absence of motifs). Our observations suggest that alteration of nucleosome occupancy is a previously uncharacterized feature related to the divergence of cell cycle expression between species.


An invasive podosome-like structure promotes fusion pore formation during myoblast fusion.
Recent studies in Drosophila have implicated actin cytoskeletal remodeling in myoblast fusion, but the cellular mechanisms underlying this process remain poorly understood. Here we show that actin polymerization occurs in an asymmetric and cell type-specific manner between a muscle founder cell and a fusion-competent myoblast (FCM). In the FCM, a dense F-actin-enriched focus forms at the site of fusion, whereas a thin sheath of F-actin is induced along the apposing founder cell membrane. The FCM-specific actin focus invades the apposing founder cell with multiple finger-like protrusions, leading to the formation of a single-channel macro fusion pore between the two muscle cells. Two actin nucleation-promoting factors of the Arp2/3 complex, WASP and Scar, are required for the formation of the F-actin foci, whereas WASP but not Scar promotes efficient foci invasion. Our studies uncover a novel invasive podosome-like structure (PLS) in a developing tissue and reveal a previously unrecognized function of PLSs in facilitating cell membrane juxtaposition and fusion.


Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis.
Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.


Association of adiponectin gene polymorphism with adiponectin levels and risk for insulin resistance syndrome.
Adiponectin is an abundant adipose tissue-derived protein with anti-atherogenic, anti-inflammatory and antidiabetic properties. Plasma adiponectin levels are decreased in obesity, type 2 diabetes, and coronary artery disease and low adiponectin levels also predict insulin resistance (IR). Case-control study in which 642 male and female subjects were participated from the North Indian population. Lipid, insulin, leptin and adiponectin level were estimated using standard protocols by commercially available test kits. Single nucleotide polymorphisms +45T>G and +276G>T of the AMP1 (adiponectin) gene was genotyped by polymerase chain reaction restriction fragment length polymorphism method. Levels of adiponectin, insulin, homeostasis model assessment-IR index (HOMA-IR index), systolic blood pressure and fat mass showed significant differences between male and female subjects. Serum adiponectin level showed highly significant association with both the +45 and the +276 genotypes. The common haplotype triglyceride (TG) showed a significantly lower adiponectin value than other haplotypes (P = 0.0001). A clear trend of decreasing adiponectin levels per copy of the common haplotype was observed. Nonobese insulin sensitive subjects showed a higher adiponectin value (P = 0.0006) than nonobese insulin resistant subjects. The values of blood pressure, adiponectin, insulin, HOMA-IR, total-cholesterol, and low-density lipoprotein-cholesterol significantly associated with TG haplotype. We observed the very strong association of the adiponectin 45-276 genotypes and haplotypes with adiponectin levels in healthy north Indian population and TG haplotypes also associated with metabolic parameters of the IR syndrome.


Characterization of nonmelanoma skin cancer for light therapy using spatial frequency domain imaging.
The dosimetry of light-based therapies critically depends on both optical and vascular parameters. We utilized spatial frequency domain imaging to quantify optical and vascular parameters, as well as estimated light penetration depth from 17 nonmelanoma skin cancer patients. Our data indicates that there exist substantial spatial variations in these parameters. Characterization of these parameters may inform understanding and optimization of the clinical response of light-based therapies.


Taxonomy, diversity, temporal and geographical distribution of Cutaneous Leishmaniasis in Colombia: A retrospective study.
Leishmaniases are tropical zoonotic diseases, caused by kinetoplastid parasites from the genus Leishmania. New World (NW) species are related to sylvatic cycles although urbanization processes have been reported in some South American Countries such as Colombia. Currently, few studies show the relative distribution of Leishmania species related to cutaneous Leishmaniasis (CL) in South America due to the lack of accurate surveillance and public health systems. Herein, we conducted a systematic estimation of the Leishmania species causing CL in Colombia from 1980 to 2001 via molecular typing and isoenzymes. A total of 327 Leishmania isolates from humans, sandflies and reservoirs were typed as L. panamensis 61.3% (201), L. braziliensis 27.1% (88), L. lainsoni 0.6% (2), L. guyanensis 0.9% (3), L. infantum chagasi 4% (12), L. equatoriensis 0.6% (2), L. mexicana 2.1% (8), L. amazonensis 2.8% (9) and L. colombiensis 0.6% (2). This is the first report of two new Leishmania species circulating in Colombia and suggests the need to convince the Colombian government about the need to deploy and standardize tools for the species identification to provide adequate management to individuals suffering this pathology.


Aldosterone Jeopardizes Myocardial Insulin and β-Adrenergic Receptor Signaling via G Protein-Coupled Receptor Kinase 2.
Hyperaldosteronism alters cardiac function, inducing adverse left ventricle (LV) remodeling either via increased fibrosis deposition, mitochondrial dysfunction, or both. These harmful effects are due, at least in part, to the activation of the G protein-coupled receptor kinase 2 (GRK2). In this context, we have previously reported that this kinase dysregulates both β-adrenergic receptor (βAR) and insulin (Ins) signaling. Yet, whether aldosterone modulates cardiac Ins sensitivity and βAR function remains untested. Nor is it clear whether GRK2 has a role in this modulation, downstream of aldosterone. Here, we show in vitro, in 3T3 cells, that aldosterone impaired insulin signaling, increasing the negative phosphorylation of insulin receptor substrate 1 (ser307pIRS1) and reducing the activity of Akt. Similarly, aldosterone prevented the activation of extracellular signal-regulated kinase (ERK) and the production of cyclic adenosine 3',5'-monophosphate (cAMP) in response to the β1/β2AR agonist, isoproterenol. Of note, all of these effects were sizably reduced in the presence of GRK2-inhibitor CMPD101. Next, in wild-type (WT) mice undergoing chronic infusion of aldosterone, we observed a marked GRK2 upregulation that was paralleled by a substantial β1AR downregulation and augmented ser307pIRS1 levels. Importantly, in keeping with the current in vitro data, we found that aldosterone effects were wholly abolished in cardiac-specific GRK2-knockout mice. Finally, in WT mice that underwent 4-week myocardial infarction (MI), we observed a substantial deterioration of cardiac function and increased LV dilation and fibrosis deposition. At the molecular level, these effects were associated with a significant upregulation of cardiac GRK2 protein expression, along with a marked β1AR downregulation and increased ser307pIRS1 levels. Treating MI mice with spironolactone prevented adverse aldosterone effects, blocking GRK2 upregulation, and thus leading to a marked reduction in cardiac ser307pIRS1 levels while rescuing β1AR expression. Our study reveals that GRK2 activity is a critical player downstream of the aldosterone signaling pathway; therefore, inhibiting this kinase is an attractive strategy to prevent the cardiac structural disarray and dysfunction that accompany any clinical condition accompanied by hyperaldosteronism.


Two-dose daclizumab, tacrolimus, mycophenolate mofetil, and steroid-free regimen in de novo cardiac transplant recipients: early experience.
Tacrolimus (TAC) with mycophenolate mofetil (MMF) and a steroid-free regimen seems to have good efficacy in preventing acute rejection in cardiac transplant recipients, although concern exists about nephrotoxicity. Induction therapy with Daclizumab seems to give protection without side effects. Data are lacking about the outcome of 2-dose Daclizumab+TAC+MMF and a steroid-free regimen. We retrospectively reviewed 28 consecutive de novo heart transplantations performed at a single center between January 2001 and June 2006. Patients received induction therapy with 2-dose Daclizumab. Maintenance immunosuppression included TAC, MMF, and prednisone during the first 6 months. The endpoints were the incidence of acute rejection, patient and graft survival, and clinical tolerability. Among 28 patients of mean age 57 +/- 9 years, 2 subjects (7%) died in the perioperative period due to infections. The mean follow-up was 2.8 +/- 1.5 years. There were no late deaths. Six patients experienced acute rejection (International Society of Heart and Lung Transplantation [ISHLT] >or=3A) that required treatment during the first 3 months. At follow-up, only 3 patients (>or=3A) required treatment. Mean creatinine level increased from 1.08 +/- 0.37 at baseline to 1.08 +/- 0.41 at 1 year (n = 23; P = not significant [NS]) to 1.39 +/- 0.68 (n = 13; P < .05) at 4 years, 1.65 +/- 0.51 (n = 8; P < .05) at 5 years. No patient required replacement therapy. A steroid-free protocol with 2-dose Daclizumab induction therapy and maintenance with TAC and MMF seemed to be safe to prevent acute rejection. Creatinine levels were slightly but significantly increased.


A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes.
We have isolated a novel cDNA clone encoding interferon (IFN) consensus sequence-binding protein in adult T-cell leukemia cell line or activated T cells (ICSAT); this protein is the human homolog of the recently cloned Pip/LSIRF. ICSAT is structurally most closely related to the previously cloned ICSBP, a member of the IFN regulatory factor (IRF) family of proteins that binds to interferon consensus sequences (ICSs) found in many promoters of the IFN-regulated genes. Among T-cell lines investigated, ICSAT was abundantly expressed in human T-cell leukemia virus type 1 (HTLV-1)-infected T cells. When the HTLV-1 tax gene was expressed or phorbol myristake acetate-A23187 stimulation was used, ICSAT expression was induced in Jurkat cells which otherwise do not express ICSAT. When the binding of ICSAT to four different ICSs was tested, the relative differences in binding affinities for those ICSs were determined. To study the functional role of ICSAT, we performed cotransfection experiments with the human embryonal carcinoma cell line N-Tera2. ICSAT was demonstrated to possess repressive function over the gene activation induced by IFN stimulation or by IRF-1 cotransfection. Such repressive function is similar to that seen in IRF-2 or ICSBP. However, we have found that ICSAT has a different repressive effect from that of IRF-2 or ICSBP in some IFN-responsive reporter constructs. These results suggest that a novel mechanism of gene regulation by "differential repression" is used by multiple members of repressor proteins with different repressive effects on the IFN-responsive genes.


Operational methods of HIV testing in emergency departments: a systematic review.
Casual review of existing literature reveals a multitude of individualized approaches to emergency department (ED) HIV testing. Cataloging the operational options of each approach could assist translation by disseminating existing knowledge, endorsing variability as a means to address testing barriers, and laying a foundation for future work in the area of operational models and outcomes investigation. The objective of this study is to provide a detailed account of the various models and operational constructs that have been described for performing HIV testing in EDs. Systematic review of PUBMED, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Web of Science through February 6, 2009 was performed. Three investigators independently reviewed all potential abstracts and identified all studies that met the following criteria for inclusion: original research, performance of HIV testing in an ED in the United States, description of operational methods, and reporting of specific testing outcomes. Each study was independently assessed and data from each were abstracted with standardized instruments. Summary and pooled descriptive statistics were reported by using recently published nomenclature and definitions for ED HIV testing. The primary search yielded 947 potential studies, of which 25 (3%) were included in the final analysis. Of the 25 included studies, 13 (52%) reported results using nontargeted screening as the only patient selection method. Most programs reported using voluntary, opt-in consent and separate, signed consent forms. A variety of assays and communication methods were used, but relatively limited outcomes data were reported. Currently, limited evidence exists to inform HIV testing practices in EDs. There appears to be recent progression toward the use of rapid assays and nontargeted patient selection methods, with the rate at which reports are published in the peer-reviewed literature increasing. Additional research will be required, including controlled clinical trials, more structured program evaluation, and a focus on an expanded profile of outcome measures, to further improve our understanding of which HIV testing methods are most effective in the ED.


Challenges and Successes in Raising a Child With Type 1 Diabetes and Autism Spectrum Disorder: Mixed Methods Study.
Self-management of type 1 diabetes (T1D) requires numerous decisions and actions by people with T1D and their caregivers and poses many daily challenges. For those with T1D and a developmental disorder such as autism spectrum disorder (ASD), more complex challenges arise, though these remain largely unstudied. This study aimed to better understand the barriers and facilitators of raising a child with T1D and ASD. Secondary analysis of web-based content (phase 1) and telephone interviews (phase 2) were conducted to further expand the existing knowledge on the challenges and successes faced by these families. Phase 1 involved a qualitative analysis of publicly available online forums and blog posts by caregivers of children with both T1D and ASD. Themes from phase 1 were used to create an interview guide for further in-depth exploration via interviews. In phase 2, caregivers of children with both T1D and ASD were recruited from Penn State Health endocrinology clinics and through the web from social media posts to T1D-focused groups and sites. Interested respondents were directed to a secure web-based eligibility assessment. Information related to T1D and ASD diagnosis, contact information, and demographics were collected. On the basis of survey responses, participants were selected for a follow-up telephone interview and were asked to complete the adaptive behavior assessment system, third edition parent form to assess autism severity and upload a copy of their child's most recent hemoglobin A1c (HbA1c) result. Interviews were transcribed, imported into NVivo qualitative data management software, and analyzed to determine common themes related to barriers and facilitators of raising a child with both ASD and T1D. For phase 1, 398 forum posts and blog posts between 2009 and 2016 were analyzed. Common themes related to a lack of understanding by the separate ASD and T1D caregiver communities, advice on coping techniques, rules and routines, and descriptions of the health care experience. For phase 2, 12 eligible respondents were interviewed. For interviewees, the average age of the child at diagnosis with T1D and ASD was 7.92 years and 5.55 years, respectively. Average self-reported and documented HbA1c levels for children with T1D and ASD were 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol), respectively. Common themes from the interviews related to increased emotional burden, frustration surrounding the amount of information they are expected to learn, and challenges in the school setting. Caregivers of children with both T1D and ASD face unique challenges, distinct from those faced by caregivers of individuals who have either disorder alone. Understanding these challenges may help health care providers in caring for this unique population. Referral to the diabetes online community may be a potential resource to supplement the care received by the medical community.


An enhanced computational platform for investigating the roles of regulatory RNA and for identifying functional RNA motifs.
Functional RNA molecules participate in numerous biological processes, ranging from gene regulation to protein synthesis. Analysis of functional RNA motifs and elements in RNA sequences can obtain useful information for deciphering RNA regulatory mechanisms. Our previous work, RegRNA, is widely used in the identification of regulatory motifs, and this work extends it by incorporating more comprehensive and updated data sources and analytical approaches into a new platform. An integrated web-based system, RegRNA 2.0, has been developed for comprehensively identifying the functional RNA motifs and sites in an input RNA sequence. Numerous data sources and analytical approaches are integrated, and several types of functional RNA motifs and sites can be identified by RegRNA 2.0: (i) splicing donor/acceptor sites; (ii) splicing regulatory motifs; (iii) polyadenylation sites; (iv) ribosome binding sites; (v) rho-independent terminator; (vi) motifs in mRNA 5'-untranslated region (5'UTR) and 3'UTR; (vii) AU-rich elements; (viii) C-to-U editing sites; (ix) riboswitches; (x) RNA cis-regulatory elements; (xi) transcriptional regulatory motifs; (xii) user-defined motifs; (xiii) similar functional RNA sequences; (xiv) microRNA target sites; (xv) non-coding RNA hybridization sites; (xvi) long stems; (xvii) open reading frames; (xviii) related information of an RNA sequence. User can submit an RNA sequence and obtain the predictive results through RegRNA 2.0 web page. RegRNA 2.0 is an easy to use web server for identifying regulatory RNA motifs and functional sites. Through its integrated user-friendly interface, user is capable of using various analytical approaches and observing results with graphical visualization conveniently. RegRNA 2.0 is now available at http://regrna2.mbc.nctu.edu.tw.


Foraging behavior of an urban bird species: molt gaps, distance to shelter, and predation risk.
Predation cost (Pc) is often regarded as a pivotal component determining foraging behavior. We hypothesized that variations in two of its major constituents, predation risk (mu) and the marginal value of energy ([see text for symbol]Fs/ [see text for symbol]e, where Fs is the survivor's fitness and e represents the amount of acquired energy), will translate into variations in patch use behavior of ground-foraging birds. We studied patch use behavior of House Sparrows (Passer domesticus), as affected by the proximity to shelter, in two large outdoor aviaries. Proximity to shelter should affect mu. We manipulated the birds' flight performance by clipping primary flight feathers from their wings to increase mu, but the clipping may also increase [see text for symbol]Fs/ [see text for symbol]e. To help distinguish between the birds' response to these confounding effects, we further augmented food in the aviaries to reduce [see text for symbol]Fs/ [see text for symbol]e. Patch use, as measured by giving-up densities (GUD, the amount of food left behind in a resource patch following exploitation) was affected by distance from shelter only slightly and mainly when the birds were feather-clipped and food was not augmented. Food augmentation had a homogenizing effect on foraging costs by increasing GUDs and washing out the effects of distance and feather clipping. We argue that mu increases with distance from shelter but that, for the highly urban House Sparrow, this increase is only slight. Feather clipping then increased mu further to the point at which patch use discernibly decreased with distance from shelter. Our experimental manipulation of feather clipping also acted to increase [see text for symbol]Fs/ [see text for symbol]e and resulted in an overall lowering of GUDs. The seed augmentation counteracted the effect of feather clipping on [see text for symbol]Fs/ [see text for symbol]e, allowing the birds to reduce their foraging efforts and washing out the qualitative effect of mu with respect to distance from shelter.


Effects of Ginkgo biloba extract on the apoptosis of oxygen and glucose-deprived SH-SY5Y cells and its mechanism.
The aim was to observe the effects of the extract of Ginkgo biloba (EGb761) on the apoptosis of oxygen and glucose-deprived (OGD) human neuroblastoma cells (SH-SY5Y) cells and explore its mechanism. SH-SY5Y cells were divided into normal control group, OGD group, OGD for 4 h and EGb761-pretreated groups including very low-concentration (20 μg/ml), low-concentration group (25 μg/ml), moderate-concentration group (50 μg/ml) and high-concentration group (100 μg/ml). Twenty four hours after reoxygenation, cell viability was determined with 3-[4, 5-dimehyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide assay, apoptosis rate was detected with annexin V-fluorescein isothiocyanate/propidium iodide double staining flow cytometry and the protein level of apoptosis-inducing factor (AIF) was observed with immunofluorescence technique in each group. Cell viability was significantly lower in OGD group than in EGb761-pretreated groups, especially in moderate-concentration group (50 μg/ml) (P < 0.005). Apoptosis rate was significantly lower in EGb761-pretreated groups than in OGD group (P < 0.001). Immunofluorescent staining showed that there was AIF nuclear translocation in both EGb761-pretreated groups and OGD group, but AIF nuclear translocation was less in EGb761-pretreated groups than in OGD group. EGb761 can reduce the apoptosis of OGD SH-SY5Y cells probably through inhibiting AIF nuclear translocation. This study provides a theoretical basis for the application of EGb761 in clinical practice.


Insulin sensitizers may attenuate lean mass loss in older men with diabetes.
To examine longitudinal changes in total and appendicular lean body mass in older men with impaired fasting glucose (IFG) or diabetes and to determine whether these changes differ by diabetes treatment. A total of 3,752 ambulatory men aged ≥ 65 years at baseline participated in a multicenter longitudinal cohort study. Baseline glycemic status was categorized as normoglycemia, IFG, undiagnosed/untreated diabetes, or treated diabetes. Insulin sensitizer medication use (metformin and/or thiazolidinediones) was assessed by prescription medication inventory. The change in total lean and appendicular lean mass was derived from dual X-ray absorptiometry scans taken at baseline and 3.5 ± 0.7 years later. This male cohort included 1,853 individuals with normoglycemia, 1,403 with IFG, 234 with untreated diabetes, 151 with diabetes treated with insulin sensitizers, and 111 with diabetes treated without insulin sensitizers. Men with untreated diabetes, diabetes treated without insulin sensitizers, or IFG had greater percentage loss in total or appendicular lean mass (P ≤ 0.05 in comparison to normoglycemic men). There remained a significantly greater percentage loss in appendicular lean mass for these groups even after adjustment for medical comorbidities or lifestyle factors. In contrast, the percentage loss in total or appendicular lean mass in men with diabetes treated with insulin sensitizers was significantly less than that in normoglycemic men in minimally and fully adjusted models. Skeletal muscle loss was accelerated in men with IFG and diabetes, except when the latter was treated with insulin sensitizers. These findings suggest that insulin sensitizers may attenuate muscle loss.


Evaluation of a theory of planned behaviour-based breastfeeding intervention in Northern Irish schools using a randomized cluster design.
The aim of this research was to evaluate the effectiveness of a school-based intervention designed to enhance young people's motivations to breastfeed. A cluster randomized controlled trial was conducted involving 50 post-primary schools from across Northern Ireland. However, dropout and exclusion criteria utilized for the current study resulted in an effective sample size of 42 schools. The intervention was delivered in two 35-min classroom sessions targeting those beliefs identified by the theory of planned behaviour (TPB) as significant in predicting motivation to breastfeed. Questionnaires incorporating the key components of the TPB were administered to all intervention and control schools at baseline, 1 and 6 months post-intervention. Multi-level modelling was used to analyse the data. Findings suggest that the intervention was effective in that it increased females' intentions to breastfeed, expanded their knowledge and led to more favourable attitudes and perceptions of subjective norms. Notably, females' knowledge increased more in secondary schools than in grammar schools irrespective of whether they were control or intervention schools. The research has provided evidence to support the use of the TPB in the design and evaluation of an intervention to increase females' intentions to breastfeed.


Reducing co-administration of clopidogrel and proton pump inhibitors in acute coronary syndromes.
Recent concerns about clopidogrel and proton pump inhibitor (PPI) co-administration in patients following an acute coronary syndrome (ACS) led us to investigate our practice. Guidance recommends that omeprazole and esomeprazole should not be co-administered with clopidogrel as they can decrease its efficacy. Pantoprazole and lansoprazole are safer for use in these cases. Patients discharged between August 2008 and July 2009 with a diagnosis of ACS, on both clopidogrel and any PPI, were identified using the pharmacy database. Their notes were retrospectively reviewed, the indication for a PPI was checked and whether an appropriate one had been prescribed was assessed. As a result of our findings a simple algorithm was introduced to set out guidance on appropriate use and junior doctors were informed of the new procedure. We then performed another audit of patients discharged between August 2009 and February 2010 to ensure that the guidelines were being followed. During the first phase of the audit 43 out of 91 patients (47.5%) received a PPI with clopidogrel. Following our intervention, re-auditing confirmed that clopidogrel and PPI co-administration had decreased significantly to 27 out of 101 patients (26.7%) (p = 0.018). Through a simple intervention with an algorithm and education of junior doctors we have shown that significant improvement and adherence to guidance can be achieved.


The clinical effectiveness of cognitive behaviour therapy for chronic insomnia: implementation and evaluation of a sleep clinic in general medical practice.
Chronic insomnia is a very common clinical condition which may respond well to non-pharmacological treatment. Indeed, the literature supports the efficacy of cognitive behaviour therapy (CBT). However, there has been no substantial study of clinical effectiveness. Since insomniacs typically present in general medical practice this is a crucial gap in the outcome research. This study, therefore, specifically investigated the clinical effectiveness of CBT delivered by Health Visitors (primary care nurses) trained as therapists. One hundred and thirty-nine insomniacs (mean age 51 yr) were randomised to CBT or Self-Monitoring Control (SMC) in a controlled trial. CBT comprised six group sessions (n=4 to 6 patients). After the controlled phase, SMC patients entered deferred treatment (CBT-DEF), allowing both treatment replication and long-term outcome to be investigated for a sizeable, treated sample. Repeated measures ANOVAs demonstrated superiority of CBT over SMC in substantially reducing sleep latency and wakefulness during the night. CBT-DEF replicated similar effects and maintained improvement was observed in both groups one year later. Furthermore, total sleep increased significantly during follow-up and 84% of patients initially using hypnotics remained drug-free. Results suggest that CBT administered by Health Visitors offers a clinically effective treatment for insomnia.


Facile template-free synthesis of multifunctional 3D cellular carbon from edible rice paper.
Edible rice paper wrapper is found to be an interesting precursor of a porous and light-weight carbon material. During pyrolysis, material samples show significant differences in length change, displaying typical 20-25% shrinking in the in-plane directions, and strongly expanding (up to 500%) across their out-of-plane direction. This results in a template-free synthesis of a 3D network of cellular carbon material. The out-of-plane expansion also allows for fabrication of 3D shapes of cellular carbon material from the 2D precursor. The rice paper derived carbon material features a hierarchical porosity, resulting in a specific surface area ranging from 6 m2 g-1 to 239 m2 g-1 depending on the synthesis temperature. The carbon material has a density of 0.02-0.03 g cm-3, and a higher modulus-density ratio than reported for other cellular carbon materials. It is mechanically stiff and exhibits excellent fire-resistant properties.


Antidepressant use and violent crimes among young people: a longitudinal examination of the Finnish 1987 birth cohort.
The use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), has been questioned due to poor efficacy and safety. We examined whether young violent offenders were more likely antidepressant users prior to their first violent offence than other young persons. The study is a follow-up of children born in Finland in 1987 (n=59 120), linking national registers to each other using personal identity codes. Data on psychotropic drug use came from a register of reimbursed drugs and data on crimes from a register on court convictions (after the age of 14 years). Participants were followed until the age of 18 years, and for some analyses until the end of the follow-up (mean 21 years). To adjust for differences in background characteristics, regression analyses for antidepressant use were made, using the no-conviction group as the reference. Proportions of young people convicted by the age of 18 years were: 5% of boys (1.7% for violent crimes) and 1% (0.5%) of girls. Antidepressant use (both overall and for SSRIs) prior to violent crime was more common among those convicted than among those without convictions. Among boys with repeated violent crimes, it was also more common than among boys with non-violent crimes. Adjustment for differences in background characteristics decreased the associations between antidepressant use and violent crime, but did not eliminate them. The results add further evidence for caution in prescribing antidepressants among young persons. It also calls for a reanalysis of violence measures in the original trial data.


Piecewise-linear models of genetic regulatory networks: equilibria and their stability.
A formalism based on piecewise-linear (PL) differential equations, originally due to Glass and Kauffman, has been shown to be well-suited to modelling genetic regulatory networks. However, the discontinuous vector field inherent in the PL models raises some mathematical problems in defining solutions on the surfaces of discontinuity. To overcome these difficulties we use the approach of Filippov, which extends the vector field to a differential inclusion. We study the stability of equilibria (called singular equilibrium sets) that lie on the surfaces of discontinuity. We prove several theorems that characterize the stability of these singular equilibria directly from the state transition graph, which is a qualitative representation of the dynamics of the system. We also formulate a stronger conjecture on the stability of these singular equilibrium sets.