Homocysteine in vascular disease: an emerging clinical perspective.
Traditionally, arterial and venous thrombo-embolism has been attributed to pathophysiological lesions in the vessel wall, or altered blood contents or flow through the lumen. Logically these fall into the category of a high-shear system, as opposed to the rather different circumstances in slowly moving columns of blood. The re-evaluation of this belief has been prompted by acknowledgement that there is currently a shift in emphasis. Recently we have recognised a common central factor in the internal dysfunction of the vessel that precedes and so initiates thrombocyte adhesion.


Design, Synthesis, and Evaluation of a Diazirine Photoaffinity Probe for Ligand-Based Receptor Capture Targeting G Protein-Coupled Receptors.
Chemoproteomic approaches to identify ligand-receptor interactions have gained popularity. However, identifying transmembrane receptors remains challenging. A new trifunctional probe to aid the nonbiased identification of such receptors was developed and synthesized using a convenient seven-step synthesis. This probe contained three functional groups: 1) an N-hydroxysuccinimide ester for ligand-coupling through free amines, 2) a diazirine moiety to capture the receptor of interest upon irradiation with UV light, and 3) a biotin group which allowed affinity purification of the final adduct using streptavidin. The interaction between the G protein-coupled tachykinin neurokinin 1 (NK1) receptor, expressed in an inducible manner, and the peptidic ligand substance P was used as a test system. Liquid chromatography-mass spectrometry analysis confirmed successful coupling of the probe to substance P, while inositol monophosphate accumulation assays demonstrated that coupling of the probe did not interfere substantially with the substance P-NK1 receptor interaction. Confocal microscopy and western blotting provided evidence of the formation of a covalent bond between the probe and the NK1 receptor upon UV activation. As proof of concept, the probe was used in full ligand-based receptor-capture experiments to identify the substance P-binding receptor via liquid chromatography-tandem mass spectrometry, resulting in the successful identification of only the NK1 receptor. This provides proof of concept toward general utilization of this probe to define interactions between ligands and previously unidentified plasma-membrane receptors.


Spectral characterisation of eight glycerolipids and their detection in natural samples using time-of-flight secondary ion mass spectrometry.
In recent years, time-of-flight secondary ion mass spectrometry (ToF-SIMS) with cluster ion sources has opened new perspectives for the analysis of lipid biomarkers in geobiology and organic geochemistry. However, published ToF-SIMS reference spectra of relevant compounds are still sparse, and the influence of the chemical environment (matrix) on the ionisation of molecules and their fragmentation is still not well explored. This study presents ToF-SIMS spectra of eight glycerolipids as common target compounds in biomarker studies, namely ester- and ether-bound phosphatidylethanolamine, ester- and ether-bound phosphatidylcholine, ester-bound phosphatidylglycerol, ester- and ether-bound diglycerides and archaeol, obtained with a Bi(3) (+) cluster ion source. For all of these compounds, the spectra obtained in positive and negative analytical modes showed characteristic fragments that could clearly be assigned to e.g. molecular ions, functional groups and alkyl chains. By comparison with the reference spectra, it was possible to track some of these lipids in a pre-characterised organic extract and in cryosections of microbial mats. The results highlight the potential of ToF-SIMS for the laterally resolved analysis of organic biomarkers in environmental materials. The identification of the target compounds, however, may be hampered by matrix effects (e.g. adduct formation) and often require careful consideration of all spectral features and taking advantage of the molecular imaging capability of ToF-SIMS.


Binding to cells of virosomes containing herpes simplex virus type 1 glycoproteins and evidence for fusion.
Envelope proteins and lipids were extracted from purified herpes simplex virus type 1 virions with octyl glucoside and mixed with phosphatidylcholine for preparation of virosomes by removal of the detergent. Greater than 85% of the extracted envelope proteins, including all the glycoproteins and the nonglycosylated protein designated VP16, were associated with virosomes, which ranged in density from ca. 1.07 to 1.13 g/cm3. All the glycoproteins except gC were as susceptible to degradation by added protease in virosomes as in virions, indicating similar orientations in both. Approximately 30 to 40% of radiolabel incorporated into virosomes bound to HEp-2 cells within 1.5 h at either 4 or 37 degrees C. The cell-bound virosomes were enriched for gB and deficient in other glycoproteins, in comparison with unbound or total virosomes. Binding of virosomes to HEp-2 cells could be inhibited by purified virus, heparin, and monospecific antiviral antibodies. Polyclonal and monoclonal anti-gB antibodies were more effective at inhibiting virosome binding than were anti-gD or anti-gC antibodies. Virosomes depleted of gB or gD did not bind to cells as efficiently as did virosomes containing all the extracted enveloped components; this loss of binding activity was especially pronounced on depletion of gB. The binding of herpes simplex virus type 1 virosomes to cells is discussed in relation to possible heterogeneity of the virosomes and comparisons with binding of virions to cells. We also present electron microscopic evidence that bound virosomes can fuse with the cell surface.


In vitro and in vivo antiherpetic effects of (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol.
In this study, we demonstrated the in vitro and in vivo antiherpetic activities of a stable furan derivative, (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol (MFPT), which had originally been isolated from Streptomyces sp. strain FV60. In the present study, we synthesized MFPT from (5-methylfuran-3-yl)methanol in 6 steps for use in the experiments. MFPT showed potent in vitro antiviral activities against two acyclovir (ACV)-sensitive (KOS and HF) strains and an ACV-resistant (A4-3) strain of herpes simplex virus type 1 (HSV-1) and an ACV-sensitive HSV type 2 (HSV-2) UW 268 strain, their selectivity indices ranging from 310 to 530. By intravaginal application of MFPT to mice, the virus yields decreased dose-dependently against the three strains of HSV-1 and HSV-2. When MFPT was applied at a dose of 1.0 mg/day, the lesion scores, as clinical signs manifested by viral infection, were extensively suppressed in HSV-1-infected mice, whereas the lesion scores in HSV-2-infected mice were not markedly decreased. Interestingly, MFPT exerted an inhibitory effect against ACV-resistant HSV-1 in mice to a similar degree as in ACV-sensitive HSV-1-infected mice. Therefore, the compound might have potential for developing a topical antiviral agent that could be also applied to the infections caused by ACV-resistant viruses.


Propensity score weighting for addressing under-reporting in mortality surveillance: a proof-of-concept study using the nationally representative mortality data in China.
National mortality data are obtained routinely by the Disease Surveillance Points system (DSPs) in China and under-reporting is a big challenge in mortality surveillance. We carried out an under-reporting field survey in all 161 DSP sites to collect death cases during 2009-2011, using a multi-stage stratified sampling. To identify under-reporting, death data were matched between field survey system and the routine online surveillance system by an automatic computer checking followed by a thorough manual verification. We used a propensity score (PS) weighting method based on a logistic regression to calculate the under-reporting rate in different groups classified by age, gender, urban/rural residency, geographic locations and other mortality related variables. For comparison purposes, we also calculated the under-reporting rate by using capture-mark-recapture (CMR) method. There were no significant differences between the field survey system and routine online surveillance system in terms of age group, causes of death, highest level of diagnosis and diagnostic basis. The overall under-reporting rate in the DSPs was 12.9 % (95%CI 11.2 %, 14.6 %) based on PS. The under-reporting rate was higher in the west (18.8 %, 95%CI 16.5 %, 21.0 %) than the east (10.1 %, 95%CI 8.6 %, 11.3 %) and central regions (11.2 %, 95%CI 9.6 %, 12.7 %). Among all age groups, the under-reporting rate was highest in the 0-5 year group (23.7 %, 95%CI 16.1 %, 35.5 %) and lowest in the 65 years and above group (12.4 %, 95%CI 10.9 %, 13.6 %). The under-reporting rates in each group by PS were similar to the results calculated by the CMR methods. The mortality data from the DSP system in China needs to be adjusted. Compared to the commonly used CMR method in the estimation of under-reporting rate, the results of propensity score weighting method are similar but more flexible when calculating the under-reporting rates in different groups. Propensity score weighting is suitable to adjust DSP data and can be used to address under-reporting in mortality surveillance in China.


Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.
Hypoxia-inducible factor-1 (HIF-1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment-resistant tumor phenotype. HIF-1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF-1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57BL/6 Gulo(-/-) mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16-F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild-type ascorbate levels led to a reduction in growth of B16-F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF-1α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF-1 target proteins CA-IX, GLUT-1, and VEGF in both B16-F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16-F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF-1 pathway activity.


Quality of diet is associated with insulin resistance in the Cree (Eeyouch) indigenous population of northern Québec.
Indigenous people worldwide have a greater disease burden than their non-aboriginal counterparts with health challenges that include increased obesity and higher prevalence of diabetes. We investigate the relationships of dietary patterns with nutritional biomarkers, selected environmental contaminants and measures of insulin resistance in the Cree (Eeyouch) of northern Québec Canada. The cross-sectional 'Nituuchischaayihitaau Aschii: A Multi-Community Environment-and-Health Study in Eeyou Istchee' recruited 835 adult participants (≥18 y) from 7 communities in the James Bay region of northern Québec. The three dietary patterns identified by principal component analysis (PCA) were: inland and coastal patterns with loadings on traditional foods, and a junk food pattern with high-fat and high-sugar foods. We investigated dietary patterns scores (in quantiles) in relation with nutritional biomarkers, environmental contaminants, anthropometry, blood pressure, fasting plasma glucose and insulin, and insulin resistance. Homeostatic model assessment (HOMA-IR) was used as surrogate markers of insulin resistance. ANCOVA ascertained relationships between dietary patterns relationship and outcomes. Greater scores for the traditional patterns were associated with higher levels of n-3 fatty acids, mercury and polychlorinated biphenyls (PCBs) (P trend <0.001). Higher scores for the junk food pattern were associated with lower levels of PCBs and Vitamin D, but higher fasting plasma insulin and HOMA-IR. Our results suggest that poor diet quality accompanied greater insulin resistance. Impacts of diet quality on insulin resistance, as a sign of metabolism perturbation, deserve more attention in this indigenous population with high rates of obesity and diabetes.


Role of outer-membrane cytochromes MtrC and OmcA in the biomineralization of ferrihydrite by Shewanella oneidensis MR-1.
In an effort to improve the understanding of electron transfer mechanisms at the microbe-mineral interface, Shewanella oneidensis MR-1 mutants with in-frame deletions of outer-membrane cytochromes (OMCs), MtrC and OmcA, were characterized for the ability to reduce ferrihydrite (FH) using a suite of microscopic, spectroscopic, and biochemical techniques. Analysis of purified recombinant proteins demonstrated that both cytochromes undergo rapid electron exchange with FH in vitro with MtrC displaying faster transfer rates than OmcA. Immunomicroscopy with cytochrome-specific antibodies revealed that MtrC co-localizes with iron solids on the cell surface while OmcA exhibits a more diffuse distribution over the cell surface. After 3-day incubation of MR-1 with FH, pronounced reductive transformation mineral products were visible by electron microscopy. Upon further incubation, the predominant phases identified were ferrous phosphates including vivianite [Fe(3)(PO(4))(2)x8H(2)O] and a switzerite-like phase [Mn(3),Fe(3)(PO(4))(2)x7H(2)O] that were heavily colonized by MR-1 cells with surface-exposed outer-membrane cytochromes. In the absence of both MtrC and OmcA, the cells ability to reduce FH was significantly hindered and no mineral transformation products were detected. Collectively, these results highlight the importance of the outer-membrane cytochromes in the reductive transformation of FH and support a role for direct electron transfer from the OMCs at the cell surface to the mineral.


Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study.
Bioidentical Hormone Replacement Therapy (BHRT) is believed it to be a safer and equally effective alternative to Conventional Hormone Therapy for the relief of menopausal symptoms; however, data are needed to support these claims. The objective of this study is to evaluate the effectiveness of compounded BHRT provided in six community pharmacies. This was an observational cohort study of women between the ages of 18-89 who received a compounded BHRT product from January 1, 2003 to April 30, 2010 in six community pharmacies. Data included patient demographics, comorbidities, therapeutic outcomes, and hormone therapies. Women self-rated menopausal symptoms as absent, mild, moderate, or severe. Descriptive statistics were used to characterize the patient population, BHRT use, and adverse events. Patient symptom severity was compared at baseline and 3 to 6 months follow-up using the Wilcoxon signed-rank test. Women (n = 296) receiving BHRT at Oakdell Pharmacy had a mean (standard deviation) age of 52 (9) years. The most common BHRT dosage forms utilized were topical (71%) and oral (43%). Compounded BHRT regimens were generally initiated at low doses regardless of route. Women experienced a 25% decrease in emotional lability (p < 0.01), a 25% decrease in irritability (p < 0.01), and a 22% reduction in anxiety (p = 0.01) within 3 to 6 months. These women also experienced a 14% reduction in night sweats (p = 0.09) and a 6% reduction in hot flashes (p = 0.50). This study demonstrates that compounded BHRT improves mood symptoms. Larger studies are needed to examine the impact on vasomotor symptoms, myocardial infarction and breast cancer.


Intraindividual variability across cognitive tasks as a potential marker for prodromal Alzheimer's disease.
Recent studies have shown that increased cognitive intraindividual variability (IIV) across accuracy scores from tests representing different cognitive domains (across-domain IIV) might indicate prodromal Alzheimer's disease (AD). Although IIV has been proposed to index cognitive control processes, IIV across accuracy scores from cognitive control tasks (within-domain IIV) has not been examined in healthy controls subjects (HCS), mild cognitive impairment (MCI), and AD patients in a single comparative study. This study examines the discriminative properties of within-domain IIV, and across-domain IIV in 149 HCS, 31 MCI, and 26 AD. Three tasks representing different cognitive domains were identified to calculate across-domain IIV. Three other tasks representing cognitive control were identified to calculate within-domain IIV. The intraindividual standard deviation was calculated across accuracy scores. To compare IIV between groups, ANCOVAs with the covariates age, gender, education, and mean performance were computed. IIV scores in general were higher in AD vs. HCS (p < 0.01). Only across-domain IIV was higher in AD vs. MCI (p = 0.001), and only within-domain IIV was higher in MCI vs. HCS (p = 0.05). Within-domain IIV may constitute a cognitive marker for the detection of prodromal AD at the MCI stage, whereas across-domain IIV may detect beginning AD at the MCI stage.


Chronic pain and comorbid mental health conditions: independent associations of posttraumatic stress disorder and depression with pain, disability, and quality of life.
Both posttraumatic stress disorder (PTSD) and depression are highly comorbid with chronic pain and have deleterious effects on pain and treatment outcomes, but the nature of the relationships among chronic pain, PTSD, and depression has not been fully elucidated. This study examined 250 Veterans Affairs primary care patients with moderate to severe chronic musculoskeletal pain who participated in a randomized controlled pain treatment trial. Baseline data were analyzed to examine the independent associations of PTSD and major depression with multiple domains of pain, psychological status, quality of life, and disability. PTSD was strongly associated with these variables and in multivariate models, PTSD and major depression each had strong independent associations with these domains. PTSD demonstrated similar relationships as major depression with psychological, quality of life, and disability outcomes and significant but somewhat smaller associations with pain. Because PTSD and major depression have independent negative associations with pain, psychological status, quality of life, and disability, it is important for clinicians to recognize and treat both mental disorders in patients with chronic pain.


Précis of statistical significance: rationale, validity, and utility.
The null-hypothesis significance-test procedure (NHSTP) is defended in the context of the theory-corroboration experiment, as well as the following contrasts: (a) substantive hypotheses versus statistical hypotheses, (b) theory corroboration versus statistical hypothesis testing, (c) theoretical inference versus statistical decision, (d) experiments versus nonexperimental studies, and (e) theory corroboration versus treatment assessment. The null hypothesis can be true because it is the hypothesis that errors are randomly distributed in data. Moreover, the null hypothesis is never used as a categorical proposition. Statistical significance means only that chance influences can be excluded as an explanation of data; it does not identify the nonchance factor responsible. The experimental conclusion is drawn with the inductive principle underlying the experimental design. A chain of deductive arguments gives rise to the theoretical conclusion via the experimental conclusion. The anomalous relationship between statistical significance and the effect size often used to criticize NHSTP is more apparent than real. The absolute size of the effect is not an index of evidential support for the substantive hypothesis. Nor is the effect size, by itself, informative as to the practical importance of the research result. Being a conditional probability, statistical power cannot be the a priori probability of statistical significance. The validity of statistical power is debatable because statistical significance is determined with a single sampling distribution of the test statistic based on H0, whereas it takes two distributions to represent statistical power or effect size. Sample size should not be determined in the mechanical manner envisaged in power analysis. It is inappropriate to criticize NHSTP for nonstatistical reasons. At the same time, neither effect size, nor confidence interval estimate, nor posterior probability can be used to exclude chance as an explanation of data. Neither can any of them fulfill the nonstatistical functions expected of them by critics.


Systematic review and meta-analysis of reduction in all-cause mortality from walking and cycling and shape of dose response relationship.
Walking and cycling have shown beneficial effects on population risk of all-cause mortality (ACM). This paper aims to review the evidence and quantify these effects, adjusted for other physical activity (PA). We conducted a systematic review to identify relevant studies. Searches were conducted in November 2013 using the following health databases of publications: Embase (OvidSP); Medline (OvidSP); Web of Knowledge; CINAHL; SCOPUS; SPORTDiscus. We also searched reference lists of relevant texts and reviews. Eligible studies were prospective cohort design and reporting walking or cycling exposure and mortality as an outcome. Only cohorts of individuals healthy at baseline were considered eligible. Extracted data included study population and location, sample size, population characteristics (age and sex), follow-up in years, walking or cycling exposure, mortality outcome, and adjustment for other co-variables. We used random-effects meta-analyses to investigate the beneficial effects of regular walking and cycling. Walking (18 results from 14 studies) and cycling (8 results from 7 studies) were shown to reduce the risk of all-cause mortality, adjusted for other PA. For a standardised dose of 11.25 MET.hours per week (or 675 MET.minutes per week), the reduction in risk for ACM was 11% (95% CI = 4 to 17%) for walking and 10% (95% CI = 6 to 13%) for cycling. The estimates for walking are based on 280,000 participants and 2.6 million person-years and for cycling they are based on 187,000 individuals and 2.1 million person-years. The shape of the dose-response relationship was modelled through meta-analysis of pooled relative risks within three exposure intervals. The dose-response analysis showed that walking or cycling had the greatest effect on risk for ACM in the first (lowest) exposure interval. The analysis shows that walking and cycling have population-level health benefits even after adjustment for other PA. Public health approaches would have the biggest impact if they are able to increase walking and cycling levels in the groups that have the lowest levels of these activities. The review protocol was registered with PROSPERO (International database of prospectively registered systematic reviews in health and social care) PROSPERO 2013: CRD42013004266.


Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma.
Cigarette smoking is a risk factor for colorectal adenoma, a precursor of colorectal cancer. Microsomal epoxide hydrolase (EPHX1) metabolizes polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Nonsynonymous variants of EPHX1 at Tyr(113)His (exon 3) and His(139)Arg (exon 4) are associated, respectively, with low ((113)His) and high ((139)Arg) predicted activity. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we evaluated risks for advanced adenoma in relation to cigarette use and these two EPHX1 variants. We compared 772 cases with advanced adenoma (adenoma >/=1 cm or containing high-grade dysplasia or villous, including tubulovillous, elements) of the distal colon (left-sided, descending colon and sigmoid or rectum) to 777 gender- and age-matched controls who were screen-negative for left-sided adenoma. Compared to those with homozygous genotypes predicting low EPHX1 activity, advanced adenoma risks tended to be elevated for carriers of (113)TyrTyr [odds ratios (OR), 1.5; 95% confidence intervals (CI), 1.0-2.2] and (139)ArgArg (OR, 1.4; 95% CI, 0.8-2.5) and for subjects who carried a greater number of the alleles ((113)Tyr or (139)Arg) associated with high predicted enzymatic activity (P(trend) = 0.03). The increased risk associated with the increasing number of putative high-activity alleles was most apparent among current and recent (quit <10 years) cigarette smokers (P(trend) = 0.02). In conclusion, EPHX1 variants at codon 113 and 139 associated with high predicted enzymatic activity appear to increase risk for colorectal adenoma, particularly among recent and current smokers.


Metabotropic glutamate receptors: physiology, pharmacology, and disease.
The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.


Oral contraceptive pill use before pregnancy and respiratory outcomes in early childhood.
Oral contraceptive pills (OCPs) are often used soon before, and sometimes during, pregnancy. A few studies have suggested that OCP use before pregnancy may increase risks for childhood respiratory outcomes, but data are inconclusive. No studies have analyzed the two types of OCPs, estrogen-progestin combined pills and progestin-only pills, separately. In the Norwegian Mother and Child Cohort Study (MoBa), we prospectively examined associations of OCP use before pregnancy, by type, with lower respiratory tract infections in 60,225 children followed to 6 months old, lower respiratory tract infections and wheezing in 42,520 children followed to 18 months old, and asthma in 24,472 children followed to 36 months old. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) crudely and with adjustment for a wide range of potential confounders. Combined pills were used much more commonly than progestin-only pills. Taking combined pills before pregnancy was not associated with lower respiratory tract infections, wheezing, or asthma. Progestin-only pill use in the year before pregnancy had a slight positive association with wheezing at 6-8 months old [adjusted OR (95% CI) = 1.19 (1.05-1.34)]. Our finding that combined pill use before pregnancy was not related to respiratory outcomes should provide reassurance to the vast majority of mothers using OCPs before becoming pregnant. The small association with progestin-only pill use and early respiratory outcomes may reflect uncontrolled confounding or other bias. Nonetheless, it does suggest that these two types of pills should be examined separately in future analyses of respiratory and other childhood outcomes.


Request fulfillment in office practice: antecedents and relationship to outcomes.
Patients communicate their desires and expectations largely by making requests. However, the antecedents and consequences of request fulfillment have received limited attention. To describe patient and physician characteristics associated with request fulfillment and to understand the consequences of request fulfillment and nonfulfillment on visit evaluations by patients and physicians, self-reported health care use, and health outcomes. Data were gathered from patient and physician surveys administered at several points before and after problem-driven outpatient visits. The study was carried out in the office practices of 45 family practice, internal medicine, and cardiology physicians working either in a large multispecialty group practice or in a group-model health maintenance organization. Data were collected at the index visit from 909 patients (cooperation rate, 68%; net response rate, 32%). A telephone follow-up survey was administered to 887 (98%) of these patients 2 weeks after the visit. Before the visit, patients provided ratings of their health concerns, physical functioning, role limitations, general health perceptions, and trust in the index physician. After the visit, patients reported on any request that they made, physician responses to these requests, and their satisfaction with care. At the 2-week follow-up evaluation, patients again reported on satisfaction, health concerns, health status, and self-reported postvisit health care use. Patients reported making at least one request in 84% of encounters; requests for medical information, examination, and tests or procedures were most common. Four-fifths of patients who made at least one request reported complete fulfillment of all requests. Perceived request fulfillment was significantly lower among patients with relatively low pr-visit trust in the treating physician. Higher request fulfillment was predictive of more positive patient evaluations of care. Visits in which requests could not be completely fulfilled were rated by physicians as more demanding and less satisfying. Request fulfillment was also positively associated with fewer health concerns and greater symptom improvement at follow up. Nonfulfillment of patient requests did not predict postvisit health care use. Request fulfillment affects patient and physician satisfaction and perceptions of health outcomes. New approaches that efficiently recognize and respond to patient requests are needed.


Spirulina prevents memory dysfunction, reduces oxidative stress damage and augments antioxidant activity in senescence-accelerated mice.
Spirulina has proven to be effective in treating certain cancers, hyperlipidemia, immunodeficiency, and inflammatory processes. In this study, we aimed to investigate the effects of Spirulina on memory dysfunction, oxidative stress damage and antioxidant enzyme activity. Three-month-old male senescence-accelerated prone-8 (SAMP8) mice were randomly assigned to either a control group or to one of two experimental groups (one receiving daily dietary supplementation with 50 mg/kg BW and one with 200 mg/kg BW of Spirulina platensis water extract). Senescence-accelerated-resistant (SAMR1) mice were used as the external control. Results showed that the Spirulina-treated groups had better passive and avoidance scores than the control group. The amyloid β-protein (Aβ) deposition was significantly reduced at the hippocampus and whole brain in both Spirulina groups. The levels of lipid peroxidation were significantly reduced at the hippocampus, striatum, and cortex in both Spirulina groups, while catalase activity was significantly higher only in the 200 mg/kg BW Spirulina group than in the control group. Glutathione peroxidase activity was significantly higher only in the cortex of the 200 mg/kg group than in that of the SAMP8 control group. However, superoxide dismutase activity in all parts of the brain did not significantly differ among all groups. In conclusion, Spirulina platensis may prevent the loss of memory possibly by lessening Aβ protein accumulation, reducing oxidative damage and mainly augmenting the catalase activity.


The biology of satellite cells and telomeres in human skeletal muscle: effects of aging and physical activity.
The decline in the neuromuscular function affects the physical performance and is a threat for independent living in later life. The age-related decrease in muscle satellite cells observed by the age of 70 can be specific to type II fibers in some muscles. Several studies have shown that different forms of exercise induce the expansion of satellite cell pool in human skeletal muscle of young and elderly. Exercise is a powerful non-pharmacological tool inducing the renewal of the satellite cell pool in skeletal muscles. Skeletal muscle is not a stable tissue as satellite cells are constantly recruited during normal daily activities. Satellite cells and the length of telomeres are important in the context of muscle regeneration. It is likely that the regulation of telomeres in vitro cannot fully mimic the behavior of telomeres in human tissues. New insights suggest that telomeres in skeletal muscle are dynamic structures under the influence of their environment. When satellite cells are heavily recruited for regenerative events as in the skeletal muscle of athletes, telomere length has been found to be either dramatically shortened or maintained and even longer than in non-trained individuals. This suggests the existence of mechanisms allowing the control of telomere length in vivo.


Misattribution, false recognition and the sins of memory.
Memory is sometimes a troublemaker. Schacter has classified memory's transgressions into seven fundamental 'sins': transience, absent-mindedness, blocking, misattribution, suggestibility, bias and persistence. This paper focuses on one memory sin, misattribution, that is implicated in false or illusory recognition of episodes that never occurred. We present data from cognitive, neuropsychological and neuroimaging studies that illuminate aspects of misattribution and false recognition. We first discuss cognitive research examining possible mechanisms of misattribution associated with false recognition. We also consider ways in which false recognition can be reduced or avoided, focusing in particular on the role of distinctive information. We next turn to neuropsychological research concerning patients with amnesia and Alzheimer's disease that reveals conditions under which such patients are less susceptible to false recognition than are healthy controls, thus providing clues about the brain mechanisms that drive false recognition. We then consider neuroimaging studies concerned with the neural correlates of true and false recognition, examining when the two forms of recognition can and cannot be distinguished on the basis of brain activity. Finally, we argue that even though misattribution and other memory sins are annoying and even dangerous, they can also be viewed as by-products of adaptive features of memory.


Dietary factors during pregnancy and atopic outcomes in childhood: A systematic review from the European Academy of Allergy and Clinical Immunology.
Allergic diseases are an increasing public health concern, and early life environment is critical to immune development. Maternal diet during pregnancy has been linked to offspring allergy risk. In turn, maternal diet is a potentially modifiable factor, which could be targeted as an allergy prevention strategy. In this systematic review, we focused on non-allergen-specific modifying factors of the maternal diet in pregnancy on allergy outcomes in their offspring. We undertook a systematic review of studies investigating the association between maternal diet during pregnancy and allergic outcomes (asthma/wheeze, hay fever/allergic rhinitis/seasonal allergies, eczema/atopic dermatitis (AD), food allergies, and allergic sensitization) in offspring. Studies evaluating the effect of food allergen intake were excluded. We searched three bibliographic databases (MEDLINE, EMBASE, and Web of Science) through February 26, 2019. Evidence was critically appraised using modified versions of the Cochrane Collaboration Risk of Bias tool for intervention trials and the National Institute for Clinical Excellence methodological checklist for cohort and case-control studies and meta-analysis performed from RCTs. We identified 95 papers: 17 RCTs and 78 observational (case-control, cross-sectional, and cohort) studies. Observational studies varied in design and dietary intakes and often had contradictory findings. Based on our meta-analysis, RCTs showed that vitamin D supplementation (OR: 0.72; 95% CI: 0.56-0.92) is associated with a reduced risk of wheeze/asthma. A positive trend for omega-3 fatty acids was observed for asthma/wheeze, but this did not reach statistical significance (OR: 0.70; 95% CI: 0.45-1.08). Omega-3 supplementation was also associated with a non-significant decreased risk of allergic rhinitis (OR: 0.76; 95% CI: 0.56-1.04). Neither vitamin D nor omega-3 fatty acids were associated with an altered risk of AD or food allergy. Prenatal supplementation with vitamin D may have beneficial effects for prevention of asthma. Additional nutritional factors seem to be required for modulating the risk of skin and gastrointestinal outcomes. We found no consistent evidence regarding other dietary factors, perhaps due to differences in study design and host features that were not considered. While confirmatory studies are required, there is also a need for performing RCTs beyond single nutrients/foods.


Improving adolescent mental health and resilience through a resilience-based intervention in schools: study protocol for a randomised controlled trial.
Research investigating the effectiveness of universal interventions to reduce the risk of mental health problems remains limited. Schools are a promising setting within which adolescents can receive interventions aimed at promoting their mental health. The aim of this study is to assess the effectiveness of a resilience-based prevention-focused intervention in reducing the risk of mental health problems among adolescents attending secondary school in socio-economically disadvantaged areas. A cluster randomised control trial will be conducted, with schools as the unit of randomisation. Initially, 32 secondary schools will be randomly allocated to a control or intervention group (12 control and 20 intervention). An intervention focused on improving student internal and external resilience factors will be implemented in intervention schools. A survey of students in Grade 7 in both intervention and control schools will be conducted (baseline) and repeated three years later when the students are in Grade 10. The Strengths and Difficulties Questionnaire will be used to measure the risk of mental health problems. At follow-up, the risk of mental health problems will be compared between Grade 10 students in intervention and control schools to determine intervention effectiveness. The study presents an opportunity to determine the effectiveness of a comprehensive resilience-based intervention in reducing the risk of mental health problems in adolescents attending secondary schools. The outcomes of the trial are of importance to youth, schools, mental health clinicians and policymakers. Australian New Zealand Clinical Trials Registry, ACTRN12611000606987, registered 14 June 2011.


Clinical effectiveness of golimumab in Crohn's disease: an observational study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).
The effectiveness of golimumab in Crohn's disease (CD) is largely unknown as it is not approved for the treatment of the disease. We aimed to identify the population of CD patients treated with golimumab in Sweden, to assess the effectiveness of golimumab (defined as the drug retention rate), and to identify predictors of drug discontinuation. Patients with CD who received at least one injection of golimumab were identified through the Swedish National Quality Registry for Inflammatory Bowel Disease, which includes prospectively collected clinical information. Cox regression models were used to identify predictors of golimumab discontinuation. The study cohort involved 94 patients of whom the majority (96.8%) had previously discontinued at least one anti-tumour necrosis factor (anti-TNF) agent. The drug retention rate at 12 weeks was 85.1%. Predictors of golimumab discontinuation at 12 weeks were previous surgery (adjusted HR = 7.52, 95% CI: 1.12-50.36), concomitant corticosteroid use at baseline (adjusted HR = 5.70, 95% CI: 1.13-28.68) and female sex (adjusted HR = 6.59; 95% CI: 1.04-41.62). The median duration of follow-up was 89 (IQR: 32-158) weeks. The drug retention at the most recent follow-up was 35.1%. Predictors of golimumab discontinuation at the most recent follow-up were corticosteroid use at baseline (adjusted HR = 2.60, 95% CI: 1.17-5.79) and female sex (adjusted HR = 2.24; 95% CI: 1.19-4.23). Patients with CD treated with golimumab were a treatment-refractory group. Despite this, more than one-third of the patients appeared to have had clinical benefit after a median follow-up of more than 1.5 years.


Improved Adherence to Antiretroviral Therapy Observed Among HIV-Infected Children Whose Caregivers had Positive Beliefs in Medicine in Sub-Saharan Africa.
A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART.


A comparison of periodization models during nine weeks with equated volume and intensity for strength.
The purpose of the present investigation was to determine if significant differences exist among 3 different periodization programs in eliciting changes in strength. Twenty-eight recreationally trained college-aged volunteers (mean +/- SD; 22.29 +/- 3.98) of both genders were tested for bench press, leg press, body fat percentage, chest circumference, and thigh circumference during initial testing. After initial testing, subjects were randomly assigned to 1 of 3 training groups: (a) linear periodization (n = 9), (b) daily undulating periodization (n = 10), or (c) weekly undulating periodization (n = 9). The training regimen for each group consisted of a 9-week, 3-day-per-week program. Training loads were assigned as heavy (90%, 4 repetition maximum [4RM]), medium (85%, 6RM), or light (80%, 8RM) for bench press and leg press exercises. Subjects were familiarized with the CR-10 rated perceived exertion scale and instructed to achieve an 8 or 9 on the final repetition of each set for all other exercises. Subjects were then retested after 4 weeks of training. Training loads were then adjusted according to the new 1RM. Subjects were then retested after 5 more weeks of exercise. For all subjects, significant (p < 0.05) increases in bench press and leg press strength were demonstrated at all time points (T1-T3). No significant differences (p > 0.05) were observed between groups for bench press, leg press, body fat percentage, chest circumference, or thigh circumference at all time points. These results indicate that no separation based on periodization model is seen in early-phase training.


Tympanostomy Tube Placement vs Medical Management for Recurrent Acute Otitis Media in TRICARE-Insured Children.
Objective To compare number of infections and health care utilization in children insured by TRICARE with recurrent acute otitis media (RAOM) managed surgically with tympanostomy tube (TT) placement compared with those managed medically. Study Design Retrospective matched cohort study. Setting TRICARE claims database from 2006 to 2010. Subjects and Methods We matched TRICARE beneficiaries ≤5 years of age diagnosed with RAOM who underwent TT placement with those managed medically using 1:1 coarsened-exact matching on age, sex, race, sponsor rank, and region. We used multivariable negative binomial regression to compare number of infections and health care utilization at 1 and 2 years. Outcomes were adjusted for rate of infection before treatment for RAOM, season of either TT placement or establishment of candidacy for TT placement, and comorbidities. Results Among 6659 pairs identified at 1-year follow-up, the TT group had fewer infections (1.96 vs 2.18, P < .001) and oral antibiotic prescriptions (1.52 vs 1.67, P < .001) but more visits to primary care physicians (4.36 vs 4.06, P < .0001) and otolaryngologists (1.21 vs 0.44, P < .0001) compared with the medically managed group. At 2-year follow-up, the benefits of TT placement were no longer seen. Conclusion TT placement for RAOM is associated with fewer infections and oral antibiotic prescriptions in the first year after surgery but more doctor visits. Benefits of TT placement do not appear to extend through the second year. Future research should investigate costs associated with TT placement vs medical management, as well as real-time health care utilization with impact on patient symptoms and quality of life.


The passive transfer of immunoglobulin G serum antibodies from patients with longstanding Complex Regional Pain Syndrome.
The aetiology of Complex Regional Pain Syndrome (CRPS) is unknown. Recent evidence suggests that there may be autoantibodies directed against peripheral nerves, but it is unclear whether such autoantibodies are merely biomarkers or whether they cause or contribute to the underlying pathology. The transfer of disease after injection of a patient's serum or IgG fraction into mice ('passive transfer') is the classic way to demonstrate a functional role of autoantibodies. Based on previous preliminary results, we wished to investigate whether the transfer of IgG antibodies affected mouse behaviour or produced signs of CRPS. We injected purified serum-IgG from 12 patients and 12 controls into groups of 6-10 mice (∼ 17 mg/mouse intraperitoneally) on 2 consecutive days and looked for any evidence for altered behaviour or signs of CRPS. The observer, blinded as to test or control group, measured behaviour in the open field, stimulus-evoked pain and motor coordination, and inspected limbs for autonomic CRPS signs. Stimulus-evoked pain and autonomic signs were not detected, but CRPS-IgG induced significant depression of rearing behaviour (17.9 rears/3 min (n = 84) vs. 22.1 rears/3 min (n = 83), p = 0.0004), confirming previous observations in a single case study. Moreover, motor impairment, one of the four cardinal signs of CRPS, was evident in the three CRPS-IgG injected groups tested with a sensitive rota-rod protocol (p < 0.0001 vs. control-IgG injected groups). These results lend support to a pathophysiological role for IgG autoantibodies in CRPS.


Metabolic signature of healthy lifestyle and its relation with risk of hepatocellular carcinoma in a large European cohort.
Studies using metabolomic data have identified metabolites from several compound classes that are associated with disease-related lifestyle factors. In this study, we identified metabolic signatures reflecting lifestyle patterns and related them to the risk of hepatocellular carcinoma (HCC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Within a nested case-control study of 147 incident HCC cases and 147 matched controls, partial least squares (PLS) analysis related 7 modified healthy lifestyle index (HLI) variables (diet, BMI, physical activity, lifetime alcohol, smoking, diabetes, and hepatitis) to 132 targeted serum-measured metabolites and a liver function score. The association between the resulting PLS scores and HCC risk was examined in multivariable conditional logistic regression models, where ORs and 95% CIs were computed. The lifestyle component's PLS score was negatively associated with lifetime alcohol, BMI, smoking, and diabetes, and positively associated with physical activity. Its metabolic counterpart was positively related to the metabolites sphingomyelin (SM) (OH) C14:1, C16:1, and C22:2, and negatively related to glutamate, hexoses, and the diacyl-phosphatidylcholine PC aaC32:1. The lifestyle and metabolomics components were inversely associated with HCC risk, with the ORs for a 1-SD increase in scores equal to 0.53 (95% CI: 0.38, 0.74) and 0.28 (0.18, 0.43), and the associated AUCs equal to 0.64 (0.57, 0.70) and 0.74 (0.69, 0.80), respectively. This study identified a metabolic signature reflecting a healthy lifestyle pattern which was inversely associated with HCC risk. The metabolic profile displayed a stronger association with HCC than did the modified HLI derived from questionnaire data. Measuring a specific panel of metabolites may identify strata of the population at higher risk for HCC and can add substantial discrimination compared with questionnaire data. This trial was registered at clinicaltrials.gov as NCT03356535.


The preparation of reach to grasp movements in adults with Down syndrome.
The aim of this study was to determine the extent to which adults with Down syndrome (DS) are able to utilise advance information to prepare reach to grasp movements. The study comprised ten adults with DS; ten children matched to an individual in the group with DS on the basis of their intellectual ability, and twelve adult controls. The participants used their right hand to reach out and grasp illuminated perspex blocks. Four target blocks were positioned on a table surface, two to each side of the midsagittal plane. In the complete precue condition, participants were provided with information specifying the location of the target. In the partial precue condition, participants were given advance information indicating the location of the object relative to the midsagittal plane (left or right). In the null condition, advance information concerning the position of the target object was entirely ambiguous. It was found that both reaction times and movement times were greater for the participants with DS than for the adults without DS. The reaction times exhibited by individuals with DS in the complete precue condition were lower than those observed in the null condition, indicating that they had utilised advance information to prepare their movements. In the group with DS, when advance information specified only the location of the target object relative to the midline, reaction times were equivalent to those obtained when ambiguous information was given. In contrast, the adults without DS exhibited reaction times that were lower in both the complete and partial precue conditions when compared to the null condition. The pattern of results exhibited by the children was similar to that of the adults without DS. The movement times exhibited by all groups were not influenced by the precue condition. In summary, our findings indicate that individuals with DS are able to use advance information if it specifies precisely the location of the target object in order to prepare a reach to grasp movement. The group with DS were unable, however, to obtain the normal advantage of advance information specifying only one dimension of the movement goal (i.e., the position of an object relative to the body midline).


The evolution of surgical telementoring: current applications and future directions.
Surgical telementoring is a concept within telemedicine that involves the use of information technology to provide real-time guidance and technical assistance for surgical procedures from an expert physician at a different geographical location. It is a means to overcome the logistic obstacles associated with traditional mentoring and can aid in the distribution of advanced surgical techniques. In addition to its perceived educational benefits, it has the potential to directly impact patient care by providing immediate access to specialized surgical expertise in areas lacking access to qualified surgeons. With advances in technology, surgical telementoring has made significant strides in the past two decades and a breadth of positive experiences have been published in the literature. Despite this growth, questions remain regarding ideal videoconferencing methodology, resolution and latency requirements, security and liability issues, and telementoring in combination with emerging technology. This review addresses the history and progression, current applications, and future directions of surgical telementoring as a means to distribute advanced surgical expertise around the world.


Distinct miRNA Profile of Cellular and Extracellular Vesicles Released from Chicken Tracheal Cells Following Avian Influenza Virus Infection.
Innate responses provide the first line of defense against viral infections, including the influenza virus at mucosal surfaces. Communication and interaction between different host cells at the early stage of viral infections determine the quality and magnitude of immune responses against the invading virus. The release of membrane-encapsulated extracellular vesicles (EVs), from host cells, is defined as a refined system of cell-to-cell communication. EVs contain a diverse array of biomolecules, including microRNAs (miRNAs). We hypothesized that the activation of the tracheal cells with different stimuli impacts the cellular and EV miRNA profiles. Chicken tracheal rings were stimulated with polyI:C and LPS from Escherichia coli 026:B6 or infected with low pathogenic avian influenza virus H4N6. Subsequently, miRNAs were isolated from chicken tracheal cells or from EVs released from chicken tracheal cells. Differentially expressed (DE) miRNAs were identified in treated groups when compared to the control group. Our results demonstrated that there were 67 up-regulated miRNAs, 157 down-regulated miRNAs across all cellular and EV samples. In the next step, several genes or pathways targeted by DE miRNAs were predicted. Overall, this study presented a global miRNA expression profile in chicken tracheas in response to avian influenza viruses (AIV) and toll-like receptor (TLR) ligands. The results presented predicted the possible roles of some DE miRNAs in the induction of antiviral responses. The DE candidate miRNAs, including miR-146a, miR-146b, miR-205a, miR-205b and miR-449, can be investigated further for functional validation studies and to be used as novel prophylactic and therapeutic targets in tailoring or enhancing antiviral responses against AIV.


The updating of clinical practice guidelines: insights from an international survey.
Clinical practice guidelines (CPGs) have become increasingly popular, and the methodology to develop guidelines has evolved enormously. However, little attention has been given to the updating process, in contrast to the appraisal of the available literature. We conducted an international survey to identify current practices in CPG updating and explored the need to standardize and improve the methods. We developed a questionnaire (28 items) based on a review of the existing literature about guideline updating and expert comments. We carried out the survey between March and July 2009, and it was sent by email to 106 institutions: 69 members of the Guidelines International Network who declared that they developed CPGs; 30 institutions included in the U.S. National Guideline Clearinghouse database that published more than 20 CPGs; and 7 institutions selected by an expert committee. Forty-four institutions answered the questionnaire (42% response rate). In the final analysis, 39 completed questionnaires were included. Thirty-six institutions (92%) reported that they update their guidelines. Thirty-one institutions (86%) have a formal procedure for updating their guidelines, and 19 (53%) have a formal procedure for deciding when a guideline becomes out of date. Institutions describe the process as moderately rigorous (36%) or acknowledge that it could certainly be more rigorous (36%). Twenty-two institutions (61%) alert guideline users on their website when a guideline is older than three to five years or when there is a risk of being outdated. Twenty-five institutions (64%) support the concept of "living guidelines," which are continuously monitored and updated. Eighteen institutions (46%) have plans to design a protocol to improve their guideline-updating process, and 21 (54%) are willing to share resources with other organizations. Our study is the first to describe the process of updating CPGs among prominent guideline institutions across the world, providing a comprehensive picture of guideline updating. There is an urgent need to develop rigorous international standards for this process and to minimize duplication of effort internationally.


Isolation and chemical characterization of antitumor agents from plants.
This paper reviews methods which have evolved at the Research Triangle Institute during the last 15 years for the isolation and characterization of antitumor agents from plants. The isolation procedures stress mild, nonchemical methods. Solvent partition and the Craig Counter Current Distribution are used during the early stages of fractionation. Subsequent purification involves many types of chromatography: adsorption, partition, thin-layer, preparative thin layer, gel-exclusion, and medium- and high-pressure liquid chromatography. The pure compound is crystallized from a suitable solvent. The fractionation is monitored with in vitro and in vivo bioassays. Physical methods used for structure determination are: ultraviolet, infrared, and nuclear magnetic resonance spectrometry, and X-ray crystallography.


Pharmacologic treatment options for cancer-related fatigue: current state of clinical research.
Fatigue is a highly distressing symptom of cancer associated with significant psychological morbidity and reduced quality of life. Cancer-related fatigue (CRF) has been underreported, underdiagnosed, and undertreated. Fatigue and depression may coexist in patients with cancer, and considerable overlap of symptoms often occurs. This has led researchers to examine the role of psychotropic medications to treat fatigue. Psychostimulants, wakefulness-promoting agents, antidepressants, and cholinesterase inhibitors have been studied for CRF treatment. Methylphenidate has been studied most and is effective and well tolerated despite common side effects. Some preliminary data support using modafinil for patients with CRF. Antidepressant studies have shown mixed results. Paroxetine shows benefit for fatigue, primarily when it is a symptom of clinical depression. Bupropion sustained release may have psychostimulant-like effects and, therefore, may be beneficial in treating fatigue. Donepezil, a cholinesterase inhibitor, has shown benefit only in open-label trials. Randomized, placebo-controlled trials with specific agents are needed to further assess the efficacy and tolerability of psychotropic medications in CRF treatment.


Employing a user-centered cognitive walkthrough to evaluate a mHealth diabetes self-management application: A case study and beginning method validation.
Self-management of chronic diseases using mobile health (mHealth) systems and applications is becoming common. Current evaluation methods such as formal usability testing can be very costly and time-consuming; others may be more efficient but lack a user focus. We propose an enhanced cognitive walkthrough (CW) method, the user-centered CW (UC-CW), to address identified deficiencies in the original technique and perform a beginning validation with think aloud protocol (TA) to assess its effectiveness, efficiency and user acceptance in a case study with diabetes patient users on a mHealth self-management application. A total of 12 diabetes patients at University of Utah Health, USA, were divided into UC-CW and think aloud (TA) groups. The UC-CW method included: making the user the main evaluator for detecting usability problems, having a dual domain facilitator, and using three other improved processes: validated task development, higher level tasks and a streamlined evaluation process. Users interacted with the same mHealth application for both methods. Post-evaluation assessments included the NASA RTLX instrument and a set of brief interview questions. Participants had similar demographic characteristics. A total of 26 usability problems were identified with the UC-CW and 20 with TA. Both methods produced similar ratings: severity across all views (UC-CW = 2.7 and TA = 2.6), numbers of problems in the same views (Main View [UC-CW = 11, TA = 10], Carbohydrate Entry View [UC-CW = 4, TA = 3] and List View [UC-CW = 3, TA = 3]) with similar heuristic violations (Match Between the System and Real World [UC-CW = 19, TA = 16], Consistency and Standards [UC-CW = 17, TA = 15], and Recognition Rather than Recall [UC-CW = 13, TA = 10]). Both methods converged on eight usability problems, but the UC-CW group detected five critical issues while the TA group identified two. The UC-CW group identified needed personalized features for patients' disease needs not identified with TA. UC-CW was more efficient on average time per identified usability problem and on the total evaluation process with patients. NASA RTLX scores indicated that participants experienced the UC-CW half as cognitively demanding. Common themes from interviews indicated the UC-CW as enjoyable and easy to perform while TA was considered somewhat awkward and more cognitively challenging. UC-CW was effective for finding severe, recurring usability problems and it highlighted the need for personalized user features. The method was also efficient and had high user acceptance. These results indicate UC-CW's utility and user acceptance in evaluating a mHealth self-management application. It provides an additional usability evaluation technique for researchers.


Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.
Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.


Children's language ability and psychosocial development: a 29-year follow-up study.
Little is known on the psychosocial adult outcomes of children's early language skills or intervening circumstances. The aim of this study was to assess the longitudinal trajectory linking childhood receptive language skills to psychosocial outcomes in later life. The study comprised 6941 men and women who participated in a nationally representative Birth Cohort Study. Direct assessment of language skills were made at age 5. The sample was studied again at age 34 to assess psychosocial outcomes and levels of adult mental health. Characteristics of the family environment, individual adjustment, and social adaptation in the transition to adulthood were assessed as potential moderating factors linking early language skills to adult mental health. In early childhood, cohort members with poor receptive language experienced more disadvantaged socioeconomic circumstances than cohort members with normal language skills and showed more behavior and psychosocial adjustment problems in the transition to adulthood. At age 34, cohort members with poor early language skills reported lower levels of mental health than cohort members with normal language. After adjustment for family background and experiences of social adaptation, early language skills maintained a significant and independent impact in predicting adult mental health. Early receptive language skills are significantly associated with adult mental health as well as psychosocial adjustment during early childhood and in later life. The needs of children with language problems are complex and call for early and continuing provision of educational support and services.


Effect of dental health education on the oral health status of a rural child population by involving target groups.
India, a developing country faces many challenges in rendering oral health needs. The majority of Indian population resides in rural areas, of which more than 40% constitute children. These children cannot avail dental facilities due to inaccessibility, financial constraints and stagnation of public dental healthcare services. This entails the health professional to adopt a more practical approach to achieve primary prevention of oral diseases. The most viable solution seems to be dental health education. Documented evidence shows that teachers and parents can augment dental health behaviour. With this background, it was decided to target children in a rural area for comparing the effect of education on children alone, children coupled with teachers and children with the involvement of their parents. An interventional study of 4 months duration was conducted on 430 children, 7 teachers and 100 parents. The parents were educated at home. Clinical oral health status was assessed prior to the delivery of dental health education and also following the intervention. Results showed that the dental health scores improved best in the group of children involving the teachers. It was concluded that teachers could be targeted in order to enhance the effect of dental health education campaigns on children.


Real-time PCR assays compared to culture-based approaches for identification of aerobic bacteria in chronic wounds.
Chronic wounds cause substantial morbidity and disability. Infection in chronic wounds is clinically defined by routine culture methods that can take several days to obtain a final result, and may not fully describe the community of organisms or biome within these wounds. Molecular diagnostic approaches offer promise for a more rapid and complete assessment. We report the development of a suite of real-time PCR assays for rapid identification of bacteria directly from tissue samples. The panel of assays targets 14 common, clinically relevant, aerobic pathogens and demonstrates a high degree of sensitivity and specificity using a panel of organisms commonly associated with chronic wound infection. Thirty-nine tissue samples from 29 chronic wounds were evaluated and the results compared with those obtained by culture. As revealed by culture and PCR, the most common organisms were methicillin-resistant Staphylococcus aureus (MRSA) followed by Streptococcus agalactiae (Group B streptococcus) and Pseudomonas aeruginosa. The sensitivities of the PCR assays were 100% and 90% when quantitative and qualitative culture results were used as the reference standard, respectively. The assays allowed the identification of bacterial DNA from ten additional organisms that were not revealed by quantitative or qualitative cultures. Under optimal conditions, the turnaround time for PCR results is as short as 4-6 h. Real-time PCR is a rapid and inexpensive approach that can be easily introduced into clinical practice for detection of organisms directly from tissue samples. Characterization of the anaerobic microflora by real-time PCR of chronic wounds is warranted.


Pathogenesis of apical periodontitis and the causes of endodontic failures.
Apical periodontitis is a sequel to endodontic infection and manifests itself as the host defense response to microbial challenge emanating from the root canal system. It is viewed as a dynamic encounter between microbial factors and host defenses at the interface between infected radicular pulp and periodontal ligament that results in local inflammation, resorption of hard tissues, destruction of other periapical tissues, and eventual formation of various histopathological categories of apical periodontitis, commonly referred to as periapical lesions. The treatment of apical periodontitis, as a disease of root canal infection, consists of eradicating microbes or substantially reducing the microbial load from the root canal and preventing re-infection by orthograde root filling. The treatment has a remarkably high degree of success. Nevertheless, endodontic treatment can fail. Most failures occur when treatment procedures, mostly of a technical nature, have not reached a satisfactory standard for the control and elimination of infection. Even when the highest standards and the most careful procedures are followed, failures still occur. This is because there are root canal regions that cannot be cleaned and obturated with existing equipments, materials, and techniques, and thus, infection can persist. In very rare cases, there are also factors located within the inflamed periapical tissue that can interfere with post-treatment healing of the lesion. The data on the biological causes of endodontic failures are recent and scattered in various journals. This communication is meant to provide a comprehensive overview of the etio-pathogenesis of apical periodontitis and the causes of failed endodontic treatments that can be visualized in radiographs as asymptomatic post-treatment periapical radiolucencies.


Bioluminescent and red-fluorescent lures in a deep-sea siphonophore.
Bioluminescence (light production) and fluorescence (re-emission of absorbed radiation as light) are found in an unaccountably diverse array of marine organisms, where their functions are largely unknown. Here we report a deep-sea siphonophore that twitches glowing lures to attract fish. This is rare evidence of bioluminescence used for prey attraction among nonvisual marine organisms. The lures also contain red fluorescent material that shifts the wavelength of emitted light. The existence of a red-luminescent invertebrate suggests that long-wavelength light plays a greater role in marine interactions than previously suspected.


Photorefractive two-wave mixing for image amplification in digital holography.
We use photorefractive two-wave mixing for coherent amplification of the object beam in digital holographic recording. Both amplitude and phase reconstruction benefit from the prior amplification as they have an increased SNR. We experimentally verify that the amplification process does not affect the phase of the wavefield. This allows for digital holographic phase analysis after amplification. As the grating formation in photorefractive crystals is just driven by coherent light, the crystal works as a coherence gate. Thus the proposed combination allows for applying digital holography for imaging through scattering media, after the image bearing light is coherence gated and filtered out of scattered background. We show experimental proof-of principle results.


A method for measuring tidal volume during high frequency jet ventilation.
A new method has been developed to measure tidal volume during high frequency jet ventilation. A pneumotachograph is placed in the expiratory limb of the breathing circuit. Using a model lung, the results from this method did not differ from the tidal volume calculated from pressure changes measured within the model lung. The results from the two methods correlated well (r = 0.99). The method enables the gas volumes entrained and spilled out of the airway during inspiration, true I:E ratios and mean driving pressures to be determined. The method is non-invasive and could easily be applied clinically.


Statistical evaluation of learning curve effects in surgical trials.
Randomized controlled trials (RCTs) in surgery have been impeded by concerns that improvements in the technical performance of a new technique over time (a "learning curve") may distort comparisons. The statistical assessment of learning curves in trials has received little attention. In this paper, we discuss what a learning curve effect is, the factors which effect it, how to display it, and how to incorporate the learning effect into the trial analysis. Bayesian hierarchical models are proposed to adjust the trial results for the existence of a learning curve effect. The implications for trial evaluation and data collection are considered.


Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype.
Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC(-/-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT(-/-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction.


Characterization of Salmonella associated with pig ear dog treats in Canada.
In the summer of 1999, the incidence of Salmonella enterica serotype Infantis infections in Alberta rose dramatically. Subsequent laboratory and epidemiological investigations established that an outbreak of human disease caused by this organism was occurring across Canada and was associated with pet treats for dogs produced from processed pig ears. Laboratory investigations using phage typing and pulsed-field gel electrophoresis (PFGE) established that isolates of Salmonella serotype Infantis from pig ear pet treats and humans exposed to pig ear pet treats comprised a well-defined subset of all isolates analyzed. Of the 53 subtypes of Salmonella serotype Infantis obtained around the time of the outbreak as defined by PFGE and phage typing, only 6 subtypes were associated with both human infection and isolation from pig ears. Together with information from epidemiological studies, these investigations established pig ear pet treats as the cause of the Salmonella serotype Infantis outbreak. The results are consistent with a model in which contaminated pig ear pet treats constitute a long-term, continuing vehicle for infection of the human population rather than causing temporally delimited point-source outbreaks. During the course of this outbreak, several other Salmonella serotypes were also isolated from pet treats, suggesting these products may be an important source of enteric infection in both humans and dogs. Though isolates of Salmonella serotypes other than Salmonella serotype Infantis from pet treats were also subjected to PFGE and phage typing, no link with human disease could be definitively established, and the contribution of pig ear pet treats to human disease remains unclear. Elimination of bacterial contamination from pet treats is required to reduce the risk of infection from these products.


The genome sequence of the soft-rot fungus Penicillium purpurogenum reveals a high gene dosage for lignocellulolytic enzymes.
The high lignocellulolytic activity displayed by the soft-rot fungus Penicillium purpurogenum has made it a target for the study of novel lignocellulolytic enzymes. We have obtained a reference genome of 36.2 Mb of non-redundant sequence (11,057 protein-coding genes). The 49 largest scaffolds cover 90% of the assembly, and Core Eukaryotic Genes Mapping Approach (CEGMA) analysis reveals that our assembly captures almost all protein-coding genes. RNA-seq was performed and 93.1% of the reads aligned to the assembled genome. These data, plus the independent sequencing of a set of genes of lignocellulose-degrading enzymes, validate the quality of the genome sequence. P. purpurogenum shows a higher number of proteins with CAZy motifs, transcription factors and transporters as compared to other sequenced Penicillia. These results demonstrate the great potential for lignocellulolytic activity of this fungus and the possible use of its enzymes in related industrial applications.


Delays and loss to follow-up before treatment of drug-resistant tuberculosis following implementation of Xpert MTB/RIF in South Africa: A retrospective cohort study.
South Africa has a large burden of rifampicin-resistant tuberculosis (RR-TB), with 18,734 patients diagnosed in 2014. The number of diagnosed patients has increased substantially with the introduction of the Xpert MTB/RIF test, used for tuberculosis (TB) diagnosis for all patients with presumptive TB. Routine aggregate data suggest a large treatment gap (pre-treatment loss to follow-up) between the numbers of patients with laboratory-confirmed RR-TB and those reported to have started second-line treatment. We aimed to assess the impact of Xpert MTB/RIF implementation on the delay to treatment initiation and loss to follow-up before second-line treatment for RR-TB across South Africa. A nationwide retrospective cohort study was conducted to assess second-line treatment initiation and treatment delay among laboratory-diagnosed RR-TB patients. Cohorts, including approximately 300 sequentially diagnosed RR-TB patients per South African province, were drawn from the years 2011 and 2013, i.e., before and after Xpert implementation. Patients with prior laboratory RR-TB diagnoses within 6 mo and currently treated patients were excluded. Treatment initiation was determined through data linkage with national and local treatment registers, medical record review, interviews with health care staff, and direct contact with patients or household members. Additional laboratory data were used to track cases. National estimates of the percentage of patients who initiated treatment and time to treatment were weighted to account for the sampling design. There were 2,508 and 2,528 eligible patients in the 2011 and 2013 cohorts, respectively; 92% were newly diagnosed with RR-TB (no prior RR-TB diagnoses). Nationally, among the 2,340 and 2,311 new RR-TB patients in the 2011 and 2013 cohorts, 55% (95% CI 53%-57%) and 63% (95% CI 61%-65%), respectively, started treatment within 6 mo of laboratory receipt of their diagnostic specimen (p < 0.001). However, in 2013, there was no difference in the percentage of patients who initiated treatment at 6 mo between the 1,368 new RR-TB patients diagnosed by Xpert (62%, 95% CI 59%-65%) and the 943 diagnosed by other methods (64%, 95% CI 61%-67%) (p = 0.39). The median time to treatment decreased from 44 d (interquartile range [IQR] 20-69) in 2011 to 22 d (IQR 2-43) in 2013 (p < 0.001). In 2013, across the nine provinces, there were substantial variations in both treatment initiation (range 51%-73% by 6 mo) and median time to treatment (range 15-36 d, n = 1,450), and only 53% of the 1,448 new RR-TB patients who received treatment were recorded in the national RR-TB register. This retrospective study is limited by the lack of information to assess reasons for non-initiation of treatment, particularly pre-treatment mortality data. Other limitations include the use of names and dates of birth to locate patient-level data, potentially resulting in missed treatment initiation among some patients. In 2013, there was a large treatment gap for RR-TB in South Africa that varied significantly across provinces. Xpert implementation, while reducing treatment delay, had not contributed substantially to reducing the treatment gap in 2013. However, given improved case detection with Xpert, a larger proportion of RR-TB patients overall have received treatment, with reduced delays. Nonetheless, strategies to further improve linkage to treatment for all diagnosed RR-TB patients are urgently required.


Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development.
The WNT/β-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of β-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate β-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for β-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived β-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with β-catenin(fx(exon3)/wt) or β-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific β-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific β-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific β-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived β-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.


The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis.
Mice infected i.v. with the virulent Erdman strain of Mycobacterium tuberculosis exhibited three distinct phases of infection within the spleen. These consisted of a primary phase, characterized by the progressive growth of the organism; a secondary phase, in which the viable organism was progressively eliminated; and a tertiary phase, characterized by a chronic or slowly recrudescing disease state. Passive transfer experiments, in which T cell-enriched spleen cells from immune donors were infused into T cell-deficient recipients and were measured for their capacity to adoptively protect these mice from challenge with M. tuberculosis, provided evidence that at least three separate populations of protective T cells were acquired in response to the infection within the time frame of the experiments. These populations of T cells could be distinguished in that they differed in their expression of the L3T4 and Lyt-2 cell surface molecules, in terms of their kinetic profiles of emergence and loss, and (c) in terms of their susceptibility to cyclophosphamide. The results may suggest that different populations of protective T cells can be generated at different times during the infection as various classes of antigens (for example, metabolic or structural antigens) become available for presentation by host macrophages. It is hypothesized, furthermore, that the kinetics of emergence and loss of these various populations may reflect switching in the mode of immunity being expressed, particularly during the chronic phase of the infection, from that of a state of active immunity to one of immunologic memory.


Acute management of vascular air embolism.
Vascular air embolism (VAE) is known since early nineteenth century. It is the entrainment of air or gas from operative field or other communications into the venous or arterial vasculature. Exact incidence of VAE is difficult to estimate. High risk surgeries for VAE are sitting position and posterior fossa neurosurgeries, cesarean section, laparoscopic, orthopedic, surgeries invasive procedures, pulmonary overpressure syndrome, and decompression syndrome. Risk factors for VAE are operative site 5 cm above the heart, creation of pressure gradient which will facilitate entry of air into the circulation, orogenital sex during pregnancy, rapid ascent in scuba (self contained underwater breathing apparatus) divers and barotrauma or chest trauma. Large bolus of air can lead to right ventricular air lock and immediate fatality. In up to 35% patient, the foramen ovale is patent which can cause paradoxical arterial air embolism. VAE affects cardiovascular, pulmonary and central nervous system. High index of clinical suspicion is must to diagnose VAE. The transesophgeal echocardiography is the most sensitive device which will detect smallest amount of air in the circulation. Treatment of VAE is to prevent further entrainment of air, reduce the volume of air entrained and haemodynamic support. Mortality of VAE ranges from 48 to 80%. VAE can be prevented significantly by proper positioning during surgery, optimal hydration, avoiding use of nitrous oxide, meticulous care during insertion, removal of central venous catheter, proper guidance, and training of scuba divers.


Quantification of Hepatitis C Virus Cell-to-Cell Spread Using a Stochastic Modeling Approach.
It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread is fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads from cell to cell and has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors. Using a multidisciplinary approach, we performed HCV spread assays and assessed the appropriateness of different stochastic models for describing HCV focus expansion. To evaluate the effect of blocking specific host cell factors on HCV cell-to-cell transmission, assays were performed in the presence of blocking antibodies and/or small-molecule inhibitors targeting different cellular HCV entry factors. In all experiments, HCV-positive cells were identified by immunohistochemical staining and the number of HCV-positive cells per focus was assessed to determine focus size. We found that HCV focus expansion can best be explained by mathematical models assuming focus size-dependent growth. Consistent with previous reports suggesting that some factors impact HCV cell-to-cell spread to different extents, modeling results estimate a hierarchy of efficacies for blocking HCV cell-to-cell spread when targeting different host factors (e.g., CLDN1 > NPC1L1 > TfR1). This approach can be adapted to describe focus expansion dynamics under a variety of experimental conditions as a means to quantify cell-to-cell transmission and assess the impact of cellular factors, viral factors, and antivirals. The ability of viruses to efficiently spread by direct cell-to-cell transmission is thought to play an important role in the establishment and maintenance of viral persistence. As such, elucidating the dynamics of cell-to-cell spread and quantifying the effect of blocking the factors involved has important implications for the design of potent antiviral strategies and controlling viral escape. Mathematical modeling has been widely used to understand HCV infection dynamics and treatment response; however, these models typically assume only cell-free virus infection mechanisms. Here, we used stochastic models describing focus expansion as a means to understand and quantify the dynamics of HCV cell-to-cell spread in vitro and determined the degree to which cell-to-cell spread is reduced when individual HCV entry factors are blocked. The results demonstrate the ability of this approach to recapitulate and quantify cell-to-cell transmission, as well as the impact of specific factors and potential antivirals.


Use of a clean delivery kit and factors associated with cord infection and puerperal sepsis in Mwanza, Tanzania.
Our objective was to determine the effectiveness of an intervention that incorporated education about the "six cleans" with the use of a clean delivery kit in preventing cord infection and puerperal sepsis. A stepped-wedge, cross-sectional study was conducted in 10 surveillance sites across two rural districts of Mwanza Region, Tanzania. A total of 3262 pregnant women between the ages of 17 and 45 years were enrolled in the study. Village health workers administered questionnaires to each mother at 5 days postpartum and inspected the infants' umbilical cord stumps for signs of infection. Newborns whose mothers used the delivery kit were 13.1 times less likely to develop cord infection than infants whose mothers did not use the kit. Furthermore, women who used the kit for delivery were 3.2 times less likely to develop puerperal sepsis than women who did not use the kit. Women who bathed before delivery were 2.6 times less likely to develop puerperal sepsis than women who did not bathe, and their infants were 3.9 times less likely to develop cord infection. Single-use delivery kits, when combined with education about clean delivery, can have a positive impact on the health of women and their newborns by significantly decreasing the likelihood of developing puerperal sepsis or cord infection.


Calibration-free wavelength modulated TDLAS under high absorbance conditions.
Currently, the method that uses a first-order Taylor series to approximate laser transmission has seriously affected the gas concentration measurement accuracy of tunable diode laser-absorption spectroscopy (TDLAS). This paper employs a second-order Taylor series to approximate laser transmission, and a high-precision second-order algorithm has been established that can determine the gas concentration directly. Then, this algorithm is used to test the NH₃ mole fraction in a cell with NH₃-Air mixtures. Experimental results show that the second-order algorithm not only effectively improves the measurement accuracy of gas concentration but also greatly broadens the scope of TDLAS.


Antihypertensive Medications and ECT.
Prominent changes in hemodynamics occur during electroconvulsive therapy (ECT) despite general anesthesia and muscle relaxation and regardless of choice of stimulating electrode placement. The most common pattern is hypertension and tachycardia during the seizure, followed by relative bradycardia and a gradual return of blood pressure to normal within minutes of the end of the seizure. The mortal and morbid risk of these changes is generally small; nevertheless, it is common practice to administer antihypertensive medications to blunt this response. Several agents have proven able to reduce ECT-related hypertension and tachycardia; however, it is unknown whether these agents reduce mortality or cardiovascular morbidity or alter efficacy or cognitive effects of ECT. A few case reports suggest intravenous antihypertensives may be positively dangerous on occasion. Based upon these findings, antihypertensives need not be given routinely during ECT, and when given, conservative doses should be used. The short-acting beta blockers may be particularly suited to this task. To prevent needless use of these agents and the possibility of an adverse event, the patient's intravascular volume, blood pressure and pulse should be optimized prior to the first ECT.


Efficacy of Simulation Using NLN/Jeffries Nursing Education Simulation Framework on Satisfaction and Self-Confidence of Undergraduate Nursing Students in a Middle-Eastern Country.
Utilizing simulation in nursing education is increasingly becoming a popular teaching pedagogy. Simulation provides opportunity to the nursing students to practice the clinical skills through various real life like situational experiences. Simulation improves the clinical decision making skills of the nursing students. A descriptive, cross sectional, correlational study was conducted to evaluate the efficacy of simulation using NLN/Jeffries Nursing Education Simulation Framework on satisfaction and self-confidence of Undergraduate nursing students. 370 undergraduate nursing students participated in the study. Educational practices, Simulation design, Student satisfaction and Self-confidence questionnaires were used. Majority of the nursing students perceived agreement on various domains of student satisfaction, self-confidence, educational practices and simulation design used in the curriculum. The students were self-confident to care for similar patients in the clinical area and satisfied with this instructional method. Satisfaction and self-confidence were correlated with educational practices and simulation design. Developing simulations using NLN/Jeffries Nursing Education Simulation framework will provide meaningful, engaging, and pedagogically sound experiences for the students. Pre-briefing and de-briefing are meaningful strategies to enhance the learning of students.


A fully photonics-based coherent radar system.
The next generation of radar (radio detection and ranging) systems needs to be based on software-defined radio to adapt to variable environments, with higher carrier frequencies for smaller antennas and broadened bandwidth for increased resolution. Today's digital microwave components (synthesizers and analogue-to-digital converters) suffer from limited bandwidth with high noise at increasing frequencies, so that fully digital radar systems can work up to only a few gigahertz, and noisy analogue up- and downconversions are necessary for higher frequencies. In contrast, photonics provide high precision and ultrawide bandwidth, allowing both the flexible generation of extremely stable radio-frequency signals with arbitrary waveforms up to millimetre waves, and the detection of such signals and their precise direct digitization without downconversion. Until now, the photonics-based generation and detection of radio-frequency signals have been studied separately and have not been tested in a radar system. Here we present the development and the field trial results of a fully photonics-based coherent radar demonstrator carried out within the project PHODIR. The proposed architecture exploits a single pulsed laser for generating tunable radar signals and receiving their echoes, avoiding radio-frequency up- and downconversion and guaranteeing both the software-defined approach and high resolution. Its performance exceeds state-of-the-art electronics at carrier frequencies above two gigahertz, and the detection of non-cooperating aeroplanes confirms the effectiveness and expected precision of the system.


Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.
The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkβ(EE)(IEC) transgenic mice expressing constitutively active IκB kinase β (IKKβ) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkβ(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikkβ(EE)(IEC) mice exhibited more β-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/ΔIEC) mice, and their survival was severely compromised. IEC of Ikkβ(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkβ(EE)(IEC)/Apc(+/ΔIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early β-catenin(+) lesions and tumor load. The results suggest that persistent NF-κB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.