[Effect of intravenous drip infusion of cyclophosphamide with high-dose Astragalus injection in treating lupus nephritis].
To observe the effect of high-dose Astragalus injection and cyclophosphamide (CTX) on infection, urine protein and immune function of the patients with lupus nephritis. Forty-three patients diagnosed as systemic lupus erythematosus (SLE) complicated by kidney damage and qi-deficiency syndrome were randomly divided into trial group (n=23) and control group (n=20). Patients in both groups were treated for 3 months. Intravenous drip infusion of 0.8 g CTX was administered to all patients once a month, while intravenous drip infusion of 20 ml Astragalus injection was only administered to patients in the trial group every day for 12 days in each month. The decrease of active clinical symptom score after the treatment in the trial group was greater than that in the control group (P<0.05). The infection rates of the trial group and the control group were 4.35% and 25% respectively. The decrease of 24-hour urine protein and CD8, and the increase of red blood cell count and serum albumin in the trial group were greater than those in the control group, and there were significant differences between the two groups (P<0.05). White blood cell count in the trial group was decreased less than that in the control group after the treatment (P<0.05). High-dose Astragalus injection used together with CTX is more effective than CTX alone in decreasing infection rate and urine protein and improving immune function for patients with lupus nephritis.


Shifting body weight-fecundity relationship in a capital breeder: maternal effects on egg numbers of the autumnal moth under field conditions.
In the literature, various environmental factors are described as being capable of influencing the reproductive output of insect females irrespective of their body size. Still, female body size or weight is widely used as a proxy for fecundity. In the present study, a seven-year data set on the autumnal moth, Epirrita autumnata (Borkhausen) (Lepidoptera: Geometridae), was used to analyze whether the body weight-fecundity relationship in this capital breeding, cyclic forest defoliating lepidopteran is constant across years. Ambient temperature conditions and density of conspecifics during larval development, the length of the pupal period, as well as moth densities in the parent generation were examined as factors capable of modifying the body weight-fecundity relationship. While the regression slope of potential fecundity (total egg numbers per female) on pupal mass was constant across years, the mean total egg number per given body weight (the regression intercept) was significantly different between years. This residual variance in egg numbers after controlling for the effect of pupal mass was best explained by the pooled geometrid density (autumnal and winter moths) in the parent generation. The total egg number per given body weight decreased with increasing density of geometrid moths in the parent generation. Thus, maternal density effects on offspring fecundity were found in this system. Their rather weak nature suggests, however, that this maternal effect alone does not have the potential of causing cyclic population dynamics in the autumnal moth.


Interaction of von Willebrand factor with the extracellular matrix and glycocalicin under static conditions.
The binding of human von Willebrand factor (vWF) to a variety of extracellular matrix components immobilized on plates and the binding of vWF to platelet glycoprotein Ib (GPIb) after interacting with these matrix components were examined by means of an enzyme-linked immunosorbent assay. vWF preferably bound to type III collagen, whereas it did not significantly bind to type I, IV, V, or VI collagen, fibronectin, laminin, elastin, or proteoglycans. Soluble type III collagen did not bind to vWF coated on plates and showed a little effect on the vWF binding to the immobilized collagen, suggesting that solid-phase collagen is important for the interaction with vWF. When glycocalicin, the N-terminal carbohydrate-rich extracellular domain of GPIb alpha exhibiting the vWF-binding activity, was added to vWF bound to collagen type III, no significant binding of glycocalicin was observed, but it bound to vWF in the presence of botrocetin, a vWF modulator protein isolated from Bothrops jararaca snake venom. These results indicate that vWF immobilized on collagen can interact with GPIb but that binding of vWF to the collagen matrix alone is insufficient for modulating vWF so that it interacts with GPIb under static conditions. Another unknown physiological modulator functionally mimicking botrocetin or high-shear stress may be involved in the platelet adhesion to extracellular matrix in the early stage of hemostasis.


Development of on-line high performance liquid chromatography (HPLC)-biochemical detection methods as tools in the identification of bioactives.
Biochemical detection (BCD) methods are commonly used to screen plant extracts for specific biological activities in batch assays. Traditionally, bioactives in the most active extracts were identified through time-consuming bio-assay guided fractionation until single active compounds could be isolated. Not only are isolation procedures often tedious, but they could also lead to artifact formation. On-line coupling of BCD assays to high performance liquid chromatography (HPLC) is gaining ground as a high resolution screening technique to overcome problems associated with pre-isolation by measuring the effects of compounds post-column directly after separation. To date, several on-line HPLC-BCD assays, applied to whole plant extracts and mixtures, have been published. In this review the focus will fall on enzyme-based, receptor-based and antioxidant assays.


The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial.
Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM). We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation. In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment. University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.


Variables associated with high olanzapine dosing in a state hospital.
Olanzapine has a U.S. Food and Drug Administration-approved dosing range of 10 to 20 mg/day but is often used at doses exceeding this range. Olanzapine is largely metabolized by cytochrome P450 (CYP) 1A2. Smoking, which induces CYP1A2, is expected to increase clearance of olanzapine by 40%; however, dosage adjustment in smokers is not currently recommended. Additionally, female gender is expected to reduce clearance by 30%. Many institutions target high-dose olanzapine prescribers in an effort to reduce unnecessary drug costs. However, factors such as smoking or gender may necessitate increased doses. A retrospective review of all patients receiving olanzapine during an inpatient stay at a state psychiatric hospital in Kentucky during 2001 was conducted. Demographic information and smoking status were collected for all patients. Olanzapine doses of > 20 mg/day were considered high doses. Nine percent (48/522) of olanzapine patients were prescribed high doses. The percentages were similar in women and men (10% vs. 9%, p =.69) and in smokers and nonsmokers (9% vs. 9%, p =.82). Moreover, the mean maximum olanzapine dose was also similar in men and women (15.4 +/- 7.2 vs. 14.9 +/- 7.3 mg/day, p =.51). The odds of receiving a high dose of olanzapine were increased 2.1 for patients with a schizophrenia spectrum diagnosis (DSM-IV schizophrenia or other psychotic disorder). The odds of receiving a high dose of olanzapine were increased with each incremental increase in length of stay (intermediate length of stay [8-60 days], OR = 5.6; long-term length of stay [> 60 days], OR = 12.0, relative to acute length of stay [< 8 days]). Neither gender nor smoking status was associated with receiving a high dose of olanzapine. The association of increased length of stay with high dose suggests that treatment resistance may be an important factor in receiving high daily doses of olanzapine.


Deliberate self-harm in rural and urban regions: a comparative study of prevalence and patient characteristics.
In countries like the U.K., people living in urban regions are more likely to suffer poor physical and mental health than rural populations, and to have increased rates of psychiatric disorder. Urban/rural differences in suicidal behaviour have most frequently focussed on variations in the occurrence of suicide. We have investigated rates of deliberate self-harm (DSH) in urban and rural districts of Oxfordshire, England, and compared characteristics of DSH patients resident in these two areas. Information was collected on 6833 DSH episodes by 4054 persons aged 15 years and over presenting to the local general hospital between 2001 and 2005. We found that urban DSH rates were substantially higher than rural rates amongst both males and females aged between 15 and 64 years. This relationship was sustained even when socio-economic deprivation and social fragmentation were taken into account. There was little difference between urban and rural rates for patients aged 65 years and over. Urban DSH patients were more likely to be younger, non-white in ethnic origin, unemployed, living alone, to have a criminal record, to have previously engaged in DSH, and to report problems with housing. Rural DSH patients were more likely to suffer from physical illness, and to have higher suicide intent scores. Results of studies such as this can help identify where resources for preventive initiatives should be primarily directed and also what types of individuals may be at most risk in different areas. However, since variation by area will in part be due to differences at the individual level, further research utilising multi-level modelling techniques would be useful.


Multidisciplinary outpatient care program for patients with chronic low back pain: design of a randomized controlled trial and cost-effectiveness study [ISRCTN28478651].
Chronic low back pain (LBP) is a major public and occupational health problem, which is associated with very high costs. Although medical costs for chronic LBP are high, most costs are related to productivity losses due to sick leave. In general, the prognosis for return to work (RTW) is good but a minority of patients will be absent long-term from work. Research shows that work related problems are associated with an increase in seeking medical care and sick leave. Usual medical care of patients is however, not specifically aimed at RTW. The objective is to present the design of a randomized controlled trial, i.e. the BRIDGE-study, evaluating the effectiveness in improving RTW and cost-effectiveness of a multidisciplinary outpatient care program situated in both primary and outpatient care setting compared with usual clinical medical care for patients with chronic LBP. The design is a randomized controlled trial with an economic evaluation alongside. The study population consists of patients with chronic LBP who are completely or partially sick listed and visit an outpatient clinic of one of the participating hospitals in Amsterdam (the Netherlands). Two interventions will be compared. 1. a multidisciplinary outpatient care program consisting of a workplace intervention based on participatory ergonomics, and a graded activity program using cognitive behavioural principles. 2. usual care provided by the medical specialist, the occupational physician, the patient's general practitioner and allied health professionals. The primary outcome measure is sick leave duration until full RTW. Sick leave duration is measured monthly by self-report during one year. Data on sick leave during one-year follow-up are also requested form the employers. Secondary outcome measures are pain intensity, functional status, pain coping, patient satisfaction and quality of life. Outcome measures are assessed before randomization and 3, 6, and 12 months later. All statistical analysis will be performed according to the intension-to-treat principle. Usual care of primary and outpatient health services isn't directly aimed at RTW, therefore it is desirable to look for care which is aimed at RTW. Research shows that several occupational interventions in primary care are aimed at RTW. They have shown a significant reduction of sick leave for employee with LBP. If a comparable reduction of sick leave duration of patients with chronic LBP of who attend an outpatient clinic can be achieved, such reductions will be obviously substantial for the Netherlands and will have a considerable impact.


Primary Percutaneous Coronary Intervention Facility Hospitals and Easy Access Can Affect the Outcomes of ST-Segment Elevation Myocardial Infarction Patients.
The reperfusion therapy using primary percutaneous coronary intervention (PPCI) in ST-segment elevation myocardial infarction (STEMI) is known to give a better result than fibrinolytic therapy. The fast access to PPCI will improve hospital outcome. We believe that patient access to PPCI facility would have improved due to enhanced public awareness and expanding evidenced-based health provision. This is a single-center retrospective study to analyze and compare data for STEMI patients. Patients were transferred to our hospital during the year 2010. Group l comprised 223 patients. Group 2 comprised 288 patients. Group 2 patients were those treated between August 2014 and August 2015. We compared their demographic and baseline characteristics, patients' access to the hospital, reasons for no access, and hospital mortality for the two groups. Among the 288 patients in Group 2, 247 patients (85%) were males with an average age of 57 years, 49% were diabetics, 48% were hypertensive, 48% were smokers, and 27% were obese. These were not different in Group 1. In Group 2, 164 patients (57%) only had access to PPCI compared to 56% in Group 1 (P = 0.536-NS). In G2, the main reasons for no PPCI were late presentation in 47% versus 53% in Group 1; P = 0.34 NS. In Group 2, 27% were due to thrombolysis versus 17% in Group 1 (P = 0.11 NS). Hospital mortality in Group 2 was 4% in those treated with PPCI compared to 2.3% in Group 1 (P = 0.522-NS). Mortality in patients who did not receive PPCI in Group 2 was 8% compared to 11.3% in Group 1 (P = 0.49-NS). Females in Group 2 have about 3 times higher mortality. Patients treated for STEMI in the last 12 months at King Abdulaziz Cardiac Center still have relatively low access to PPCI due mainly to persistent pattern of late presentation and prior thrombolysis, which reflect apparent lack of direct access to hospitals with PPCI facilities. Comparing the two periods, there was no change in cardiology practice. The low access to PPCI was mainly due to late presentation and prior thrombolysis. Hospital mortality rate for patients treated with PPCI remained low during the two era. This seemingly relates to both lack of public awareness and health provision factors in PPCI organizations.


Carcinogenesis Bioassay of Disperse Yellow 3 (CAS No. 2832-40-8) in F344 Rats and B6C3F1 Mice (Feed Study).
A carcinogenesis bioassay of C.I. Disperse Yellow 3 (87.6% dye), a textile dye, was conducted by feeding diets containing 5,000 or 10,000 ppm of the test substance to groups of 50 F344 rats of either sex for 103 weeks. Similar groups of 50 B6C3F1 mice received diets containing 2,500 or 5,000 ppm of the test substance for 103 weeks. Groups of 50 untreated rats and mice of each sex served as controls. Throughout the bioassay, mean body weights of dosed rats and mice of either sex were lower than those of the controls. Survival of dosed rats of either sex was significantly greater than that of the corresponding controls. No other compound-related clinical signs or effects on survival were observed. A significant increase in neoplastic nodules of the liver occurred in dosed male rats as compared to controls (controls 1/49, 2%; low-dose 15/50, 30%; P<0.001; high-dose, 10/50, 20%; P<0.01). No increase was observed for female rats. Stomach tumors, rare in F344 rats (10/2960, 0.3%), were found in the dosed male rats: one adenocarcinoma and a sarcoma in a high-dose male and in the low-dose group a squamous cell papilloma, fibrosarcoma, adenoma, and mucinous adenocarcinoma. The incidence of these tumors was not significantly greater than that in controls; thus, the association between the administration of C.I. Disperse Yellow 3 and the stomach tumors in male rats is not clearly established. Negative trends in the incidences of certain primary tumors in dosed rats included: decreased lymphocytic leukemia in both sexes; decreased malignant mesothelioma and C-cell carcinoma of the thyroid in males; and decreased pituitary chromophobe adenoma and endometrial stromal polyps in females. Hepatocellular adenomas occurred in dosed female mice at incidences significantly higher than that in the controls (control 0/50, 0%; low-dose 6/50, 12%, P<0.05; high-dose 12/50, 24%, P<0.001). The incidences of hepatocellular carcinomas were also higher in the dosed female mice than in the controls, but the increased incidences were not statistically significant (2/50, 4/50, 5/50). A significantly (P<0.05) lower incidence of hepatocellular adenomas was detected among low-dose (7/50, 1/49, 7/49) male mice. Alveolar/bronchiolar adenomas occurred in high-dose male mice at an incidence significantly (P%lt;0.05) higher than that in the controls (control 2/50, 4%; low-dose 6/49, 12%; high-dose 9/49, 18%). However, the high-dose effect was not significant when adenomas and carcinomas were combined; the incidence among low-dose female mice was significantly reduced as compared with controls. Thus, the incidence of alveolar/bronchiolar adenomas among males is not considered to be related to treatment with C.I. Disperse Yellow 3. Malignant lymphomas occurred in a dose-related (P<0.05) trend in female mice and at incidences greater (P<0.05) in the high-dose group than that in the controls (10/50; 16/50; 19/50). However, because of the range of variability in the historical incidence of this tumor and because of the lack of a similar effect in male mice or in male and female rats, this increase was not regarded as being unequivocally related to the administration of C.I. Disperse Yellow 3. Under the conditions of this bioassay, C.I. Disperse Yellow 3 was considered to be carcinogenic for male F344 rats, causing an increased incidence of neoplastic nodules of the liver; this dye was not carcinogenic for female F344 rats. In addition, the stomach tumors found in the male rats may have been induced by the administration of the test chemical. C.I. Disperse Yellow 3 was carcinogenic for female B6C3F1 mice, as evidenced by the increased incidence of hepatocellular adenomas; C.I. Disperse Yellow 3 was not carcinogenic for male B6C3F1 mice. Also, the increased incidence of malignant lymphoma in female mice may have been associated with the administration of C.I. Disperse Yellow 3. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Positive Synonyms: Disperse Fast Yellow 6; Acetamine Yellow CG


Ethical considerations when conservation research involves people.
Social science is becoming increasingly important in conservation, with more studies involving methodologies that collect data from and about people. Conservation science is a normative and applied discipline designed to support and inform management and practice. Poor research practice risks harming participants and, researchers, and can leave negative legacies. Often, those at the forefront of field-based research are early-career researchers, many of whom enter their first research experience ill-prepared for the ethical conundrums they may face. We draw on our own experiences as early-career researchers to illuminate how ethical challenges arise during conservation research that involves human participants. Specifically, we considered ethical review procedures, conflicts of values, and power relations, and devised broad recommendations on how to navigate ethical challenges when they arise during research. In particular, we recommend researchers apply reflexivity (i.e., thinking that allows researchers to recognize the effect researchers have on the research) to help navigate ethical challenges and encourage greater engagement with ethical review processes and the development of ethical guidelines for conservation research that involves human participants. Such guidelines must be accompanied by the integration of rigorous ethical training into conservation education. We believe our experiences are not uncommon and can be avoided and hope to spark discussion to contribute to a more socially just conservation.


Quality of life and meaning of illness of women with lung cancer.
To describe the quality of life (QOL) of women with non-small cell lung cancer (NSCLC) and examine relationships of demographic, clinical, health status, and meaning of illness (MOI) characteristics to QOL. Descriptive, cross-sectional survey. In-person interviews in homes or research offices. 217 women with NSCLC (greater than 6 months and less than 5 years since diagnosis, mean = 2 years); 19% of the women had advanced disease. The mean age was 65 years. Assessments of QOL with cancer-specific (QOL Scale-Patient Version) and generic (Short Form-36) self-reports, health status (i.e., number and type of comorbid conditions, presence of depressed mood using the Center for Epidemiologic Studies Depression Scale, smoking status), and MOI (positive and negative perceptions). QOL, health status, MOI, and demographic and clinical characteristics. Serious disruptions in psychological and social aspects of QOL were common. Depressed mood, negative conceptualizations of MOI, and younger age explained 37% of the variance of global QOL and were correlated with poorer physical, psychological, and social dimensions of QOL. Thirty-six percent reported negative ascriptions of MOI; 35% experienced depressed mood; more than 75% reported distress with their diagnosis, family distress, and impact of sexual function as lowering their QOL; and 67% reported comorbid conditions, the most common being chronic obstructive pulmonary disease (31%). Women with lung cancer experience a range of disruptions in QOL, and more than a third associate lung cancer with negative meaning. Younger age, depressed mood, and number of comorbid diseases are risk factors for negative QOL. These findings support the importance of assessing the QOL, MOI, and health status of women with lung cancer even after treatment is completed. Younger women may be at higher risk for disruptions.


A highly conserved lysine residue in phi29 DNA polymerase is important for correct binding of the templating nucleotide during initiation of phi29 DNA replication.
DNA polymerases that initiate replication by protein-priming are able to catalyze terminal protein (TP)-primed initiation, the following transition steps and finally DNA-primed elongation. Therefore, their structures must be able to position sequentially both primers, TP and DNA, at a common binding site. For DNA-templated initiation, these DNA polymerases have to bind the origin of replication as template and TP as primer. It is likely that very precise interactions are required to position both TP and templating nucleotide at the polymerization active site. Such a specificity during TP-priming must rely on specific amino acids that must be evolutionarily conserved in this subfamily of DNA polymerases. By site-directed mutagenesis, we have analyzed the functional significance of Lys392 of phi29 DNA polymerase, immediately adjacent to the Kx3NSxYG motif, and specifically conserved among protein-primed DNA polymerases. During TP-primed initiation, mutations in this residue did not affect untemplated TP-dAMP formation, indicating that the interaction with the initiating nucleotide and TP were not affected, whereas the template-directed initiation activity was severely inhibited. Both mutant DNA polymerases had a wild-type-like (overall) DNA binding activity. We thus infer that residue Lys392 of phi29 DNA polymerase is important for the correct positioning of the templating nucleotide at the polymerization active site, a critical requirement during template-directed TP-priming at phi29 DNA origins. Consequently, mutation of this residue compromised the fidelity of the initiation reaction, not controlled by the 3'-5' exonuclease activity. During DNA-primed polymerization, the mutant polymerases showed a defect in translocation of the template strand. This translocation problem could be the consequence of a more general defect in the stabilization and positioning of a next templating nucleotide at the polymerization active site, during DNA-primed DNA synthesis.


Generation of paired photons in a quantum separable state in Bragg reflection waveguides.
This work proposes and analyses a novel approach for the generation of separable (quantum uncorrelated) photon pairs based on spontaneous parametric down-conversion in Bragg reflection waveguides composed of semiconductor AlGaN layers. This platform allows the removal of any spectral correlation between paired photons that propagate in different spatial modes. The photons can be designed to show equal or different spectra by tuning the structural parameters and hence the dispersion of the waveguide.


Correlation of the ratio of metastatic to non-metastatic cancer cases with the degree of socioeconomic deprivation among Texas counties.
Previous studies have demonstrated that cancer registrations and hospital discharge rate are closely correlated with census data-based socioeconomic deprivation indices. We hypothesized that communities with higher degrees of socioeconomic deprivation tend to have a higher ratio of metastatic to non-metastatic cancer cases (lung, breast, prostate, female genital system, colorectal cancers or all types of cancers combined). In this study, we investigate the potential link between this ratio and the Wellbeing Index (WI) among Texas counties. Cancer data in 2000 were provided by the Texas Cancer Registry, while data on the ten socioeconomic variables among the 254 Texas counties in 2000 for building the WI were obtained from U.S. Census Bureau. The ten socioeconomic status variables were subjected to the principal component analysis, and the first principal component scores were grouped into deciles for the WI (1 to 10) and the 254 Texas counties were classified into 10 corresponding groups. Weighted linear regression analyses and a Cochran-Armitage trend test were performed to determine the relationship between the ratio of age-adjusted metastatic to non-metastatic cancer incidence cases and WI. The ratios of metastatic to non-metastatic cases of female genital system cancer (r2 = 0.84, p = 0.0002), all-type cancers (r2= 0.73, p = 0.0017) and lung cancer (r2= 0.54, p = 0.0156) at diagnosis were positively correlated with WI. The ratios of metastatic to non-metastatic cases of all-type, female genital system and lung cancers at diagnosis were statistically correlated with socioeconomic deprivation. Potential mediators for the correlation warrant further investigation in order to reduce health disparities associated with socioeconomic inequality.


Comparison of AUDIT-C collected via electronic medical record and self-administered research survey in HIV infected and uninfected patients.
Using electronic medical record (EMR) data for clinical decisions, quality improvement, and research is common. While unhealthy alcohol use is particularly risky among HIV infected individuals (HIV+), the validity of EMR data for identifying unhealthy alcohol use among HIV+ is unclear. Among HIV+ and uninfected, we: (1) assess agreement of EMR and research AUDIT-C at validated cutoffs for unhealthy alcohol use; (2) explore EMR cutoffs that maximize agreement; and (3) assess subpopulation variation in agreement. Using data from the Veterans Aging Cohort Study (VACS), EMR AUDIT-C cutoffs of 2+, 3+, and 4+ for men (2+ and 3+ for women) were compared to research AUDIT-C 4+ for men (3+ for women). Agreement was compared by demographics, HIV, hepatitis C infection, and alcohol related diagnosis. Among 1082 HIV+ and 1160 uninfected men, 14% and 22% had an EMR and research AUDIT-C 4+, respectively. Among 32 HIV+ and 115 uninfected women, 9% and 14% had an EMR and research AUDIT-C 3+. For men, EMR agreement with the research AUDIT-C 4+ was highest at a cutoff of 3+ (kappa=0.49). For women, EMR agreement with AUDIT-C 3+ was highest at a cutoff of 2+ (kappa=0.46). Moderate agreement was consistent across subgroups. EMR AUDIT-C underestimates unhealthy alcohol use compared to research AUDIT-C in both HIV+ and uninfected individuals. Methods for improving quality of clinical screening may be in need of investigation. Researchers and clinicians may consider alternative EMR cutoffs that maximize agreement given limitations of clinical screening.


Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder.
Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels-a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction. Future studies need to identify additional parallels between the PPA rodent model of ASD and this subset of ASD individuals with this unique pattern of acyl-carnitine abnormalities. A better understanding of this animal model and subset of children with ASD should lead to better insight in mechanisms behind environmentally induced ASD pathophysiology and should provide guidance for developing preventive and symptomatic treatments.


Ionic Liquids: evidence of the viscosity scale-dependence.
Ionic Liquids (ILs) are a specific class of molecular electrolytes characterized by the total absence of co-solvent. Due to their remarkable chemical and electrochemical stability, they are prime candidates for the development of safe and sustainable energy storage systems. The competition between electrostatic and van der Waals interactions leads to a property original for pure liquids: they self-organize in fluctuating nanometric aggregates. So far, this transient structuration has escaped to direct clear-cut experimental assessment. Here, we focus on a imidazolium based IL and use particle-probe rheology to (i) catch this phenomenon and (ii) highlight an unexpected consequence: the self-diffusion coefficient of the cation shows a one order of magnitude difference depending whether it is inferred at the nanometric or at the microscopic scale. As this quantity partly drives the ionic conductivity, such a peculiar property represents a strong limiting factor to the performances of ILs-based batteries.


Dietary CdSe/ZnS quantum dot exposure in estuarine fish: bioavailability, oxidative stress responses, reproduction, and maternal transfer.
Continued development, use, and disposal of quantum dots (QDs) ensure their entrance into aquatic environments where they could pose a risk to biological organisms as whole nanoparticles or as degraded metal constituents. Reproductive Fundulus heteroclitus were fed a control diet with lecithin, diets containing 1 or 10 μg of lecithin-encapsulated CdSe/ZnS QD/day, or a diet containing 5.9 μg CdCl2/day for 85 days. Cadmium concentrations in liver, intestine, and eggs were quantified with inductively coupled plasma mass spectrometry. In fish fed 10 μg QD/day, QDs or their degradation products traversed the intestinal epithelia and accumulated in the liver. Less than 0.01% of the QD's cadmium was retained in the liver or intestinal tissues. This compares to 0.9% and 0.5% of the cadmium in the intestine and liver, respectively of fish fed a CdCl2 diet. Cadmium was also detected in the eggs from parents fed 10 μg QD/day. No significant changes in hepatic total glutathione, lipid peroxidation, or expression of genes involved in metal metabolism or oxidative stress were observed. While QDs in the diet are minimally bioavailable, unusual levels of vitellogenin transcription in male fish as well as declining fecundity require further investigation to determine if endocrine disruption is of environmental concern.


The LysR homolog LrhA promotes RpoS degradation by modulating activity of the response regulator sprE.
Synthesis of the OmpF porin of Escherichia coli is regulated in response to environmental and growth phase signals. In order to identify constituents of the various regulatory pathways involved in modulating ompF transcriptional expression, transposon insertion mutagenesis was performed and mutations that increased ompF'-lacZ activity were identified as previously described. Mutations mapping to a previously identified gene of unknown function, lrhA, were obtained. We found that LrhA, a LysR homolog, functions as a regulatory component in the RpoS-dependent growth phase repression of ompF. In addition to altered growth phase regulation of ompF, these lrhA mutants have pleiotropic stationary-phase defects as a result of decreased RpoS levels. We provide evidence that LrhA promotes degradation of RpoS by functioning within a genetic pathway that includes the response regulator SprE and the ClpXP protease. LrhA functions upstream of the other components in the pathway and appears to modulate the activity of SprE.


Pt nanocrystals on nitrogen-doped graphene for the hydrogen evolution reaction using Si nanowires as a sacrificial template.
Cost-effective catalysts for electrocatalytic water splitting play a key role in the renewable energy research. Although Pt has been regarded as the best catalyst, its wide applications have been impeded by its high cost and scarce natural abundance. Therefore, decreasing the Pt usage for electrocatalyst design is significant toward the hydrogen evolution reaction (HER). Herein, flower-like Pt nanocrystals were loaded on the surface of nitrogen-doped graphene using Si nanowires as the sacrificial template. The experimental results showed that the optimal Pt nanocrystals/N-doped graphene with superior HER activity and excellent stability only has a low Pt loading of 5.0 wt%. It is noted that the HER mass activity of the Pt nanocrystals/N-doped graphene is 5 fold higher than that of the 20.0 wt% Pt/C commercial catalyst. This optimal catalyst also achieved a low Tafel slope (28.0 mV dec-1), large apparent exchange current density (0.989 mA cm-2) and high turnover frequency (2.05 s-1). This work may provide an effective avenue for developing highly efficient electrochemical catalysts for the HER.


Kinetic simulations of ladder climbing by electron plasma waves.
The energy of plasma waves can be moved up and down the spectrum using chirped modulations of plasma parameters, which can be driven by external fields. Depending on whether the wave spectrum is discrete (bounded plasma) or continuous (boundless plasma), this phenomenon is called ladder climbing (LC) or autoresonant acceleration of plasmons. It was first proposed by Barth et al. [Phys. Rev. Lett. 115, 075001 (2015)PRLTAO0031-900710.1103/PhysRevLett.115.075001] based on a linear fluid model. In this paper, LC of electron plasma waves is investigated using fully nonlinear Vlasov-Poisson simulations of collisionless bounded plasma. It is shown that, in agreement with the basic theory, plasmons survive substantial transformations of the spectrum and are destroyed only when their wave numbers become large enough to trigger Landau damping. Since nonlinear effects decrease the damping rate, LC is even more efficient when practiced on structures like quasiperiodic Bernstein-Greene-Kruskal (BGK) waves rather than on Langmuir waves per se.


Mutant alleles at the rugosus loci in pea affect seed moisture sorption isotherms and the relations between seed longevity and moisture content.
Pea (Pisum sativum L.) mutant near-isogenic lines (RRrbrb, rrRbRb, rrrbrb) with lower starch but higher lipid contents, brought about by lesions in the starch biosynthetic pathway, had seed moisture sorption isotherms displaced below that of the wild type (RRRbRb). The negative logarithmic relationship between seed longevity and seed storage moisture content (%, f.wt basis), determined in hermetic storage at 65 degrees C, also differed: longevity in the mutant near-isogenic lines was poorer and less sensitive to moisture content than in the wild type (i.e. C(W) was lower). The low-moisture-content limit (m(c)) to this relation also differed, being lower in the mutant near-isogenic lines (5.4-5.9%) than in the wild type (6.1%). In contrast, all four near-isogenic lines showed no difference (P >0.25) in the negative semi-logarithmic relationship between equilibrium relative humidity (ERH) and seed longevity. It is concluded that the effect of these alleles at the r and rb loci on seed longevity was largely indirect; a consequence of their effect on seed composition and hence on moisture sorption isotherms. However, this explanation could not be invoked at moisture contents below m(c) where differences in longevity remained substantial (RRRbRb double that of rrrbrb). Hence, these mutant alleles affected seed longevity directly at very low moisture contents.


The Global Limb Anatomic Staging System (GLASS) for CLTI: Improving Inter-Observer Agreement.
The 2020 Global Vascular Guidelines aim at improving decision making in Chronic Limb-Threatening Ischemia (CLTI) by providing a framework for evidence-based revascularization. Herein, the Global Limb Anatomic Staging System (GLASS) serves to estimate the chance of success and patency of arterial pathway revascularization based on the extent and distribution of the atherosclerotic lesions. We report the preliminary feasibility results and observer variability of the GLASS. GLASS is a part of the new global guideline and posed as a promising additional tool for EBR strategies to predict the success of lower extremity arterial revascularization. This study reports on the consistency of GLASS scoring to maximize inter-observer agreement and facilitate its application. GLASS separately scores the femoropopliteal (FP) and infrapopliteal (IP) segment based on stenosis severity, lesion length and the extent of calcification within the target artery pathway (TAP). In our stepwise approach, we used two angiographic datasets. Each following step was based on the lessons learned from the previous step. The primary outcome was inter-observer agreement measured as Cohen's Kappa, scored by two (step 1 + 2) and four (step 3) blinded and experienced observers, respectively. Steps 1 (n = 139) and 2 (n = 50) were executed within a dataset of a Dutch interventional RCT in CLTI. Step 3 (n = 100) was performed in randomly selected all-comer CLTI patients from two vascular centers in the United States. In step 1, kappa values were 0.346 (FP) and 0.180 (IP). In step 2, applied in the same dataset, the use of other experienced observers and a provided TAP, resulted in similar low kappa values 0.406 (FP) and 0.089 (IP). Subsequently, in step 3, the formation of an altered stepwise approach using component scoring, such as separate scoring of calcification and adding a ruler to the images resulted in kappa values increasing to 0.796 (FP) and 0.730 (IP). This retrospective GLASS validation study revealed low inter-observer agreement for unconditioned scoring. A stepwise component scoring provides acceptable agreement and a solid base for further prospective validation studies to investigate how GLASS relates to treatment outcomes.


The importance of bank vole density and rainy winters in predicting nephropathia epidemica incidence in Northern Sweden.
Pathogenic hantaviruses (family Bunyaviridae, genus Hantavirus) are rodent-borne viruses causing hemorrhagic fever with renal syndrome (HFRS) in Eurasia. In Europe, there are more than 10,000 yearly cases of nephropathia epidemica (NE), a mild form of HFRS caused by Puumala virus (PUUV). The common and widely distributed bank vole (Myodes glareolus) is the host of PUUV. In this study, we aim to explain and predict NE incidence in boreal Sweden using bank vole densities. We tested whether the number of rainy days in winter contributed to variation in NE incidence. We forecast NE incidence in July 2013-June 2014 using projected autumn vole density, and then considering two climatic scenarios: 1) rain-free winter and 2) winter with many rainy days. Autumn vole density was a strong explanatory variable of NE incidence in boreal Sweden in 1990-2012 (R2 = 79%, p<0.001). Adding the number of rainy winter days improved the model (R2 = 84%, p<0.05). We report for the first time that risk of NE is higher in winters with many rainy days. Rain on snow and ground icing may block vole access to subnivean space. Seeking refuge from adverse conditions and shelter from predators, voles may infest buildings, increasing infection risk. In a rainy winter scenario, we predicted 812 NE cases in boreal Sweden, triple the number of cases predicted in a rain-free winter in 2013/2014. Our model enables identification of high risk years when preparedness in the public health sector is crucial, as a rainy winter would accentuate risk.


[Withholding medical care as physical injury--refusal to treat from the viewpoint of the lawyer. Special aspects of therapy in children].
Medical treatment as well as refusal of treatment may be a source for tortious liability. Omitting treatment is generally accepted if the patient refuses consent. Special problems arise however, if the patient is not capable of consenting to therapeutic procedures. Assessing the patient's capability to consent is then the primary obligation. In absence of a respective capability the parents' will has to be accepted as the basis of therapeutic decision, as long as the objective medical needs of the patient remain in consideration. Omitting medically necessary treatment may not be justified with the opposing will of the parents.


Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair.
A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event. Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives. A locus for the syndrome was identified at 8p11.21-q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3-related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients. Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections.


Brightly fluorescent single-walled carbon nanotubes via an oxygen-excluding surfactant organization.
Attaining high photoluminescence quantum yields for single-walled carbon nanotubes (SWNTs) in order to broaden their optoelectronics and sensing applications has been a challenging task. Among various nonradiative pathways, sidewall chemisorption of oxygen provides a known defect for exciton quenching through nanotube hole doping. We found that an aliphatic (dodecyl) analog of flavin mononucleotide, FC12, leads to high dispersion of SWNTs, which tend to aggregate into bundles. Unlike other surfactants, the surface organization of FC12 is sufficiently tight to exclude oxygen from the SWNT surface, which led to quantum yields as high as 20%. Toluene-dispersed, FC12-wrapped nanotubes exhibited an absorption spectrum with ultrasharp peaks (widths of 12 to 25 milli-electron volts) devoid of the characteristic background absorption of most nanotube dispersions.


Making standards for quantitative real-time pneumococcal PCR.
Quantitative lytA PCR is often performed using in-house standards. We hypothesised equivalence when measuring a standard suspension of Streptococcus pneumoniae by colony-forming-units (CFU) or genome-copies. Median (IQR) ratio of CFU/genome-copies was 0.19 (0.1-1.2). Genome-copies were less variable than CFU, but the discrepancy between the methods highlights challenges with absolute quantification.


Meta-analysis and systematic review of population-based epidemiological studies in idiopathic intracranial hypertension.
Idiopathic intracranial hypertension (IIH) is positively associated with obesity, mostly in young women. The global increase in obesity may influence the burden of IIH. Using the PubMed, Embase, MEDLINE and Web of Science databases, a meta-analysis and systematic review of epidemiological studies of IIH were performed up to June 2017. Temporal changes in IIH incidence were measured, and incidence rates of IIH were correlated with country-specific World Health Organization obesity rates. Prevalence data and shunting rates of IIH were recorded. The quality of epidemiological studies was assessed using the Standards of Reporting of Neurological Disorders (STROND) criteria. In 15 identified studies, there were 889 patients (87% women), mean age 29.8 years. The incidence of IIH ranged from 0.03 to 2.36 per 100 000 per year. The pooled incidence of IIH was 1.20 per 100 000 per year although there was very high heterogeneity (I2 98%). The incidence rates of IIH were correlated with country-specific prevalence of obesity (Spearman's correlation 0.82, P < 0.01). The prevalence of IIH was rarely recorded. A shunting procedure was reported in 8% of patients. STROND criteria were variably reported, median of 26.5 of 43 (range 16-35). IIH is a public health concern as increased obesity prevalence is associated with increased incidence of IIH. A better quality of epidemiological studies is required to improve understanding of IIH and inform health policy for IIH management.


Muscle sympathetic responses during orthostasis in heat-stressed individuals.
Whole-body heat stress compromises the control of blood pressure during an orthostatic challenge, although the extent to which this occurs can vary greatly between individuals. The mechanism(s) responsible for these varying responses remain unclear. This study tested the hypothesis that the individuals who are best able to tolerate an orthostatic challenge while heat stressed are the ones with the largest increase in sympathetic activity during orthostasis, indexed from recordings of muscle sympathetic nerve activity (MSNA). MSNA, arterial blood pressure, and heart rate were recorded from 11 healthy volunteers throughout passive whole-body heating and during 15 min of 60° head-up tilt (HUT) or until the onset of pre-syncopal symptoms. Whole-body heating significantly increased core temperature (~0.9°C), supine heart rate and MSNA. Eight of 11 subjects developed pre-syncopal symptoms resulting in early termination of HUT. The HUT tolerance time was positively correlated (R = 0.82, P = 0.01) with the increase in MSNA by HUT. These data suggest that the individuals with the largest increase in MSNA during upright tilt have the greatest capacity to withstand the orthostatic challenge while heat stressed.


Anatomy of the female pelvic nerves: a macroscopic study of the hypogastric plexus and their relations and variations.
The autonomic nerves of the lesser pelvis are particularly prone to iatrogenic lesions due to their exposed position during manifold surgical interventions. Nevertheless, the cause of rectal and urinary incontinence or sexual dysfunctions, for example after rectal cancer resection or hysterectomy, remains largely understudied, particularly with regard to the female pelvic autonomic plexuses. This study focused on the macroscopic description of the superior hypogastric plexus, hypogastric nerves, inferior hypogastric plexus, the parasympathetic pelvic splanchnic nerves and the sympathetic fibres. Their arrangement is described in relation to commonly used surgical landmarks such as the sacral promontory, ureters, uterosacral ligaments, uterine and rectal blood vessels. Thirty-one embalmed female pelvises from 20 formalin-fixed and 11 Thiel-fixed cadavers were prepared. In all cases explored, the superior hypogastric plexus was situated anterior to the bifurcation of the abdominal aorta. In 60% of specimens, it reached the sacral promontory, whereas in 40% of specimens, it continued across the pelvic brim until S1. In about 25% of the subjects, we detected an accessory hypogastric nerve, which has not been systematically described so far. It originated medially from the inferior margin of the superior hypogastric plexus and continued medially into the presacral space. The existence of an accessory hypogastric nerve was confirmed during laparoscopy and by histological examination. The inferior hypogastric plexuses formed fan-shaped plexiform structures at the end of both hypogastric nerves, exactly at the junction of the ureter and the posterior wall of the uterine artery at the uterosacral ligament. In addition to the pelvic splanchnic nerves from S2-S4, which joined the inferior hypogastric plexus, 18% of the specimens in the present study revealed an additional pelvic splanchnic nerve originating from the S1 sacral root. In general, form, breadth and alignment of the autonomic nerves displayed large individual variations, which could also have a clinical impact on the postoperative function of the pelvic organs. The study serves as a basis for future investigations on the autonomic innervation of the female pelvic organs.


Green tea supplementation in rats of different ages mitigates ethanol-induced changes in brain antioxidant abilities.
Oxidative stress induced by chronic ethanol consumption, particularly in aging subjects, has been implicated in the pathophysiology of many neurodegenerative diseases. Antioxidants with polyphenol structures, such as those contained in green tea, given alone for 5 weeks in liquid Lieber de Carli diet followed by administration with ethanol for 4 weeks with ethanol have been investigated as potential therapeutic antioxidant agents in the brain in rats of three ages (2, 12, and 24 months). Ethanol consumption caused age-dependent decreases in brain superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase activities. In addition, ethanol consumption caused age-dependent decreases in the levels of GSH, selenium, vitamins, E, A and C, and beta-carotene and increases in the levels of oxidized glutathione (GSSG). Changes in the brain's antioxidative ability were accompanied by enhanced oxidative modification of lipids (increases in lipid hydroperoxides, malondialdehyde, and 4-hydroxynonenal levels) and proteins (increases in carbonyl groups and bistyrosine). Reduced risk of oxidative stress and protection of the central nervous system, particularly in young and adult rats, after green tea supplementation were observed. Green tea partially prevented changes in antioxidant enzymatic as well as nonenzymatic parameters induced by ethanol and enhanced by aging. Administration of green tea significantly protects lipids and proteins against oxidative modifications in the brain tissue of young and adult rats. The beneficial effect of green tea can result from the inhibition of free radical chain reactions generated during ethanol-induced oxidative stress and/or from green tea-induced increases in antioxidative abilities made possible by increases in the activity/concentration of endogenous antioxidants.


Energy Sovereignty: A Values-Based Conceptual Analysis.
Achieving energy sovereignty is increasingly gaining prominence as a goal in energy politics. The aim of this paper is to provide a conceptual analysis of this principle from an ethics and social justice perspective. We rely on the literature on food sovereignty to identify through a comparative analysis the elements energy sovereignty will most likely demand and thereafter distinguish the unique constituencies of the energy sector. The idea of energy sovereignty embraces a series of values, among which we identified: (i) accessibility, to allow access to everyone, (ii) empowerment and recognition, to develop and sustain capabilities to collaboratively produce solution-oriented energy system knowledge and effectively participate in governance, (iii) stewardship and sustainability, to be able to design and manage decentralised renewable systems in view of protecting the environment, (iv) self-sufficiency, to reduce the negative shocks of exploitative business practises, (v) resilience, to maintain production capacities while withstanding socioeconomic, political, environmental and climatic shocks, (vi) peace, to establish production systems that do not involve hostile relations, (vii) transparency and self-determination, to establish democratic decision-making mechanisms that give a voice to previously underrepresented groups and limit corporate takeover (viii) gender-justice, by acknowledging the contributions of women and eliminate barriers to their empowerment. With a conceptual framework of energy sovereignty, we present a rationale that draws on the key values to be considered when formulating policy solutions for the energy sector.


Endothelin-1 and endothelin-2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries.
Endothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this differs among vascular beds. Segments of rat mesenteric resistance artery (MRA) and basilar artery (BA) were studied in wire myographs with and without functional antagonists. Sensitivity and maximum of MRA contractile responses to ET-1 were not, or only moderately, reduced by stimulation of soluble GC, AC or K(+) -channels and by an inhibitor of receptor-operated ion channels. However, each of these reduced maintenance of ET-1 effects and relaxed ET-1-induced contractions in MRA. A calcium channel antagonist did not alter sensitivity, maximum and maintenance of ET-1 effects, but relaxed ET-1-induced contractions in MRA. A PLC inhibitor prevented contractile responses to ET-1 and ET-2 in MRA and BA, and relaxed ET-1- and ET-2-induced responses in MRA and ET-1 effects in BA. A Rho-kinase inhibitor did not modify sensitivity, maximum and maintenance of responses to both peptides in both arteries but relaxed ET-2, but not ET-1, effects in MRA and ET-1 effects in BA. PLC played a key role in arterial contractile responses to ETs, but ET-1 and ET-2 initiated and maintained vasoconstriction through different mechanisms, and these differed between MRA and BA. Selective functional antagonism may be considered for agonist- and vascular bed selective pharmacotherapy of ET-related diseases.


Whale Shark Tourism: Impacts on Coral Reefs in the Philippines.
Reef-based tourism has been developing rapidly in recent decades yet its impacts on reef ecosystems are often overlooked. In Tan-awan, Oslob, Philippines, whale sharks are attracted to the shallow reefs where they are provisioned up to 50 tons y-1 of feed and this phenomenon in turn attracts >300,000 y-1 visitors. Given the intensive provisioning and concentrating tourism activities, we hypothesized that the whale shark tourism-impacted site (IS) will have greater impacts on reef degradation and higher anthropogenic nitrogen pollution level compared to its reference site (RS). Ecological surveys revealed that relative to the RS, the IS had 36% higher relative abundance of Pocillopora and Porites coral over other genera, >2.5-fold lower coral density, and 20% higher macroalgal cover, which we concluded are signs of reef degradation. Also, we conducted stable nitrogen isotope analysis on gorgonian skeletons to trace nitrogen sources at both sites through time. Although an average 1‰ isotope enrichment found in the IS relative to the RS could indicate anthropogenic nitrogen inputs in the IS, this enrichment was consistent over time and existed before the tourism developed. Despite that, we cautioned against the imminent threat of local eutrophication caused by the continued inputs of nitrogen derived from provisioning and tourism activities. In summary, this study provided the first documentation of the impacts of provisioned whale shark tourism on the local reefs in Tan-awan and established an ecological baseline for future comparisons. Such assessments can offer important information on reef health, coastal development, and tourism management.


Single-specimen bile cytology: a prospective study of 80 patients with obstructive jaundice.
To determine the sensitivity, specificity, and charges associated with single-specimen bile cytologic study in patients with obstructive jaundice. Eighty consecutive patients with presumed malignant biliary strictures underwent percutaneous biliary drainage (PBD). Cytologic evaluation was performed on a single bile specimen from each patient collected at the time of the PBD. Final diagnoses were obtained from either percutaneous (n = 14) or surgical (n = 66) histologic specimens (gold standard). Both data sets were then compared to determine the sensitivity and specificity of bile cytology. The charges associated with bile cytodiagnosis were compared to those for other biopsy procedures utilized in the same setting. Eighty bile specimens were obtained with a mean of 14 mL (range, 3-65 mL) per patient with 79 (99%) specimens adequate for cytologic processing. Eleven (13%) specimens were acellular. The overall sensitivity was 15% and specificity was 100%; these values were not dependent on the volume of the bile specimen (P > .10) or type of malignancy (P = .10). For bile cytodiagnosis, the mean charge was $160 and the successful biopsy rate (true-positive plus true-negative results/total number procedures) was 27%. Single-specimen bile cytology has a low sensitivity; however, because of its convenience, simplicity, atraumatic nature, and low relative charge versus comparable procedures, it may be useful as an adjunct to PBD in patients with suspected malignant biliary disease.


Dietary factors and risk of t(14;18)-defined subgroups of non-Hodgkin lymphoma.
To evaluate the associations between diet and non-Hodgkin lymphoma (NHL) according to t(14;18) status, one of the most common chromosomal abnormalities in NHL, as t(14;18)-positive NHL represents a genetically more homogeneous group than NHL overall. We determined the presence of the t(14;18)(q32;q21) by fluorescence in situ hybridization in 172 of 175 tumor blocks from a population-based, case-control study conducted in Nebraska during 1983-1986. Information on the frequency of consumption as an adult of 30 food items was derived from the parent case-control study. Dietary factors in 60 t(14;18)-positive and 87 t(14;18)-negative cases were compared with 1,075 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using polytomous logistic regression. The risk of t(14;18)-positive NHL for the highest versus the lowest approximate tertile of intake was elevated for milk (OR = 2.2; 1.0-5.0) and dietary nitrite (OR = 2.8; 1.3-6.1), whereas coffee consumption was inversely associated with risk (OR = 0.4; 0.2-0.7). We also found inverse associations between the intake of fish (OR = 0.5; 0.3-1.0) and carotene (OR = 0.5; 0.2-0.9) and risk of t(14;18)-negative NHL. There was no association between the intake of meats, vegetables, protein, or vitamin C and risk of either t(14;18)-positive or t(14;18)-negative NHL. We observed differences in associations between diet and t(14;18)-defined subgroups of NHL. These findings should be interpreted cautiously because of the small sample.


The Lyme Disease Pathogen Borrelia burgdorferi Infects Murine Bone and Induces Trabecular Bone Loss.
Lyme disease is caused by members of the Borrelia burgdorferi sensu lato species complex. Arthritis is a well-known late-stage pathology of Lyme disease, but the effects of B. burgdorferi infection on bone at sites other than articular surfaces are largely unknown. In this study, we investigated whether B. burgdorferi infection affects bone health in mice. In mice inoculated with B. burgdorferi or vehicle (mock infection), we measured the presence of B. burgdorferi DNA in bones, bone mineral density (BMD), bone formation rates, biomechanical properties, cellular composition, and two- and three-dimensional features of bone microarchitecture. B. burgdorferi DNA was detected in bone. In the long bones, increasing B. burgdorferi DNA copy number correlated with reductions in areal and trabecular volumetric BMDs. Trabecular regions of femora exhibited significant, copy number-correlated microarchitectural disruption, but BMD, microarchitectural, and biomechanical properties of cortical bone were not affected. Bone loss in tibiae was not due to increased osteoclast numbers or bone-resorbing surface area, but it was associated with reduced osteoblast numbers, implying that bone loss in long bones was due to impaired bone building. Osteoid-producing and mineralization activities of existing osteoblasts were unaffected by infection. Therefore, deterioration of trabecular bone was not dependent on inhibition of osteoblast function but was more likely caused by blockade of osteoblastogenesis, reduced osteoblast survival, and/or induction of osteoblast death. Together, these data represent the first evidence that B. burgdorferi infection induces bone loss in mice and suggest that this phenotype results from inhibition of bone building rather than increased bone resorption.


Nonpolar InGaN/GaN Core-Shell Single Nanowire Lasers.
We report lasing from nonpolar p-i-n InGaN/GaN multi-quantum well core-shell single-nanowire lasers by optical pumping at room temperature. The nanowire lasers were fabricated using a hybrid approach consisting of a top-down two-step etch process followed by a bottom-up regrowth process, enabling precise geometrical control and high material gain and optical confinement. The modal gain spectra and the gain curves of the core-shell nanowire lasers were measured using micro-photoluminescence and analyzed using the Hakki-Paoli method. Significantly lower lasing thresholds due to high optical gain were measured compared to previously reported semipolar InGaN/GaN core-shell nanowires, despite significantly shorter cavity lengths and reduced active region volume. Mode simulations show that due to the core-shell architecture, annular-shaped modes have higher optical confinement than solid transverse modes. The results show the viability of this p-i-n nonpolar core-shell nanowire architecture, previously investigated for next-generation light-emitting diodes, as low-threshold, coherent UV-visible nanoscale light emitters, and open a route toward monolithic, integrable, electrically injected single-nanowire lasers operating at room temperature.


Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise.
Preservation of lean body mass (LBM) may be important during dietary energy restriction (ER) and requires equal rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Currently, the relative contribution of MPS and MPB to the loss of LBM during ER in humans is unknown. We aimed to determine the impact of dietary protein intake and resistance exercise on MPS and MPB during a controlled short-term energy deficit. Adult men (body mass index, 28.6 ± 0.6 kg/m2; age 22 ± 1 yr) underwent 10 d of 40%-reduced energy intake while performing unilateral resistance exercise and consuming lower protein (1.2 g/kg/d, n = 12) or higher protein (2.4 g/kg/d, n = 12). Pre- and postintervention testing included dual-energy X-ray absorptiometry, primed constant infusion of ring-[13C6]phenylalanine, and 15[N]phenylalanine to measure acute postabsorptive MPS and MPB; D2O to measure integrated MPS; and gene and protein expression. There was a decrease in acute MPS after ER (higher protein, 0.059 ± 0.006 to 0.051 ± 0.009%/h; lower protein, 0.061 ± 0.005 to 0.045 ± 0.006%/h; P < 0.05) that was attenuated with resistance exercise (higher protein, 0.067 ± 0.01%/h; lower protein, 0.061 ± 0.006%/h), and integrated MPS followed a similar pattern. There was no change in MPB (energy balance, 0.080 ± 0.01%/hr; ER rested legs, 0.078 ± 0.008%/hr; ER exercised legs, 0.079 ± 0.006%/hr). We conclude that a reduction in MPS is the main mechanism that underpins LBM loss early in ER in adult men.-Hector, A. J., McGlory, C., Damas, F., Mazara, N., Baker, S. K., Phillips, S. M. Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise.


Racial differences in colorectal cancer incidence and mortality in the Women's Health Initiative.
Colorectal cancer (CRC) incidence and mortality rates are higher in African-Americans as compared with other racial/ethnic groups. The women's health initiative (WHI) study sample was used to determine whether differences in CRC risk factors explain racial/ethnic differences in incidence and mortality. The WHI is a longitudinal study of postmenopausal women recruited from 40 centers. Baseline questionnaires were used to collect sociodemographic and health status information. All CRC diagnoses were centrally adjudicated. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for invasive CRC by race/ethnicity. The study sample included 131,481 (83.7%) White, 14,323 (9.1%) African-American, 6,362 (4.1%) Hispanic, 694 (0.4%) Native American and 4,148 (2.6%) Asian/Pacific Islanders. After a mean follow-up of 10.8 years (SD 2.9), CRC incidence was the highest in African-Americans (annualized rate = 0.14%), followed by Whites and Native Americans (0.12% each), Asian/Pacific Islanders (0.10%), and Hispanics (0.08%). After adjustment for age and trial assignment, Hispanics had a lower risk compared with Whites, HR 0.73 (95% CI: 0.54-0.97) (P = 0.03), and African-Americans had a marginally greater risk, HR 1.16 (95% CI: 0.99-1.34), P = 0.06. Multivariable adjustment attenuated the difference in incidence between African-Americans and Whites (HR 0.99, 95% CI: 0.82-1.20), while strengthening the lower HR for Hispanics (HR 0.68, 95% CI: 0.48-0.97). African-American/White differences in CRC risk are likely due to sociodemographic/cultural factors other than race. A number of modifiable exposures could be a focus for reducing CRC risk in African-Americans.


Neutralizing B-cell activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model.
B-cell-activating factor (BAFF) is a tumor necrosis factor superfamily member critical for the maintenance and homeostasis of normal B-cell development. It has been implicated in conferring a survival advantage to B-cell malignancies, including multiple myeloma (MM). Here, we validate the role of BAFF in the in vivo pathogenesis of MM examining BAFF and its receptors in the context of patient MM cells and show activity of anti-BAFF antibody in a severe combined immunodeficient model of human MM. Gene microarrays and flow cytometry studies showed increased transcripts and the presence of all three receptors for BAFF in CD138+ patient MM cells, as well as an increase in plasma BAFF levels in 51 MM patients. Functional studies show that recombinant BAFF protects MM cells against dexamethasone-induced apoptosis accompanied by an increase in survival proteins belonging to the BCL family. These in vitro studies led to the evaluation of a clinical grade-neutralizing antibody to BAFF in a severe combined immunodeficient human MM model. Anti-BAFF-treated animals showed decreased soluble human interleukin 6 receptor levels, a surrogate marker of viable tumor, suggesting direct anti-MM activity. This translated into a survival advantage of 16 days (P < 0.05), a decrease in tartrate-resistant acid phosphatase-positive osteoclasts, and a reduction in radiologically evident lytic lesions in anti-BAFF-treated animals. Our data show a role for BAFF as a survival factor in MM. Importantly, the in vivo antitumor activity of neutralizing anti-BAFF antibody provide the preclinical rationale for its evaluation in the treatment of MM.


Cerebral sinovenous thrombosis in children.
Cerebral sinovenous thrombosis in children is a serious disorder, and information is needed about its prevention and treatment. The Canadian Pediatric Ischemic Stroke Registry was initiated in 1992 at the 16 pediatric tertiary care centers in Canada. Children (newborn to 18 years of age) with symptoms and radiographic confirmation of sinovenous thrombosis were included. During the first six years of the registry, 160 consecutive children with sinovenous thrombosis were enrolled, and the incidence of the disorder was 0.67 cases per 100,000 children per year. Neonates were most commonly affected. Fifty-eight percent of the children had seizures, 76 percent had diffuse neurologic signs, and 42 percent had focal neurologic signs. Risk factors included head and neck disorders (in 29 percent), acute systemic illnesses (in 54 percent), chronic systemic diseases (in 36 percent), and prothrombotic states (in 41 percent). Venous infarcts occurred in 41 percent of the children. Fifty-three percent of the children received antithrombotic agents. Neurologic deficits were present in 38 percent of the children, and 8 percent died; half the deaths were due to sinovenous thrombosis. Predictors of adverse neurologic outcomes were seizures at presentation and venous infarcts. Sinovenous thrombosis in children affects primarily neonates and results in neurologic impairment or death in approximately half the cases. The occurrence of venous infarcts or seizures portends a poor outcome.


Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis.
To date it has been difficult to characterize completely a genetic disorder, such as hemophilia A, in which the involved gene is large and unrelated affected individuals have different mutations, most of which are point mutations. Toward this end, we analyzed the DNA of 29 patients with mild-to-moderate hemophilia A in which the causative mutation is likely to be a missense mutation. Using computer analysis, we determined the melting properties of factor VIII gene sequences to design primer sets for PCR amplification and subsequent denaturing gradient gel electrophoresis (DGGE). A total of 45 primer sets was chosen to amplify 99% of the coding region of the gene and 41 of 50 splice junctions. To facilitate detection of point mutations, we mixed DNA from two male patients, and both homoduplexes and heteroduplexes were analyzed. With these 45 primer sets, 26 DNAs containing previously identified point mutations in the factor VIII gene were studied, and all 26 mutations were easily distinguishable from normal. After analyzing the 29 patients with unknown mutations, we identified the disease-producing mutation in 25 (86%). Two polymorphisms and two rare normal variants were also found. Therefore, DGGE after computer analysis is a powerful method for nearly complete characterization of disease-producing mutations and polymorphisms in large genes such as that for factor VIII.


Distant regulatory elements in a Sox10-beta GEO BAC transgene are required for expression of Sox10 in the enteric nervous system and other neural crest-derived tissues.
Sox10 is an essential transcription factor required for development of neural crest-derived melanocytes, peripheral glia, and enteric ganglia. Multiple transcriptional targets regulated by Sox10 have been identified; however, little is known regarding regulation of Sox10. High sequence conservation surrounding 5' exons 1 through 3 suggests these regions might contain functional regulatory elements. However, we observed that these Sox10 genomic sequences do not confer appropriate cell-specific transcription in vitro when linked to a heterologous reporter. To identify elements required for expression of Sox10 in vivo, we modified bacterial artificial chromosomes (BACs) to generate a Sox10betaGeoBAC transgene. Our approach leaves endogenous Sox10 loci unaltered, circumventing haploinsufficiency issues that arise from gene targeting. Sox10betaGeoBAC expression closely approximates Sox10 expression in vivo, resulting in expression in anterior dorsal neural tube at embryonic day (E) 8.5 and in cranial ganglia, otic vesicle, and developing dorsal root ganglia at E10.5. Characterization of Sox10betaGeoBAC expression confirms the presence of essential regulatory regions and additionally identifies previously unreported expression in thyroid parafollicular cells, thymus, salivary, adrenal, and lacrimal glands. Fortuitous deletions in independent Sox10betaGeoBAC lines result in loss of transgene expression in peripheral nervous system lineages and coincide with evolutionarily conserved regions. Our analysis indicates that Sox10 expression requires the presence of distant cis-acting regulatory elements. The Sox10betaGeoBAC transgene offers one avenue for specifically testing the role of individual conserved regions in regulation of Sox10 and makes possible analysis of Sox10+ derivatives in the context of normal neural crest development.


S100 immunophenotypes of uveal melanomas.
To determine whether ocular melanomas are immunophenotypically identical to cutaneous melanomas, 34 primary and metastatic choroidal melanomas representing all major histotypes defined by the Callender's classification, plus one melanoma of the iris and one conjunctival melanoma, were subjected to a panel of immunostains designed to distinguish anaplastic biopsies of cutaneous melanomas from carcinomas and lymphomas. All ocular melanomas were found to express the intermediate filament vimentin but not keratin, and all but 2 were melanotic by immunostaining. Thirty-three of 34 (97%) choroidal melanomas were strongly stained with a rabbit polyclonal antibody (P-S100) developed against the S100 protein family. In contrast, none of 14 spindle cell type primary lesions was stained with a monoclonal antibody (MAB-079) specific for both S100 alpha and S100 beta, the best-characterized S100 polypeptides. Furthermore, only 2 of 5 epithelioid and 3 of 10 mixed-cell-type melanomas were weakly reactive. Overall, 14.7% (5 of 29) were stained. In comparison, MAB079 stained 85% of all cutaneous melanomas. Five metastases of choroidal melanomas (spindle B, epithelioid, and mixed cell types) from different organ sites also were stained by P-S100 but not by MAB079. These findings were corroborated by immunostaining with another monoclonal antibody (MAB4D4) specific for S100 beta. Differential staining by the polyclonal but not the monoclonal antibodies suggests the possible presence of a variant S100 polypeptide(s) in choroidal melanomas. Since S100 alpha, S100 beta, and related proteins appear to be physiologically important, additional studies of these S100 proteins may shed light on the etiology or pathology of choroidal melanomas.


Matrix metalloproteinase-2 promoter genotype as a marker of cutaneous T-cell lymphoma early stage.
The aim of the study was to investigate the DNA polymorphic genotype in MMP-2 promoter gene as a potential candidate region for the development of the cutaneous T-cell lymphoma (CTCL) and/or its progression. A total of 89 Czech patients with CTCL (including 23 patients with large plaque parapsoriasis) were compared to 198 controls of similar age and sex distribution, without personal or family history of chronic skin diseases and without personal history of malignancy. The three selected polymorphisms in the promoter of MMP-2 gene (-1575G/A, -1306C/T, and -790T/G) were determined using the PCR-based methodology with RFLP. In our cohort, the associated GGCCTT MMP-2 promoter genotype was highly significantly more frequent in CTCL-Ia stage patients compared to patients with parapsoriasis, the tests having high sensitivity and specificity (78%, 83%, resp.). To conclude, use of associated MMP-2 promoter genotype as a DNA marker might make it possible to distinguish between the patients with parapsoriasis and those with CTCL stage Ia, which could substantially improve possibilities of clinical diagnostics, therapy design, and prognosis of this serious condition in the early stages.


A spiritually based caregiver intervention with telephone delivery for family caregivers of veterans with dementia.
Caring for veterans with dementia is burdensome for family caregivers. This exploratory study tested the efficacy of an innovative, spiritually based mantram caregiver intervention delivered using teleconference calls. A prospective, within-subjects, mixed-methods, and 3-time repeated-measures design with 36-week follow-up telephone interviews was conducted. Sixteen caregivers (94% women, 94% Whites with mean age 69.2 years, SD = 10.35 years) completed the intervention. Significant effects for time and linear terms were found for decreasing caregiver burden, perceived stress, depression, and rumination and for increasing quality of life enjoyment and satisfaction, all with large effect sizes. Findings suggest that teleconference delivery of a spiritually based caregiver intervention is feasible.


Test order effects in simultaneous protocols.
Simultaneous protocols typically yield poorer stimulus equivalence outcomes than do other protocols commonly used in equivalence research. Two independent groups of three 3-member equivalence sets of stimuli were used in conditional discrimination procedures in two conditions, one using the standard simultaneous protocol and the other using a hybrid simultaneous training and simple-to-complex testing. Participants completed the two conditions in one long session in Experiment 1, but in separate sessions in Experiment 2. The same stimulus sets used in Experiment 1 were randomized for the two conditions in Experiment 2. Overall, accuracy was better with the hybrid than with the standard protocol in both experiments. The equivalence yield was also better under the hybrid than under the standard protocol in each experiment. The results suggest that the order of testing for emergent relations may account for the difficulty often encountered with the standard simultaneous protocol.


Primiparous women's preferences for care during a prolonged latent phase of labour.
To investigate primiparous women's preferences for care during a prolonged latent phase of labour. A qualitative study based on focus groups and individual interviews and analysed with inductive content analysis. Sixteen primiparous women with a prolonged latent phase of labour >18 hours were interviewed in five focus groups (n = 11) or individually (n = 5). One main category emerged "Beyond normality - a need of individual adapted guidance in order to understand and manage an extended latent phase of labour" which covers the women's preferences during the prolonged latent phase. Five categories were generated from the data: "A welcoming manner and not being rejected", "Individually adapted care", "Important information which prepares for reality and coping", "Participation and need for feedback" and "Staying nearby the labour ward or being admitted for midwifery support". Women with a prolonged latent phase of labour sought to use their own resources, but their needs for professional support increased as time passed. A welcoming attitude from an available midwife during the latent phase created a feeling of security, and personally adapted care was perceived positively. Women with a prolonged latent phase of labour preferred woman-centred care. Midwives play an important role in supporting these women. Women's need for midwifery-support increases as the time spent in latent phase increases.


Impact of Public Reporting of 30-day Mortality on Timing of Death after Coronary Artery Bypass Graft Surgery.
Recent reports have raised concerns that public reporting of 30-day mortality after cardiac surgery may delay decisions to withdraw life-sustaining therapies for some patients. The authors sought to examine whether timing of mortality after coronary artery bypass graft surgery significantly increases after day 30 in Massachusetts, a state that reports 30-day mortality. The authors used New York as a comparator state, which reports combined 30-day and all in-hospital mortality, irrespective of time since surgery. The authors conducted a retrospective cohort study of patients who underwent coronary artery bypass graft surgery in hospitals in Massachusetts and New York between 2008 and 2013. The authors calculated the empiric daily hazard of in-hospital death without censoring on hospital discharge, and they used joinpoint regression to identify significant changes in the daily hazard over time. In Massachusetts and New York, 24,864 and 63,323 patients underwent coronary artery bypass graft surgery, respectively. In-hospital mortality was low, with 524 deaths (2.1%) in Massachusetts and 1,398 (2.2%) in New York. Joinpoint regression did not identify a change in the daily hazard of in-hospital death at day 30 or 31 in either state; significant joinpoints were identified on day 10 (95% CI, 7 to 15) for Massachusetts and days 2 (95% CI, 2 to 3) and 12 (95% CI, 8 to 15) for New York. In Massachusetts, a state with a long history of publicly reporting cardiac surgery outcomes at day 30, the authors found no evidence of increased mortality occurring immediately after day 30 for patients who underwent coronary artery bypass graft surgery. These findings suggest that delays in withdrawal of life-sustaining therapy do not routinely occur as an unintended consequence of this type of public reporting.


How do psychosocial determinants in migrant women in the Netherlands differ from these among their counterparts in their country of origin? A cross-sectional study.
Migration of non-Western women into Western countries often results in an increase in smoking prevalence among migrant women. To gain more insight into how to prevent this increase, we compared psychosocial determinants of smoking between Surinamese women in Suriname and those in the Netherlands. Data were obtained between 2000 and 2004 from two cross-sectional studies, the CVRFO study in Suriname (n = 702) and the SUNSET study in the Netherlands (n = 674). For analyses of determinants, we collected additional data in CVRFO study population (n = 85). Differences between the two groups were analysed by chi-square analyses and logistic regression analyses. As was found in other studies among migrant women, more Surinamese migrant women in the Netherlands smoked (31%) than women in Suriname (16%). More Surinamese women in the Netherlands than in Suriname had a positive affective and cognitive attitude towards smoking (OR = 2.6 (95%CI 1.05;6.39) and OR = 3.3 (95%CI 1.31;8.41)). They perceived a positive norm within their partners and friends regarding smoking more frequently (OR = 6.5 (95%CI 2.7;15.6) and OR = 3.3 (95%CI 1.50;7.25)). Migrant women are more positive towards smoking and perceived a more positive norm towards smoking when compared with women in the country of origin. Interventions targeted at the psychosocial determinants regarding smoking for newly migrated women, in particular the consequences of smoking and the norm towards smoking might help to prevent an increase in smoking in those populations.


Genome Editing for the Understanding and Treatment of Inherited Cardiomyopathies.
Cardiomyopathies are diseases of heart muscle, a significant percentage of which are genetic in origin. Cardiomyopathies can be classified as dilated, hypertrophic, restrictive, arrhythmogenic right ventricular or left ventricular non-compaction, although mixed morphologies are possible. A subset of neuromuscular disorders, notably Duchenne and Becker muscular dystrophies, are also characterized by cardiomyopathy aside from skeletal myopathy. The global burden of cardiomyopathies is certainly high, necessitating further research and novel therapies. Genome editing tools, which include zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) systems have emerged as increasingly important technologies in studying this group of cardiovascular disorders. In this review, we discuss the applications of genome editing in the understanding and treatment of cardiomyopathy. We also describe recent advances in genome editing that may help improve these applications, and some future prospects for genome editing in cardiomyopathy treatment.


Mapping and deciphering neural codes of NMDA receptor-dependent fear memory engrams in the hippocampus.
Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for "what at when" information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.


Visuomotor competencies and primary monosymptomatic nocturnal enuresis in prepubertal aged children.
Primary monosymptomatic nocturnal enuresis (PMNE) is a common problem in the developmental ages; it is the involuntary loss of urine during the night in children older than 5 years of age. Several clinical observations have suggested an association between bedwetting and developmental delays in motricity, language development, learning disability, physical growth, and skeletal maturation. The aim of the present study is to evaluate the prevalence of fine motor coordination and visuomotor integration abnormalities in prepubertal children with PMNE. The study population included 31 children (16 males, 15 females; mean age 8.14 years ± 1.36 years), and the control group comprised 61 typical developing children (32 males, 29 females; mean age 8.03 years ± 1.44 years). The whole population underwent a clinical evaluation to assess total intelligence quotient level, visuomotor integration (VMI) skills, and motor coordination performance (using the Movement Assessment Battery for Children, or M-ABC). No significant differences between the two study groups were found for age (P = 0.725), gender (P = 0.886), z-body mass index (P = 0.149), or intellectual abilities (total intelligence quotient) (P = 0.163). The PMNE group showed a higher prevalence of borderline performance on M-ABC evaluation and in pathologic performance on VMI Total Task compared to controls (P < 0.001). No significant differences between the two study groups were found for pathologic performances on the M-ABC (P = 0.07), VMI Visual Task (P = 0.793), and VMI Motor Task (P = 0.213). Our findings pinpointed that PMNE should not be considered as a voiding disorder alone and, consequently, the children affected should be referred to specific rehabilitative programs that aim to improve motor coordination and visuomotor integration.


Include, differentiate and manage: gay male youth, stigma and healthcare utilization.
In Canada, there has been a recent increase in HIV incidence among young men who have sex with men. However, gay male youth (GMY) may forego HIV testing due to fear of stigmatization. Therefore, the aim of this research was to explore the perceptions of stigma in health care within this population. The research was conducted through a series of semi-structured interviews with eight GMY aged 20-29, who frequented a gay-friendly clinic in downtown Ottawa, Canada. In a sub-analysis of the interviews utilizing the work of Hardt and Negri's three-part sequence - inclusion, differentiation and management - we found that homosexuality-related stigmatization affects the interaction between GMY and health professionals. Interview participants perceived HIV-related risk counselling as a manifestation of stigma. These findings reveal that the experience of stigma and stigmatization is not necessarily based on health professionals' intentions, but rather, on patients' perceptions of the interactions they have with health professionals. Specific modifications to the delivery of health care may help to overcome stigmatization.


Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States.
Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.